PROTOCOL DATE:
NCIC CTG TRIAL:
AMENDED:
AMENDED:
AMENDED:
AMENDED:
REVISED:
96-MAY-15
MA.14
96-AUG-12
97-SEP-18
99-DEC-09
00-JUL-12
03-APR-23
NATIONAL CANCER INSTITUTE OF CANADA
CLINICAL TRIALS GROUP (NCIC CTG)
A RANDOMIZED TRIAL OF ANTIESTROGEN THERAPY VERSUS COMBINED
ANTIESTROGEN AND OCTREOTIDE LAR THERAPY IN THE ADJUVANT TREATMENT
OF BREAST CANCER IN POST-MENOPAUSAL WOMEN
NCIC CTG Protocol Number:
STUDY CHAIR:
TRIAL COMMITTEE:
PHYSICIAN COORDINATOR:
BIOSTATISTICIAN:
QUALITY OF LIFE COORDINATOR:
STUDY COORDINATOR:
SPONSOR:
MA.14
DR. MICHAEL POLLAK
DR.
DR.
DR.
DR.
DAVID BOWMAN
MARGOT BURNELL
SUSAN O'REILLY
KATHY PRITCHARD
DR. LOIS SHEPHERD
DR. DONGSHENG TU
DR. TIM WHELAN
PAULA RICHARDSON
NOVARTIS PHARMACEUTICALS CANADA INC.
PROTOCOL DATE:
NCIC CTG TRIAL:
STUDY SYNOPSIS
96-MAY-15
MA.14
AMENDED: 00-JUL-12
COMPOUND
Octreotide pamoate (SMS 201-995 pa LAR)
STUDY TITLE
A Randomized Trial of Antiestrogen Therapy versus Combined Antiestrogen and
Octreotide LAR Therapy in the Adjuvant Treatment of Breast Cancer in PostMenopausal Women.
DEVELOPMENT
PHASE
Phase III
INVESTIGATORS
Dr. Michael Pollak et al.
CENTRES
Canada: Approximately 45
TARGET DATES
Protocol approval:
Recruitment initiation:
Accrual Completion:
Study Report:
OBJECTIVES
1. To compare event-free survival in post-menopausal adjuvant breast cancer
patients randomly allocated to Tamoxifen or Tamoxifen plus Octreotide LAR
2. To compare recurrence-free and overall survival in the two treatment arms
3. To compare the two treatment arms with respect to treatment toxicity and
quality of life
4. To compare the two treatment arms with respect to effects of treatment on
insulin-like growth factor physiology, and to study relationships between insulinlike growth factor physiology and outcome
STUDY DESIGN
Multi-centre, parallel group, non-blinded randomized trial.
SUBJECTS
Post-menopausal breast cancer patients with satisfactory surgical removal of disease
by segmental or total mastectomy; adjuvant chemotherapy prior to or concurrent
with protocol treatment acceptable; ECOG performance status 0,1,2; no metastatic
disease beyond ipsilateral axillary nodes; no previous or concurrent malignancies
except adequately treated carcinoma of the skin (basal cell), cervix, endometrium,
colon or thyroid treated more than 5 years prior to study entry and presumed cured.
SAMPLE SIZE
Total: 650 eligible patients Per Group: 325 eligible patients Sample size
rationale provided.
TREATMENTS
Investigational Drug:
Octreotide LAR (SMS 201-995 pa LAR) 90 mg depot
injection monthly for 2 years (plus Tamoxifen 20 mg PO
daily for 5 years)
Comparative Drug:
Tamoxifen
20 mg PO daily for 5 years
May 1996
August 1996
August 2000
June 2005
i
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 00-JUL-12
EFFICACY
VARIABLES
SAFETY
VARIABLES
Primary:
Event-free survival
Secondary:
Recurrence-free and overall survival
Insulin-like growth factor measures
Quality of Life
Primary:
Toxicity assessment using NCIC CTG Expanded
Common Toxicity Criteria
PHARMACOKINETICS
Pharmacokinetic studies will not be carried out in this trial.
STATISTICAL
METHODS
Sample Size
The event-free survival at 5 years for the control arm is
estimated to be about 73%. In order to have 80% power
to detect a hazards ratio of 1.5 using a two-sided 5% level
test, 650 eligible patients will be entered over 4 years. All
patients will be followed for about 4.7 years before the
final analysis.
Statistical Methods:
All eligible patients randomized to one of the two treatment
arms will be included in the efficacy analysis. A log-rank
test and a Cox regression model will be used to compare
the event-free survival between the two arms. Interim
analysis will be performed once we have observed 96
events in the study at approximately 2 years after the end
of the accrual period. A test of qualitative interaction
between treatment and adjuvant chemotherapy will be
carried out to determine whether a formal subgroup
analysis is needed. All patients who have received at least
one dose of study treatment will be included in the safety
analysis.
ii
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 00-JUL-12
TREATMENT SCHEMA
Post-menopausal women with histologically proven adenocarcinoma of the breast who have undergone
resection of the primary by either total mastectomy or segmental mastectomy (lumpectomy). Patients may
be treated with adjuvant chemotherapy prior to randomization (sequential) or during treatment with
tamoxifen +/- octreotide LAR (concurrent).
Stratification:
1. no adjuvant chemotherapy versus concurrent chemotherapy versus sequential chemotherapy
2. axillary nodal status (unknown, negative, 1-3, 4+)
3. estrogen and/or progesterone receptor status (ER and/or PR+ (> 10 fmol/mg or positive by
immunohistochemistry), ER and PR-, unknown)
ARM 1 (Tamoxifen)
R
A
N
D
O
M
I
Z
E
Tamoxifen: 20 mg po daily for 5 years
or until
recurrence/second
malignancy
is demonstrated
ARM 2 (Combination)
Octreotide LAR: 90 mg by depot injection
monthly for 2 years
Tamoxifen: 20 mg po daily for 5 years
Objectives:
1.
2.
3.
4.
event-free survival (defined in section 14.2)
recurrence-free and overall survival (defined in section 14.2)
treatment toxicity and quality of life
effects of treatment on insulin-like growth factor physiology
iii
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
TABLE OF CONTENTS
STUDY SYNOPSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i
SCHEMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii
1.0
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2.0
2.1
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
BACKGROUND INFORMATION AND RATIONALE . . . . . . . . . . . . . . . . . . . . .
Adjuvant Treatment of Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Combination of Octreotide and an Antiestrogen: a Candidate
Novel Adjuvant Breast Cancer Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Preclinical Data and Scientific Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Clinical Data Regarding Antiestrogens in Breast Cancer Treatment . . . . . . . . . . . . . . .
Clinical Data Regarding Octreotide in Breast Cancer Treatment . . . . . . . . . . . . . . . . .
Clinical Data Regarding Octreotide for Indications Other Than Breast Cancer . . . . . . . . .
Clinical Data Concerning Antiestrogen-Somatostatin Combination . . . . . . . . . . . . . . . .
Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Growth Factor Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.0
3.1
3.2
PHARMACOLOGICAL DATA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Octreotide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
4.0
4.1
4.2
TRIAL DESIGN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
5.0
5.1
5.2
STUDY POPULATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Eligibility Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Ineligibility Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
6.0
PRE-TREATMENT EVALUATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
7.0
7.1
7.2
7.3
ENTRY/RANDOMIZATION PROCEDURES . . . . . . . . . . . . . . . . . . . . . . . . . .
Entry Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
20
20
20
20
8.0
8.1
8.2
8.3
8.4
TREATMENT PLAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Tamoxifen Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Octreotide LAR Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Unanticipated Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
21
21
22
22
23
iv
1
1
2
2
5
5
5
5
6
7
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
9.0
9.1
9.2
EVALUATION DURING AND AFTER PROTOCOL TREATMENT . . . . . . . . . . 24
Evaluation DURING Protocol Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Evaluation AFTER Protocol Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
10.0
10.1
10.2
10.3
10.4
10.5
10.6
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS . . . . . . . . . . . . . . .
Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Evidence of Disease Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Contralateral Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dating of Recurrence/Second Malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Management Following Recurrence/Second Malignancy . . . . . . . . . . . . . . . . . . . . .
Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
26
26
28
28
28
28
11.0
11.1
11.2
11.3
TOXICITY AND ADVERSE EVENT REPORTING . . . . . . . . . . . . . . . . . . . . . .
Toxicity Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Adverse Event Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Adverse Event Reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
29
29
29
12.0 PROTOCOL TREATMENT DISCONTINUATION
AND THERAPY AFTER STOPPING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.1 Criteria for Discontinuing Protocol Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.2 Therapy After Protocol Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12.3 Follow-up After Protocol Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
31
31
31
31
13.0 CENTRAL REVIEW PROCEDURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
13.1 Data Review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
14.0
14.1
14.2
14.3
14.4
14.5
STATISTICAL CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Objectives and Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Endpoints and Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sample Size and Duration of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Safety Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Interim Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
32
32
32
33
34
34
15.0
15.1
15.2
15.3
PUBLICATION POLICY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Authorship of Papers, Meeting Abstracts, Etc. . . . . . . . . . . . . . . . . . . . . . . . . . . .
Responsibility for Publication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Submission of Material for Presentation or Publication . . . . . . . . . . . . . . . . . . . . . .
35
35
35
35
16.0
16.1
16.2
16.3
16.4
16.5
16.6
16.7
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES . . . . . . . . . . . . . .
Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REB (Research Ethics Board) Approval for Protocols . . . . . . . . . . . . . . . . . . . . . . .
Informed Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Centre Performance Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Monitoring and Auditing Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Case Report Forms and the Reporting and Recording of Data . . . . . . . . . . . . . . . . . .
Forms Submission and Required Supporting Documentation . . . . . . . . . . . . . . . . . . .
36
36
36
37
37
38
39
40
17.0 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
v
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 96-AUG-12
18.0
18.1
18.2
18.3
CONSENT FORM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Required Elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sample Consent Form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Exemple de Formulaire de Consentement . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46
46
48
52
19.0 COMPANION STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
19.1 IGF-I Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
19.2 Other Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
APPENDIX I
APPENDIX II
APPENDIX III
APPENDIX IV
APPENDIX V
APPENDIX VI
APPENDIX VII
-
APPENDIX VIII
APPENDIX IX APPENDIX X APPENDIX XI APPENDIX XII APPENDIX XIII
PATIENT EVALUATION FLOW SHEET . . . . . . . . . . . . . . . . . . .
PERFORMANCE STATUS (ECOG) . . . . . . . . . . . . . . . . . . . . . . .
DRUG DISTRIBUTION, SUPPLY AND CONTROL . . . . . . . . . . . .
DOCUMENTATION FOR STUDY . . . . . . . . . . . . . . . . . . . . . . .
NCIC CTG EXPANDED COMMON TOXICITY CRITERIA . . . . . .
GROWTH FACTOR STUDY . . . . . . . . . . . . . . . . . . . . . . . . . .
COLLECTION OF SERUM SAMPLES FOR
GROWTH FACTOR STUDY . . . . . . . . . . . . . . . . . . . . . . . . . . .
-OCTREOTIDE LAR ADMINISTRATION TECHNIQUE . . . . . . . . .
LIST OF "CONTACTS" . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
QUALITY OF LIFE ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . .
INVESTIGATOR STATEMENT/SIGNATURE PAGE . . . . . . . . . . .
STUDY PROTOCOL SIGNATURE PAGE . . . . . . . . . . . . . . . . . .
-GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
vi
58
59
60
61
62
69
79
80
82
83
94
95
96
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 00-JUL-12
1.0
OBJECTIVES
1.1
To compare event-free survival in patients following random allocation to one of the following
treatment groups following definitive surgical management of primary breast cancer in postmenopausal women:
Tamoxifen 20 mg orally daily for 5 years
or
Tamoxifen 20 mg orally daily for 5 years together with octreotide LAR 90 mg by depot injection
monthly for 2 years.
1.2
To compare recurrence-free and overall survival in the two treatment arms.
1.3
To compare the two treatment arms with respect to treatment toxicity and quality of life.
1.4
To compare the two treatment arms with respect to effects of treatment on insulin-like growth
factor physiology, and to study relationships between insulin-like growth factor physiology and
outcome.
2.0
BACKGROUND INFORMATION AND RATIONALE
2.1
Adjuvant Treatment of Breast Cancer
Breast cancer is the most common malignancy among non-smoking women in Western societies,
where lifetime risk may be as high as 1 in 91. The incidence of this disease is increasing in many
parts of the world where it has previously been low, particularly among post-menopausal
women2. Despite therapeutic advances over the past decades, breast cancer with clinically evident
distant metastases is rarely if ever curable3,4. This situation has led to extensive clinical research
regarding ‘adjuvant’ therapies. Such therapies are designed to reduce the risk of clinically evident
metastatic disease following resection of the primary neoplasm.
As summarized in a meta-analysis of 133 randomized clinical trials involving more than 70,000
women5,6, the adjuvant use of the antiestrogen tamoxifen is clearly efficacious in reducing the
likelihood of developing clinically evident metastases post-operatively. Adjuvant oophorectomy
and adjuvant chemotherapy also are effective for certain groups of patients. Current adjuvant
treatments provide a relative risk reduction for recurrence of less than 20%. This degree of risk
reduction has been sufficient to justify very widespread clinical use of adjuvant therapy for breast
cancer; it has been estimated that more than a million women worldwide are presently prescribed
adjuvant tamoxifen therapy. However, the fact that systemic relapse of breast cancer is common
even when current adjuvant therapies are used motivates research to improve adjuvant therapy
efficacy.
For post-menopausal women, antiestrogen adjuvant therapy is regarded by many authorities as
standard7-9. There are data to suggest a small but statistically significant further degree of
protection when tamoxifen is combined with 'traditional dose' cytotoxic chemotherapy10, but this
has not been seen in all trials11,12. The possibility of enhancing outcome by the use of bone
1
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
marrow transplant with high dose chemotherapy is currently being studied, but such therapies are
generally directed to poor prognosis premenopausal patients5. In many countries, there is a desire
to explore non-chemotherapy approaches to improving the results of adjuvant therapy, particularly
for post-menopausal patients. This is in keeping with the concept that there may be inherent
limitations in the concept that cancer therapies must act by killing every neoplastic cell64.
Clinical research regarding novel adjuvant therapies is challenging for a variety of reasons.
Obviously, since appropriate endpoints such as survival and disease-free survival must be
evaluated years following surgery, follow-up must be longer than in trials for metastatic disease
where applicable endpoints include response rate and duration. Since even an absolute 5%
improvement in survival or disease-free survival would likely be sufficient to change clinical
practice, adjuvant trials must enroll large numbers of patients to allow for a high degree of
statistical confidence in even small outcome differences between treatment groups. Finally, short
and especially long-term toxicity are key considerations in adjuvant therapy as many patients are
expected to have long life expectancies. This situation is quite distinct from that in metastatic
cancer. Unavailability of long-term toxicity data has been an obstacle for clinical evaluation of
many novel compounds proposed for adjuvant therapy on the basis of preclinical studies.
2.2
Combination of Octreotide and an Antiestrogen: a Candidate Novel Adjuvant Breast Cancer
Treatment
This combination deserves study because of strong preclinical data suggesting enhancement of
antineoplastic activity of antiestrogens by octreotide, and because octreotide is known to have a
favourable long-term toxicity profile (when used in the treatment of acromegaly), relative to many
current antineoplastic therapies.
2.3
Preclinical Data and Scientific Rationale
There are more than 25 reports describing antineoplastic activity of somatostatin analogues in
preclinical experimental systems, as summarized in relevant reviews13,16. Somatostatin analogues
such as octreotide may inhibit breast cancer proliferation by direct or indirect mechanisms of
action13-19, 51. These mechanisms are not mutually exclusive. Information regarding mechanism
remains incomplete, but current hypotheses are summarized below.
2.3.1
The direct mechanism involves binding of the drug to specific somatostatin receptors on the cancer
cells, thereby triggering growth-inhibitory intracellular signal transduction pathways, including,
for example, phosphotyrosine phosphatase activity16,19,20,52. Activation of cellular growth inhibitory
signal transduction pathways is regarded as a promising direction in anticancer drug development
(reviewed in (21)). While much attention has been given to inhibition of phosphotyrosine kinaserelated pathways that are activated by growth stimulatory peptides, activation of phosphotyrosine
phosphatase pathways (such as those implicated in certain aspects of somatostatin signal
transduction20) is also an attractive therapeutic possibility.
Recent studies indicate that more than 2/3 of breast cancers have somatostatin receptors22, and
work regarding the contribution of each of the somatostatin receptor subtypes will soon be
possible23. In the context of the direct mechanism of action, a specific rationale for combining
2
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
octreotide with an antiestrogen comes from the observation that estradiol appears to attenuate the
growth inhibitory activity of octreotide on breast cancer cells in vitro24.
2.3.2
The indirect mechanism involves actions of the drug on the host that would be expected to inhibit
breast cancer cell proliferation. The best characterised indirect effect is reduction of insulin-like
growth factor I (IGF-I) serum levels. This is of potential significance in view of the large body
of evidence that suggests IGF-I is a potent mitogen for breast cancer (reviewed in 25,53,61,62,63).
Octreotide suppresses IGF-I by inhibiting growth hormone secretion18. Tamoxifen also reduces
IGF-I serum levels and gene expression in target organs for metastasis25-29. It has been proposed
that this contributes to its antineoplastic effect, particularly as insulin-like growth factors are
capable of stimulating breast cancer cell proliferation to a greater extent than estradiol. There is
evidence that estradiol and IGF-I act co-operatively to stimulate breast cancer cell proliferation51,
and this provides a further rationale for attempts to pharmacologically reduce IGF-I gene
expression while blocking estradiol receptors. Importantly, there is pre-clinical evidence that the
co-administration of tamoxifen and octreotide results in more suppression of IGF-I serum level
and IGF-I gene expression than either agent alone30.
2.3.3
The DMBA mammary tumour model was used to demonstrate the antineoplastic activity of
tamoxifen prior to its introduction into clinical use, and has proven to be a reasonably accurate
predictor of clinical activity of a variety of non-cytotoxic therapies for breast cancer, including
oophorectomy, aromatase inhibitors and others31. In view of the data described above, a study was
undertaken to compare the efficacy of tamoxifen to that of tamoxifen co-administered with
octreotide in this model14. A substantial enhancement in antineoplastic activity of tamoxifen was
seen with the combination, as evidenced by data shown below. Octreotide also inhibited the
tumor regrowth seen in this model after initial response to oophorectomy. In this pre-clinical
work, as in other studies (reviewed in (13)), the combination was reproducibly more effective in
preventing the growth of small neoplasms than in causing regression of large tumours. This
provides a specific rationale for clinical trials in the adjuvant setting. The basis of this
phenomenon is unclear at present, but speculation has included progressive loss of somatostatin
receptors or defects in somatostatin signal transduction pathways during neoplastic progression,
as well as the possibility that part of the efficacy of somatostatin analogues is related to an
antiangiogenic effect54 (which would be expected to inhibit growth of small metastatic deposits,
but not necessarily to cause regression of large metastases).
3
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
When enhanced antineoplastic activity was seen, the possibility of enhanced uterine toxicity was
considered. However, uterine weight gain, which has been used as a surrogate endpoint for
uterotrophic toxicity of antiestrogens, was in fact greater in animals treated with tamoxifen alone
as compared to animals treated with the combination of octreotide and tamoxifen14.
4
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 96-AUG-12
2.4
Clinical Data Regarding Antiestrogens in Breast Cancer Treatment
The efficacy and toxicity of antiestrogens in general and tamoxifen in particular have been the
subject of many reviews6,32,33. Despite concerns about uterine toxicity (which may have some
relevance to risk/benefit analysis concerning proposed use of the drug for breast cancer
prevention), tamoxifen compares favourably with other antineoplastics with respect to its short and
long term toxicities and efficacy. However, there is a clear need to improve efficacy in the
adjuvant setting, as discussed in Section 2.1.
2.5
Clinical Data Regarding Octreotide in Breast Cancer Treatment
There is no evidence to suggest that single agent octreotide has antineoplastic activity for breast
cancer as great as existing hormonal treatments such as tamoxifen, despite several small studies
which showed some responses (for example 34). However, these negative phase II studies (data
on file, Sandoz) involved treatment of patients already resistant to a wide variety of systemic
therapies. In such patients, even tamoxifen would be expected to show little activity. Presently
available preclinical data do demonstrate single agent activity of octreotide13, but this activity is
comparable to or less than that of currently used hormonal treatments such as tamoxifen.
Therefore, rationale for a new round of phase II studies of single agent octreotide in untreated
breast cancer patients is weak, and such studies might be regarded as inappropriate from an ethical
viewpoint. It is unlikely that the question of single agent activity of octreotide in previously
untreated breast cancer will be resolved.
2.6
Clinical Data Regarding Octreotide for Indications Other Than Breast Cancer
Octreotide has been used for a number of indications other than breast cancer at high doses and/or
for extended periods of administration35,36,52. Indications have included acromegaly, carcinoid
syndrome, VIPoma and other neuroendocrine tumours, cytotoxic chemotherapy-induced diarrhea,
and others. A recent report documented activity in lymphoma58. Dangerous toxicities have not
been observed. In a normal volunteer study, at doses of 90 mg, some change in bowel habit
with mild cramping pain and transient diarrhea (< 24 hours) has been seen in about 50% of
patients. Frequently, this toxicity subsides in less than 3 weeks with continuing use of the drug.
Gallstone formation has also been noted.
2.7
Clinical Data Concerning Antiestrogen-Somatostatin Combination
Even in the absence of much of the recent compelling preclinical data concerning the
combination, the Mayo Clinic/North Central group opened in 1989 a phase III trial in
metastatic breast cancer that compared tamoxifen (20 mg daily) as a single agent to tamoxifen
in combination with octreotide given three times daily as a 150 microgram injection, in patients
not previously treated with tamoxifen. This trial was recently closed to accrual before the
planned accrual target was reached due to a patient recruitment problem. This was related to
[1] the increasing paucity of tamoxifen-naive patients with metastatic breast cancer, as this drug
is now used so widely in adjuvant treatment, and [2] patient resistance to the possibility of
randomization to the inconvenient three times daily subcutaneous injection regime. No outcome
data are available at this time. However, a recent companion study carried out on a small
subset of participants (Pollak M, et al, Abstract 1167, Proceedings AACR, 1996) suggested
that suppression of serum IGF-I was significantly greater in the combination group,
5
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 96-AUG-12
in keeping with the preclinical data cited in section 2.3.2. No unexpected toxicity was observed
in patients receiving the combination treatment, including a subset on continuous treatment for
more than a year. The plasma levels of octreotide LAR achieved in this trial are lower (1-2 ng/ml)
than those required in animal models to produce tumour regression (5-20 ng/ml). The dose and
formulation of octreotide LAR specified in the MA.14 protocol is expected to achieve plasma
levels in the 5-20 ng/ml range.
Other somatostatin analogues have also been well tolerated in combination with antiestrogens37,
but no adjuvant trials have been carried out.
2.7.1
Rationale for proceeding with the adjuvant trial in the absence of final analysis of the Mayo Clinic
metastatic study. A decision was taken to proceed with the present trial without waiting for the
final analysis of the Mayo Clinic metastatic study for reasons including [1] uncertainty of the
power of that study, given the failure to meet the original accrual target, [2] the question of
compliance of patients in that study to the prescribed self-administration of multiple daily
injections, [3] the possibility that the octreotide dose used in the Mayo Clinic trial was suboptimal
and [4] the suggestion from preclinical data13,14 that the combination may be more effective in an
adjuvant rather than metastatic setting; even if the Mayo Clinic study were completed without
problems and was negative, this would not prove lack of enhancement by octreotide of the activity
of tamoxifen in the adjuvant treatment of breast cancer.
2.7.2
Precedents for combination therapies in adjuvant cancer therapy. There are several relevant
precedents for improvements in the efficacy of adjuvant therapy by combining agents. For
example, an NSABP study suggested an improvement in outcome of certain cohorts of patients
when antiestrogen therapy was supplemented by cytotoxic chemotherapy10. Although more
controversial, the use of levamisole in the adjuvant therapy of colorectal cancer provides an
example of an agent that has no single agent activity in either the metastatic setting or the adjuvant
setting, and no influence on outcome when co-administered with 5-FU in the metastatic setting,
but nevertheless is FDA-approved for co-administration with 5-FU in the adjuvant setting because
of randomized trials which showed superior outcome of a 5-FU+levamisole arm to a 5-FU alone
arm in a randomized study in the adjuvant setting38.
2.8
Quality of Life
There is the possibility that the two treatment regimes used on this study will have differential
effects on quality of life. A difference in quality of life between the two treatment arms could be
attributable to the monthly depot injection of octreotide LAR on the combination arm. The
octreotide LAR could affect quality of life by reducing recurrence and/or adding toxicity. In
addition, the monthly depot injection routine in itself could have an affect on quality of life.
The EORTC quality of life instrument (QLQ C30+1)57 plus a trial-specific checklist will be used.
The questionnaire will be administered prior to randomization and during protocol treatment at
month 1, 4, 8 and 12 and then annually until year 5 or treatment discontinuation. A
questionnaire will also be required at the time of recurrence/second malignancy. A detailed
description of the Quality of Life component of the study is in Appendix X.
6
PROTOCOL DATE:
NCIC CTG TRIAL:
2.9
96-MAY-15
MA.14
Growth Factor Study
This trial includes a basic science component which will measure serum levels of specific growth
factors. This basic science component of MA.14 which will examine the IGF-I growth factor as
well as others is expected to provide important information with regard to the mechanisms of
action of the treatments under study. The specific objectives of the growth factor study are to
determine the relationship between growth factor levels and tumour characteristics, the effects of
treatments on growth factor levels and to determine the relationship between growth factor levels
and relapse. All patients participating on MA.14 will be required to participate on this component
of the study and provide serum samples at specified times.
7
PROTOCOL DATE:
NCIC CTG TRIAL:
3.0
96-MAY-15
MA.14
PHARMACOLOGICAL DATA
References regarding tamoxifen and octreotide are cited in the following sections. It should be
noted that the antiestrogen tamoxifen has been selected for this study based on its current status as
the most widely used antiestrogen. The compounds droloxifene and toremifene represent
alternatives in the unlikely event that the status of tamoxifen changes during the course of the
present trial.
3.1
Tamoxifen
3.1.1
Structure, Chemistry and Pharmacokinetics
Tamoxifen is a non-steroidal trans isomer of triphenylethylene and is given as the citrate salt. It
has at least seven metabolites. These include N-desmethytamoxifen which is known to be active
in vivo and has a t ½ of 9.8-14 days. Five of the known metabolites bind to the estrogen receptor
but only 4-hydroxytamoxifen has a high binding affinity relative to the parent drug tamoxifen39.
The half life of tamoxifen is biphasic with t ½ alpha of 4-14 hours and t ½ beta of more than
7 days. Steady state levels occur between 4 and 16 weeks of treatment. Tamoxifen is conjugated
and excreted in the bile.
3.1.2
Mechanism of Action
The mechanism of tamoxifen actions remains uncertain. Most data support the hypothesis that its
action is mediated by direct binding to the estrogen receptor32,33. However, as it may inhibit
growth in 10-15% of ER negative tumours40, it may have additional actions.
Tamoxifen does not cause estrogen receptor degradation to be accelerated, neither does it stop
receptor synthesis. It does, however, lead to a conformational change in the receptor which is
postulated to alter RNA transcription and result in decreased cell proliferation. In MCF-7 cells,
tamoxifen causes cells in the rapid cycling G1 pool to move into the slowly cycling G1 pool and
thus increases overall cell cycle transit time, so leading to a decrease in proliferation. It is also
able, at high concentrations (>7.5 µM), to cause cytotoxicity via a block in G1. In MCF-7 cells,
tamoxifen is also known to stimulate TGF-$ secretion. This growth factor is known to inhibit
growth of many epithelial cell lines. In other ER positive cell lines, tamoxifen has also been
shown to reduce secretion of growth stimulating factors, such as TGF alpha41,42. The nature of
the action (if any) of tamoxifen on ER negative cell lines is at present unclear43. TGF-$ induction
by tamoxifen in human breast cancer occurs in stroma of breast rather than in epithelial cells,
which suggests that tamoxifen may act by an ER independent mechanism to induce TGF-$44 or
that tamoxifen interacts with ER-positive epithelial cells in a way that leads them to induce TGF-$
production by neighboring stromal cells. Antiestrogens also have effects on IGF physiology and
IGF binding protein physiology that may contribute to their antineoplastic activity25,27,28,55,59,60.
3.1.3
Side Effects
Tamoxifen is generally well tolerated and discontinuation of treatment due to side effects is low
at 3-4%45. Commonly recognized side effects include hot flashes (20%), vaginal dryness or
discharge (9%), and very occasionally nausea (10%). Vaginal bleeding, hypercalcemia,
8
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED:
97-SEP-18
depression, dizziness, alopecia, headache, skin rash, and edema occur rarely (3%). Up to 20%
of patients develop a mild leukopenia or thrombocytopenia, usually during the second week of
therapy which resolves spontaneously within a week and does not require discontinuation of the
drug. Recently a small companion study to NSABP-B14 evaluating the prevalence of ocular
changes in women on Tamoxifen has been analysed. The study demonstrated that women
on Tamoxifen or those who have received Tamoxifen for an average of 4.8 years have a
statistically significant increased chance of developing posterior subscapular opacities over
women who have never received Tamoxifen (9.3% and 9.2% vs 2.5%). Normal guidelines
for eye care should be followed for all women on Tamoxifen therapy.
An increased risk of uterine cancer (twice normal) has been observed in patients taking tamoxifen.
Rarely, these cancers can be fatal in some patients. This may be due to paradoxical effects of
tamoxifen on IGF-I expression in the uterus. In general, tamoxifen suppresses IGF-I expression28,
but tamoxifen-induced uterine hypertrophy is correlated with upregulation of IGF-I expression in
this organ by the drug59,60. Any pelvic complaints should be evaluated promptly. Yearly
gynecological examinations for any woman on tamoxifen are recommended56. Patients with cancer
have an increased risk of thromboembolic disease and the use of tamoxifen may increase this risk.
3.1.4
Formulation: Tamoxifen is available in 10 mg and 20 mg tablets.
Storage and Stability: Tamoxifen is stable for at least 5 years under normal storage conditions and
should be protected from light and moisture. Minimal shelf life appears to be two years.
Administration: Oral
Supplier: Tamoxifen is commercially available for the indications outlined in this study.
3.2
Octreotide
3.2.1
Structure, Chemistry and Pharmacokinetics
Octreotide pamoate (Sandostatin, SMS 201-995 pa LAR) is a synthetic octopeptide which
possesses similar activity to that of endogenous somatostatin. Somatostatin is a naturally occurring
cyclic tetradecapeptide which was isolated from hypothalamic extracts and considered to have the
main function of regulation of growth hormone secretion. The synthetic analogue octreotide
pamoate is microencapsulated by a biodegradable polymer and when given intramuscularly has
shown measurable plasma levels up to 90 to 100 days post injection.
3.2.2
Mechanism of Action
Octreotide is believed to act as a growth inhibitor via somatostatin receptors and/or by modulating
physiology of growth stimulatory peptides such as insulin growth factor-1 (IGF-I). See also
section 2. IGF-I has been implicated as a growth factor in human breast cancer.
3.2.3
Preclinical Antitumour Activity (see section 2)
The anti-tumour effect of octreotide pamoate was tested in nude rats bearing somatostatin receptorpositive tumours (AR42J). A single injection of octreotide pamoate at 330 :g/kg induced a highly
significant inhibition (p<0.01) of the tumour growth over a period of 35 days as compared to
controls which received the vehicle only. These data initially suggested that octreotide pamoate
is useful for suppression of neoplastic proliferation (data on file, Sandoz).
9
PROTOCOL DATE:
NCIC CTG TRIAL:
3.2.4
96-MAY-15
MA.14
AMENDED: 96-AUG-12
Human Anti-tumour Activity
A phase I safety/tolerability study of high dose octreotide was carried out by Sandoz in twenty
Stage IV heavily pretreated breast cancer patients. The drug was administered at doses of 500,
800, 1500 and 2000 :g subcutaneously tid for eight weeks. Patients who had stable disease or
a response to therapy continued on treatment until disease progression. Two patients had stable
disease lasting 24 and 34 weeks with one patient demonstrating a decrease in liver metastasis but
no change in bony lesions. High dose octreotide was generally well tolerated in these patients.
Two phase II octreotide studies for patients with metastatic breast cancer have been carried out.
These patients received 2000 :g subcutaneously tid. Of 15 patients with ER-negative disease, one
patient had stable disease for > 12 weeks. Seventeen ER-positive patients were studied and one
partial response was observed.
The present clinical trial is not designed to evaluate single agent activity of octreotide in adjuvant
treatment of breast cancer, but rather is designed to test the clinical relevance of preclinical data
suggesting that the combination of octreotide and tamoxifen is superior to single agent tamoxifen
in the adjuvant treatment of breast cancer. No prior randomized clinical trial outcome data on
this combination are available.
Efficacy data of single agent octreotide in acromegaly, carcinoid, lymphoproliferative disease and
APUDomas has recently been reviewed52,58.
3.2.5
Side Effects
A phase I study (Sandoz Study L103) using SMS 201-995 pa LAR - octreotide pamoate assigned
patients with advanced cancer to one of three cohorts as defined by increasing dose and/or
frequency of dosing for up to 169 days.
Cohort 1 - 90 mg q 4 weeks
Cohort 2 - 160 mg q 4 weeks
Cohort 3 - 160 mg q 2 weeks
There was no clear dose limiting toxicity noted even in patients treated at greater than three times
the dose planned for the present study. Significant toxicities included:
P transient injection site discomfort (7% of subjects)
P diarrhea and/or abdominal discomfort (generally at onset of treatment, typical duration 4 days,
P
50% of subjects)
asymptomatic increased gallbladder sludge accumulation (12% of subjects)
A randomized phase III trial has been performed by the North Central Cancer Treatment
Group in which women with metastatic breast cancer were randomized between tamoxifen
10 mg bid or tamoxifen 10 mg bid with octreotide given subcutaneously 150 :g tid. These
patients are still being followed and results of this study are not yet available. However,
toxicity data are available. The octreotide-tamoxifen combination was generally well tolerated
10
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
by the 68 patients for whom data are available. Of these patients, adverse events possibly related
to treatment different from those observed on the tamoxifen-alone arm included: transient
abdominal pain (4 patients), grade I-III alopecia (4 patients), transient anorexia (8 patients),
transient diarrhea (21 patients), pulmonary embolism (1 patient) injection site discomfort (9
patients), mild transient nausea (19 patients), grade 3 transient nausea (2 patients), and transient
mild steatorrhea (7 patients). No patients discontinued protocol therapy due to toxicity.
Somatostatin analogues in general and octreotide pamoate in particular appear to be well tolerated.
The subcutaneous formulation has been used extensively in the treatment of acromegaly and
carcinoid tumour. The most commonly observed side effects are GI toxicity with mild to
moderate diarrhea. Nausea and stomach pain were occasionally reported. Mild to moderate pain
at the injection site has also been noted. Less frequently observed side effects have included mild
dizziness, headache, odd tastes, hot flashes, myalgia and blurred vision. These have all resolved
within 24 hours of onset. Very rarely hypothyroidism, aggravation of diabetes mellitus or cardiac
abnormalities have been seen. These have been associated with prolonged use in acromegalics and
may be related to the underlying disease rather than the drug. Gallbladder abnormalities such as
stone formation have been reported.
The majority of information on toxicity associated with octreotide LAR formulation comes from
the experience in treating patients with acromegaly. These patients receive lower doses of
octreotide LAR than will be given in this study, up to 30 mg every 4 weeks. Reported side effects
in a recent cohort are summarized in the following table:
Tolerability Studies in Acromegalic Patients
Adverse Event
Dose of Octreotide LAR
10 mg
20 mg
30 mg
Abdominal pain
3/16 (18.8%)
12/39 (30.8%)
15/38 (39.5%)
Diarrhea
3/16 (18.8%)
19/39 (48.7%)
20/38 (52.6%)
Flatulence
6/16 (37.5%)
12/39 (30.2%)
15/38 (39.5%)
Steatorrheic stools
2/16 (12.5%)
2/39 (5.1%)
5/38 (13.2%)
Sandostatin (octreotide acetate) when used in clinical trials to treat acromegaly or psoriasis, has
been associated with an incidence of biliary tract abnormalities of up to 52% (27% gallstones, 22%
sludge without stones, and 3% biliary duct dilatation). The incidence of stones or sludge in
patients who received octreotide acetate for 12 months or longer was 48%, but it is not clear to
what extent this is treatment-related as acromegalics may have subtle disorders of biliary
physiology.
Less common abnormalities associated with the use of octreotide acetate have included pancreatitis,
malabsorption of dietary fats, decreased Vitamin B12 levels with associated abnormalities in the
Schilling’s test.
3.2.6
Formulation: Octreotide LAR (SMS 201-995 pa LAR) is microencapsulated by a biodegradable
11
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 99-DEC-09
polymer. It will be given by a monthly IM depot injection at a dose of 90 mg of free peptide.
(Volume of injection is 2 ml.)
Storage and Stability: Octreotide LAR vials should be refrigerated at 2-8°C and protected from
light in an appropriate, secure, locked area.
Administration: Intramuscular depot injection monthly. See Appendix VIII for detailed
instructions. Each medication set consists of 1 vial of medication and 1 vial of diluent (0.5%
sodium carboxymethyl cellulose).
Supplier: Octreotide LAR will be supplied for the purpose of this study by Novartis
Pharmaceuticals Canada Inc. See Appendix III for drug supply and distribution.
12
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 99-DEC-09; AMENDED: 00-JUL-12
4.0
TRIAL DESIGN
This is a multi-centre (approximately 45 centres), parallel group, non-blinded randomized phase
III trial conducted by the NCIC CTG and sponsored by Novartis Pharmaceuticals Canada Inc.
4.1
Stratification
Post-menopausal women with histologically proven adenocarcinoma of the breast who have
undergone resection of the primary by either total mastectomy or segmental mastectomy
(lumpectomy). Patients may be treated with adjuvant chemotherapy prior to randomization or
during treatment with tamoxifen +/- octreotide LAR.
This flexibility takes into account the fact that current clinical practice varies from centre to centre,
and that new data concerning the value (or lack of value) of chemotherapy in the adjuvant
treatment of post-menopausal women is expected to emerge during the planned five year accrual
period of this trial.
Patients will be stratified according to the following criteria:
1. no adjuvant chemotherapy versus concurrent chemotherapy versus sequential chemotherapy
(defined in section 5.1.5)
2. axillary nodal status (unknown, negative, 1-3, 4+)
3. estrogen and/or progesterone receptor status (ER and/or PR+ (> 10 fmol/mg or positive by
immunohistochemistry), ER and PR-, unknown)
4.2
Randomization
Patients will be randomized to one of the following two arms:
Arm
1
2
Agent(s)
Dose
Route
tamoxifen
20 mg
PO
daily for 5 years
tamoxifen
20 mg
PO
daily for 5 years
octreotide LAR
90 mg
depot injection
13
Duration
monthly for 2 years
PROTOCOL DATE:
NCIC CTG TRIAL:
AMENDED:
5.0
STUDY POPULATION
5.1
ELIGIBILITY CRITERIA
96-MAY-15
MA.14
97-SEP-18
There will be no exceptions to eligibility requirements at the time of randomization. Questions
about eligibility criteria should be addressed prior to calling for a randomization.
Patients must fulfill all of the following criteria to be eligible for admission to the study:
5.1.1
Diagnosis and Local Management
Patients must be females with histologically proven adenocarcinoma of the breast which is
potentially curable and has been treated in one of the following ways:
i. Segmental Mastectomy (lumpectomy):
These patients must have breast irradiation following surgery which should be administered in
accordance to institutional guidelines. Chest wall irradiation should only be given to patients
with T4 dermal involvement on pathological diagnosis; chest wall irradiation for other than T4
dermal involvement must be discussed with NCIC CTG prior to randomization.
If there is microscopic disease at the lumpectomy margins further excision is recommended.
If further excision is not undertaken a boost to the tumor bed must be delivered in addition to
the required breast irradiation.
ii. Total Mastectomy:
If there is microscopic disease at the mastectomy margins, chest wall irradiation must be
delivered.
5.1.2
Clinical Stage
Clinical staging information should be obtained when possible and must be provided when
available. When clinical staging is known, patients must be classified prior to surgery as T1,
T2, T3a; N0, N1, N2; M0. Patients classified as T4, that is, as having extension to chest wall,
edema (including peau d’orange), skin ulceration, satellite skin nodules confined to the same breast,
or inflammatory carcinoma will not be eligible.
Patients with simultaneous bilateral breast carcinoma will be eligible for the study. Complete
tumour resection on both sides must be carried out.
5.1.3
Pathologic Stage
Following surgery eligible patients will be classified as T1, T2, T3a, T4 (eligible T4 patients are
those with dermal involvement on pathology assessment only), Nx, N0, N1 or N2; M0.
14
PROTOCOL DATE:
NCIC CTG TRIAL:
AMENDED:
96-MAY-15
MA.14
97-SEP-18
Pathological examination of axillary lymph nodes should be carried out. Patients in whom this
has not been done and whose nodal status is clinically N0 may still be eligible provided other
criteria are met.
5.1.4
Menopausal Status
Patients must be post-menopausal. To be considered post-menopausal patients must meet at least
one of the following criteria:
P amenorrhea > 1 year in women < 50 years provided hysterectomy has not been performed
P no menses for 6 months prior to breast surgery in women > 50 years provided hysterectomy
has not been performed
P documented oophorectomy prior to breast cancer diagnosis
P LH and FSH values diagnostic of post-menopausal status by local laboratory criteria
P women > 50 with hysterectomy
5.1.5
Use of Adjuvant Chemotherapy and Timing of Randomization
Adjuvant chemotherapy may be given at physician discretion. If given, CMF, CEF or AC are
recommended regimens. If chemotherapy will be given concurrently with protocol treatment the
regimen must be defined prior to randomization. The following timing restrictions must be
adhered to:
Patients receiving NO ADJUVANT CHEMOTHERAPY or CHEMOTHERAPY
CONCURRENTLY WITH PROTOCOL TREATMENT: must be randomized within 12 weeks
of definitive surgery* and begin treatment within 2 working days of randomization (see section
5.1.15).
Patients receiving protocol treatment SEQUENTIAL TO CHEMOTHERAPY: must begin
adjuvant chemotherapy within 12 weeks of definitive surgery* and must be randomized within
6 weeks of the last intravenous drug administration. Protocol treatment must be started within
2 working days of randomization (see section 5.1.15).
* Definitive surgery is defined as the most recent surgical procedure (including axillary
dissection or re-excision of margins) performed for the treatment of breast cancer.
5.1.6
Estrogen and Progesterone Receptor Data
Estrogen and progesterone receptor data from the primary neoplasm should be obtained when
possible. Quantitative biochemical methods or immunohistochemistry may be used. In the case
of immunohistochemistry, results should be recorded as positive or negative. Patients in whom
this information is unavailable may still be entered provided other criteria are met.
15
PROTOCOL DATE:
NCIC CTG TRIAL:
AMENDED:
5.1.7
96-MAY-15
MA.14
97-SEP-18
Radiologic Investigations:
Radiologic investigations must be negative for metastases.
Investigations: P chest x-ray (mandatory)
P gallbladder ultrasound* (mandatory unless patient has undergone a
cholecystectomy)
P bone scan (required only if alkaline phosphatase is > 2 x normal and/or
there are symptoms of metastatic disease). A confirmatory x-ray is required
if the results from the bone scan are questionable.
P abdominal ultrasound or liver scan or CT abdomen (required only if
AST/ALT or alkaline phosphatase are > 2 x normal)
Timing: P for patients receiving no chemotherapy or chemotherapy concurrently with
protocol treatment investigations must be done within 16 weeks prior to
randomization*
P for patients receiving protocol treatment sequential to chemotherapy
investigations must be done within 16 weeks prior to the initiation of
chemotherapy. (Exceptions will be made only for the chest x-ray which
may be done up to 14 days following day 1 of chemotherapy and the
gallbladder ultrasound which may be done anytime from 16 weeks
prior to chemotherapy up until one month following randomization.)
*
5.1.8
The gallbladder ultrasound may be performed up to one month following randomization but
should be scheduled prior to randomization and the scheduled date provided at the time of
randomization. If the gallbladder can be assessed in an abdominal ultrasound performed for
abnormal liver function tests or as part of routine staging procedures, a separate gallbladder
ultrasound is not required.
Performance Status
ECOG performance status must be 0, 1, or 2 (see Appendix II).
5.1.9
Life Expectancy
Patients must have no intercurrent illness expected to reduce life expectancy to less than 5 years
from the date of surgery.
5.1.10
Availability of Baseline Blood Sample
Patients must have provided a baseline blood sample including a serum sample for IGF-I levels
(see Appendix VII and the Central Lab manual for instructions) and be willing to provide
further samples in the future.
16
5.1.11
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12; AMENDED: 97-SEP-18
Laboratory Requirements
Screening hematologic and biochemical samples must be taken within 14 days prior* to
randomization and the Central Lab results be available prior to randomization. The
following values are required for patients to be eligible:
WBC
Platelets
Alkaline phosphatase
AST and/or ALT
*
5.1.12
>
>
<
<
3x109/L
100 x 109/L
2 x normal } unless radiological examinations have
2 x normal } ruled out metastatic disease
Patients receiving protocol treatment sequential to chemotherapy should also have
biochemical investigations (alkaline phosphatase and AST and/or ALT) done prior to
the initiation of chemotherapy to rule out metastatic disease. (These should be done
at the centre, not through the central lab). If elevated (> 2x normal), radiologic
examinations must be conducted prior to chemotherapy to rule out metastatic disease
for the patient to be eligible.
Participation in Quality of Life Study
Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires in
either English or French. The baseline assessment must have been completed prior to
randomization. Inability (illiteracy in English or French, loss of sight, or other equivalent reason)
to complete the questionnaires will not make the patient ineligible for the study. However, ability
but unwillingness to complete the questionnaires will make the patient ineligible.
5.1.13
Consent
Patient consent must be obtained according to local Institutional and/or University Human
Experimentation Committee requirements. It will be the responsibility of the local participating
investigators to obtain the necessary local clearance, and to indicate in writing to the NCIC CTG
Clinical Trials Coordinator that such clearance has been obtained, before the trial can commence
in that centre. Because of differing requirements, a standard consent form for the trial will not
be provided but a sample form is given in section 18.0. The patient must sign the consent form
prior to randomization. Please note that the consent form for this study must contain a statement
which gives permission for the NCIC CTG and monitoring agencies to review patient records (see
section 18.0 for further details). A copy of the signed and witnessed form must be maintained in
the investigator’s study file.
5.1.14
Patient Availability for Follow-up
Patients must be accessible for treatment and follow-up. Investigators must assure themselves the
patients randomized on this trial will be available for complete documentation of the treatment,
toxicity, and follow-up.
5.1.15
Timing of Treatment Initiation
Protocol treatment must begin within 2 working days of patient randomization. In exceptional
cases treatment may begin up to 7 calendar days following randomization provided that
authorization from NCIC CTG has been obtained prior to randomization.
17
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 97-SEP-18
5.2
INELIGIBILITY CRITERIA
Patients who fulfill any of the following criteria are not eligible for admission to the study:
5.2.1
Any evidence of metastatic disease beyond the ipsilateral axillary nodes.
5.2.2
Prior or concurrent malignancies except adequately treated basal cell carcinoma of the skin, or in
situ cancer of the cervix, or any other cancer treated more than five years prior to study entry
and presumed cured.
5.2.3
Patients receiving any estrogen, progestins, or androgen therapy for a period of more than 30 days
following pathologic diagnosis of breast cancer. Tamoxifen prior to randomization is permitted;
however all other hormonal therapy must be discontinued prior to randomization.
5.2.4
Patients with symptomatic gallbladder disease or cholecystitis.
5.2.5
Patients with any major medical illness, including psychiatric illness, judged by the local
investigator to preclude safe administration of the planned therapy or required follow-up.
18
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12; AMENDED: 97-SEP-18
PRE-TREATMENT EVALUATION (See Appendix I)
6.0
History and
Physical Exam
including:
Hematology3
Biochemistry3
P
P
P
P
P
Radiology
P
P
P
P
P
P
Other Investigations
P
Toxicity
P
Quality of Life
P
Investigations
height & weight
performance status
gynecological history and examination1
CBC, differential WBC, platelet count
alkaline phosphatase5, AST or ALT5,
bilirubin
random blood sugar
HgbAlc, TSH, FT4, Methylmalonic acid
Chest x-ray
Gallbladder ultrasound2
Bone scan (if alkaline phosphatase is > 2 x
normal and/or there are symptoms of
metastatic lesions). Confirmatory x-ray
required if results from bone scan are
questionable)
Abdominal ultrasound, liver scan or CT
abdomen if AST/ALT or alkaline
phosphatase is elevated > 2 x normal
serum collection for growth factor studies
(see Appendix VII)
baseline toxicity evaluation (to document
residual toxicity from previous therapy and
baseline symptoms). Toxicities graded
according to the NCIC CTG Expanded
Common Toxicity Criteria (Rev. 94-DEC21). See Appendix V.
EORTC QLQ-C30+1 plus trial-specific
checklist
Timing
within 14 days prior to
randomization
no chemotherapy or
concurrent adjuvant
chemotherapy:
within 16 weeks prior to
randomization
sequential adjuvant
chemotherapy:
within 16 weeks prior to the
start of chemotherapy4
within 14 days prior to
randomization
1
An adequate gynecological history must be obtained at baseline. For women who have not undergone a
hysterectomy, a pelvic examination and pap smear should have been performed within a year prior to
randomization and the results available.
2
The gallbladder ultrasound may be performed up to one month following randomization but should be
scheduled prior to randomization and the scheduled date provided at the time of randomization (see
5.1.7). Gallbladder ultrasounds are not required for patients who have had a cholecystectomy.
3
Hematology and biochemistry tests will be conducted by a Central Lab. The Central Lab manual
should be consulted for specimen preparation and shipping instructions.
4
Chest x-ray may be done up to 14 days following day 1 of chemotherapy. Gallbladder ultrasound
may be done anytime from 16 weeks prior to chemotherapy initiation until one month following
randomization.
5.
Should also be done prior to chemotherapy for patients receiving protocol treatment sequential to
chemotherapy.
19
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09
7.0
ENTRY/RANDOMIZATION PROCEDURES
7.1
Entry Procedures
All eligible patients enrolled on the study by a participating treatment centre will be entered into
a patient registration log provided by the NCIC CTG. This will automatically provide a serial
number for that patient which should be used on all documentation and correspondence with the
NCIC CTG.
All randomizations will be done centrally by the NCIC CTG and will be obtained by calling the
NCIC CTG Clinical Trials Assistant at (613) 533-6430 or by faxing the eligibility checklist to
(613) 533-2941. At the time of randomization, a copy of the completed eligibility checklist must
be available.
The following information will be required:
P trial code (NCIC CTG MA.14)
P treatment centre and investigator
P date of REB approval for study at participating centre
P patient's initials, hospital number and NCIC CTG serial number
P confirmation of the requirements listed in Section 5.0, including dates of essential tests and
actual laboratory values
P completed eligibility checklist
P stratification parameters
7.2
Stratification:
1. no adjuvant chemotherapy versus concurrent chemotherapy versus sequential chemotherapy
2. axillary nodal status (unknown, negative, 1-3, 4+)
3. estrogen and/or progesterone receptor status (ER and/or PR+ (> 10 fmol/mg or positive by
immunohistochemistry), ER and PR-, unknown)
7.3
Randomization: Randomization will be given by telephone and confirmed by fax or mail. A
biased coin minimization procedure for randomization will be used.
All patients are assigned an alpha-numeric patient ID code. The first two letters reflect the centre
from which the patient is being randomized. The remainder of the code is assigned sequentially
as patients are randomized for individual centres.
Note: The validity of results of the trial depends on the authenticity of and the follow-up of all
patients entered into the trial. Under no circumstances, therefore, may an allocated patient’s data
be withdrawn prior to final analysis, except on disclosure of initial ineligibility.
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed
eligible before requesting randomization.
All randomized patients are to be followed until death. The follow-up requirement for ineligible
patients is minimal follow-up using a Form 5M (Minimal Follow-up). Should a patient be
declared ineligible following randomization the only documentation required is a Form 5M yearly
until death.
20
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09; AMENDED: 00-JUL-12
8.0
TREATMENT PLAN
Although the National Cancer Institute of Canada Clinical Trials Group acts as the coordinating
agency for the trial, the responsibility for treatment of patients rests with the individual
investigator.
Octreotide LAR, for the purposes of this study, will be supplied by Novartis Pharmaceuticals
Canada Inc. (See Appendix III for Drug Supply and Distribution.)
Protocol treatment is to begin within 2 working days of patient randomization (see section 5.1.15).
8.1
Drug Administration
Patients will be randomized to one of the following two arms:
Arm
1
2
8.1.1
Agent(s)
Dose
Route
Duration
tamoxifen
20 mg
PO
daily for 5 years
tamoxifen
20 mg
PO
daily for 5 years
octreotide LAR
90 mg
depot injection
monthly for 2 years
Violations of Protocol Therapy Plan
Patients must follow the treatment plan. No interruptions in tamoxifen administration should
occur. Octreotide LAR injections must be given on scheduled days, although to allow for
holidays, transportation difficulties, etc. injections may be given up to 2 days before or 5 days
after the target date. In extraordinary circumstances a delay of up to 14 days is permissible.
8.1.2
Administration of Octreotide LAR
Octreotide LAR injections may be performed by a physician, a licensed nurse or other health
professional who has been trained in the intramuscular injection technique. In all cases,
responsibility for correct injection rests with the treating physician. Local investigators may make
arrangements for injections to be given at patients' homes or elsewhere at time points where
administration is mandated. Efforts should be made not to require that all injections be given at
the 'oncology’ facility, providing that appropriate arrangements can be made for injections
elsewhere, if requested by patients. Appendix VIII provides information regarding the storage,
preparation and administration of octreotide LAR depot injections.
Assessment of toxicities in patients receiving octreotide LAR injections will be carried out at
regularly scheduled followup visits by the treating physician as per section 9.1. No special effort
should be made to collect toxicity data at the time of monthly injections.
21
PROTOCOL DATE:
NCIC CTG TRIAL:
8.2
96-MAY-15
MA.14
Tamoxifen Toxicity
Toxicity of tamoxifen is generally minor. The most frequent side effect is hot flashes.
Occasionally patients may experience gastric discomfort or nausea. Even less frequent are side
effects such as lightheadedness, mood disturbance, and vaginal dryness or itching. At high doses
for prolonged periods, retinal and corneal changes have been observed rarely, but this is not well
recorded at a dose of 20 mg/day. A low white cell count or thrombocytopenia or skin rash have
rarely been reported. Deep vein thrombosis has occasionally been reported but usually when
tamoxifen is used in conjunction with chemotherapy. Occasionally patients receiving tamoxifen
for metastatic bone disease will experience an initial exacerbation of bone pain “tamoxifen flare”
before obtaining pain relief.
There is an increased incidence of uterine cancer in long-term tamoxifen users relative to controls,
but the protective effects of the drug outweigh its toxicities33. Patients on this trial should have
annual gynecological examinations and prompt investigation of any gynecological symptoms, as
should all women receiving tamoxifen.
8.2.1
Tamoxifen Dose Modification
If a patient finds that hot flashes or other symptoms are disabling, the dose should be temporarily
reduced to 10 mg daily for 2 weeks and then increased to 20 mg a day. If this is not effective the
following measures can be tried: Vitamin E, 800 units/day. If this fails to relieve the symptoms
of hot flashes, Clonidine 0.1 mg od may be used. Other non-hormonal therapies may be used at
investigator discretion. If these measures do not mitigate toxicity, the patient will be removed
from protocol therapy.
If post-menopausal bleeding, pelvic pain or pressure occur, appropriate clinical evaluation must
be carried out as these may be symptoms of atypical endometrial hyperplasia or endometrial
cancer.
8.3
Octreotide LAR Toxicity
Octreotide LAR at a dose of 90 mg monthly by depot injection is expected to be well tolerated by
a large majority of patients, but at least 10-20% of patients may experience minor diarrhea and/or
abdominal cramping which usually subsides with time. (See section 3 for details.)
Long term usage of octreotide acetate has resulted in biliary tract abnormalities (sludge or stones)
in up to 48% of patients treated for greater than 12 months. Although gallbladder ultrasound is
required at randomization and at treatment completion (if patient has received at least one year of
protocol therapy), additional ultrasound assessment of the gallbladder should be performed if
clinically indicated. The development of asymptomatic gallbladder and biliary tract abnormalities
will not be an indication to alter octreotide LAR therapy. Patients who develop symptomatic
disease should discontinue octreotide LAR. If these patients undergo a cholecystectomy, treatment
may be restarted.
Hypoglycemia: Patients who develop symptomatic hypoglycemia (not on insulin or oral
hypoglycemics) should discontinue octreotide LAR therapy.
22
PROTOCOL DATE:
NCIC CTG TRIAL:
AMENDED:
96-MAY-15
MA.14
97-SEP-18
Hyperglycemia: Patients who develop hyperglycemia while on octreotide LAR should have
appropriate treatment with diet, oral hypoglycemic agents or insulin introduced.
Hypothyroidism: Patients who develop hypothryoidism while on protocol should be treated with
thyroid hormone replacement therapy as medically indicated.
8.3.1
Octreotide LAR Dose Modification
Patients experiencing significant toxicity (grade 3 or greater and possibly, probably or definitely
related to protocol treatment) at the 90 mg dosage level will be allowed to have a dosage reduction
to 60 mg for subsequent injections. If this dose is well tolerated, it will be given for two months
and then an attempt will be made to re-escalate to 90 mg. If significant toxicity (grade 3 or
greater) is again experienced at the 90 mg dosage level after re-escalating, the dose may be
reduced again to 60 mg and be maintained at 60 mg for the remainder of protocol
treatment. Patients experiencing significant toxicity (grade 3 or greater) even at 60 mg will be
required to discontinue octreotide LAR treatment. Tamoxifen can be continued at physician
discretion.
Patients experiencing grade 1 or 2 diarrhea should be managed with Kaopectate, Pepto-Bismol,
Lomotil or Immodium.
8.4
Unanticipated Toxicity
Treating physicians should keep in mind the unlikely possibility of significant unanticipated toxicity
or toxicities not previously described. All toxicities that occur while patients are receiving protocol
treatment and up to 120 days following the last dose of protocol treatment must be reported.
Previously reported toxicities include abdominal pain, nausea and/or diarrhea, pain at the injection
site and more rarely dizziness, headache and myalgia. Hypothyroidism, hyper or hypoglycemia,
and cardiac abnormalities have been reported in patients on long term octreotide LAR therapy for
acromegaly but it is not clear these are treatment related.
23
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12; AMENDED: 97-SEP-18;
AMENDED:00-JUL-12; REVISED: 03-APR-23
9.0
EVALUATION DURING AND AFTER PROTOCOL TREATMENT
All patients entered on study must be evaluated according to the schedule outlined in Appendix I
with documentation submitted according to the schedule in Appendix IV.
9.1
Evaluation DURING Protocol Treatment
History and
Physical Exam
including:
Hematology+
Investigations
• weight
• performance status
Timing
every month x 4 then every 4 months until 3 years
post-randomization, then every 6 months for the
remainder of treatment
• gynecologic history and
examination*
• CBC
annually from randomization
•
•
•
•
• differential WBC, platelet count
Biochemistry+
• alkaline phosphatase, AST or
ALT, bilirubin
• random blood sugar
• HgbAlc, TSH, FT4
Other
Investigations
Toxicity**
Quality of Life
*
**
+
++
every 4 months for the 1st year; at month 24; at
treatment discontinuation only if discontinuation
is prior to mth 24.
at mth 12 and mth 24; at treatment discontinuation only if discontinuation is prior to mth 24.
at 24 months; at treatment discontinuation only
if discontinuation is prior to mth 24.
annually from randomization
at month 24; at treatment completion
/discontinuation
• Methylmalonic acid
Radiology
every 4 months x 4
months 24, 36 and 60
at treatment completion/discontinuation
at recurrence/second malignancy
• mammography
• gallbladder ultrasound
• chest x-ray
• abdominal ultrasound/CT
abdomen/MRI
• bone scan
• serum collection for growth
factor studies (see Appendix
VII)
as indicated to evaluate possible disease
recurrence/second malignancy
•
•
•
•
• Toxicities graded according to
the NCIC CTG Expanded
Common Toxicity Criteria
(Rev. 94-DEC-21) See
Appendix V
• EORTC QLQ C30+1 plus trial
specific checklist
every 4 months x 4
months 24, 36 and 60
at treatment completion/discontinuation
at recurrence/second malignancy
every month x 4, then every 4 months until 2 years
post-randomization, then every 6 months for the
remainder of treatment
• month 1, 4, 8, 12 then annually thereafter until
treatment completion/discontinuation
• at recurrence/second malignancy
This may be done by the family physician and the results made available to the MA.14 investigator. Not required if the
patient has had a hysterectomy.
Toxicity assessment should only occur at scheduled follow-up visits. No attempt should be made to assess toxicities in Arm 2
patients (tamoxifen + octreotide LAR) more frequently than in Arm 1 (tamoxifen only) patients who do not receive monthly
injections.
Hematology and biochemistry tests will be conducted by a Central Lab. The Central Lab manual should be consulted for
preparation and shipping instructions.
Gallbladder ultrasound required at treatment completion/discontinuation for all patients who have received at least 1 year of
protocol therapy. Not required for patients who have had a cholecystectomy.
24
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12; AMENDED: 97-SEP-18
9.2
Evaluation AFTER Protocol Treatment
Investigations
Timing
History and Physical
Exam including:
• weight
• performance status
• gynecologic history and
examination**
Radiology*
• mammography
annually (from
randomization) until
recurrence/second malignancy
• chest x-ray
• abdominal ultrasound/CT
abdomen/MRI
• bone scan
as indicated to evaluate
possible disease
recurrence/second malignancy
Toxicity
Other Investigations
Quality of Life
*
annually starting one year
from last day of protocol
treatment
• All toxicities occurring within
120 days following last dose of
protocol therapy
at 4 months following
discontinuation of treatment
• Delayed toxicities considered
probably or definitely related to
protocol treatment
annually starting one year
from last day of protocol
treatment
• serum collection for growth factor
studies (see Appendix VII)
• EORTC QLQ C30+1 plus trial
specific checklist
at recurrence/second
malignancy
Radiology investigations are only required for patients prior to recurrence/second malignancy.
** Gynecologic exam not required for patients who have had a hysterectomy.
If recurrence/second malignancy is suspected, attempts should be made to investigate the
recurrence/second malignancy to determine status in accordance with the criteria provided in
Section 10.0. Following a recurrence/second malignancy subsequent investigations are at the
discretion of the investigator.
All patients will be followed until death.
Patients determined to be ineligible should be followed annually until death with a Form 5M.
25
10.0
PROTOCOL DATE:
NCIC CTG TRIAL:
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS
96-MAY-15
MA.14
Event-free survival is the primary endpoint in this study. An event is defined as recurrence of the
primary disease, second malignancy and death due to any cause.
As recurrence is an important variable in this study, it is crucial that it be precisely documented.
Patients who have recurrence of disease within the involved breast, chest wall, regionally or
distantly are considered to have recurred.
Patients with contralateral breast cancer are considered to have developed a second primary
malignancy.
10.1
Definitions
10.1.1
Evaluable for Toxicity
All patients who have received at least one dose of study treatment are evaluable for toxicity.
10.1.2
Evaluable for Quality of Life
All patients who have completed the baseline Quality of Life questionnaire are evaluable for quality
of life.
10.1.3
Recurrence
Recurrence will be categorized as local (breast or chest wall), regional or distant.
Breast Recurrence
A recurrence of disease WITHIN the involved breast (this excludes skin lesions). This may be
detected by mammography or clinically, but must be proven pathologically. No attempt is made
to distinguish between a new ipsilateral breast cancer and a recurrence of the original neoplasm;
both meet the definition of breast recurrence. The development of a lesion in the contralateral
breast is considered a second malignancy for the purposes of this study.
Chest Wall Recurrence
A recurrence in skin or subcutaneous tissue bounded superiorly by the clavicle, inferiorly by the
lower level of the xiphisternum, medially by the midline, and laterally by the posterior axillary line.
This is detected clinically and proven pathologically.
Regional Recurrence
A recurrence in the ipsilateral axilla or internal mammary chain. This is detected clinically and
proven pathologically.
Distant Recurrence
Recurrence of disease other than breast, chest wall or regional as described above.
10.2
Evidence of Disease Recurrence
10.2.1
Local (ipsilateral breast and chest wall) and Regional Recurrences
1. Definite - positive cytology, aspiration or biopsy
2. Suspicious - a visible or palpable lesion
26
PROTOCOL DATE:
NCIC CTG TRIAL:
10.2.2
96-MAY-15
MA.14
Distant Recurrence
A) Bone Marrow
1. Definite - positive cytology, aspiration or biopsy
2. Suspicious - leukoerythroblastic blood picture
B) Lungs and Pleura
1. Definite a) positive cytology, aspiration or biopsy, or
b) presence of multiple pulmonary nodules which are felt to be consistent with pulmonary
metastases
Note: If a solitary lung lesion is found and no other lesions are present on lung tomograms, further
investigation, such as biopsy or needle aspiration, should be performed.
C) Bone
1. Definite a) X-ray evidence of lytic, blastic, or mixed lytic-blastic lesions on skeletal films with or
without bone scan confirmation
b) Biopsy proof of bone metastases
c) Progressive bone scan changes over at least a four week period showing development of
new lesions is necessary in asymptomatic patients with only bone scan abnormalities
Note: In the absence of progressive disease by scan a biopsy is strongly recommended. Any
positive bone scan in joints or in a recent area of trauma (surgical or otherwise) cannot be
used as a criterion of treatment failure.
D) Ascites and Pleural Effusions
1. Definite - positive cytology
2. Suspicious - radiographic or clinical evidence
E) Liver
1. Definite a) Liver enlargement, especially if the liver is nodular, with additional confirmation by an
abnormal liver scan, ultrasound or CT scan demonstrating solid space occupying lesions
b) Liver biopsy confirmation of metastatic disease
Note: If the liver scan, ultrasound or CT scan findings are not definitive a liver biopsy is
mandatory.
F) Central Nervous System
1. Definite a) positive CT scan, usually in a patient with neurological symptoms
b) biopsy or cytology (for a diagnosis of meningeal involvement)
27
PROTOCOL DATE:
NCIC CTG TRIAL:
10.3
96-MAY-15
MA.14
Contralateral Breast Cancer
A lesion in the opposite breast will be assumed to be a second malignancy (see Section 10.5 for
treatment management) unless obviously contiguous with recurrent chest wall disease or proven on
cytology/biopsy to be of metastatic origin.
10.4
Dating of Recurrence/Second Malignancy
This should always be based on the onset of a sign but never on the onset of a symptom. The date
of first detection of a palpable lesion is acceptable only when the diagnosis of tumor involvement
is subsequently established.
The diagnosis of recurrent disease by radiographs or scans should be dated from the date of the first
positive record, even if this is determined in retrospect.
Initial recording of dates of first recurrence, second malignancy and death should be made as they
occur by those who are responsible for the care of the patient. Dates that are based on suspicion
alone will be reviewed by the NCIC CTG coordinating office in order to establish their accuracy
through subsequent behaviour. In addition, the case records of those patients not reported as having
recurrent disease/second malignancy will be scrutinized regularly to check that review is continuing
and to ensure consistency of recording.
10.5
Management Following Recurrence/Second Malignancy
Patient management following recurrence or the development of a second malignancy is at the
discretion of the investigator.
10.6
Quality of Life
Failure to complete quality of life assessments will not render the patient ineligible for the main
objectives of the study.
28
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12; AMENDED: 97-SEP-18; AMENDED: 99-DEC-09
11.0
TOXICITY AND ADVERSE EVENT REPORTING
Octreotide LAR is an investigational agent when used for the adjuvant treatment of breast cancer.
Toxicities occurring as a result of this treatment must be reported in the manner described below.
11.1
Toxicity Reporting
During Protocol Treatment and within 120 Days Following Last Treatment Dose
All toxicities, adverse events and intercurrent illnesses experienced by the patient during protocol
treatment (tamoxifen +/- octreotide LAR) and within 120 days after the last dose of protocol
treatment are to be graded by the NCIC CTG Expanded Common Toxicity Criteria (see Appendix
V) and recorded on the Summary Toxicity Form.
Following Protocol Treatment
Toxicities, adverse events and intercurrent illnesses occurring after 120 days following protocol
treatment (tamoxifen +/- octreotide LAR) has stopped should only be recorded on the relevant
case report forms if they are considered delayed toxicities which are probably or definitely related
to protocol treatment.
11.2
Adverse Event Definition
P any death (grade 5 toxicity) or life threatening (grade 4 toxicity) which occurs while a patient
P
P
P
11.3
is receiving protocol treatment
any death which occurs during the following 120 days after the last dose of protocol treatment
any death which occurs after protocol treatment has ended which is felt to be probably or
definitely related to treatment
any experience or event which meets the following criteria
- requires or prolongs hospitalization (excluding hospitalization solely for elective surgery or
procedures)
- causes permanent disability
- congenital abnormality
- constitutes an overdose, second malignancy or myeloid dysplasia
Adverse Event Reporting
Any adverse event occurring in a subject receiving study medication or during the following
120 days must be reported to NCIC CTG (by telephone and telefax) and to Novartis
Pharmaceuticals Canada Inc. (by telefax) within 24 hours even if the adverse event does not
appear to be drug related. Adverse events occurring later than 120 days after receiving the last
dose of study medication have to be reported within 24 hours only if they are considered by
the investigator as being probably or definitely related to protocol treatment. The Adverse
Event form must be signed by the responsible investigator. The adverse event must also be
recorded in the toxicity tables of relevant case report forms. In addition, your local Research
Ethics Board (REB) should be notified.
29
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 97-SEP-18; AMENDED: 99-DEC-09; AMENDED: 00-JUL-12
Reporting Instructions:
Within 24 hours of the Adverse Event:
1. Telephone NCIC CTG central office (Paula Richardson @ (613) 533-6430).
AND
Fax a copy of the MA.14 Adverse Event Form to:
Paula Richardson
Study Coordinator
NCIC CTG
Fax No.: (613) 533-2941
2. Fax a copy of the MA.14 Adverse Event Form to:
Dr. Patrick Le Morvan
Novartis Pharmaceuticals Canada Inc.
Fax No.: (514) 636-3175
Within 10 working days of the Adverse Event:
3. Mail the original (white) copy of the AER to:
Dr. Patrick LeMorvan
Novartis Pharmaceuticals Canada Inc.
385 Bouchard Boulevard
Dorral, Quebec
H9S 1A9
AND
4. Mail the green copy of the AER to:
Paula Richardson
Study Coordinator
NCIC CTG
82-84 Barrie Street
Kingston, Ontario
K7L 3N6
30
12.0
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING
12.1
Criteria for Discontinuing Protocol Treatment
12.1.1
Withdrawal of consent.
12.1.2
Detection of an ipsilateral breast, chest wall, regional or distant recurrence or a second malignancy,
including a contralateral breast cancer.
12.1.3
Unacceptable toxicity.
12.1.4
Intercurrent illness which is severe enough to render protocol management inappropriate in the
view of the attending physician.
12.1.5
Completion of the treatment plan described in section 8.
Efforts should be made to maintain the investigations schedule and continue follow-up, even if
patients discontinue protocol treatment prematurely and/or no longer attend the participating
institution.
12.2
Therapy After Protocol Treatment
Treatment following the discontinuation of protocol therapy is at the discretion of the investigator.
12.3
Follow-up After Protocol Treatment
Follow-up must be continued after protocol therapy has been discontinued according to the schedule
outlined in section 9.2.
13.0
CENTRAL REVIEW PROCEDURES
13.1
Data Review
Study reporting forms plus pertinent supporting documentation (see Appendix IV) will be reviewed
centrally on an ongoing basis by the responsible NCIC CTG study coordinator. On an ongoing
basis, the responsible NCIC CTG physician coordinator will review baseline and endpoint data,
and will provide medical expertise as required.
In addition, the study chair will review baseline and outcome data, at intervals during the study to
be determined.
31
14.0
STATISTICAL CONSIDERATIONS
14.1
Objectives and Study Design
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 00-JUL-12
The objectives of this study are to compare event-free survival, recurrence-free survival and overall
survival in post-menopausal breast cancer patients given tamoxifen for five years with or without
octreotide LAR for two years. Patients will be stratified by: 1) adjuvant chemotherapy (sequential
chemotherapy, concurrent chemotherapy, no chemotherapy); 2) axillary nodal status (unknown,
negative, 1-3, 4+); 3) estrogen and/or progesterone receptor status (ER and/or PR+, ER and PR, unknown). A biased coin minimization procedure65 will be used to allocate patients to one of the
two treatment arms. We will compare the incidence of toxicities and quality of life between the
two arms. The effect of treatment on insulin-like growth factor physiology will also be assessed.
14.2
Endpoints and Analysis
Event-free survival is defined as the time from randomization to the time of recurrence of the
primary disease, the time of a second malignancy or death due to any cause, whichever comes first.
Recurrence-free survival is defined as the time from randomization to the time of recurrence of the
primary disease alone. Local nodal recurrence and metastatic disease are considered a recurrence
of the primary tumour. The occurrence of contralateral breast tumour is considered a treatment
failure and counted as a failure in the event-free survival but not in the recurrence-free survival
analysis. Overall survival is defined as the time from randomization to the time of death from any
cause. We will use a stratified log-rank statistic to compare the event-free survival and other timeto-event endpoints adjusted for the stratification factors as defined in the protocol. An unadjusted
analysis will also be performed. A Cox proportional hazards model will be used to assess and
adjust for factors significantly related to the time-to-event outcomes. The final Cox model66 will be
determined using a stepwise model building procedure. A global treatment by covariate interaction
effect will be tested under the final Cox model using a likelihood ratio test statistic. No further
formal subgroup analysis will be performed if the test of interaction is not significant; however,
further exploratory subgroup analysis will be performed.
It is useful to determine whether the difference between the two treatment arms varies according
to whether patients received adjuvant chemotherapy. A significance level of less than 0.1 is an
indication of the need of further analysis on qualitative interaction as described by Gail and Simon
(1985)46. A likelihood ratio test for the interaction between treatment arms and the use of adjuvant
chemotherapy under the Cox proportion hazards model will be performed. A test of qualitative
interaction as suggested by Gail & Simon (1985)46 will be carried out if the significance value of
the likelihood ratio test is less than 0.1. We would consider that a significant qualitative interaction
at 0.1 level provides strong evidence that the effect of octreotide LAR plus tamoxifen in patients
with adjuvant chemotherapy differs from those who did not receive adjuvant chemotherapy. A
subset analysis by adjuvant chemotherapy will be performed when there is a significant qualitative
interaction with sufficient number of events.
All patients who have received at least one dose of study treatment will be included in the safety
analysis. Toxicities will be graded using the NCIC CTG Expanded Common Toxicity Criteria. It
is not anticipated that the toxicity level of the regimens will be high. The incidence
32
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 00-JUL-12
of toxicities will be summarized by type of adverse event, severity and relationship to the study
drug. A Fisher’s exact test will be used to compare toxicities between the two arms.
Follow-up data as described in the protocol will be summarized using the mean changes from
baseline. Shift tables may be presented. These tables will summarize the change from baseline
status for a subject's worst value, defined as that of greatest pathological significance observed
during the study for a given variable.
Laboratory data will be summarized using the mean change from baseline status for a subject's
worst value, defined as that of greatest pathological significance observed during the study for a
given variable. A two sample t-test will be used to compare the two treatment arms.
Patients' health related quality of life will be assessed using the EORTC QLQ C30+1
questionnaire. The EORTC quality of life questionnaire is a self-administered cancer specific
questionnaire with multi-dimensional scales. The validity and reliability of this instrument have
been studied by the EORTC Study Group on Quality of Life47. Since quality of life will be
assessed longitudinally, the method of analysis of variance for repeated measures48 will be used for
overall quality of life and domains represented by aggregate scores. The symptom check lists
represented single items in the form of repeat categorical data; they will be analyzed using the
generalized least squares method proposed by Koch et al (1977)49. The profiles of the quality of
life scores will be displayed and compared between the two treatment arms.
14.3
Sample Size and Duration of Study
The population of patients for this study is a blend of patients with different levels of risk. Nodenegative patients were studied in the NSABP trial B14 where their five-year event-free survival was
82%. Node-positive patients are similar to the patient population studied in the NCIC CTG trial
MA.4. The overall 5-year survival was 80% and the event-free survival was about 60% at five
years.
The following sample size calculations are based on an event-free survival rate of 73% at five
years. This number is arrived at by blending the 60% event-free survival rate for node-positive
patients with the 82% event-free survival rate for node-negative patients using a 40% - 60% split.
The reason for this split is that the incidence of node-negative breast cancer is approximately 1.5
times that of node-positive cancer. In order to have 80% power to detect a hazards ratio of 1.5 (i.e.
an improvement of 8.2% event-free survival from 73% at 5-year) using a two-sided 5% level test,
we would need to observe a total 191 events. The formula can be found in the appendix of George
and Desu (1973)67. We would enter 650 eligible patients in about 4 years and follow all patients
for about 4.7 years before the final analysis. The final analysis will be performed when 191
events are observed.
Since the majority of node-negative patients would not receive adjuvant chemotherapy and about
50% of node-positive patients would receive chemotherapy, we expect to find a total of 80% of
patients in the study who have not received adjuvant chemotherapy. The 5-year event-free survival
of patients in the subset of no adjuvant chemotherapy is therefore about 77%. At the time of final
analysis, we will have more than 80% power to detect a 8% improvement at 5 years for the subset
of patients who did not receive chemotherapy.
33
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 00-JUL-12
14.4
Safety Monitoring
Toxicities will be monitored on an ongoing basis by the central office and their frequencies reported
annually at the investigators’ meeting. Interim analyses and other decisions regarding early
termination of the study will be referred to the Data and Safety Monitoring Committee of the
Group.
14.5
Interim Analysis
We are planning one interim analysis to allow early termination of the study if the results are
extreme. After observing a half of the expected events from the event-free survival analysis, i.e.,
96 events, we will perform a log-rank test on the primary endpoint using the O’Brien-Fleming type
boundaries as proposed by Lan and DeMets (1983)50. We expect to have 96 events approximately
2 years after the end of accrual. The results of the interim analysis will be presented to the
monitoring committee. Early termination will be considered when the significance level of the
interim analysis is less than 0.005. The nominal significance value for the final analysis is 0.048.
This group sequential procedure is based on the type I error spending function as proposed by Lan
and DeMets (1983)50 such that the overall significance level will be maintained at 5%.
34
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09
15.0
PUBLICATION POLICY
15.1
Authorship of Papers, Meeting Abstracts, Etc.
15.1.1
Prior to trial activation, the chair will decide whether to publish the trial under a group title, or
with naming of individual authors. If the latter approach is taken, the following rules will apply:
P The first author will generally be the chair of the study.
P A limited number of the members of the NCIC Clinical Trials Group and Novartis
Pharmaceuticals Canada Inc., may be credited as authors depending upon their level of
involvement in the study.
P Additional authors, up to a maximum of 15, will be those who have made the most significant
contribution to the overall success of the study. This contribution will be assessed, in part but
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the
study chair.
15.1.2
In an appropriate footnote or at the end of the article the following statement will be made:
"A study coordinated by the Clinical Trials Group of the National Cancer Institute
of Canada in collaboration with Novartis Pharmaceuticals Canada Inc.
Participating investigators included: (a list of the individuals who have contributed
patients and their institutions)."
15.2
Responsibility for Publication
It will be the responsibility of the study chair to write up the results of the study within a reasonable
time of its completion. If after a period of six months following the analysis of study results the
draft is not substantially complete, the central office reserves the right to make other arrangements
to ensure timely publication.
15.3
Submission of Material for Presentation or Publication
Material may not be submitted for presentation or publication without prior review by Novartis
Pharmaceuticals Canada Inc., the NCIC CTG physician and study coordinator, and approval of
the study chair. Individual participating centres may not present outcome results from their own
centres separately. Supporting groups and agencies will be acknowledged.
35
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09
16.0
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES
16.1
Documentation
Novartis Pharmaceuticals Canada Inc. will be collecting the following documents as they are
required to obtain a Drug Shipment Clearance for each centre.
Documents submitted by the investigator prior to study initiation:
1. CVs of the principal investigator and all co/sub-investigators.
2. Signature page of the protocol and any amendments.
3. Completed FDA Form 1572 (principal investigator) and Statement of Investigator/Compliance
with the Declaration of Helsinki Form (principal investigator) and HPB 3005 (principal
investigator and co/sub-investigators).
4. Sample of the approved Informed Consent Form and Patient Information Sheet on hospital
letterhead.
5. Ethics Committee documentation:
- Approval of the final protocol and any amendments (A signed and dated statement stipulating
that the protocol and informed consent have been approved by the REB. The same applies
to amendments.)
- Membership list and occupation if appropriate.
6. Authorization of CRF Entries and Corrections form.
7. List of the Study Team.
16.2
REB (Research Ethics Board) Approval for Protocols
REB Composition: Research Ethics Boards will be constituted according to local interpretation of
the Canadian Medical Research Council (MRC) Guidelines and the U.S. Food and Drug
Administration (FDA) guidelines.
Initial Approval
Member centres wishing to participate in the trial are required to obtain local ethics approval of the
protocol by the appropriate research ethics board (REB).
Continuing Approval
Annual re-approval is required for as long as the trial is open to patient accrual.
36
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09
Amendments
Any change or addition to this protocol requires a written protocol amendment and this must be
approved by the NCIC-CTG, Novartis Pharmaceuticals Canada Inc. and the investigator before
the change or addition can be considered effective
Protocol amendments will be circulated in standard format with clear instructions regarding REB
review. HPB submission of all amendments will take place. After approval by the REB and
HPB, an amendment becomes an integral part of the protocol.
16.3
Informed Consent
The investigator must explain to each subject (or legally authorized representative) the nature of the
study, its purpose, procedures, expected duration and the potential risks and benefits involved in
study participation along with any discomfort it may entail. Each subject must be informed that
participation in the study is voluntary and that she may withdraw from the study at any time and
that withdrawal of consent will not affect her right to the most appropriate medical treatment or
affect the doctor/subject relationship.
This informed consent should be given by means of a standard written statement. It should be
written so as to be easily understood by the subject. The subject should be given the time to read
and understand the statement herself before signing her consent and dating the document. The
subject should receive a copy of the written statement once signed.
The informed consent form must be considered as part of the protocol with which it is to be
submitted by the investigator for approval to the IRB/Ethics Committee.
A standardized informed consent form is contained in section 18.2 which complies with regulatory
requirements. The investigator may suggest changes to the proposed informed consent form, but
these must be agreed to by Novartis Pharmaceuticals Canada Inc. and NCIC CTG.
A copy of the final informed consent form and patient information sheet (if used), submitted by the
investigator for approval by the IRB/Ethics Committee, must be supplied to NCIC CTG and
Novartis Pharmaceuticals Canada Inc.
No subject is to be entered into the study until her informed consent has been obtained.
16.4
Centre Performance Monitoring
Ineligibility and timeliness are monitored for all centres and the results are reported in the Centre
Performance Index. This index is generated twice a year and there are minimum standards for
performance.
37
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09
16.5
Monitoring and Auditing Procedures
Monitoring Procedures
UP TO JANUARY 1, 2000
At the time the study is initiated, a Novartis Pharmaceuticals Canada Inc. representative
(monitor) will thoroughly review the protocol and case report forms with the investigators and their
staff.
During the course of the study the investigator will be visited regularly by a Novartis
Pharmaceuticals Canada Inc. monitor. The investigator must set aside a reasonable amount of
his/her time and the time of the designated members of his/her staff who are involved in the study
for monitoring visits.
At the time of each monitoring visit, the monitor will review the case report forms (CRFs) of each
subject in the study to make certain that all items have been completed and that the data provided
are accurate and obtained in the manner specified in the protocol.
The investigator must agree to allow the monitor to review relevant hospital/other clinical records
to confirm that required study procedures are being followed and that there is consistency between
these records and the CRFs. Items which will be checked in this manner include:
• informed consent form signed by the subject
• the statement in the hospital records that the subject is participating in the clinical study
• values of all variables recorded in the CRFs and also in the hospital records (i.e. source
documents)
• schedule and dosage of study/concomitant medication according to dispensing records
The investigator must also allow the monitor to verify that the storage specifications and inventory
for study medication are being followed.
Incorrect, inappropriate or illegible entries onto the CRFs will result in queries being sent to the
investigator for resolution.
No data disclosing the identity of subjects should leave the study centre as a result of the monitoring
procedure. Novartis Pharmaceuticals Canada Inc. will maintain confidentiality of all subject
records.
Completed CRFs will be collected by Novartis Pharmaceuticals Canada Inc. as soon as the
monitor has validated the data. Usually CRFs will be gathered for completed subject visits at each
monitoring visit. A copy of the CRFs will remain in the possession of the investigator. The
investigator must ensure that the CRFs and other study documentation are stored in a secure
location.
During the course of the study, the responsible Novartis Pharmaceuticals Canada Inc. staff will
be available to discuss any matters relating to the conduct of the study.
38
AFTER JANUARY 01, 2000
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09;AMENDED: 00-JUL-12
Novartis Pharmaceuticals Canada Inc. will no longer regularly visit the investigator.
Completed CRFs will be submitted in a timely fashion (following NCIC CTG submission
schedule) without waiting for on site monitoring (see Appendix IV).
Auditing Procedures
In addition to the routine monitoring procedures outlined above, other Novartis Pharmaceuticals
Canada Inc. representatives or NCIC CTG may carry out an audit or a regulatory body may
wish to carry out an inspection (even after the study has been completed).
The procedures of such a visit would be similar to those of a monitoring visit, and data already
checked by the regular Novartis Pharmaceuticals Canada Inc. monitor may be checked again.
The investigator is required to inform Novartis Pharmaceuticals Canada Inc. immediately of an
inspection requested by a regulatory authority.
16.6
Case Report Forms and the Reporting and Recording of Data
The list of forms to be completed is found in Appendix IV.
Data on subjects collected on CRFs in the course of this trial will be documented in an anonymous
fashion, i.e. the subject will be identified only by a subject number and by subject initials if so
required. Should knowledge of subject identity become necessary for safety or regulatory reasons,
confidentiality by both Novartis Pharmaceuticals Canada Inc. and the investigator will be
maintained.
All information required by the protocol should be provided. An explanation must be given for
any omissions. All CRFs must be completed and be made available as soon as possible after the
subject visit in order that NCIC CTG may review the forms and permit prompt transmission of
the data to NCIC CTG and Novartis Pharmaceuticals Canada Inc. Prior to being sent to
NCIC CTG, CRFs should be reviewed by the investigator for completeness, accuracy and
legibility, and signed by the investigator.
All data and information on these case report forms are to be neatly and legibly recorded in black
ballpoint pen (to ensure legibility of self-copying or photocopied pages). All corrections on the
CRFs are made by crossing out the error with a single line through the original entry (so that the
original entry remains discernible). The revised entry is made alongside, and must be initialled and
dated by a member of the investigator's research team authorized to make CRF entries (as
identified to Novartis Pharmaceuticals Canada Inc. elsewhere). The use of correction fluid is
not permitted.
The investigator must agree to complete and maintain source documents for each subject
participating in the study. For monitoring and auditing purposes, and to the greatest extent
possible, all information recorded on CRFs must be traceable back to these source documents
39
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09
which are generally maintained in the subject's file. The source documents should contain all
demographic and medical information including laboratory data, electrocardiograms, etc. The
subject's file should also indicate that she is participating in the clinical study referencing the study
number and the trial medication.
The investigator must arrange for the retention at the investigational site a list of the subjects and
their numbers in the clinical study for at least 15 years after completion or discontinuation of the
trial. Subject files and other source documents must be kept for the maximum period of time
permitted by the hospital/institution/private practice, but for not less than 15 years. The study
documents, all source documents and laboratory records, CRF copies, subjects' informed consent
forms and any other pertinent study documents. The investigator agrees to supply Novartis
Pharmaceuticals Canada Inc. with a written confirmation that these procedures are in place and
will be adhered to.
16.7
Forms Submission and Required Supporting Documentation
As indicated in section 16.5 up to January 01, 2000, Novartis Pharmaceuticals Canada Inc.
monitors will be reviewing all case report forms and supporting documentation on site. All copies
of all forms, with the exception of the Form 1 as described below, will be retained at the centre
until reviewed by a monitor. After January 01, 2000, since supporting documentation will no
longer be reviewed on site, the following procedures for the submission of forms and supporting
documentation should be followed.
P On-Study Documentation (Form 1: Eligibility Checklist and Initial Evaluation)
The Form 1's will be printed on NCR paper with 3 copies included. The white and yellow
copies must be submitted to NCIC CTG within 6 weeks of randomization with a copy of the
operative and pathology reports for confirmation of eligibility, diagnosis and staging. NCIC
CTG will also require copies of the consent, ER/PR status reports and baseline radiology
reports.
P Documentation during and after protocol therapy:
Treatment/Follow-up Forms (Forms 5, 5S, Adjuvant Treatment Report)
These forms will be printed on NCR paper with 3 copies included. The white and yellow
copies of these forms will be sent directly to NCIC CTG. It is not necessary to send
supporting documentation to NCIC CTG with these forms unless reports indicate disease.
Suspicious or ambiguous medical reports can be sent to NCIC CTG for a medical review at
any time.
Recurrence/Second Malignancy and Death Forms (Forms 9 & 6)
Supporting documentation confirming recurrence/second malignancy (see section 10.2) must
be sent to NCIC CTG with the Form 9. Supporting documentation at the time of death (i.e.,
autopsy report if one was conducted) must be sent with the Form 6.
40
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
17.0
REFERENCES
1.
Helzlsouer, K.J. Epidemiology, prevention, and early detection of breast cancer. Current Opinion
in Oncology, 6: 541-548, 1994.
2.
Love, R.R. and Koroltchouk, V. Tamoxifen therapy in breast cancer control worldwide. Bull.
WHO, 71: 795-803, 1993.
3.
Pritchard, K.I. Chemotherapy and endocrine therapy in metastatic disease. Current Opinion in
Oncology, 1: 324-332, 1989.
4.
Saunders, C.M. Current management of breast cancer. British J Hosp. Med. 50: 588-590, 1993.
5.
Kennedy, M.J. Systemic adjuvant therapy for breast cancer. Current Opinion in Oncology, 6:
570-577, 1994.
6.
Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by
hormonal, cytotoxic, or immune therapy. Lancet, 339: 1-15,-71-85, 1992.
7.
Nolvadex Adjuvant Trial Organization Controlled trial of tamoxifen as a single adjuvant agent in
the management of early breast cancer: analysis at eight years. Br. J. Cancer, 57: 608-611, 1988.
8.
Breast Cancer Trials Committee. Adjuvant tamoxifen in the management of operable breast cancer:
The Scottish trial. Lancet, 171-175, 1987.
9.
Fisher, B., Costantino, J., Redmond, C., and et al. A randomized clinical trial evaluating
tamoxifen in the treatment of patients with node-negative breast cancer who have
estrogen-receptor-positive tumours. New Eng. J. Med., 320: 479-484, 1989.
10.
Fisher, B. and et al. Post operative chemotherapy and tamoxifen compared with tamoxifen alone
in treatment of positive-node breast cancer patients aged 50 years and older with tumours responsive
to tamoxifen. J. Clin. Oncol. 8: 1005-1018, 1990.
11.
Pritchard, K.I. Clinical cooperative trials of the National Cancer Institute of Canada Clinical Trials
Group breast cancer site group. Cancer, 74: 1150-1155, 1994.
12.
Pritchard, K.I., Zee, B., and Paul, N. CMF added to tamoxifen as adjuvant therapy in
post-menopausal women with node-positive (+ve) estrogen (ER) and/or progesterone receptor
(PgR) +ve breast cancer: negative results from a randomized clinical trial (meeting abstract).
Proc.Annu.Meet.Am.Soc.Clin.Oncol. 13: A61, 1994.
13.
Weckbecker, G., Raulf, F., Stolz, B., and Bruns, C. Somatostatin analogs for diagnosis and
treatment of cancer (Review). Pharmac Ther, 60: 245-264, 1993.
41
14.
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
Weckbecker, G., Tolcsvai, L., Stolz, B., Pollak, M., and Bruns, C. Somatostatin analogue
octreotide enhances the antineoplastic effects of tamoxifen and ovariectomy on
7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas. Cancer Res. 54: 6334-6337,
1994.
15.
Lamberts, S.W.J., Krenning, E.P., and Reubi, J.C. The role of somatostatin and its analogs in the
diagnosis and treatment of tumours. Endocrine Rev. 12: 450-482, 1991.
16.
Schally, A.V. Oncological applications of somatostatin analogues. Cancer Res. 48: 6977-6985,
1988.
17.
Weckbecker, G., Liu, R., Tolcsvai, L., and Bruns, C. Antiproliferative effects of the somatostatin
analogue octreotide (SMS 201-995) on ZR-75-1 human breast cancer cells in vivo and in vitro.
Cancer Res. 52: 4973-4978, 1992.
18.
Pollak, M., Polychronakos, C., and Guyda, H. Somatostatin analogue SMS 201-995 reduces serum
IGF-I levels in patients with neoplasms potentially dependent on IGF-I. Anticancer Res. 9: 889-892,
1989.
19.
Lee, M.T., Liebow, C., Kamer, A.R., and Schally, A.V. Effects of epidermal growth factor and
analogues of luteinizing hormone-releasing hormone and somatostatin on phosphorylation and
dephosphorylation of tyrosine residues of specific protein substrates in various tumors. Proc. Natl.
Acad. Sci. USA, 88: 1656-1660, 1991.
20.
Buscail, L., Delesque, N., Esteve, J.P., Saint-Laurent, N., Prats, H., Clerc, P., Robberecht, P.,
Bell, G.I., Liebow, C., Schally, A.V., Vaysse, N., and Susini, C. Stimulation of tyrosine
phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human
somatostatin receptor subtypes SSTR1 and SSTR2. Proc. Natl. Acad. Sci. USA, 91: 2315-2319,
1994.
21.
Powis, G. and Kozikowski, A. Growth factor and oncogene signalling pathways as targets for
rational anticancer drug development. Clinical Biochemistry, 24: 385-397, 1995.
22.
van Eijck, C.H., Krenning, E.P., Bootsma, A., Lindemans, J., Jeekel, J., Reubi, J.C., and
Lamberts, S.W. Somatostatin-receptor scintigraphy in primary breast cancer. Lancet, 343: 640-643,
1994.
23.
Patel, Y.C. and Srikant, C.B. Subtype selectivity of peptide analogs for all five cloned human
somatostatin receptors (hsstr 1-5). Endocrinol. 135: 2814-2817, 1994.
24.
Setyono-Han, B., Henkelman, M.S., Foekens, J.A., and Klijn, G.M. Direct inhibitory effects of
somatostatin (analogues) on the growth of human breast cancer cells. Cancer Res. 47: 1566-1570,
1987.
25.
Pollak, M. Effects of adjuvant tamoxifen therapy on growth hormone and insulin-like growth factor
I (IGF-I) physiology. In: S.E. Salmon (ed.), Adjuvant Therapy of Cancer VII, J.B.Lippincott
Company. 1993.
42
26.
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
Friedl, A., Jordan, V.C., and Pollak, M. Suppression of serum IGF-I levels in breast cancer
patients during adjuvant tamoxifen therapy. Eur. J. Cancer, 29A: 1368-1372, 1993.
27.
Pollak, M., Costantino, J., Polychronakos, C., Blauer, S., Guyda, H., Redmond, C., Fisher, B.,
and Margolese, R. Effect of tamoxifen on serum insulin-like growth factor I levels in stage I breast
cancer patients. JNCI, 82: 1693-1697, 1990.
28.
Huynh, H.T., Tetenes, E., Wallace, L., and Pollak, M. In vivo inhibition of insulin-like growth
factor-I gene expression by tamoxifen. Cancer Res. 53: 1727-1730, 1993.
29.
Tannenbaum, G.S., Gurd, W., Lapointe, M., and Pollak, M. Tamoxifen attenuates pulsatile
growth hormone secretion: mediation in part by somatostatin. Endocrinol. 130: 3395-3401, 1992.
30.
Huynh, H.T. and Pollak, M. Enhancement of tamoxifen-induced suppression of insulin-like growth
factor I gene expression and serum level by a somatostatin analogue. Biochem. Biophys. Res.
Comm. 203: 253-259, 1994.
31.
Welsch, C.W. Host factors affecting the growth of carcinogen-induced rat mammary carcinomas:
A review and tribute to Charles Brenton Huggins. Cancer Res. 45: 3415-3443, 1985.
32.
Jordan, V.C. and Murphy, C.S. Endocrine pharmacology of antiestrogens as antitumor agents.
Endo. Rev. 11: 578-611, 1990.
33.
Lerner, L. and Jordan, V.C. Development of antiestrogens and their use in breast cancer: Eighth
Cain Memorial award lecture. Cancer Res. 50: 4177-4189, 1990.
34.
Somlo, G., Vogel, C., Flamm Honig, S., Linnartz, R., and Israel, R. A phase I study of
octreotide (SMS) in patients with advanced breast cancer. Proc.Annu.Meet.Am.Soc.Clin.Oncol.
12: A172, 1993.(Abstract)
35.
Brown, N.J. Octreotide: A long-acting somatostatin analog. Amer. J. Med. Sci. 300: 267-273,
1990.
36.
Editorial. All aboard for octreotide. Lancet, 336: 909-911, 1990.
37.
Canobbio, L., et al. Somatuline plus tamoxifen in postmenopausal breast cancer patients. NY
Acad. Sci. Vol. 698, 362-368, 1993.
38.
Laurie, J., et al. Surgical Adjuvant Therapy of Large Bowel Cancer: an evaluation of levamisole
and the combination of levamisole and fluorouracil. J. Clin. Onc. 7: 1447-56, 1989.
39.
Johnston, S. and Dowsett, M. Tamoxifen metabolism and estrogen receptor function. In: Kelen
(ed.), Tamoxifen: Beyond the Antiestrogen, Birkhauser, Boston, 1996.
40.
Patterson, J.S. "Nolvadex" (tamoxifen) as an anti-cancer agent in humans. In Sutherland &
43
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
Jordan (eds) Non-steroidal antioestrogens, pp 143-163, Academic Press, Sydney, 1981.
41.
Dickson, R.B., Lippman, M.E. Estrogenic regulation of growth and polypeptide growth factor
secretion in human breast carcinoma. Endocrine Reviews 8: 29-43, 1987.
42.
Buckley, MM-T., Goa, K.L. Tamoxifen. A reappraisal of its pharmacodynamic and
pharmacokinetic properties, and therapeutic use. Drugs 37: 451-490, 1989.
43.
Reddel, R.R., Murphy, L.C., Hall, R.E., Sutherland, R.L. Differential sensitivity of human
breast cancer cell lines to the growth-inhibitory effects of tamoxifen. Cancer Res 45: 1525-1531,
1985.
44.
Butta, A., MacLennan, K., Flanders, K.C. Induction of transforming growth factor $1 in human
breast cancer in vivo following tamoxifen treatment. Cancer Res 52: 4261-4264, 1992.
45.
Heel, R.C., Brogden, R.N., Speight, T.M., Avery, G.S. Tamoxifen: a review of its
pharmacological properties and therapeutic use in the treatment of breast cancer. Drugs 16: 1-24,
1987.
46.
Gail, M. and Simon, R. "Testing for Qualitative Interaction Between Treatment Effects and
Patients Subsets", Biometrics 41: 361-372, 1985.
47.
Aaronson, N., Ahmedzai, S., Bullinger, M., et al. The EORTC Core Quality of Life
Questionnaire: Interim Results of an International Field Study. In The Effect of Cancer on Quality
of Life, Ed. Osoba,D., Ch. 14, CRC Press, 1991.
48.
Zee, B. and Pater, J. Statistical analysis of trials assessing quality of life. In The Effect of Cancer
on Quality of Life, Ed. Osoba,D., Ch. 9, CRC Press, 1991
49.
Koch, G.G., Landis, J.R., Freeman, J.L., Freeman, D.H., Lehnen, R.G. A general methodology
for the analysis of repeated measurement of categorical data. Biometrics, 33, 133-158, 1977.
50.
Lan, G. and DeMets, D. Discrete sequential boundaries for clinical trials. Biometrika 70,
659-663, 1983.
51.
Pollak, M., et al. Rationale for combined antiestrogen-somatostatin analogue therapy of breast
cancer. In Salmon, S.E. (ed) Adjuvant Therapy of Cancer VIII. Proceedings of the 8th
International Conference on the Adjuvant Therapy of Cancer, Phoenix, Arizona, March 1996.
(J.B. Lippincott, Philadelphia, 1996, in press).
52.
Lamberts, et al. Octreotide. New Eng J Med, 334: 246-254, 1996.
53.
Yang, X., Beamer, W., Pollak, M. Reduced growth of human breast cancer xenografts in hosts
homozygons for the ‘lit’ mutation. Cancer Res, 56: 1509-11, 1996.
54.
Barrie, R., Woltering, E.A., Hajarizedeh, H., Mueller, C., Ure, T., Fletcher, W.S.
Inhibition of angiogenesis by somatostatin and somatostatin-like compounds is structurally
44
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
dependent. J Surg Res, 55(4): 446-50, 1993.
55.
Huynh, H., Yang, X., Pollak, M. Estradiol and antiestrogens regulate a growth inhibitory
insulin-like growth factor binding protein 3 loop in human breast cancer cells. J Biol Chem, 271:
1016-21, 1996.
56.
Tamoxifen and Endometrial Cancer: The American College of Obstetrics and Gynecology,
Committee Opinion Number 169, February 1996.
57.
Aaronson, N.K., Ahmedzai, S., Bergman, B., et al. The European Organization for Research
and Treatment of Cancer QLQ-C30: A quality of life instrument for use in international clinical
trials in oncology. J Natl Cancer Inst, 85: 365-376, 1993.
58.
Witzig, T., et al. Evaluation of a somatostatin analogue in the treatment of lymphoproliferative
disorders. J Clin Onc, 13: 2012-2015, 1995.
59.
Huynh, H.T., Pollak, M. Uterophic actions of estradiol and tamoxifen are associated with
inhibition of uterine IGF binding protein 3 gene expression. Cancer Res, 54: 3115-3119, 1994.
60.
Huynh, H.T., Pollak, M. IGF-I gene expression in the uterus is stimulated by tamoxifen and
inhibited by the pure antiestrogen ICI 182780. Cancer Res, 53: 5585-5588, 1993.
61.
Vennin, P., Peyrat, J., Bonnetenne, J., Louchez, M., Harris, A. and Demaille, A. Effect of
SMS 201-995 in advanced breast cancer. Anticancer Res, 9: 153-5, 1989.
62.
Arteaga, C., et al. Blockade of the type I somatomedin receptor inhibits growth of human breast
canceer cells in athymic mice. J Clin Invest, 84: 1418-23, 1989.
63.
Macaulay, V. Insulin-like growth factors and cancer. Br J Cancer, 65: 311-320, 1992.
64.
Schipper, H., Goh, C., Wang, T. Shifting the cancer paradigm: must we kill to cure? J Clin
Onc, 13: 801-7, 1995.
65.
White, S.J. and Freedman, L.S. Allocation of patients to treatment groups in a controlled clinical
study. British J Cancer, 37: 849-857, 1978.
66.
Cox, D.R. Regression models and life tables (with discussion). J Roy Statist Soc Ser, B34: 187220, 1972.
67.
George, S.L. and Desu, M.M. Planning the size and duration of a clinical trial studying the time
to some critical event. J of Chronic Dis, 27: 15-24, 1973.
45
18.0
CONSENT FORM
18.1
Required Elements
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09
A sample consent form has been provided (section 18.2) . This consent may be modified to
satisfy local REB requirements; however, please note that the consent form must contain the
following elements. A review of your sample consent form prior to REB submission can be
performed by NCIC CTG upon request to the Study Coordinator.
1.
A statement that the study involves research, an explanation of the purposes of the research,
a description of the study design, the expected duration of the subject's participation, a
description of the procedures to be followed and identification of any procedures which are
experimental.
2.
A description of any reasonably foreseeable risks or discomforts to the subject.
3.
A description of any potential side effects.
4.
A description of any potential benefits to the subject or to others which may reasonably be
expected from the research.
5.
A disclosure of appropriate alternative procedures or courses of treatment, if any, that might
be advantageous to the subject.
6.
A statement describing the extent, if any, to which confidentiality of records identifying the
subject will be maintained and that notes the possibility that regulatory authorities or sponsor
may inspect or review the records.
7.
For research involving more than minimal risk, an explanation as to whether any
compensation and any medical treatments are available if injury occurs and, if so, what they
consist of, or where further information may be obtained.
8.
An explanation of whom to contact for answers to pertinent questions about the research and
research subject's rights, and whom to contact in the event of research-related injury to the
subject.
9.
A statement that participation is voluntary, that refusal to participate will involve no penalty
or loss of benefits to which the subject is otherwise entitled, and that the subject may
discontinue participation at any time without penalty or loss of benefits to which the subject
is otherwise entitled.
10. A statement that significant new findings developed during the course of the research which
may relate to the subject's willingness to continue participation will be provided to the
subject.
11. A statement that gives permission for patient data to be sent to the central office of the
National Cancer Institute of Canada (NCIC) Clinical Trials Group, Novartis
46
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09
Pharmaceuticals Canada Inc., the Health Protection Branch (HPB) of the Department of Health
and Welfare Canada and the Food and Drug Administration (FDA) of the Department of Health
and Human Services in the United States. A statement must also be included that provides these
agencies with the permission to review patient records.
When appropriate, one or more of the following elements of information shall also be provided
to each subject:
1.
A statement that the particular treatment or procedure may involve risks to the subject (or
to the embryo or fetus, if the subject is or may become pregnant) which are currently
unforeseeable.
2.
Anticipated circumstances under which the subject's participation may be discontinued by the
investigator without regard to the subject's consent.
3.
Any additional costs to the subject which may result from participation in the research.
4.
The consequences of a subject's decision to withdraw from the research and procedures for
orderly termination of participation by the subject.
5.
The approximate number of subjects involved in the study.
6.
That with the subject's agreement and when appropriate the investigator will inform the
subject's family doctor about his/her participation in the study.
47
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
18.2
Sample Consent Form
A Research Study Comparing Antiestrogen Therapy to Combined
Antiestrogen and Octreotide LAR Therapy in the Adjuvant Treatment
of Breast Cancer in Post-Menopausal Women
Le formulaire de consentement est disponible en francais sur demande
Purpose and Description of Study
I understand that I have had a breast cancer removed by surgery and that there is a chance the
cancer may come back. Tamoxifen, which is an antiestrogen treatment, has been shown to
decrease the chance that the cancer may come back in women who have had breast cancer
removed. This research study will compare two different treatments. Treatment 1, which is
a usual way for doctors to treat women with my disease, consists of tamoxifen only.
Treatment 2 consists of tamoxifen plus an experimental drug for my type of disease called
octreotide LAR.
I have been asked to take part in this research study. The study will take place at many
hospitals in Canada. About 850 patients will take part. This study will compare these two
different treatments for my disease. The main reason for this study is to see if there is a
difference in the number of women who have cancer come back depending on which treatment
they get.
Study Treatment
I understand that if I get Treatment 1 I will take tamoxifen by mouth each day for 5 years. If
I get Treatment 2 I will take taxomifen by mouth each day plus I will receive a single dose of
octreotide LAR by injection once per month for 5 years.
No one knows which treatment is better for me. For this reason, which treatment I get will be
decided by chance (like the flip of a coin). This is called randomization. My chances of
getting either treatment is equal. I will be told which treatment I am getting.
I have been told that should my cancer come back, the side effects of the treatment become
very severe or if new information comes to light indicating that this treatment is no longer in
my best interests that my physician would stop the treatment. Further treatment would be
discussed. It is expected that I will be on study treatment for 5 years. After I stop study
treatment my progress will be checked every year.
Alternatives to participating in this study which could be considered in my case would be to
receive standard care, which at the present time, would most likely be similar to Treatment 1
in this study.
NCIC CTG Pt. Serial No: ________
48
PROTOCOL DATE:
NCIC CTG TRIAL:
Possible Benefits
96-MAY-15
MA.14
AMENDED: 96-AUG-12; AMENDED: 97-SEP-18; AMENDED: 99-DEC-09
Treatment 1 and Treatment 2 may be the same in almost every way. I understand that the
chance of my cancer coming back could be the same with both treatments.
It is unknown if I will derive any personal benefit from participation in this study; however,
other patients like me may benefit from the information this study will provide.
Possible Side Effects of Treatment
Side effects I might have from tamoxifen are:
1. hot flashes (20% of patients)
2. low white blood cells or low platelets which usually resolves spontaneously during the
second week of treatment (20% of patients)
3. nausea (10% of patients)
4. vaginal dryness or discharge (9% of patients)
Other side effects I may experience but which rarely occur (in less than 3% of patients)
include vaginal bleeding, too much calcium in the blood, depression, dizziness, hair loss,
headache, skin rash and swelling. Rarely cataracts have occurred in patients receiving higher
doses of tamoxifen. Patients with cancer have an increased risk of developing blood clots and
the use of tamoxifen may increase this risk.
Women taking Tamoxifen may be at a slightly increased risk for developing cataracts (a
clouding of the lens inside the eye). As women age, they are more likely to develop
cataracts whether or not they take Tamoxifen. Cataracts may lead to a decrease in
vision. Eye surgery may be required to remove the cataract and improve vision. Women
who have a cataract before beginning to take Tamoxifen may be more likely to have
cataract surgery. Other eye problems, such as corneal scarring and retinal changes, have
been reported in a few patients. I have been told that I should report any changes in my
vision, or other eye problems, to my physician.
Women taking tamoxifen have been shown to have a greater risk of developing uterine cancer
(twice normal) and yearly gynaecological examinations have been recommended to me by my
physician. I should get in touch with my physician if I develop menstrual bleeding, lower
abdominal pressure or pain.
Mild to moderate side effects I might have from octreotide LAR are:
1.
2.
3.
4.
5.
6.
diarrhea (up to 50% of patients, transient, <24 hours)
nausea (30-50% of patients)
stomach pains (30-50% of patients)
pain at the injection site (7% of patients)
gallstones or sludge with no symptoms (48% of patients)
gallstones or sludge with symptoms [(5% of patients) including surgery for gallbladder removal]
Other side effects I may experience but which rarely occur in patients include mild dizziness,
headache, odd tastes, hot flashes, muscle pain and blurred vision. If these effects do occur
they usually resolve within 24 hours of when they begin; however, some of the side effects
may continue for a prolonged time. Patients who have undergone prolonged use of octreotide
LAR for acromegaly (a growth disorder) have very rarely experienced decreased production of
thyroid hormone, aggravation of diabetes mellitus, cardiac abnormalities or a decrease in
Vitamin B12 which is a vitamin necessary for healthy red cell production.
49
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09
Tests, Questionnaires
While I am on study I will have some tests done (eg. blood tests, x-rays). These tests may be
done more frequently than if I was not participating in the study.
From time to time I will be asked to provide blood samples which will allow researchers to
study how the treatments work.
I understand that at specified intervals while on the study I will be asked to fill out a
questionnaire that asks me how well I feel and how well I am tolerating the treatment. This is
an important part of the study. The questionnaire will take less than a 1/2 hour to fill out each
time. The information that I provide is for research purposes and will remain strictly
confidential. The individuals (e.g. doctors, nurses, etc) directly involved in my care will not
usually see my responses to these questions. If I wish them to know this information, I will
bring it to their attention.
Confidentiality and Access to Medical Records
Information from my medical records about my treatment and disease, which will not identify
me by name, will be made available to the central office of the National Cancer Institute of
Canada Clinical Trials Group (NCIC CTG) which is coordinating the study and to Novartis
Pharmaceuticals Canada Inc., which is supplying the octreotide LAR and supporting the study.
This information could include tests results, blood or tissue samples, x-rays, other medical
information and quality of life questionnaires.
This information may be inspected by the Health Protection Branch (HPB) of the Department
of Health and Welfare Canada and the Food and Drug Administration (FDA) of the
Department of Health and Human Services in the United States. This information will be kept
strictly confidential to the extent permitted by law. In addition, representatives of the NCIC
CTG and/or Novartis Pharmaceuticals Canada Inc. may wish to examine my hospital or clinic
records, again observing strict confidentiality. Information collected during this study will be
submitted to the HPB and the FDA and it may also be used for research purposes. However,
if it is used for research, it will not primarily identify me, nor will I be identified by name in
any presentation or publication.
Study Participation
I have talked with my doctor about the study and he/she has answered my questions. I am
taking part in this study of my own free will. I can refuse to take part and am free to stop
taking part at any time. If I do so, my doctor will continue to treatment me with the best
means available. To stop participating in this study I need to only tell my physician I no
longer wish to continue. With my permission, when appropriate my physician who put me on
this study may tell my family physician about my participation.
50
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 96-AUG-12; AMENDED: 99-DEC-09
I understand that there will be no cost to me for the study drug (octreotide LAR) or for any
tests or procedures that are done as a part of this study. Octreotide LAR is given as monthly
injections and this may mean I will have more frequent medical visits than if I receive
tamoxifen alone which is currently standard treatment for my disease. If I suffer a physical
injury or illness as a result of receiving study treatment, Novartis Pharmaceuticals Canada Inc.
will pay for any reasonable medical expenses not paid for by my Provincial Health Care Plan
or personal health insurance.
If I have questions about taking part in this study, I can meet with the doctor who is in charge
of the study and/or the head of the university department. I have been given a copy of this
consent form.
I can talk to ____________________________________, who is not involved in this study,
about taking part in the study and about research subject’s rights. His/her telephone number is
___________________________.
The person whom I should contact in the event of a research related injury is
__________________________________ and his/her telephone number is ________________.
The name of the doctor in charge of this study at this centre who I can contact to ask questions
about the study is:
___________________________________
_________________________________
Telephone
The Head of the university department is:
___________________________________
_________________________________
Telephone
By signing this consent form, I agree to take part in this study.
___________________________________
Signature of Patient
_________________________________
Date
___________________________________
Signature of Doctor
_________________________________
Date
___________________________________
Signature of Witness
_________________________________
Date
also, if applicable:
___________________________________
Signature of Translator
_________________________________
Date
NCIC CTG Pt. Serial No: ________
51
PROTOCOL DATE:
NCIC CTG TRIAL:
18.3
Exemple de Formulaire de Consentement
96-MAY-15
MA.14
AMENDED: 96-AUG-12
Étude visant à comparer un anti-œstrogène avec une combinaison
d'anti-œstrogène et d'octréotide LAR comme traitement adjuvant du
cancer du sein chez des femmes postménopausées
Objectif et description de l'étude
Je comprends que j'ai eu une tumeur cancéreuse au sein qu'on m'a enlevée par chirurgie
et qu'il existe une possibilité que le cancer réapparaisse. Le tamoxifène, un médicament
anti-œstrogène, s'est révélé efficace pour réduire les probabilités de réapparition du
cancer chez des femmes qui s'étaient fait enlever une tumeur cancéreuse au sein. La
présente recherche vise à comparer deux traitements. Le traitement 1, qui est la façon
habituelle de soigner les femmes ayant un cancer comme le mien, consiste à administrer
du tamoxifène seul. Le traitement 2 consiste à donner, en plus du tamoxifène, de
l'octréotide LAR, un médicament expérimental dans le traitement de ma maladie.
On m'a demandé de participer à une recherche clinique. Cette recherche sera menée
dans plusieurs hôpitaux du Canada. Environ 850 patientes y prendront part. L'étude
comparera l'efficacité des deux traitements mentionnés plus haut contre mon type de
cancer du sein. Le principal objectif de l'étude est de déterminer s'il existe une
différence dans le nombre de femmes chez qui le cancer réapparaît selon le traitement
qu'elles ont reçu.
Description des traitements à l'étude
Je comprends que si je reçois le traitement 1, je prendrai du tamoxifène par voie orale
chaque jour pendant 5 ans. Si je reçois le traitement 2, je prendrai du tamoxifène par
voie orale chaque jour et on me donnera une injection d'octréotide LAR une fois par
mois, et ce pendant 5 ans.
Personne ne sait quel est le meilleur traitement dans mon cas. C'est pourquoi mon
traitement me sera assigné purement au hasard, selon une méthode de sélection appelée
randomisation. J'ai autant de chances de recevoir un traitement que l'autre. On me dira
quel traitement je recevrai.
On m'a expliqué que si mon cancer réapparaissait, si les effets secondaires du traitement
devenaient très graves ou si de nouvelles données indiquaient que le traitement que je
reçois n'est pas dans mon meilleur intérêt, mon médecin y mettrait fin. On discuterait
alors des prochaines étapes de mon traitement. On prévoit que je recevrai le traitement à
l'étude pendant 5 ans. Par la suite, lorsque j'aurai cessé de prendre le traitement à
l'étude, on vérifiera l'évolution de ma santé chaque année.
GEC INCC - N/ de la patiente : _________
52
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 96-AUG-12; AMENDED: 97-SEP-18
Le traitement de rechange qui pourrait être envisagé dans mon cas serait le traitement
standard qui, pour l'instant, serait fort probablement le même que le traitement 1 de la
présente étude.
Avantages possibles
Les avantages possibles du traitement 1 et du traitement 2 risquent d'être les mêmes dans
presque tous les aspects. Je comprends que les probabilités que mon cancer réapparaisse
sont les mêmes, que je prenne un traitement ou l'autre.
On ignore si je retirerai un avantage personnel de ma participation à cette étude.
Cependant, d'autres patientes dans ma situation pourraient profiter de l'information
obtenue à la suite de l'étude.
Effets secondaires possibles
Les effets secondaires que je pourrais ressentir à cause du tamoxifène sont les suivants :
1.
2.
3.
4.
bouffées de chaleur (20 % des patientes);
réduction du nombre de globules blancs et de plaquettes dans mon sang, situation qui
revient généralement à la normale au cours de la deuxième semaine de traitement
(20 % des patientes);
nausées (10 % des patientes);
sécheresse ou pertes vaginales (9 % des patientes).
Les principaux autres effets secondaires que je risque de ressentir mais qui surviennent
rarement (chez moins de 3 % des patientes) sont : des saignements vaginaux, un taux de
calcium trop élevé dans le sang, une dépression, des étourdissements, une perte de
cheveux, des maux de tête, des éruptions cutanées et de l'enflure. À de rares occasions,
on a rapporté des cas de cataractes chez des patientes recevant des doses plus fortes de
tamoxifène. Les personnes atteintes d'un cancer courent un plus grand risque de
formation de caillots dans leur sang, et l'utilisation de tamoxifène peut augmenter ce
risque.
Les femmes qui prennent du tamoxifène peuvent présenter un risque légèrement accru de
cataractes (le cristallin de l’oeil devient opaque). À mesure qu’elles vieillissent, les
femmes sont plus sujetes aux cataractes, qu’elles prennent du tamoxifène ou non. Les
cataractes peuvent diminuer la vue. Il faut parfois une chirugie pour enlever la cataracte
et améloirer la vue. Les femmes qui ont déjà des cataractes avant de commencer à
prendre du tamoxifène sont plus susceptibles de devoir être opérées. On a aussi rapporté
d’autres problèmes oculaires tel que la formation de cicatrices sur la cornée ou des
changements de la rétine ches quelques patients. On m’a informée que je devrais
informer mon médecin de tout changement à ma vue ou de tout autre problème oculaire.
Des études ont révélé que les femmes qui prennent du tamoxifène courent un plus grand
risque (le double de la normale) d'avoir un cancer de l'utérus; c'est pourquoi mon
médecin m'a recommandé de passer un examen gynécologique annuel. Je devrais
contacter mon médecin si j'avais des saignements menstruels ou si je ressentais de la
pression ou de la douleur dans le bas de l'abdomen.
53
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 96-AUG-12; AMENDED: 99-DEC-09
Les effets secondaires (d'intensité faible à modérée) que je risque de ressentir à cause de
l'octréotide LAR sont les suivants :
1.
2.
3.
4.
5.
6.
diarrhée (passagère, moins de 24 heures, jusqu'à 50 % des patientes);
nausées (de 30 % à 50 % des patientes);
maux d'estomac (de 30 % à 50 % des patientes);
douleur au point d'injection (7 % des patientes);
calculs ou boues biliaires sans symptômes (48 % des patientes);
calculs ou boues biliaires avec symptômes [(5 % des patientes) Incluant l’enlèvement
de la chirurgie pour la vésicule biliaire].
Les principaux autres effets secondaires que je risque de ressentir mais qui surviennent
rarement sont : de légers étourdissements, des maux de tête, une altération du goût, des
bouffées de chaleur, des douleurs musculaires et une vue brouillée. Bien qu'ils se
produisent parfois, ces effets durent généralement moins de 24 heures; cependant,
certains de ces effets secondaires peuvent continuer pour une période prolongée. Dans de
très rares cas, on a relevé chez des patient(e)s ayant fait un usage prolongé
d'octréotide LAR pour soigner une acromégalie (trouble de croissance) une réduction de
la production d'hormone thyroïdienne, une aggravation du diabète sucré, des anomalies
cardiaques ou une diminution du taux de vitamine B12, une vitamine nécessaire à la
production de globules rouges sains.
Examens, questionnaires
Pendant que je participerai à l'étude, je devrai passer un certain nombre d'examens
(analyses de sang, radiographies, etc.). Ces examens seront peut-être faits plus
fréquemment que si je ne participais pas à l'étude.
De temps en temps, on me demandera de fournir des échantillons de sang qui permettront
aux chercheurs d'étudier de quelle façon agissent les médicaments.
Je comprends qu'à des intervalles spécifiques de l'étude on me demandera de remplir un
questionnaire pour savoir comment je me sens et comment je tolère le traitement. Ces
questionnaires constituent une partie importante de l'étude. Ils prennent moins d'une
demi-heure à remplir à chaque fois. L'information que je fournirai servira à la recherche
et elle demeurera strictement confidentielle. Les personnes (médecins, infirmières, etc.)
qui me donneront des soins ne verront peut-être pas mes réponses à ces questions. Si je
désire qu'elles les voient, je les en aviserai.
Confidentialité et accès aux dossiers médicaux
De l'information tirée de mon dossier médical au sujet de mon traitement et de
l'évolution de ma maladie, mais ne mentionnant pas mon nom, sera envoyée au bureau
central du Groupe des essais cliniques de l'Institut national du cancer du Canada (GEC
54
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 96-AUG-12; AMENDED: 99-DEC-09
de l'INCC) qui organise la présente étude et à Novartis Pharmaceuticals Canada Inc., qui
fournit l'octréotide LAR et apporte un soutien à l'étude. Cette information pourrait
comprendre des résultats d'examens, des échantillons de sang ou de tissus, des rapports
de radiographies et d'autres renseignements médicaux, de même que des questionnaires
sur la qualité de vie.
Il est possible que cette information soit vérifiée par la Direction générale de la protection
de la santé (DGPS) de Santé et Bien-être social Canada, ainsi que par la Food and Drug
Administration (FDA) du le Department of Health and Human Services des États-Unis.
Cette information sera gardée strictement confidentielle dans les limites permises par la
loi. De plus, il se peut que des représentants du GEC de l'INCC et de Novartis
Pharmaceuticals Canada Inc. désirent examiner mes dossiers de l'hôpital ou de la clinique,
encore une fois en respectant de façon stricte la confidentialité des renseignements. De
l'information recueillie au cours de l'étude sera soumise à la DGPS et à la FDA et elle
pourrait être utilisée à des fins de recherche. Toutefois, si cette information était utilisée
pour la recherche, elle ne contiendra pas de renseignements permettant de m'identifier
personnellement, et on ne pourra mentionner mon nom dans aucune présentation ni
aucune publication.
Participation volontaire
J'ai discuté de l'étude avec mon médecin, et il (elle) a répondu à toutes mes questions.
Ma participation à la présente étude est tout à fait volontaire. Je peux refuser d'y
participer et je serai libre de m'en retirer en tout temps. Si je choisis de ne pas participer
à l'étude, ou de m'en retirer, mon médecin continuera à me soigner en ayant recours aux
meilleurs traitements disponibles. Pour cesser de participer à l'étude, je n'aurai qu'à
aviser mon médecin que je ne désire plus continuer. Le médecin qui m'a fait entrer dans
l'étude pourra, au moment approprié et avec mon autorisation, informer mon médecin
de famille de ma participation à l'étude.
Je comprends que je n'aurai rien à payer pour le médicament à l'étude (octréotide LAR)
ou pour les procédures ou examens qui seront faits dans le cadre de l'étude. L'octréotide
LAR est donné sous forme d'injections mensuelles, ce qui veut dire que je devrai
peut-être visiter mon médecin plus souvent que si je prenais le tamoxifène seul, qui est le
traitement standard dans des cas comme le mien. Si vous subissez une blessure physique
liée directement à la prise du principe actif que contient le médicament à l’étude, vos
droits sont protégés par les lois en viguer au Québec.
Si j'ai des questions concernant ma participation à l'étude, je peux rencontrer le médecin
responsable de l'étude ou le chef du département universitaire responsable de l'étude.
J'ai reçu un exemplaire du présent formulaire de consentement.
55
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
AMENDED: 96-AUG-12
Je peux discuter de ma participation à l'étude et de mes droits en tant que sujet de
recherche avec ________________________ qui n'est aucunement relié(e) à l'étude. Son
numéro de téléphone est le _______________________ .
En cas de blessure reliée à la recherche, je devrais contacter ____________________ ; son
numéro de téléphone est le _________________ .
Le médecin responsable de l'étude au centre où je suis suivie, que je pourrai contacter si
j'ai des questions sur cette étude est :
___________________________________
Nom
____________________
Téléphone
Le (la) chef du département universitaire responsable de l'étude est :
___________________________________
Nom
____________________
Téléphone
Ma signature au bas du présent formulaire indique que j'accepte de participer à l'étude.
___________________________________
Signature de la patiente
____________________
Date
___________________________________
Signature de l'investigateur(trice)
____________________
Date
___________________________________
Signature du témoin
____________________
Date
et, le cas échéant :
___________________________________
Signature du traducteur ou de la traductrice
____________________
Date
GEC INCC - N/ de la patiente : _________
56
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
19.0
COMPANION STUDIES
19.1
IGF-I Physiology
Studies regarding the effect of treatments on IGF-I physiology, and relationships between IGF-I
physiology and outcome are an integral part of the study, as described in sections 1.0 and 2.9.
Blood specimens for these studies are required for all patients, as described in section 5.1.10 and
9.1.
19.2
Other Studies
Other optional companion studies are being developed. These studies will be offered only at
centres where investigators have indicated an interest and have the necessary facilities available.
At these centres, patients may participate in the basic protocol with or without participating in one
or more companion study. The sample size requirements for each of these companion studies is
considerably lower than the sample size required for the primary objectives of the MA.14 study.
These studies will allow for a more comprehensive comparison of the treatment arms with respect
to several areas of clinical and/or basic science interest. Tamoxifen is known to have effects
serum lipids, bone density, and the uterus. MA.14 will provide an opportunity to determine if
any of these effects are altered by co-administration of octreotide LAR. In addition, there will
be an optional study to investigate the effect of each treatment on mammographic findings, an
optional study examining peak and trough tamoxifen and octreotide LAR levels, and an
opportunity for patient tumour samples to be flash frozen for studies including IGF-I receptor
abundance and somatostatin receptor subtyping and abundance.
57
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12; AMENDED: 97-SEP-18; AMENDED: 00-JUL-12; REVISED: 03-APR-23
APPENDIX I - PATIENT EVALUATION FLOW SHEET
Mth 36
Mth 48,
60
Mth 16,
20, 28, 32,
42, 54
Post protocol
treatment
annually from
treatment
completion/
discontinuation
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
annual gyn exam
is
recommended10
During Protocol Treatment
Required
Investigations
Physical
History & Physical
Exam
Height
Weight
Performance status
Gynecologic history
and exam
Prestudy
Mth 1,
2, 3
Mth 4
&8
Mth
12, 24
x
x
x
x
x
x
x
x
x
x
annual gyn exam is
recommended10
x10
Hematology1
CBC, differential
WBC, platelet count
Biochemistry1
Alkaline 11
phosphatase, AST or
ALT11, bilirubin,
random blood sugar
HgbAlc, TSH, FT4
Methylmalonic Acid
Radiology
Mammography
Gallbladder
ultrasound
Chest x-ray
Bone scan
Abdominal imaging
Other Investigations
Serum collection
x
x
x6
x
x
x6
x
x2
x3
CBC at
mth 60
only4,7
x6
required at mth 24 or discontinuation if discontinuation is prior to mth 24
x
x
x9
CBC4,7
x5
x5
9
at mth 24 and treatment completion/discontinuation
(required only for patients who have received at least 1 year of protocol therapy)
as clinically indicated to evaluate possible disease recurrence/second malignancy
as clinically indicated to evaluate possible disease recurrence/second malignancy
as clinically indicated to evaluate possible disease recurrence/second malignancy
x4,7
x
x4,7
x4,7
at mth 60 at 16 mths
only4,7
only4
at recurrence /
2nd malignancy
Toxicity
Assessment according
to NCIC CTG
Expanded Criteria
Quality of Life
EORTC QLQ C30+1
plus trial specific
checklist
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
x
x
x
x
x
at mth
1 only
x
x4
x
x
x
x
delayed
toxicities8 related
to protocol
treatment
at recurrence /
2nd malignancy
Hematology and biochemistry tests will be conducted by a Central Lab. Consult the Central Lab manual for specimen preparation and shipping
instructions.
Only necessary if alkaline phosphatase is > 2 x normal and/or there are symptoms of metastatic lesions. Confirmatory x-ray required if results from bone
scan are questionable.
Ultrasound, liver scan or CT abdomen are necessary only if AST/ALT or Alkaline Phosphatase are elevated >2 x normal.
Also required at recurrence/2nd malignancy.
Required annually until recurrence.
Also required at treatment discontinuation if discontinuation is prior to 24 months.
Also required at treatment discontinuation.
All toxicities, regardless of relation, occurring within 120 days after the end of protocol treatment must be assessed at 4 months following discontinuation
of treatment and reported.
Not required for patients who have had a cholycystectomy.
Gynecologic exam not required for patients who have had a hysterectomy.
Should also be done prior to chemotherapy for patients receiving protocol treatment sequential to chemotherapy.
58
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
APPENDIX II - PERFORMANCE STATUS (ECOG)
Grade
0
Fully active, able to carry on all pre-disease performance without restriction (Karnofsky 90-100).
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or
sedentary nature (eg, light housework, office work) (Karnofsky 70-80).
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about
more than 50% of waking hours (Karnofsky 50-60).
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
(Karnofsky 30-40).
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
(Karnofsky 10-20).
59
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12; AMENDED: 99-DEC-09
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL
Handling Study Medication
Octreotide LAR will be supplied to the principal investigator by Novartis Pharmaceuticals Canada Inc.
Drug supplies must be kept in an appropriate, secure area (eg. locked cabinet) and according to the storage
conditions specified in the protocol. The procedure of drug ordering will be provided to investigators by
Novartis Pharmaceuticals Canada Inc.
Each medication set will be labelled with a two panel label. The pharmacist will be required to
record on both panels the NCIC CTG patient ID code, the centre name and the date the medication
is dispensed. Once completed, the tear off portion of the label will be removed and retained for
attachment to the CRF drug label case report form.
The investigator must maintain an accurate record on the shipment and dispensing of the test drug, using a
drug accountability ledger provided by Novartis Pharmaceuticals Canada Inc. An accurate drug
disposition record will be kept specifying the date and amount dispensed to each subject. This inventory
record and the medication must be available for inspection by the Novartis Pharmaceuticals Canada Inc.
monitor or during an audit (by Novartis Pharmaceuticals Canada Inc. or a regulatory agency). Copies of
drug accountability ledger will be provided to Novartis Pharmaceuticals Canada Inc. by the investigator
at the end of the study.
Drug supplies are to be used only in accordance with this protocol and under the supervision of the
investigator. The investigator must not destroy any labels, or any partly used or unused drug supply.
At the conclusion of the study and if appropriate during the course of the study, with the authorization of the
Novartis Pharmaceuticals Canada Inc. monitor, the investigator will return all used and unused drug
containers, labels and a copy of the completed drug and code label disposition form to Novartis
Pharmaceuticals Canada Inc. at the following address:
Novartis Pharmaceuticals Canada Inc.
111 Consumers Drive
Whitby, Ontario
L1N 5Z5
Attention: Pat Aldridge
60
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12; AMENDED: 97-SEP-18; AMENDED: 00-JUL-12
APPENDIX IV - DOCUMENTATION FOR STUDY (see section 16.7 for details)
Follow-up is required for patients from the time of randomization and will apply to all eligible patients.
Form
Due in
Central Office
To be Completed
Eligibility
Checklist/Form 1
Initial Evaluation
prior to calling NCIC CTG
to randomize the patient
Form 5
Treatment/Follow-up
Report
on each scheduled follow-up within 6 weeks of the
visit to the clinic
date the patient was
seen at the clinic
• quality of life questionnaire
(QLQ-C30+1 plus trial specific
checklist)
Form 5S
Short Follow-up
Report
on each scheduled follow-up within 8 weeks of the
visit to the clinic after
date the patient was
treatment discontinuation seen at the clinic
(4 months and annually
from the date of treatment
discontinuation)
none
Form 5M
Minimal Follow-up
annually until death (for
ineligible patients only)
within 8 weeks of the
date of followup
none
Form 6
Final Report
at the time of the patient’s
death
within 8 weeks of
patient’s death
• autopsy report if one was done
Form 9
Recurrence/Second
Malignancy Report
at the first evidence of
recurrence and at all
second malignancies
within 4 weeks of the
event
• radiology/cytology/pathology/bi
opsy reports used to confirm
disease
• quality of life questionnaire
(QLQ-C30+1 plus trial specific
checklist)
Adjuvant Therapy
Report
at the completion of adjuvant within 6 weeks of the
therapy
end of the treatment
period
none
Summary Toxicity
Form
on each scheduled followup visit to the clinic up to
and including 120 postprotocol treatment toxicity
assessment
within 6 weeks of the
date the patient was
seen at clinic
none
Summary
Concomitant
Medication Form
on each scheduled followup visit to the clinic until
the patient discontinues
protocol treatment
within 6 weeks of the
date the patient was
seen at clinic
none
within 10 working
days of the event
• see section 11.0 for adverse
event reporting details
Adverse Event Report at the time of the event
Form
within 6 weeks of
randomization
Supporting Documentation/Quality
of Life Questionnaires Required
by NCIC CTG
61
• operative and pathology reports
• baseline quality of life
questionnaire (QLQ-C30+1
plus trial specific checklist)
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
APPENDIX V - NCIC CTG EXPANDED COMMON TOXICITY CRITERIA
Explanatory Notes
1.
Toxicities are grouped into the following categories based on body system:
Allergy
Blood/Bone Marrow
Cancer-related Symptoms
Cardiovascular
Coagulation
Dentition (teeth)
Endocrine
Flu-Like Symptoms
Gastrointestinal
Genitourinary
Hepatic
Infection
Metabolic
Neurologic
Ocular
Osseous (bone)
Other
Pulmonary
Skin
Weight
2.
Protocols requiring detailed hyposensitivity reaction reporting will include a Hypersensitivity Reaction Module.
3.
Categories are listed alphabetically, with toxicity variables (eg. dysrhythmia, nausea, dizziness) listed
alphabetically within each category.
4.
Toxicity codes are composed of a 2-character "prefix" based on toxicity category, and a 3-character
"description" based on variable name.
For example:
(cardiovascular) dysrhythmia
(gastrointestinal) nausea
(neurologic) dizziness
H = hyper (or high)
L = hypo (or low)
= CD DYS
= GI NAU
= NE DIZ
5.
Some conventions:
(eg. CD HBP = hypertension)
(eg. MT LCA = hypocalcemia)
6.
Codes are usually derived from the first 3 letters of the toxicity variable (eg. nausea = GI NAU). Exceptions
to this rule have been made in the following cases:
6
where the first 3 letters are not particularly helpful or descriptive (eg. mouth dryness has been coded GI DRY
instead of GI MOU)
6
where the first 3 letters are potentially confusing (eg. flushing, facial has been coded SK FAC instead of
SK FLU)
6
where a "common" 3 letter abbreviation already exists (eg. hemoglobin has been coded BL HGB instead of
BL HEM)
7.
For toxicities which do not have an existing code, but do fit into an existing toxicity category, use "other"
variable in the appropriate toxicity category (eg. code pathologic fracture OSSEOUS OTHER (OS OTH)). For
toxicities which do not have existing codes, and do NOT fit into existing categories, code
OTHER OTHER (OT OTH).
8.
Please note that ONLY the codes listed in the criteria may be used. Data managers should not "create"
new toxicity codes. If a new toxicity is identified which doesn't have an existing code or doesn't fit an
existing category, use OTHER and OTHER OTHER variables as outlined above. If you're unsure how to
code a particular toxicity, please record toxicity type only on the form. A coding decision will then be
made at the NCIC CTG central office.
Explanatory Notes Revised 94-Dec-21
* denotes NCIC CTG specific criteria
Any toxicity which causes death should be given grade 5.
62
PROTOCOL DATE:
NCIC CTG TRIAL:
NCIC CTG EXPANDED COMMON TOXICITY CRITERIA
Grade
0
1
2
3
96-MAY-15
MA.14
REVISED: 94-DEC-21
4
A LLERGY
AL LER Allergy
AL OTH Other*
BL WBC White Blood Count
(WBC)
BL PLT Platelets
BL HGB Hemoglobin (Hgb)
BL GRA Granulocytes
(i.e. neuts + bands)
BL LYM Lymphocytes
BL HEM Hemorrhage
resulting from
thrombocytopenia
(clinical)
BL OTH Other*
none
transient rash, fever
< 38°C, 100.4°F
urticaria, fever=38°C,
serum sickness,
anaphylaxis
100.4°F, mild
bronchospasm, req
bronchospasm
parenteral meds
Fever felt to be caused by drug allergy should be coded as ALLERGY (AL LER). Non-allergic drug fever (eg. as from biologics) should
be coded under FLU-LIKE SYMPTOMS (FL FEV). If fever is due to infection, code INFECTION only (IN FEC or IN NEU). NB:
Protocols requiring detailed reporting of hypersensitivity reactions, will include a Hypersensitivity Reaction module.
none
mild
moderate
severe
life threatening
BLOOD/B ONE MARROW (SI UNITS)
109/L
3.0-3.9
2.0-2.9
1.0-1.9
<1.0
>4.0
WNL
WNL
>2.0
109/L
g/L
109/L
75.0-normal
100-normal
1.5-1.9
50.0-74.9
80-99
1.0-1.4
25.0-49.9
65-79
0.5-0.9
<25.0
<65
<0.5
>2.0
none
109/L
1.5-1.9
mild, no transfusion (incl
bruise/hematoma,
petechiae)
1.0-1.4
gross, 1-2 units
transfusion per episode
0.5-0.9
gross, 3-4 units
transfusion per episode
<0.5
massive, >4 units
transfusion per episode
mild
moderate
severe
life threatening
none
C ANCER R ELATED SYMPTOMS
CA DEA Death from
malignant disease
within 30 days of
treatment* (grade=5)
CA PAI Cancer pain*
none
CA SEC
Second
malignancy*
CA OTH Other*
--
--
--
--
--
pain controlled with nonopioids
--
pain controlled with
opioids
present
uncontrollable pain
none
pain, but no treatment
req
--
none
mild
moderate
severe
life threatening
transient events
(eg. transient ischemic
attack)
deep vein thrombosis
req anticoagulant
therapy
req trt
permanent event
(eg. cerebral vascular
accident)
pulmonary embolism
--
C ARDIOVASCULAR
CD ART
Arterial*
(non myocardial)
none
--
--
CD VEN Venous*
none
superficial (excl IV site
reaction6code SK LTO)
deep vein thrombosis not
req anticoagulant therapy
CD DYS
Dysrhythmias
none
asymptomatic, transient,
req no therapy
recurrent or persistent,
no therapy req
CD EDE
none
1+ or dependent in
evening only
2+ or dependent
throughout day
3+
CD FUN
Edema*
(eg. peripheral
edema)
Function
none
severe or refractory
CHF
Hypertension
none or no change
req therapy
hypertensive crisis
CD LBP
Hypotension
none or no change
asymptomatic, decline of
resting ejection fraction
by >20% of baseline
value
recurrent or persistent
increase by >20mm Hg
(D) or to >150/100 if
previously WNL. No trt
req
req fluid replacement or
other therapy but not
hospitalization
mild CHF, responsive
to therapy
CD HBP
asymptomatic, decline of
resting ejection fraction
of > 10% but < 20% of
baseline value
asymptomatic, transient
increase by >20mm Hg
(D) or to >150/100 if
previously WNL. No trt
req
changes req no therapy
(incl transient orthostatic
hypotension)
CD ISC
Ischemia
(myocardial)
none
non-specific T wave
flattening
asymptomatic, ST & T
wave changes suggesting
ischemia
req therapy &
hospitalization;
resolves within 48hrs of
stopping agent
angina without evidence
for infarction
req therapy &
hospitalization for
>48hrs after stopping
agent
acute myocardial
infarction
* denotes NCIC CTG specific criteria
Any toxicity which causes death should be given grade 5.
req monitoring, or
hypotension, or
ventricular tachycardia, or fibrillation
4+, generalized
anasarca
63
PROTOCOL DATE:
NCIC CTG TRIAL:
NCIC CTG EXPANDED COMMON TOXICITY CRITERIA
Grade
0
1
CD PAI
Pain (chest)*
none
CD PER
Pericardial
none
pain controlled with nonopioids
pericarditis (rub, chest
pain, ECG changes)
3
pain controlled with
opioids
symptomatic effusion;
drainage req
uncontrollable pain
severe
severe
WNL
WNL
WNL
moderate
moderate
C OAGULATION
0.99-0.75 x N
0.74-0.50 x N
1.01-1.25 x N
1.26-1.50 x N
1.01-1.66 x N
1.67-2.33 x N
tamponade, drainage
urgently req; or
constrictive pericarditis
req surgery
life threatening
life threatening
0.49-0.25 x N
1.51-2.00 x N
2.34-3.00 x N
<0.24 x N
>2.00 x N
>3.00 x N
none
mild
severe
life threatening
severe
pain controlled with
opioids
severe
uncontrollable pain
CD TAC Sinus tachycardia*
CD OTH Other*
none
none
CG FIB
CG PT
CG PTT
Fibrinogen
Prothrombin time
Partial thromboplastin time
CG OTH Other*
2
pain, but no treatment
req
asymptomatic, effusion,
no intervention req
96-MAY-15
MA.14
REVISED: 94-DEC-21
4
mild
mild
moderate
D ENTITION (TEETH)
DE DEC Tooth decay*
DE PAI Toothache*
none
none
DE OTH Other*
none
mild
pain, but no treatment
req
mild
moderate
pain controlled with nonopioids
moderate
life threatening
ENDOCRINE *
EN AME Amenorrhea
EN CUS Cushingoid
EN FLA Hot flashes
none
normal
none
irregular menses
mild
mild or <1/day
> 3 mths
pronounced
moderate & >1/day
EN GYN Gynecomastia
EN IMP Impotence/
Libido
EN OTH Other
normal
normal
mild
decrease in normal
function
mild
pronounced or painful
--
--frequent & interferes
with normal function
-absence of function
moderate
severe
none
-----life threatening
FLU-L IKE SYMPTOMS
FL FEV
Fever in absence of
infection*
(incl drug fever)
FL HAY Hayfever*
(incl sneezing, nasal
stuffiness, post-nasal drip)
FL JOI Arthralgia*
(joint pain)
FL LET Lethargy*
(fatigue, malaise)
FL MYA Myalgia*
(muscle ache)
FL RIG Rigors/Chills*
(Gr 3 incl cyanosis)
FL SWE Sweating*
(diaphoresis)
FL OTH Other*
none
37.1-38.0°C
98.7-100.4°F
38.1-40.0°C
100.5-104.0°F
>40.0°C
>104.0°F
for <24hrs
>40.0°C (104.0°F)
for >24hrs or fever
accompanied by
hypotension
Fever felt to be caused by drug allergy should be coded as ALLERGY (AL LER). Non-allergic drug fever (eg. as from biologics) should
be coded under FLU-LIKE SYMPTOMS (FL FEV). If fever is due to infection, code INFECTION only (IN FEC or IN NEU).
none
mild
moderate
severe
-none
mild
moderate
severe
--
none
moderate, or fall of 2
levels in perf. status
moderate
severe, or fall of 3
levels in perf. status
severe
--
none
mild, or fall of 1 level in
performance status
mild
none
mild or brief
cyanosis
--
none
mild
pronounced and/or
prolonged
moderate
severe
--
none
mild
moderate
severe
--
life threatening
GASTROINTESTINAL
GI
GI
GI
ANO Anorexia*
APP Appetite-increased*
ASC Ascites (nonmalignant)*
none
none
mild
mild
moderate
moderate
severe
none
mild
moderate
severe
* denotes NCIC CTG specific criteria
Any toxicity which causes death should be given grade 5.
--
dehydration
-life threatening
64
PROTOCOL DATE:
NCIC CTG TRIAL:
NCIC CTG EXPANDED COMMON TOXICITY CRITERIA
Grade
0
1
96-MAY-15
MA.14
REVISED: 94-DEC-21
4
2
3
GI
DIA
Diarrhea
none
increase of 2-3
stools/day; or mild
increase in loose watery
colostomy output
compared to pre-trt
increase of 4-6
stools/day, or nocturnal
stools; or moderate
increase in loose watery
colostomy output
compared to pre-trt
increase of 7-9
stools/day, or incontinence, malabsorption;
or severe increase in
loose watery colostomy
output compared to pretrt
GI
DPH Esophagitis/
dysphagia/
odynophagia*
(incl recall reaction)
DRY Mouth, nose
dryness*
FIS
Fistula
(intestinal, esophageal,
rectal)*
GAS Flatulence*
HEA Heartburn*
(incl dyspepsia)
HEM Gastrointestinal
bleeding*
none
dys. or odyn. not req trt,
or painless ulcers on
esophagoscopy
dys. or odyn. req trt
dys. or odyn. lasting
>14 days despite trt
none
mild
moderate
severe
GI
GI
GI
GI
GI
none
--
--
none
none
mild
mild
moderate
moderate
none
mild, no transfusion
req intervention
severe
severe
gross, 1-2 units
transfusion per episode
Bleeding resulting from thrombocytopenia should be coded under BL HEM, not GI
none
able to eat reasonable
intake significantly
intake
decreased but can eat
none
-intermittent, no
intervention
none
pain, but no treatment
pain controlled with nonreq
opioids
gross, 3-4 units
transfusion per episode
none
perianal itch,
hemorrhoids
none
GI
Taste, sense of
smell altered*
ULC Gastritis/ulcer*
GI
GI
GI
NAU Nausea
GI
OBS
GI
GI
Small bowel
obstruction*
PAI Gastrointestinal
pain/cramping*
(incl rectal pain)
PRO Proctitis
(rectal)
no significant intake
increase of>10
stools/day or grossly
bloody diarrhea; or
grossly bloody
colostomy output or
loose watery colostomy
output req parenteral
support; dehydration
dys. or odyn. with 10%
loss of body wt,
dehydration, hosp. req
-req operation
--massive, >4 units
transfusion per episode
--
req intervention
req operation
pain controlled with
opioids
uncontrollable pain
tenesmus or ulcerations
relieved with therapy,
anal fissure
tenesmus or ulcerations
or other symptoms not
relieved with therapy
painless ulcers,
erythema, or mild
soreness
painful erythema, edema,
or ulcers but can eat
painful erythema,
edema, or ulcers, and
cannot eat
none
mild
moderate
severe
mucosal necrosis with
hemorrhage or other
life threatening
proctitis
mucosal necrosis and/or
req parenteral or
enteral support,
dehydration
--
none
antacid
req vigorous medical
management or nonsurgical trt
VOM Vomiting
none
1 episode in 24hrs
2-5 episodes in 24hrs
uncontrolled by medical
management; req
surgery for GI
ulceration
6-10 episodes in 24hrs
OTH Other*
none
mild
moderate
severe
GI
STO
GI
TAS
Stomatitis/oral
perforation or bleeding
>10 episodes in 24hrs
or req parenteral
support, dehydration
life threatening
GENITOURINARY
GU BLA Bladder changes*
none
GU CRE
GU CYS
Creatinine
Cystitis*
(non-bacterial)
WNL
none
GU FIS
Fistula* (vaginal,
vesicovaginal)
Frequency*
GU FRE
light epithelial atrophy,
or minor telangiectasia
generalized
telangiectasia
<1.5 x N
1.5-3.0 x N
mild symptoms req no
symptoms relieved
intervention
completely with therapy
Urinary tract infection should be coded under infection, not GU.
none
---
none
* denotes NCIC CTG specific criteria
freq of urination or
nocturia twice pre-trt
habit
freq of urination or
nocturia <hourly
Any toxicity which causes death should be given grade 5.
severe generalized
telangiectasia (often
with petechiae) or
reduction in bladder
capacity (<150ml)
3.1-6.0 x N
symptoms not relieved
despite therapy
necrosis, or contracted
bladder (capacity
<100ml), or fibrosis
req intervention
req operation
freq with urgency and
nocturia >hourly
>6.0 x N
severe (life threatening)
cystitis
--
65
PROTOCOL DATE:
NCIC CTG TRIAL:
NCIC CTG EXPANDED COMMON TOXICITY CRITERIA
Grade
0
1
GU HEM Hematuria,
bleeding per vagina
GU INC Incontinence*
GU OBS Ureteral
obstruction*
GU PAI
GU PRT
Genito-urinary
pain* (eg: dysuria,
dysmenorrhea,
dyspareunia)
Proteinuria
GU VAG Vaginitis*
(+/- vaginal
discharge) (non-infectious)
GU OTH Other*
2
3
96-MAY-15
MA.14
REVISED: 94-DEC-21
4
neg
micro only
gross, no clots
gross + clots
Bleeding resulting from thrombocytopenia should be coded under BL HEM not GU.
none
mild
moderate
severe
none
unilateral, no surgery
bilateral, no surgery req
not complete bilateral,
but stents, nephrostomy
tubes or surgery req
none
pain, but no treatment
pain controlled with nonpain controlled with
req
opioids
opioids
req transfusion
no change
none
1+
or <0.3 g%
or <3g/L
mild, no trt req
none
mild
-complete bilateral
obstruction
uncontrollable pain
2-3+
or 0.3-1.0g%
or 3-10g/L
moderate, relieved with
trt
4+
or >1.0g%
or >10g/L
severe, not relieved
with trt
nephrotic syndrome
moderate
severe
life threatening
life threatening
HEPATIC
HP ALK Alk Phos or
5'nucleotidase
HP ALT Transaminase
SGPT (ALT)
HP AST Transaminase
SGOT (AST)
HP BIL Bilirubin
HP CLI Liver (clinical)
HP LDH LDH*
HP OTH Other*
WNL
<2.5 x N
2.6-5.0 x N
5.1-20.0 x N
>20.0 x N
WNL
<2.5 x N
2.6-5.0 x N
5.1-20.0 x N
>20.0 x N
WNL
<2.5 x N
2.6-5.0 x N
5.1-20.0 x N
>20.0 x N
1.5-3.0 x N
precoma
>3.0 x N
hepatic coma
5.1-20.0 x N
severe
>20.0 x N
life threatening
severe, systemic infect
req parenteral trt,
specify site
present
life threatening sepsis,
specify site
WNL
-<1.5 x N
no change from
--baseline
WNL
<2.5 x N
2.6-5.0 x N
none
mild
moderate
Viral Hepatitis should be coded as infection rather than liver toxicity.
INFECTION
IN
FEC
Infection
IN
NEU Febrile
neutropenia*
Absolute gran. count
<1.0x109/L, fever
>38.5°C treated with (or
ought to have been treated
with) IV antibiotics
none
mild, no active trt
none
moderate, localized
infect req active trt
--
--
--
Fever felt to be caused by drug allergy should be coded as ALLERGY (AL LER). Non-allergic drug fever (eg. as from biologics) should
be coded under FLU-LIKE SYMPTOMS (FL FEV). If fever is due to infection, code INFECTION only (IN FEC or IN NEU).
METABOLIC (SI UNITS)
MT
MT
MT
MT
MT
MT
AMY
HCA
LCA
HGL
LGL
LKA
Amylase
Hypercalcemia
Hypocalcemia
Hyperglycemia
Hypoglycemia
Hypokalemia*
MT LMA Hypomagnesemia
MT LNA Hyponatremia*
MT OTH Other*
WNL
<2.64
>2.10
<6.44
>3.55
no change
or >3.5
>0.70
no change
or >135
none
* denotes NCIC CTG specific criteria
mmol/L
mmol/L
mmol/L
mmol/L
mmol/L
mmol/L
mmol/L
<1.5 x N
2.64-2.88
2.10-1.93
6.44-8.90
3.03-3.55
3.1-3.5
1.5-2.0 x N
2.89-3.12
1.92-1.74
8.91-13.8
2.19-3.02
2.6-3.0
2.1-5.0 x N
3.13-3.37
1.73-1.51
13.9-27.8
1.66-2.18
2.1-2.5
>5.1 x N
>3.37
<1.50
>27.8 or ketoacidosis
<1.66
<2.0
0.70-0.58
131-135
0.57-0.38
126-130
0.37-0.30
121-125
<0.29
<120
mild
moderate
severe
life threatening
Any toxicity which causes death should be given grade 5.
66
PROTOCOL DATE:
NCIC CTG TRIAL:
NCIC CTG EXPANDED COMMON TOXICITY CRITERIA
Grade
0
1
2
3
96-MAY-15
MA.14
REVISED: 94-DEC-21
4
N EUROLOGIC
NE CER Cerebellar
none
slight incoordination,
dysdiadochokinesis
NE CON Constipation
NE COR Cortical
none or no change
none
mild
mild somnolence
intention tremor,
dysmetria, slurred
speech, nystagmus
moderate
moderate somnolence
locomotor ataxia
cerebellar necrosis
severe, obstipation
severe somnolence,
confusion, disorientation, hallucinations
severe (incl fainting)
ileus >96hrs
coma, seizures, toxic
psychosis
(incl drowsiness)
NE DIZ Dizziness*
(incl lightheadedness)
NE EXT Extrapyramidal/
Involuntary
movement*
NE HED Headache
none
mild
moderate
none
mild agitation (incl
restlessness)
moderate agitation
torticollis, oculogyric
crisis, severe agitation
--
none
mild
unrelenting & severe
--
NE HER Altered hearing
none or no change
asymptomatic, hearing
changes on audiometry
only
moderate or severe but
transient
tinnitus, symptomatic
hearing changes not req
hearing aid or trt
NE INS Insomnia*
NE MOO Mood
none
no change
NE MOT Motor
none or no change
mild
mild anxiety or
depression
subjective weakness; no
objective findings
NE PAI
none
NE SEN
Neurologic pain*
(eg: jaw pain)
Personality
Change*
Sensory
NE VIS
Vision
none or no change
pain, but no treatment
req
change, not disruptive to
pt or family
mild paresthesias, loss of
deep tendon reflexes
(incl tingling)
blurred vision
none
mild
NE PER
NE OTH Other*
no change
none or no change
moderate
moderate anxiety or
depression
mild objective weakness
without significant
impairment of function
pain controlled with nonopioids
disruptive to pt or family
mild or moderate
objective sensory loss;
moderate paresthesias
-moderate
hearing changes interfering with function but
correctable with
hearing aid or trt
severe
severe anxiety or
depression
objective weakness
with impairment of
function
pain controlled with
opioids
harmful to others or
self
sensory loss or
paresthesias that
interfere with function
symptomatic subtotal
loss of vision
severe
--
hearing changes or
deafness not correctable
-suicidal ideation
paralysis
uncontrollable pain
psychosis
-blindness
life threatening
OCULAR
OC CAT
OC CJN
Cataract*
Conjunctivitis/
Keratitis
none
none
OC DRY Dry eye
OC GLA Glaucoma
OC PAI Eye pain*
normal
no change
none
OC TEA Tearing*
(watery eyes)
OC OTH Other
none
mild
erythema or chemosis
not req steroids or
antibiotics
mild
-pain, but no treatment
req
mild
none
mild
moderate
req trt with steroids or
antibiotics
severe
corneal ulceration or
visible opacification
---
req artificial tears
-pain controlled with nonopioids
moderate
severe
yes
pain controlled with
opioids
severe
req enucleation
-uncontrollable pain
moderate
severe
life threatening
pain controlled with
opioids
severe
uncontrollable pain
--
OSSEOUS (BONE )
OS PAI
Bone pain*
OS OTH Other*
(eg: avascular
necrosis)
OT OTH Other
none
pain, but no treatment
req
mild
none
pain controlled with nonopioids
moderate
life threatening
OTHER
none
mild
moderate
severe
life threatening
For toxicities which do not have an existing code, but do fit into an existing toxicity category, use "other" variable in the appro-priate
toxicity category. Only toxicities which do not fit into existing categories should be coded OTHER OTHER (OT OTH).
Pulmonary
PU CMD Carbon Monoxide
Diffusion Capacity
(DLCO)*
PU COU Cough*
>90% of
pretreatment value
decrease to 76-90% of
pre-trt
decrease to 51-75% of
pre-trt
decrease to 26-50% of
pre-trt
none
mild
moderate
severe
* denotes NCIC CTG specific criteria
Any toxicity which causes death should be given grade 5.
decrease to <25% of
pre-trt
--
67
PROTOCOL DATE:
NCIC CTG TRIAL:
NCIC CTG EXPANDED COMMON TOXICITY CRITERIA
Grade
0
1
PU EDE
PU EFF
Pulmonary Edema*
Pleural effusion*
(non-malignant)
PU FIB Pulmonary
Fibrosis*
PU HEM Hemoptysis*
PU HIC
PU PAI
Hiccoughs*
Pulmonary pain*
PU PNE
Pneumonitis*
(non-infectious)
PU SOB
Shortness of breath
(SOB)
(incl wheezing)
PU VOI Voice changes*
(incl hoarseness,
loss of voice)
PU OTH Other*
none
none
normal
none
-mild
2
out-pt management
moderate
radiographic changes, no
symptoms
mild, no transfusion
--
gross, 1-2 units
transfusion per episode
Bleeding resulting from thrombocytopenia should be coded under BL HEM, not PU
none
mild
moderate
none
pain, but no treatment
pain controlled with nonreq
opioids
normal
radiographic changes,
steroids req
symptoms do not req
steroids
none or no change
asymptomatic, with
dyspnea on significant
abnormality in PFT's
exertion
none
mild
moderate
SK CHA Skin changes* (eg:
photosensitivity)
none
mild
moderate
Pneumonia is considered infection and not graded as pulmonary toxicity unless felt
induced by treatment.
SKIN
no loss
mild hair loss
pronounced or total head
hair loss
none
localized pigmentation
generalized pigmentachanges
tion changes or atrophy
SK DES
none
dry desquamation
moist desquamation
none
none
mild
mild
moderate
moderate
none
mild, no transfusion
SK ALO Alopecia
Desquamation*
SK DRY Dry skin*
SK FAC Flushing*
(eg: facial)
SK HEM Bruising/bleeding
SK LTO Local Toxicity
(reaction at IV site)
SK NAI Nail changes*
SK PAI Skin pain*
(incl scalp pain)
SK RAS Rash/Itch*
(not due to allergy)
(incl recall
reaction)
SK OTH Other*
WT GAI
WT LOS
Weight Gain
Weight Loss
gross, 1-2 units
transfusion per episode
Bleeding resulting from thrombocytopenia should be coded under BL HEM, not SK
none
pain
pain & swelling, with
inflammation or phlebitis
none
mild
moderate
none
pain, but no treatment
pain controlled with nonreq
opioids
none or no change
scattered macular or
scattered macular or
papular eruption or
papular eruption or
erythema that is
erythema with pruritus
asymptomatic
or other associated
symptoms
none
mild
moderate
WEIGHT
<5.0%
5.0-9.9%
10.0-19.9%
<5.0%
5.0-9.9%
10.0-19.9%
* denotes NCIC CTG specific criteria
Any toxicity which causes death should be given grade 5.
3
96-MAY-15
MA.14
REVISED: 94-DEC-21
4
in-pt management
severe
changes with symptoms
req intubation
life threatening
--
gross, 3-4 units
transfusion per episode
massive, >4 units
transfusion per episode
severe
pain controlled with
opioids
oxygen req
-uncontrollable pain
dyspnea at normal level
of activity, apnea
without cyanosis
severe
dyspnea at rest, apnea
with cyanosis
req assisted ventilation
--
severe
life threatening
to be resultant from pulmonary changes directly
total body hair loss
--
subcut. fibrosis or
localized shallow
ulceration
confluent moist
desquamation
severe
severe
generalized ulcerations
or necrosis
gross, 3-4 units
transfusion per episode
massive, >4 units
transfusion per episode
ulceration
plastic surgery
indicated
-uncontrollable pain
severe
pain controlled with
opioids
generalized
symptomatic macular,
papular, or vesicular
eruption
severe
>20.0%
>20.0%
----
exfoliative dermatitis
or ulcerating dermatitis
life threatening
---
68
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
APPENDIX VI - GROWTH FACTOR STUDY
Introduction
In keeping with current trends in clinical cancer research the objectives of this trial include not
only determining the standard end points of survival, disease-free survival, and measures of quality
of life and toxicity, but also to provide new knowledge with respect to the mechanisms of action
of the treatments under study and to use the study to obtain new information concerning cancer
biology.
To undertake this important basic science component serum levels of specific growth factors will
be measured for patients in this trial. All patients randomized to MA.14 will be required to
participate in the growth factor study and provide serum samples at specified times (see
Appendix I).
Background
Tamoxifen is the most widely used compound in breast cancer treatment. The history of its
development and introduction into clinical practice has been reviewed elsewhere1. The first
application of tamoxifen in breast cancer management was in the palliative treatment of metastatic
disease. In this setting, the drug clearly had an extremely favourable risk/benefit profile.
Dramatic responses to tamoxifen are not rare and for many patients long-term control of metastatic
proliferation by tamoxifen leads to major improvements in quality of life. The positive experience
in the metastatic setting justified initial trials of the drug in post-surgical adjuvant treatment. This
clinical research showed that for patients in several important prognostic groups, improvements
in disease-free survival and survival result from adjuvant tamoxifen therapy. In general, the
risk/benefit profile of the drug remains favourable when it is used as post-surgical adjuvant
therapy, particularly for post-menopausal patients. There is a low incidence of uterine toxicity,
particularly if the drug is given at levels higher than 20 mg/day. This risk is clearly outweighted
by reduction in risk of breast cancer recurrence, and perhaps by favourable effects on serum lipid
profiles and bone density. Adjuvant therapy accounts for the majority of tamoxifen usage in the
1990's. The possibility that tamoxifen will also be useful for breast cancer prevention in certain
women at high risk is being addressed in ongoing clinical trials.
While data from clinical trials do not support the opinion that toxicity is a major problem
associated with tamoxifen, there remains a serious limitation to tamoxifen therapy. The problem
is the limited nature of its efficacy, even in patients with estrogen receptor positive tumours.
Although responses to the drug in metastatic disease are common and clinically useful, such
responses are rarely long-term. The development of tamoxifen resistance and progression of
metastatic disease while patients are receiving the drug is commonplace. Similarly, in the adjuvant
setting, while it is clear that the risk of developing clinically obvious metastases is significantly
decreased in many groups of patients by post-operative tamoxifen treatment, such therapy by no
means guarantees that progression of micrometastases will not occur, and the failure of adjuvant
tamoxifen therapy to prevent development of macrometastatic disease is frequently seen.
69
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
Thus, an important research goal is to develop ways to enhance tamoxifen efficacy or delay the
emergence of tamoxifen resistance. In this regard, recent preclinical data suggest that it may be
beneficial to combine tamoxifen with somatostatin analogues, and several large scale trials are now
planned to determine the clinical relevance of these preclinical results. An example of another
approach to this problem is the combination of retinoids with antiestrogens. Relative to other
approaches that are immediately ready for clinical testing, the antiestrogen-somatostatin approach
has the advantage of a favourable and documented long-term toxicity profile and demonstrated
improvement of efficacy over single-agent tamoxifen in a preclinical model system. Other
promising approaches suggested by recent laboratory work are not presently ready for clinical
testing because they involve novel compounds for which long-term toxicity information is
unavailable. The long-term toxicity information is a particularly important issue with respect to
proposed novel adjuvant therapies.
Mechanisms of antineoplastic activity of somatostatin analogues
Somatostatin was originally isolated as a hypothalamic factor that inhibited release of growth
hormone by the pituitary gland. It is now recognized that somatostatin has many functions apart
from the inhibition of growth hormone release and that somatostatin receptors are widely
distributed beyond the pituitary. In general, the functions of somatostatin are inhibitory:
inhibition of growth hormone release, inhibition of gastric acid secretion, inhibition of
proliferation, etc (reviewed in 2). Therapeutic use of native somatostatin is impractical because of
its short serum half-life (~ 1 minute). Several analogues such as octreotide (SMS 201-995) and
RC-160 that have substantially longer serum half lives and retain bioactivity have been synthesized.
It is now recognized that there are at least 5 distinct somatostatin receptor subtypes3. The
specificity of action of various analogues in each type of receptor is the subject of ongoing
investigation. Recent data suggest that at least some of the antiproliferative effects of somatostatin
are mediated in large part by the type 2 somatostatin receptor4. Both octreotide and RC-160 bind
to this receptor.
There is substantial literature demonstrating considerable antineoplastic activity of somatostatin
analogues in many in vitro and in vivo experimental systems (reviewed in 5,6). Increasing
information concerning mechanisms of action has emerged over the past decade. There are two
proposed mechanisms, and it is important to emphasize that these mechanisms are not mutually
exclusive.
Direct mechanism: The ‘direct’ mechanism of antineoplastic action refers to inhibition of
proliferation and/or induction of apoptosis that arise as a consequence of a somatostatin analogue
binding to a somatostatin receptor on the target neoplastic cell. Although somatostatin-receptornegative cells clearly cannot be influenced by the direct mechanism, recent data show that a large
proportion of breast cancers (and others) are in fact somatostatin receptor positive7.
Characterization of the molecular basis of the signal transduction pathways associated with each
of the 5 somatostatin receptor subtypes in ongoing. There is evidence that one important signal
transduction pathway involves upregulation of phosphotyrosine phosphatase activity following
binding of somatostatin or a somatostatin analogue to somatostatin receptors8. This activity is the
opposite of that associated with tyrosine kinase - type peptide growth factor receptors, and
therefore it is not unexpected that proliferation inhibition would be a consequence of upregulation
of this activity.
70
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
Indirect mechanism: The ‘indirect’ mechanism of action refers to inhibition of proliferation that
arises as a consequence of systemic effects of administration of somatostatin analogues, rather than
binding of somatostatin analogues to neoplastic cells. Even somatostatin-receptor negative
neoplasms might be inhibited by indirect mechanisms. Several indirect antineoplastic actions of
somatostatin analogues have been proposed. The indirect mechanism that has received the most
attention to date concerns the effect of somatostatin analogues on systemic IGF-1 physiology.
IGF-1 is an important mitogen for many neoplastic cell types9,10, and also inhibits apoptosis 11 and
encourages cell motility 12. This indirect mechanism of somatostatin analogue action may involve
suppression of angiogenesis, as there is data to suggest that IGF-1 facilitates endothelial cell
proliferation 13. It is well established that somatostatin analogues lower acromegalic growth
hormone and IGF-1 levels towards normal. It also has been shown that these agents can lower
normal GH and IGF-1 levels14. The dose-response characteristics here differ from the acromegalic
situation, as a result of physiological efforts at counter-regulation, for example by increased growth
hormone releasing hormone secretion. The concept proposed is that a modest growth hormone
/ IGF-1 deficiency in an adult might be associated with substantial inhibition of IGF-1 responsive
neoplasms, with only minor symptoms for the patient. An implicit assumption is that reduction
in serum IGF-1 level correlates with changes in tissue IGF-1 bioactivity. There are in vivo
experimental systems in which a somatostatin analogue has been found to inhibit the growth of a
somatostatin-receptor negative, IGF-1 receptor positive neoplasm 15.
In the case of breast cancer, it has been suggested 16,17 that a rationale for reduction of IGF-1 level
can be derived from the epidemiological evidence that breast cancer incidence is higher18-23 and
prognosis worse18,19,21 in taller women, and that height is related in part to IGF-1 level, which varies
considerably between normal individuals 24. It also has been shown that human breast cancer
xenograft growth is reduced in mice that are genetically IGF-1 deficient relative to controls, despite
equal estrogen supplementation 25. This line of reasoning is speculative, but does deserve study,
particularly in the light of separate supportive data from skeletal morphometry studies26.
Rational for coadministration of antiestrogens and somatostatin analogues
With respect to the proposed direct mechanism of action of somatostatin analogues: It has been
demonstrated in an early report27, and since confirmed, that a direct antineoplastic effect of
octreotide on estrogen-receptor positive breast cancer cells can be detected using in vivo tissue
culture systems. Interestingly, the antiproliferative effect of octreotide was clearly maximized in
the absence of estrogens27. The molecular basis for the attenuation of the antiproliferative effect
of octreotide by estrogens is uncharacterized, but this observation provides a rationale for coadministrating an antiestrogen with octreotide. Perhaps consistent with this result is the
observation that the antineoplastic action of the somatostatin analogue RC-160 in the MXT breast
tumour model is enhanced by co-administration of an LHRH analogue, which lowers estradiol
levels28.
With respect to the proposed indirect mechanism of action of somatostatin analogues: A recently
characterized effect of antiestrogen therapy in both clinical16,29 and laboratory30,31 studies is a
suppression of IGF-1 gene expression and serum IGF-1 level. These were somewhat unexpected
observations, as inhibition of IGF-1 gene expression was not obviously an “antiestrogenic” effect.
There are now data that suggest that this inhibitory action is related in part to inhibition of
pituitary growth hormone output32,33, and in part to direct inhibition of IGF-1 gene expression in
various target organs for metastasis31.
71
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
It has been shown that octreotide and tamoxifen combined suppress serum IGF-1 levels and IGF-1
gene expression more potently than either agent alone in short-term experiments carried out on
rats34. This demonstrates a potentially relevant biological interaction, and is compatible with an
additive antineoplastic effect. Furthermore, recent clinical data demonstrate an enhanced
suppression of IGF-1 serum level in patients receiving the combination of octreotide and tamoxifen
relative to those receiving tamoxifen alone35. However, this result cannot be extrapolated to a
conclusion regarding a benefit in terms of efficacy, as the hypothesis that decline in serum IGF-1
is a surrogate endpoint related to efficacy is unproven.
Preclinical results of combined somatostatin and antiestrogen therapy
Combined octreotide - tamoxifen therapy has been studied using the DMBA-induced rat mammary
tumour model36. Despite some limitations, this model has proven reliable in predicting clinical
activity of hormonal therapies for breast cancer37. The model detects antineoplastic activity of
tamoxifen, which is greater than the activity of octreotide. However, the incidence and growth of
DMBA-induced tumours is significantly reduced in animals co-treated with both agents relative to
either agent alone. Furthermore, we were able to detect enhancement of the inhibitory effect of
oophorectomy on growth of DMBA-induced tumours36. These neoplasms reproducibly regress
following oophorectomy, but later regrow. This phenomenon may have features in common with
certain forms of resistance to hormonal therapy seen clinically. When octreotide was administered
post-oophorectomy, the incidence of re-growth of tumours resistant to endocrine treatment was
greatly reduced.
In all experimental systems, a consistent observation has been that the response to octreotidecontaining regimes is greater in smaller neoplasms than large neoplasms. The basis for this is
unclear. It is consistent with the proposal that at least a part of the antineoplastic activity is an
antiangiogenic one. It also is possible that with neoplastic progression, tumours become less
dependent on exogenous IGF-1 and/or lose a somatostatin-receptor-positive phenotype, either or both
of which would reduce responsivity to somatostatin analogues. This fact suggests that somatostatin
analogues would be more effective in the adjuvant setting than in the management of
macrometastatic disease.
Clinical results of combined somatostatin and antiestrogen therapy
Single agent activity of somatostatin analogues in advanced, heavily treated breast cancer is very low,
despite some isolated reports of disease stabilization. There are no substantial data regarding the
use of any somatostatin analogue as first-line therapy, and such trials are not anticipated because
preclinical data do not suggest that somatostatin analogues as single agents have greater activity than
currently used hormonal therapies. Rather, they support the hypothesis that the efficacy of
antiestrogen therapy may be enhanced by co-administration of somatostatin analogues.
A recent trial at the Mayo Clinic attempted to compare the efficacies of octreotide, tamoxifen, and
the combination as first line therapy for metastatic breast cancer. There were no serious adverse
effects among participants. Interim analysis of this trial suggested that single agent octreotide was
inferior to the other two arms, and focused interest on the possibility of enhanced progression-free
survival in the combination group over the tamoxifen-alone group. However, this trial has recently
been closed to further accrual due to problems in accrual rate. These arose because of practical
72
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
considerations related to the inconvenient dosage formulation of octreotide used (multiple daily
subcutaneous injections) and to the increased use of adjuvant tamoxifen, which was in most cases
considered an exclusion criteria. Final outcome analysis of this trial is not yet available as patients
remain on protocol treatment at this time. Analysis of blood samples obtained in a subset of
participants in this trial, however, has demonstrated that the treatment-related decline in serum IGF1 levels was significantly greater in the combination group than in the tamoxifen-alone group35. This
trial contributed to the justification for a new trial in metastatic disease that will be carried out in
part in countries where adjuvant tamoxifen therapy is less frequently used than in North America,
and will use the more convenient monthly depot formulation.
Conclusion
There is a clear clinical need to improve the efficacy of antiestrogen therapy. Co-administration of
a somatostatin analogue is one of several approaches that have been suggested in this regard. The
preclinical evidence of improved efficacy in the DMBA model is clear, and the development of a
depot formulation of octreotide, together with the established long-term safety profile of this agent,
make clinical trials feasible. In 1996, the U.S. National Cancer Institute, through the NSABP trials
group, intends to launch a major adjuvant trial for node-negative breast cancer patients, and a
similar adjuvant trial directed at node-negative and node-positive patients is planned by the National
Cancer Institute of Canada. In addition, a multinational trial of this combination in previously
untreated metastatic breast cancer is to begin. All of these trials will involve randomization to
tamoxifen vs. tamoxifen plus octreotide. In addition to the standard clinical endpoints, these trials
will have an important ‘translational’ research component that will generate data regarding, for
example, the effect of each treatment arm on IGF-I physiology, and the relationship of this to
outcome.
Objectives
Three objectives of the growth factor study are:
1. To determine the relationship between the growth factor levels and patient tumour
characteristics. Growth factor levels will be compared to parameters such as body mass index,
height, weight, age, tumour size, tumour receptor status, and nodal status.
2. To examine the effects of treatments on growth factor levels. Prior research suggests that
tamoxifen reduces IGF-1 levels. An objective of the growth factor study will be to evaluate the
possibility that the patients on the somatostatin analogue and tamoxifen combination arm will
have a greater decrease in IGF I levels than patients receiving tamoxifen alone. Roughly
speaking, the decrease previously observed with tamoxifen therapy has been approximately 20
to 30%; however it is important to recognize that there is considerable heterogeneity between
patients. Firstly, the baseline levels vary considerably from person to person, and secondly, the
amount of decline also varies. Therefore, when examining the effects of treatment several
measures should be used. These would include studies of the pre and intro-treatment absolute
levels as well as second intra-treatment level as a percentage of the pre-treatment level. This
measure is a very important one as it allows us to look at the decline independent of the
heterogeneity of the baseline.
73
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
3. To determine the relationship between growth factor levels and relapse. This third objective is
designed to determine if there are differences between the growth factor levels in patients at the
time of relapse compared to patients who continue to enjoy disease-free survival at comparable
time following randomization. A related hypothesis will be to determine if for individual
patients, there is a change in growth factor levels at the time of relapse relative to the growth
factor levels in the same patient six months prior to relapse. The biological hypothesis here is
that the suppression of growth factor levels that is associated with treatment during the period
of disease-free survival will be lost at relapse where there is ‘escape’ from suppression.
Statistical Considerations
1. Objectives
The objectives of the companion studies are: 1) to determine the relationship of growth factor
levels to patient characteristics and tumor characteristics; 2) to determine the effects of treatments
on growth factor levels; 3) to assess the average pattern of changes in IGF-I levels in a
longitudinal fashion and determine whether a significant change in IGF-I levels occurs at the
time of relapse.
Blood samples from all randomized patients will be collected and assayed to determine IGF-I
levels. Data resulting from the assays will be sent to the NCIC CTG directly when available. The
timing of various analyses will be discussed in the sample size section.
2. Endpoints and Analysis
1.
The association between pre-treatment IGF-I and other growth factor levels and patient
characteristics will be assessed using a Pearson’s correlation for continuous variables and
a two sample t-test for dichotomous variables. In particular, we are interested in parameters
such as patient height, weight (or body mass index), age, tumor size, receptor status, and
nodal status. A generalized linear model will be used to determine the joint association of
the patient characteristics with the pre-treatment IGF-I level. A coefficient of
determination will be used to estimate the amount of reduction of total variation of pretreatment IGF-I levels associated with the use of a subset of patient characteristics.
2.
Patients who received tamoxifen alone will be compared to those who received tamoxifen
plus octreotide with respect to the percent change in IGF-1 levels or other parameters using
a chi-square test. The IGF-I change scores from baseline to month 4 assessment will be
used as an endpoint in this analysis. The absolute change will also be used in the analysis.
A logarithmic transformation on the absolute IGF-I levels may be used to preserve
normality of the variable. A stepwise regression method will be used to assess prognostic
factors. The comparison of IGF-I change scores between the two treatment arms will be
adjusted by the significant prognostic factors determined in the regression analysis.
74
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
3.
The average change in IGF-I levels along time will be plotted for each of the two treatment
arms. A repeated measure analysis of variance will be used to analyze the pattern of
change of IGF-I levels. A similar analysis will be done for patients who have relapsed and
those who are still in remission. Two endpoints will be used for this analysis: i) absolute
IGF-1 levels at baseline, month 4, month 8, etc.; ii) change scores of IGF-1 levels from
baseline to month 4, month 8, etc. If there is no significant difference in patterns between
the two treatment arms, we will simplify the plots by combining the two treatment arms.
A Cox regression model with time-dependent IGF-I levels will be used to explore the effect
of the change in IGF-I levels to relapse. Other exploratory analyses will be performed, for
example, defining “the time to a specific amount of change in the IGF-I levels” as another
endpoint and comparing the Kaplan-Meier estimates with that of the time-to-relapse
survival curve. As well, we will determine whether the "time to a specific change in IGF-I
levels" mimics that of the time-to-relapse experience.
In addition to the longitudinal data analysis, we will also use the change score from the
minimum post-treatment IGF-I level to the maximum post-treatment IGF-I level as another
endpoint. We will compare the difference between treatment arms, and compare patients
who relapse to those in remission using a two sample t-test.
3. Sample Size
1.
In order to have 80% power of determining a simple correlation coefficient of 0.3 at a level
of 5% for the IGF-I level at baseline, we require a total of 84 patients in the study. For
a smaller correlation of 0.25, we need 123 patients. The smaller the correlation the larger
the number of patients required in the study. For a multiple correlation of 0.3 with patient
height, weight (or body mass index), age, tumor size, receptor status, and nodal status, we
need a total of 147 patients. For a correlation of 0.25, we need a total of 214 patients. For
objective 1, since multiple correlations between IGF-I and variables other than the one
listed above may be included (eg. other growth factors binding proteins), we would
perform this analysis once we have a minimum of 250 patients.
2.
For objective 2, we expect to see a drop of about 40% to 45% in the IGF-I level for the
octreotide plus tamoxifen arm compared to a drop of 25% to 30% in the tamoxifen alone
arm. In order to have 80% power to detect the 15% difference in percent change of the
IGF-I level using a two-sided 5% level test, we need about 350 patients. The sample size
of this analysis is therefore set at a minimum of 350 patients. We would perform this
analysis at the time of the first interim analysis. This would be done in about 4.2 years
after the activation of the study according to the estimated accrual and relapse rates from
the main study.
3.
The analysis of objective 3 requires patients' relapse status, which is a primary outcome
of the study. The results of this analysis could have a major impact on the interpretation
of the results from previous objectives. In order to avoid drawing pre-mature conclusions
regarding the efficacy of the study treatment, the analysis for objective 3 will be done at
the time of the final analysis for the overall study. A more detailed analysis plan than the
current plan will be developed just prior to the time of analysis in order to incorporate
methods that may have been developed during the next couple of years while the study is
being carried out.
75
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
Studies of Breast Tumor Tissue
The provision of tumor tissue is not required but is an option available to interested investigators.
The scientific goals are to survey our study population for the frequency of expression of
somatostatin and IGF-I receptors and to study the relationships between receptor expression and
other tumor characteristics such as tumor size and nuclear grade.
A detailed statistical statement of achievable hypoheses to test will be developed when we have
estimates of accrual rates of neoplastic tissue.
For studies of expression of somatostatin and IGF-I receptors fresh frozen tissue is required.
Present techniques are not suitable for fixed blocks of tissue although this is an area of rapid
technical progress. Analysis of archived fixed specimens may become possible before the trial is
completed. Interested centres should contact the principal investigator for details of tumor collection
procedures and for information regarding suppplemental funding to cover expenses.
References
1.
Lerner L, Jordan VC. Development of antiestrogens and their use in breast cancer: eight cain
memorial ward lecture. Cancer Res 1990; 50:4177-89.
2.
Reichlin S. Somatostatin. New Engl J Med 1983; 309:1495-501.
3.
Patel YC, Srikant CB. Subtype selectivity of peptide analogs for all five cloned human
somatostatin receptors (hsstr 1-5). Endocrinol 1994; 135:2814-7.
4.
Buscail L, Esteve JP, Saint-Laurent N, Bertrand V, Reisine T, O’Carroll AM, Bell GI,
Schally AV, Vaysse N, Susini C. Inhibition of cell proliferation by the somatostatin analogue
RC-160 is mediated by somatostatin receptor subtypes SSTR2 and SSTR5 through different
mechanisms. Proc Natl Acad Sci USA 1995; 92:1580-4.
5.
Schally AV. Oncological applications of somatostatin analogues. Cancer Res 1988; 48:6877-85.
6.
Weckbecker G, Raulf F, Stolz B, Bruns C. Somatostatin analogs for diagnosis and treatment
of cancer (Review). Pharmac Ter 1993; 60:245-264.
7.
van Eijck CH, Krenning EP, Bootsma A, Lindemans J, Jeekel J, Reubi JC, Lamberts SW.
Somatostatin-receptor scintigraphy in primary breast cancer. Lancet 1994; 343:640-3.
8.
Buscail L, Delesque N, Esteve JP, Saint-Laurent N, Prats H, Clerc P, Robberecht P, Bell GI,
Liebow C, Schally AV, et al. Stimulation of tyrosine phosphatase and inhibition of cell
proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes
SSTR1 and SSTR2. Proc Natl Acad Sci USA 1994; 91:2315-9.
9.
Macaulay VM. Insulin-like growth factors and cancer. Br J Cancer 1992; 65:311-20.
10.
Pollak M, Perdue JF, Margolese RG, Baer K, Richard M. Presence of somatomedin receptors
on primary human breast and colon carcinomas. Cancer Lett 1987; 38:223-30.
76
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
11.
Resnicoff M, Abraham D, Yutanawiboonchai W, Rotman HL, Kajstura J, Rubin R, Zoltick
P, Baserga R. The Insulin-Like Growth Factor I Receptor Protects Tumor Cells from
Apoptosis in Vivo. Cancer Res 1995; 55:2463-9.
12.
Stracke ML, Kohn EC, Aznavoorian SA, Wilson LL, Salomon D, Krutsch HC, Liotta LA,
Schiffmann E. Insulin-like growth factors stimulate chemotaxis in human melanoma cells.
Biochem Biophys Res Comm 1988; 153:1076-83.
13.
Nako-Hayshi J, Jto H, Kanayasu T, Morita I, Murota S. Stimulatory effects of insulin and
IGF-I on migration and tude formation by vascular endothelial cells. Athero 1992; 92:141-9.
14.
Pollak M, Polychronakos C, Guyda H. Somatostatin analogue SMS 201-995 reduces serum
IGF-I levels in patients with neoplasms potentially dependent on IGF-I. Anticancer Res 1989;
9:889-92.
15.
Reubi JC. A somatostatin analogue inhibits chondrosarcoma and insulinoma tumour growth.
Acta Endo 1985; 109:108-14.
16.
Pollak M, Costantino J, Polychronakos C, Blauer S, Guyda H, Redmond C, Fisher B,
Margolese R. Effect of tamoxifen on serum insulin-like growth factor I levels in stage I breast
cancer patients. JNCI 1990; 82:1693-7.
17.
Stoll B. Breast cancer risk in Japanese women with special reference to the growth hormoneinsulin-like growth factor axis. Jpn J Clin Oncol 1992; 22:1-5.
18.
deWaard F, Cornelis J, Aoki K, Yoshida M. Breast cancer incidence according to weight and
height in two cities of the Netherlands and in Aichi prefecture, Japan. Cancer 1995; 40:126975.
19.
Vatten L, Kvikstad A, Nymoen E. Incidence and mortality of breast cancer related to body
height and living conditions during childhood and adolescence. Eur J Cancer 1992; 28:128-31.
20.
Murata M, Kuno K, Sakamoto G. Epidemiology of family predisposition for breast cancer
in Japan. JNCI 1982; 69:1229-34.
21.
Tretli S. Height and weight in relation to breast cancer morbidity and mortality. A
prospective study of 570,000 women in Norway. Int J Cancer 1989; 44:23-30.
22.
Vatten LJ, Kvinnsland S. Body height and risk of breast cancer. A prospective study of
23,831 Norwegian women. Br J Cancer 1990; 61:881-5.
23.
Hunter D, Willett W. Diet, body size, and breast cancer. Epidemiological Reviews 1993;
15:110-32.
24.
Juul A, Bang P, Ertel N, et al. Serum insulin-like growth factor I in 1030 healthy children,
adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass
index. J Clin Endocrinol Metab 1995; 78:744-52.
77
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
25.
Yang X, Beamer W, Huynh HT, Pollak M. Reduced growth of human breast cancer
xenografts in hosts homozygous for the ‘lit’ mutation. Submitted for publication, 1995.
26.
Mondina R, Borsellino G, Poma S, Baroni M, Di Nubila B, Sacchi P. Breast carcinoma and
skeletal formation. Eur J Cancer 1992; 28A:1068-70.
27.
Setyono-Han B, Henkelman MS, Foekens JA, Klijn GM. Direct inhibitory effects of
somatostatin (analogues) on the growth of human breast cancer cells. Cancer Res 1987;
47:1566-70.
28.
Szepeshazi K, Milovanovic S, Lapis K, Groot K, Schally AV. Growth inhibition of estrogen
independent MXT mouse mammary carcinomas in mice treated with an agonist or antagonist
of LH-RH, an analog of somatostatin, or a combination. Breast Cancer Res Treat 1992;
21:181-92.
29.
Friedl A, Jordan VC, Pollak M. Suppression of serum IGF-I levels in breast cancer patients
during adjuvant tamoxifen therapy. Eur J Cancer 1993; 29A:1368-72.
30.
Pollak M. in Effects of adjuvant tamoxifen therapy on growth hormone and insulin-like
growth factor I (IGF-I) physiology. Salmon SE, editors. Adjuvant Therapy of Cancer VII.
J.B. Lippincott Company. 1993.
31.
Huynh HT, Tetenes E, Wallace L, Pollak M. In vivo inhibition of insulin-like growth factor-I
gene expression by tamoxifen. Cancer Res 1993; 53:1727-30.
32.
Tannenbaum GS, Gurd W, Lapointe M, Pollak M. Tamoxifen attenuates pulsatile growth
hormone secretion: mediation in part by somatostatin. Endocrinol 1992; 130:3395-401.
33.
Malaab SA, Pollak M, Goodyer CG. Direct effects of tamoxifen on growth hormone secretion
by pituitary cells in vitro. Eur J Cancer 1992; 28A:788-93.
34.
Huynh HT, Pollak M. Enhancement of tamoxifen-induced suppression of insulin-like growth
factor I gene expression and serum level by a somatostatin analogue. Biochem Biophys Res
Comm 1994; 203:253-9.
35.
Pollak M, Ingle JN, Deroo B, Nickerson T. Coadministration of octreotide enhances
tamoxifen-induced suppression of serum IGF-1 levels in patients with metastatic breast cancer.
Submitted for publication, 1995.
36.
Weckbecker G, Tolosvai L, Stolz B, Pollak M, Bruns C. Somatostatin analogue octreotide
enhances the antineoplastic effects of tamoxifen and ovariectomy on 7,12dimethylbenz(a)anthracene-induced rat mammary carcinomas. Cancer Res 1994; 54:6334-7.
37.
Welsch CW. Host factors affecting the growth of carcinogen-induced rat mammary
carcinomas: A review and tribute to Charles Brenton Huggins. Cancer Res 1985; 45:3415-43.
78
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
APPENDIX VII - COLLECTION OF SERUM SAMPLES FOR GROWTH FACTOR STUDY
Blood samples for growth factor assays will be collected and sent to a central lab for analysis. The
frequency of serum collection is specified in Appendix I.
First Sample Only (Pre-Randomization)
i. Collect 2 anticoagulant (purple top) tubes of whole blood, total volume approximately 10 ml.
ii. These tubes should not be frozen but simply labelled with the labels provided and placed in a chill pack
provided by the Central Lab. The chill pack contains a tube protector, a picnic type cold pak, a small
styrofoam box, and an outer cardboard box. The coldpack must have been prefrozen in a regular
freezer. No spinning is needed.
iii. The chill pack should be be sent to the central lab by courier using the pre-prepared labels and account
number supplied by the Central Lab, preferably on the same day as collected. If this is not possible,
the tubes should be refrigerated (not frozen) overnight and sent the next day. Tubes collected on a
Friday should be for Saturday delivery.
First Sample and All Subsequent Samples
i. Collect approximately 6 ml of blood in a red top tube.
ii. Allow to clot and as soon as possible (no more than 4 hours) centrifuge to separate serum. Pipette out
the serum (2-3 ml) and place the serum in the screw-top plastic freezer vials provided by the Central
Lab. Label the vials with the labels provided.
iii. These tubes should not be frozen but simply labelled with the labels provided and placed in a
chill pack provided by the Central Lab. The chill pack contains a tube protector, a picnic type
cold pak, a small styrofoam box, and an outer cardboard box. The coldpack must have been
prefrozen in a regular freezer.
iv. The chill pack should be be sent to the central lab by courier using the pre-prepared labels and
account number supplied by the Central Lab, preferably on the same day as collected. If this
is not possible, the tubes should be refrigerated (not frozen) overnight and sent the next day.
Tubes collected on a Friday should be for Saturday delivery.
Note:
Collection of these samples will, when possible, be integrated with the collection of the samples
obtained for routine hematology and biochemistry, with all samples being shipped to a central
laboratory for immediate analysis and/or banking. Details will be provided at the time of study
initiation.
79
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 97-SEP-18; AMENDED: 99-DEC-09
APPENDIX VIII - OCTREOTIDE LAR ADMINISTRATION TECHNIQUE
INSTRUCTIONS FOR INJECTION OF SMS 201-995 PA LAR FOR INTRAMUSCULAR USE ONLY
60 mg SMS - Vial / Ampoule set
Note: The injection should be given immediately after reconstitution. It is stable for only 30 minutes post
mixing. If the suspension settles, it will clog the needle.
1.
Open cap by bending (but not completely removing) the tongue of the alu-seal.
2.
Wipe the top of the vial (grey rubber) with a sterilized swab.
3.
Insert the short brown needle (0.45 x 12 mm; 26G x 1/2") through the centre of the rubber
stopper (for pressure compensation).
4.
Open ampoule, containing the vehicle.
5.
Attach a yellow needle (0.9 x 55 mm; 20G x 1 1/2") to a 5 ml single-use syringe.
6.
Draw 2 ml diluent into the syringe.
7.
Insert the needle (with attached syringe) through the center of the rubber stopper of the vial,
beside the short brown needle. Slowly inject contents of the syringe into the vial.
8.
Pull out syringe with the attached needle. Leave the brown needle in the vial.
9.
Shake vial for 1 min (or longer if needed) until the vial contains a homogeneous, milky
suspension.
10.
Again insert syringe with needle through the rubber stopper. Aim to reach the bottom of the vial
on the side wall of the vial. Tilt the vial so that the end of the needle reaches the lowest point of
the vial and slowly draw up the entire content of the suspension into the syringe.
11.
Remove the syringe from the vial and assemble syringe with a new yellow needle.
12.
Shortly shake syringe, eliminate air from syringe and immediately insert needle into upper outer
quadrant of right or left gluteus and draw back to ensure that no blood vessel has been penetrated.
13.
If a blood vessel has been penetrated, withdraw the needle and syringe, replace the needle with
a new one, select another injection site and repeat step 12.
14.
If a blood vessel has not been penetrated, inject at once into gluteus.
15.
Withdraw needle at once.
16.
Discard the needle and syringe.
17.
Retain vials for return to Novartis Pharmaceuticals Canada Inc.
NOTE: In case of clogging of the needle during injection, withdraw syringe with needle from patient.
Detach and withdraw the needle, shake syringe until suspension is homogenous. Attach a fresh yellow
needle (0.9 x 55 mm; 20G x 2 1/2"), remove air from syringe and inject again into patient (see step 12 and
following).
80
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 97-SEP-18; AMENDED: 99-DEC-09
INSTRUCTIONS FOR INJECTION OF SMS 201-995 PA LAR FOR INTRAMUSCULAR USE ONLY
90 mg SMS - Vial / Ampoule set
Note: The injection should be given immediately after reconstitution. It is stable for only 30 minutes post
mixing. If the suspension settles, it will clog the needle.
1.
Open cap by bending (but not completely removing) the tongue of the alu-seal.
2.
Wipe the top of the vial (grey rubber) with a sterilized swab.
3.
Insert the short brown needle (0.45 x 12 mm; 26G x 1/2") through the centre of the rubber
stopper (for pressure compensation).
4.
Open ampoule, containing the vehicle.
5.
Attach a yellow needle (0.9 x 55 mm; 20G x 1 1/2") to a 5 ml single-use syringe.
6.
Draw 2 ml diluent into the syringe.
7.
Insert the needle (with attached syringe) through the center of the rubber stopper of the vial,
beside the short brown needle. Slowly inject contents of the syringe into the vial.
8.
Pull out syringe with the attached needle. Leave the brown needle in the vial.
9.
Shake vial for 1 min (or longer if needed) until the vial contains a homogeneous, milky
suspension.
10.
Again insert syringe with needle through the rubber stopper. Aim to reach the bottom of the vial
on the side wall of the vial. Tilt the vial so that the end of the needle reaches the lowest point of
the vial and slowly draw up the entire content of the suspension into the syringe.
11.
Remove the syringe from the vial and assemble syringe with a new yellow needle.
12.
Shortly shake syringe, eliminate air from syringe and immediately insert needle into upper outer
quadrant of right or left gluteus and draw back to ensure that no blood vessel has been penetrated.
13.
If a blood vessel has been penetrated, withdraw the needle and syringe, replace the needle with
a new one, select another injection site and repeat step 12.
14.
If a blood vessel has not been penetrated, inject at once into gluteus.
15.
Withdraw needle at once.
16.
Discard the needle and syringe.
17.
Retain vials for return to Novartis Pharmaceuticals Canada Inc.
NOTE: In case of clogging of the needle during injection, withdraw syringe with needle from patient.
Detach and withdraw the needle, shake syringe until suspension is homogenous. Attach a fresh yellow
needle (0.9 x 55 mm; 20G x 2 1/2"), remove air from syringe and inject again into patient (see step 12 and
following).
81
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 97-SEP-18; AMENDED: 99-DEC-09; AMENDED: 00-JUL-12
APPENDIX IX - LIST OF "CONTACTS"
Contact
ELIGIBILITY
CHECKLIST
Must be completed prior to
the telephone call to
request an allocation.
STUDY SUPPLIES
Forms, Protocols
Tel. #
Fax #
(613) 533-6430
(613) 533-2941
(514) 340-8222
(514) 340-8302
May Mak
Clinical Trials Assistant
NCIC CTG
E-Mail:
[email protected]
Paula Richardson
Study Coordinator
NCIC CTG
E-Mail:
[email protected]
GENERAL PROTOCOLRELATED QUERIES
or:
Dr. Lois Shepherd
Physician Coordinator
NCIC CTG
E-Mail:
[email protected]
or:
Dr. Michael Pollak
Study Chair
E-Mail:
[email protected]
ADVERSE EVENT
REPORTING
Dr. Patrick Le Morvan
Novartis Pharmaceuticals Canada Inc.
See protocol Section 11.0
for details of reportable
events.
AND:
DRUG ORDERING
Linda Chupa
Clinical Study Manager
Novartis Pharmaceuticals Canada Inc.
See Appendix III for full
details.
Paula Richardson
Study Coordinator
NCIC CTG
82
(514) 636-3175
(613) 533-6430
(613) 533-2941
(905) 668-3368
(905) 430-4268
APPENDIX X - QUALITY OF LIFE ASSESSMENT
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12
Introduction
The assumption that control of symptoms will automatically improve quality of life is probably true but has
not yet been tested, especially in determining how certain symptoms may or may not affect quality of life.
Current literature reveals interesting things; two in particular are:
P additional and useful information may be obtained from quality of life measurements
P a growing consensus that the goal of medical care today for most patients is the preservation of function
and well-being in everyday life.
We have reached the stage where the collection of information about psychological distress, social disruption,
emotional trauma and painful side-effects is not only necessary but a routine component in many protocols.
Quality of life data can be used in a variety of ways:
P
P
P
P
P
P
to try and achieve the best possible outcome for patients
to evaluate the extent of change in the quality of life of an individual or group across time
to evaluate new treatments and technologies
to support approval of new drug applications
to try to provide the best value for health care dollars
to compare costs and benefits of various financial and organizational aspects of health care services
In the future, approval of not only drugs but new therapies or methods of delivery will most likely be based
on a combination of quality of life, survival, response, and toxicity data.
Specific Objectives
Primary Objective:
To compare the profile of quality of life scores over time between patients
randomized to tamoxifen alone to those randomized to tamoxifen plus octreotide
LAR in post-menopausal women with carcinoma of the breast who have undergone
resection of the primary by either mastectomy or partial mastectomy (lumpectomy).
Secondary Objective:
(Under consideration for a subset of patients) To assess the effect of disease
recurrence/second malignancy on quality of life scores by comparing scores for
patients who recurred to those followed for the same duration who do not recur.
General Considerations
The Investigational arm of this trial combines octreotide LAR with tamoxifen. If the combination
improves survival over tamoxifen alone, it will be important in how much octreotide LAR reduces (if
at all) the quality of that survival. Common adverse effects of octreotide LAR include nausea, abdominal
cramps, diarrhea, malabsorption of fat and flatulence. These symptoms start within hours of the first
injection of the drug, but usually subside in 10-14 days with continuous treatment. Octreotide LAR
suppresses excretion of insulin, but again, this effect is very short-lived. Long term treatment may be
83
PROTOCOL DATE: 96-MAY-15
NCIC CTG TRIAL: MA.14
AMENDED: 96-AUG-12; AMENDED: 97-SEP-18
associated with increased risk of asymptomatic cholesterol gallstones.
It is anticipated that quality of life will not be greatly impacted on by the additional use of octreotide LAR.
The questions regarding inconvenience, discomfort and monthly injections will be included in the treatmentspecific checklist. Octreotide LAR, through its central or peripheral action, may ameliorate menopausal-type
symptoms associated with tamoxifen, thus questions related to menopause and sexual health have also been
included in the treatment-specific checklist. The use of the treatment-specific checklist in this study will be
for descriptive purposes only and the EORTC QLQ 30+157 will be the primary outcome measure.
Description of Instruments to be Used
EORTC Quality of Life Core Questionnaire:
The EORTC QLQ 30+1 is a self-administered core quality of life instrument for cancer patients that is
often accompanied by modules that are specific to cancer types. Different versions of the core questionnaire
have been validated in different cancer populations.
The QLQ 30+1 consists of 31 questions and includes six multi-item function scales (physical, role,
cognition, social, emotional, and quality of life): three symptom scales (pain, fatigue, emesis); and items of
symptoms. Items are scored using a Likert scale with higher scores on the functioning scales reflecting
higher levels of functioning and higher scores on the symptom scale reflecting increases in symptoms.
The Trial-Specific Module Checklist:
This checklist includes a combination of questions from a variety of menopausal questionnaires together with
questions generated specifically for this trial. The total number of items is 16 (questions 32-47). The trial
specific checklist has been incorporated with the EORTC QLQ 30+1 as one questionnaire.
Timing of Questionnaires
The Quality of Life questionnaire should be administered as follows:
•
•
•
prior to randomization (within 14 days)
during protocol treatment at month 1, 4, 8 and 12 of the first year post-randomization and then
annually until year 5 or treatment discontinuation
at recurrence/second malignancy
Instructions for Administration of a Quality of Life Questionnaire. The instructions below are intended as
a guide for the administration of the Quality of Life questionnaire.
1. Preamble
Quality of life data are collected for research purposes, and will usually not be used for the patient’s
individual medical care. The assessment is in the form of a self report questionnaire. Therefore, it must
be completed by the patient only, without translation, coaching or suggestions as to the
84
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
"correct" answer by relatives or health care personnel.
The usual scheduled times to obtain the questionnaires are as follows:
P pre-randomization or pre-registration (baseline)
P during treatment
P during follow-up
The information provided by the patient in the completed questionnaire is confidential and should not be
discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient.
A quality of life cover sheet MUST be completed for each questionnaire whether or not the questionnaire
is completed by the patient. The information provided on the cover sheet is vital to monitoring
compliance. The cover sheet should be kept separate from the questionnaire and filled in by the CRA
after obtaining the completed questionnaire from the patient. The cover sheet should then be attached
to the questionnaire and sent to the NCIC CTG with the appropriate reporting form. (The questionnaire
is sometimes supplied with the cover sheet attached to ensure the questionnaire has one but it should be
removed prior to the questionnaire being given to the patient.)
If a particular question or, indeed, the whole questionnaire has not been answered please document the
reason(s) in the appropriate space on the cover sheet.
2. Pretreatment Assessment
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of
treatment on different areas of the patient's life, eg: psychological distress, social disruption, side-effects,
et cetera.
The CRA should collect the questionnaire as soon as it has been completed, check to see that each
question has been answered and gently remind the patient to answer any inadvertently omitted questions.
If a patient states that she prefers not to answer some questions and gives a reason(s), the reason(s)
should be noted on the cover sheet. If a specific reason is not given, this also should be noted on the
cover sheet.
3. Assessments During Treatment
The quality of life questionnaire should be given to the patient PRIOR to treatment on the day of
treatment, as required by the schedule in the protocol. If possible, the patient should complete the
questionnaires before being seen by the doctor.
4. Assessments During Follow-up
The quality of life questionnaire should be given to the patient before being seen by the doctor, on
follow-up visits as required by the schedule.
A patient may, on occasion, be reluctant to complete the questionnaire because they feel
unwell. In that case, you may express sympathy that things are below par, but state that
this is exactly the information we require if we are to understand more about how quality
of life is affected. You may also remind them that it takes only a few
85
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
minutes to complete.
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!
5. What If . . .
The patient should complete the questionnaires at the clinic. The exception is that the design of some
trials may require the patient to take the questionnaire home with them after leaving the clinic, and
complete it on the specific day, because a return visit to the clinic is not scheduled.
There may be circumstances when the patient does not complete the questionnaire as required in the
clinic. Three situations are described below. In these cases, it is beneficial if quality of life data can
still be collected.
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to
give the questionnaire to the patient.
Contact the patient by phone informing her that the questionnaire was not completed. Ask the
patient if she is willing to complete one:
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the
questionnaire in a timely fashion. Complete a cover sheet and note that the questionnaire was mailed
to the patient. Record the date it was mailed, the date completed, and the date received on the cover
sheet.
If this is not feasible, then ask the patient if she is willing to complete a questionnaire over the
phone. If the patient agrees, read out the questions and range of possibilities, and record the
answers. Complete a cover sheet and note that the questionnaire was completed over the phone.
If no, complete a cover sheet and note the reason why the questionnaire was not completed.
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular
visit(s).
Ensure that the patient has a supply of questionnaires, with instructions about when to complete
them, and how to return them. If it is known beforehand, give the patient blank questionnaires at
the last clinic visit; if the extended absence is not known in advance, mail the blank questionnaires
to the patient. Written instructions may help ensure that the patient stays on schedule as much as
possible.
C. The patient does not want to complete the questionnaire in clinic.
Should the patient not wish to answer the questionnaire in the clinic but insist on taking it home,
and failing to comply with the patient's wishes is likely to result in the questionnaire not being
completed at all, then the patient may take the questionnaire home with instructions that it is to be
completed the same day. When the questionnaire is returned, the date on which the questionnaire
was completed should be noted and a comment made on the cover sheet as to why the patient took
it away from the clinic before completion.
86
PROTOCOL DATE:
NCIC CTG TRIAL:
96-MAY-15
MA.14
6. Waiving the Quality of Life Component
The only time that we will not require a patient to complete the quality of life questionnaires is if she
is not literate in either English or French (or other languages that the questionnaire may be available in).
In other words, if the assistance of a translator is required to comprehend the questions and reply, the
questionnaires should not be completed. Translation of the questions is not acceptable. Please indicate
on cover sheet.
7. Unwillingness to Complete Quality of Life Questionnaire
If a patient speaks and reads English or French (or other languages that the questionnaires may be
available in), but does not wish to complete the questionnaires then she is NOT eligible and should NOT
be put on study.
8. Inability to Complete Quality of Life Questionnaire (for reason other than illiteracy in English or French)
An eligible patient may be willing but physically unable to complete the questionnaires, because of
blindness, paralysis, etc. If the patient is completing the QOL assessment in the clinic, the questionnaire
should be read to them and the answers recorded by a health care professional (e.g., preferably the
clinical research associate assigned to the trial, but another clinic nurse, a doctor or social worker who
is familiar with the instructions for administering the questionnaires would be acceptable). If the patient
is completing the questionnaire at home, and a telephone interview by the clinical research associate is
not possible, then a spouse or friend may read the questions to the patient and record the answers.
However, this method should be a last resort, and the spouse or friend should be instructed to not coach
or suggest answers to the patient. Whichever method is used, it should be recorded on the cover page.
If these special arrangements are not possible or feasible, then the patient would not be required to
complete the questionnaires, and this should be reported on the cover page.
87
AMENDED: 96-AUG-12
NCIC CTG Trial MA.14
A Randomized Trial of Antiestrogen Therapy Versus Combined Antiestrogen and
Octreotide LAR Therapy in the Adjuvant Treatment of Breast Cancer in Post-Menopausal Women
Quality of Life Questionnaire
Instructions: This cover sheet is to be completed by clinical research associate/investigator.
This cover sheet must be completed for all patients whether the questionnaire is completed or not by the patient.
Attach the completed cover sheet to the Questionnaire when returned by the patient.
Please check that all questions have been answered and no question has more than one answer.
Note: If the entire questionnaire is not completed, please complete and return this cover page with the case report form.
Patient NCIC CTG Serial #: ____________ Patient Hospital #: __________________
_____ _____ _____
(first, middle, last)
Investigator: _________________________________
Institution: _______________________________________
Patient Initials:
Scheduled time to obtain quality of life assessment: please check (T)
G Prior to randomization
G During protocol treatment: G month 1 G month 4 G month 8 G year 1 G year 2 G year 3 G year 4 G
year 5
G At recurrence/second malignancy
Was questionnaire completed?
Yes
<<<
Date questionnaire completed: __ __ - __ __ __ - __ __
yy
mmm
dd
Were ALL questions answered?
Yes
Was assistance required?
Where was questionnaire completed?
No
<<<
No
Yes
G home
If no, reason:
No
If yes, reason:
G clinic
G another centre
G other____________
Please fill in today's date: __ __ - __ __ __ - __ __
yy
mmm
dd
Specify reason questionnaire not completed (check one):
___ 1. Patient kept appointment for examination, but could not complete Questionnaire due to illness.
___ 2. Patient kept appointment for examination, but refused to complete Questionnaire for reason other than illness.
Specify reason:
___ 3. Patient did not keep appointment. Specify reason:
___ 4. Patient could not be contacted.
___ 5. Questionnaire not administered due to institution error.
___ 6. Other reason, specify:
NCIC CTG use only
Logged: _______
___ - ____ - ___
Study Coord:______
Data Ent'd:
___ - ____ - ___
______
NCIC CTG Trial MA.14
(96-01-12)
88
This box to be completed by the clinical research associate: Pt. Serial #: ______
Pt. Initials: ___ ___ ___
European Organization for Research and Treatment of Cancer (EORTC)
Quality of Life Questionnaire (MA.14)
We are interested in some things about you and your health. Please answer all the questions yourself by
circling the number that best applies to you. There are no 'right' or 'wrong' answers. Choose the best
single response that applies to you. The information that you provide is for research purposes and will
remain strictly confidential. The individuals (e.g. doctors, nurses, etc.) directly involved in your care will
not usually see your responses to these questions -- if you wish them to know this information, please bring
it to their attention.
Not
at All
A
Little
Quite
a Bit
Very
Much
1. Did you have any trouble doing strenuous activities,
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2. Did you have any trouble taking a long walk?
1
2
3
4
3. Did you have any trouble taking a short walk outside
of the house?
1
2
3
4
4. Did you need to stay in a bed or a chair during the
day?
1
2
3
4
5. Did you need help with eating, dressing, washing
yourself or using the toilet?
1
2
3
4
6. Were you limited in doing either your work or other
daily activities?
1
2
3
4
7. Were you limited in pursuing your hobbies or other
leisure time activities?
1
2
3
4
8. Were you short of breath?
1
2
3
4
During the past week:
NCIC CTG Trial MA.14
Page 1 of 5
EORTC QLQ-C30+1 (Core 30 Questionnaire © copyright 1992 EORTC Study Group on Quality of Life.
89
All rights reserved.)
Please go on to the next page
L
This box to be completed by the clinical research associate: Pt. Serial #: ______
Pt. Initials: ___ ___ ___
During the past week:
Not
at All
A
Little
Quite
a Bit
Very
Much
9. Have you had pain?
1
2
3
4
10. Did you need to rest?
1
2
3
4
11. Have you had trouble sleeping?
1
2
3
4
12. Have you felt weak?
1
2
3
4
13. Have you lacked appetite?
1
2
3
4
14. Have you felt nauseated?
1
2
3
4
15. Have you vomited?
1
2
3
4
16. Have you been constipated?
1
2
3
4
17. Have you had diarrhea?
1
2
3
4
18. Were you tired?
1
2
3
4
19. Did pain interfere with your daily activities?
1
2
3
4
20. Have you had difficulty in concentrating on things
like reading a newspaper or watching television?
1
2
3
4
21. Did you feel tense?
1
2
3
4
22. Did you worry?
1
2
3
4
NCIC CTG Trial MA.14 EORTC QLQ-C30+1
Page 2 of 5
90
Please go on to the next page
L
This box to be completed by the clinical research associate: Pt. Serial #: ______
Pt. Initials: ___ ___ ___
Not
at All
A
Little
Quite
a Bit
Very
Much
23. Did you feel irritable?
1
2
3
4
24. Did you feel depressed?
1
2
3
4
25. Have you had difficulty remembering things?
1
2
3
4
26. Has your physical condition or medical treatment
interfered with your family life?
1
2
3
4
27. Has your physical condition or medical treatment
interfered with your social activities?
1
2
3
4
28. Has your physical condition or medical treatment
caused you financial difficulties?
1
2
3
4
During the past week:
For the following questions please circle the number between 1 and 7 that best
applies to you.
29. How would you rate your overall physical condition during the past week?
1
Very Poor
2
3
4
5
6
7
Excellent
6
7
Excellent
6
7
Excellent
30. How would you rate your overall health during the past week?
1
Very Poor
2
3
4
5
31. How would you rate your overall quality of life during the past week?
1
Very Poor
2
NCIC CTG Trial MA.14. EORTC QLQ-C30+1
3
4
Page 3 of 5
91
5
Please go on to the next page
L
This box to be completed by the clinical research associate: Pt. Serial #: ______
Pt. Initials: ___ ___ ___
Patients sometimes report that they have the following symptoms. Please indicate the extent to
which you have experienced these symptoms during the past week.
Not
at All
A
Little
Quite
a Bit
Very
Much
32. Did you have pain in your abdomen (stomach or
belly)?
1
2
3
4
33. Did you have bloating of your abdomen?
1
2
3
4
34. Did you have sweating at night?
1
2
3
4
35. Did you have sweating during the day?
1
2
3
4
36. Did you have hot flushes?
1
2
3
4
37. Were you bothered by a vaginal discharge?
1
2
3
4
38. Did you have vaginal bleeding or spotting of
blood?
1
2
3
4
39. Were you bothered by vaginal or genital
dryness?
1
2
3
4
40. Were you bothered by weight gain?
1
2
3
4
41. Did you have headaches?
1
2
3
4
42. Did you have breast tenderness or pain?
1
2
3
4
During the past week:
NCIC CTG Trial MA.14 Study-Specific Checklist
Page 4 of 5
92
Please go on to the next page
L
This box to be completed by the clinical research associate: Pt. Serial #: ______
Pt. Initials: ___ ___ ___
Not
at All
A
Little
Quite
a Bit
Very
Much
43. Did you have pain/tenderness related to the
treatments you were receiving?
1
2
3
4
44. Did you find the treatments you were receiving
inconvenient?
1
2
3
4
45. Did you feel less interested in physical intimacy?
1
2
3
4
46. Have you been sexually active?
1
2
3
4
47. Have you been satisfied with your sexual
functioning?
1
2
3
4
During the past month:
Please check to make sure you have answered all the questions.
Please fill in your initials to indicate that you have completed this questionnaire: ______________
Today's date (Year, Month, Day): ________________________________
Thank you.
NCIC CTG Trial MA.14 Study-Specific Checklist
Page 5 of 5
93
NCIC CTG TRIAL: MA.14
AMENDED: 99-DEC-09
APPENDIX XI - INVESTIGATOR STATEMENT/SIGNATURE PAGE
The ORIGINAL of this page is to be filed in the standard study file Vol. 1.
NOVARTIS PHARMACEUTICALS CANADA INC. MONITOR
_______________________
Print name
_______________________________
Signature
______/______/______
day
month
year
INVESTIGATOR
M centre number
__________
M the study will begin on
______/______/______
day
month
year
M I anticipate my centre recruiting the following number of subjects
__________
M I have received and reviewed the Investigators’ Brochure of
______/______/______
day
month
year
M I have carefully read this protocol and appendices and agree to its terms including principles of
disclosure and confidentiality.
M I agree to submit this protocol to the appropriate Institutional Review Board or Ethics Committee
to obtain its approval prior to initiation of the study.
M I understand that I may be nominated by Novartis Pharmaceuticals Canada Inc. to review and
approve the final study report on behalf of all participating investigators.
_______________________
Print name
_______________________________
Signature
94
______/______/______
day
month
year
APPENDIX XII - STUDY PROTOCOL SIGNATURE PAGE
95
AMENDED: 96-AUG-12
APPENDIX XIII - GLOSSARY
5-FU
AC
AER
ALT
AST
CBC
CEF
CMF
CRA
CRF
CT
ECOG
EORTC QLQ
ER
FDA
FSH
FT4
HgbAlc
HPB
IGF-I
IRB
LAR
LH
MRC
MRI
Mth
NCIC CTG
NCR
NSABP
Octreotide LAR
PO
PR
REB
RNA
SMS
TGF
tid
TSH
WBC
5-fluorouracil
adriamycin/cyclophosphamide
adverse event report
alanine aminotransferase
aspartate aminotransferase
complete blood count
cyclophosphamide/epirubicin/5-fluorouracil
cyclophosphamide/methotrexate/5-fluorouracil
clinical research associate
case report form
computed tomography
Eastern Cooperative Oncology Group
European Organization for Research and Treatment of Cancer:Quality of Life
Questionnaire
estrogen receptor
Food and Drug Administration of the Dept. of Health and Human Services, U.S.
follicle-stimulating hormone
free thyroxine
glycosylated hemoglobin
Health Protection Branch - Dept of Health and Welfare, Canada
insulin-like growth factor I
Institutional Review Board
long acting release
lutenizing hormone
Medical Research Council
magnetic resonance imaging
month
National Cancer Institute of Canada - Clinical Trials Group
no copy required
National Surgical Adjuvant Bowel and Breast Project
SMS 201-995 pa LAR
per os (by mouth)
progesterone receptor
Research Ethics Board
ribonucleic acid
somatostatin
transforming growth factor
three times a day
thyroid-stimulating hormone
white blood count
96