NIHR/Wellcome UCLH Clinical Research Facility
Cancer Trials Portfolio
November 2016
NIHR UCLH Clinical Research Facility News Update
Expanding Immunotherapy Portfolio
Whilst there has been notable success with immunotherapy, there is
a need to improve response rates and increase the
number of patients who benefit. Novel targets and combination strategies are a potential means of this. The combination of
Nivolumab and Ipilimumab, which has proven benefit in melanoma, is undergoing further evaluation in virally driven cancers including
cervix, Merkel cell and head and neck tumours within the BMS CA209358 study. Similarly, the MEDI4736 trial is evaluating the
combination of the anti-PD-L1 antibody, MEDI4736, with Tremelimumab. This is now open for patients with advanced bladder
cancer. The FIH bi-specific antibody targeting PDL1 and TGFb, (Merck) is due to open soon with dose expansion in a number of
tumour sub-types. This is a bi-functional fusion protein that combines anti-PD-L1 antibody and a TGFb ‘trap’ into a single molecule.
TGFb, produced by cancer cells contributes directly to tumour progression and indirectly through the down–regulation of effector Tcells and induction of regulatory T-cells, therefore this compound represents a novel immunotherapy combination strategy.
As with PD-1 up-regulation in cancer cells, T-cell activity is also dampened by other proteins produced by the tumour. Antibodies
against such proteins; T- cell immunoglobulin and mucin domain-3 (TIM3) and lymphocyte activating gene 3 (LAG3) are already in
clinical development as single agents. CA224020 evaluates the combination of Nivolumab with the anti-LAG-3 monoclonal antibody
(BMS-936558) in a variety of tumour types, including a cohort of melanoma and NSCLC patients previously treated with
immunotherapy as well as HCC, renal, head and neck tumours naïve to immunotherapy.
Novel immune pathway agonists, such as OX40 are under development in early phase trials. OX40, found on multiple T-cell subsets
plays a role in the survival of activated T - cells. We have two OX40 antibody studies in the pipeline, a dose expansion study in a
number of tumour sub-types and a FIH dose escalation study.
Abstracts - ESMO 2016, Copenhagen
Clinical Outcomes and Predicting Early Death in Early Phase Trials: The UCLH/NIHR Clinical Research Facility Experience
N.F. Brown, S. Ganguli, A. Kirkwood, G. Imseeh, M. Forster, R. Kristeleit, T.Meyer
We evaluated the outcomes of 296 patients with advanced cancer who commenced treatment on early phase clinical trials in the
CRF between 2009 and 2015. We analysed baseline variables and identified that low serum albumin and sodium were most
predictive of early death (less than 90 days), an important consideration in selecting appropriate patients for early phase trials. The
radiological response rate in those analysed was 13.5%, with median survival of 10.3 months.
The Use of Next Generation Sequencing (NGS) to Guide Patient Selection for Phase 1 Clinical Trials
R.E. Miller, N.F. Brown, A. Speirs, M. Mitchison, H. Shaw, S. Adeleke, P. Gougis, P. Bennett, C. Swanton, T.Meyer, M.D. Forster
and R.S. Kristeleit
Evaluation of patients’ tumours using next generation sequencing (NGS) gene panels is increasingly being utilised in early phase trial
units. Targeting actionable mutations in cancer may increase response rates in Phase I trials. We undertook a pilot study to assess
the feasibility and therapeutic benefit of incorporating NGS screening into the patient pathway in the CRF and performed NGS
profiling in 123 consecutive patients. NGS was successful in 92% of patients. 81% of patients had a detected variant in ≥ 1 gene and
52 (45%) of patients had ≥ 1 potentially actionable mutation. Over this period, 61 patients were enrolled onto a clinical trial of which
21 (34.4%) were genotype directed. Genotype directed trials included AKT, MEK, BRAF and PI3K inhibitor studies. For patients on
NGS directed studies there was an ORR of 29% and a 57% clinical benefit rate. This compares to an ORR of 15% and a clinical
benefit rate of 53% for non-genotype directed trials. This pilot study has demonstrated that NGS is feasible in real time and may
affect clinical outcome in phase 1 trials. We are now looking to utilise a broader NGS panel which includes translocation fusion
proteins.
A First-in-human (FIH) Phase I/II, Dose Escalation, Pharmacokinetic (PK) Study to Assess the Safety and Tolerability of VAL201 in
Patients with Advanced Prostate Cancer (APC) and Other Advanced Solid Tumours
R.S. Kristeleit, R.E. Miller, L. Sellers, N.F. Brown, P. Gougis, A. Boyd, G. Morris, H. Payne, S. Hughes, M.D. Forster and M Linch
We presented to the initial results of the first-in-human dose escalation study of VAL 201, a synthetic decapeptide that inhibits
interaction of the androgen and oestradiol receptors with Src tyrosine kinase, disrupting steroid or epithelial growth factor (EGF)
dependent DNA synthesis. Eight patients with prostate cancer have been recruited to date with escalating doses. No DLTs have
been observed and VAL 201 is well tolerated with mild fatigue and injection site rash the only adverse events to date. Four patients
had an improvement in PSA doubling time and one patient with metastatic castrate resistant prostate cancer had a >30% PSA
response. The MTD has not yet been identified and the study is ongoing.
2
How to Refer a Patient
By post:
NIHR UCLH Clinical Research Facility,
University College London Hospitals NHS Foundation Trust,
UCLH, 4th Floor, 170 Tottenham Court Road,
London, W1T 7HA
By telephone:
Reception:
020344 72929/72930
Reception Fax: 020344 72994
By email:
Name
Email
Mr H Ahmed
[email protected]
Dr J Bridgewater
[email protected]
Prof M Emberton
[email protected]
Dr M Forster
[email protected]
Prof D Hochhauser
[email protected]
Dr R Kristeleit
[email protected]
Prof T Meyer
[email protected]
Dr R Popat
[email protected]
Dr R Roylance
[email protected]
Dr S Strauss
[email protected]
Dr A Wechalekar
[email protected]
Dr M Linch
[email protected]
Dr D Papadatos-Pastos
[email protected]
Trial Portfolio Contents
Gastro-Intestinal
Lung
Gynaecological
Neuroendocrine
Haematology
Sarcoma
Head and Neck
Solid Tumours
Hepatobiliary
Urology
3
Gastro-Intestinal
Drug Class / PI / Status
Description
First in class nucleotide analogue
(ProTide)
A phase Ib, multi-centre, open-label study of a first-in-class
nucleotide analogue Acelarin (NUC-1031) in combination with
cisplatin in patients with locally advanced/metastatic biliary
tract cancers
PI: Dr John Bridgewater
Status: In set-up (planned opening Nov 16)
Anti-VEGF
PI: Dr John Bridgewater
Status: Open to recruitment
Stratified –multi-agent
PI: Dr John Bridgewater
Status: Open to recruitment
Inhibitor of EGFR, ERBB2 and ERBB3
PI: Prof Daniel Hochhauser
Status: Open to recruitment
A phase I/II dose finding study evaluating the safety and
tolerability of Capecitabine and Afilbercept in patients with
unresectable metastatic colorectal cancer deemed unsuitable
for double/ triplet chemotherapy
FOCUS-4: Molecular selection of therapy in metastatic
colorectal cancer: a molecularly stratified randomised
controlled trial programme
AZD8931, an inhibitor of EGFR, ERBB2 and ERBB3
signalling, in combination with FOLFIRI: A phase I/II study to
determine the importance of schedule and activity in colorectal
cancer
Gynaecological
Drug Class / PI / Status
Description
PARP inhibitor + anti-PD-L1 Ab
A phase ib combination study of Rucaparib (CO-338) and
Atezolizumab (MPDL3280a) in patients with solid
tumours and advanced gynecologic cancers, with a focus
on ovarian cancer
PI: Rebecca Kristeleit
Status: In set-up
4
Haematology
Drug Class / PI / Status
Description
Bcl2 inhibitor
Phase I dose-escalation study of oral administration of the
selective Bcl2 inhibitor S 55746 in patients with refractory or
relapsed chronic lymphocytic leukaemia and B-Cell nonHodgkin lymphoma
PI: Dr Rakesh Popat
Status: In set-up
PI3K inhibitor + proteasome inhibitor
PI: Dr Rakesh Popat
Status: Open to recruitment
CRL4 Cereblon E3 Ubiquitin Ligase
Modulator
PI: DR Rakesh Popat
Status: In set-up (planned opening Nov 16)
Anti-PD-L1
PI: Dr Rakesh Popat
Phase Ib study of Buparlisib with Bortezomib in defined
genetic subgroups of patients with relapsed or refractory
multiple myeloma
A phase Ib/IIa multicentre, open-label, dose-escalation study
to determine the maximum tolerated dose, assess the safety
and tolerability, pharmacokinetics and preliminary efficacy of
CRL4 Cereblon E3 ubiquitin ligase modulator monotherapy
and in combination with dexamethasone in subjects with
relapsed and refractory Multiple Myeloma
A phase I pharmacokinetic, pharmacodynamic study of
Avelumab in patients with previously treated advanced stage
classical Hodgkin’s lymphoma
Status: open to recruitment
DTP3 Protein
PI: Dr Ashutosh Wechaleckar
Status: open to recruitment
SYK inhibitor
PI: Dr Rakesh Popat
Status: Open to recruitment
PI3K and mTOR inhibitor
PI: Dr Rakesh Popat
A phase I/II dose escalation, and subsequent cohort
expansion study of safety, tolerability, pharmacokinetics,
pharmacodynamics and preliminary clinical efficacy of
intravenous DTP3 in patients with R/R Multiple Myeloma
An open-label, dose escalation, phase I, first-in-human study
of TAK-659 in adult patients with advanced solid tumour and
lymphoma malignancies
Phase I study of oral PQR309 in patients with relapsed or
refractory Lymphomas
Status: Open to recruitment
IL3-receptor
PI: Dr Rakesh Popat
Status: Open to recruitment
5
FiM Anti-IL-3Ra (CD123) mAb; fully human IgG1 for patients
with previously untreated AML, relapsed/refractory AML,
relapsed/refractory MDS or MDS who are not candidates to
receive a hypomethylating agent
Haematology continued
Drug Class / PI / Status
Description
Humanized IgG1 antibody drug conjugate
(ADC)
A phase I open-label, dose escalation study to investigate the
safety, pharmocokinetics, pharmacodynamics, immunogenicity
and clinical activity of the antibody drug conjugate
GSK2857916 in subjects with relapsed/refractory multiple
myeloma and other advanced hematologic malignancies
expressing BCMA
PI: Dr Rakesh Popat
Status: Open to recruitment
BTK Inhibitor
PI: Dr Rakesh Popat
Status: In set-up
Phase I/II, first in human, dose escalation trial of the Bruton’s
tyrosine kinase inhibitor M7583 in patients with relapsed/
refractory B cell malignancies and expansion cohorts in
patients with mantle cell lymphoma and diffuse large B cell
lymphoma (ABC subtype) that have progressed after at least 1
but not more than 3 prior lines of therapy
Hepatobiliary
Drug Class / PI / Status
Description
FGFR4 inhibitor
A phase I study to assess the safety, tolerability,
pharmacokinetics, pharmacodynamics and preliminary efficacy
of BLU-554 in patients with hepatocellular carcinoma and
cholangiocarcinoma
PI: Prof Tim Meyer
Status: Open to recruitment
Small activating RNA (saRNA)
PI: Prof Tim Meyer
Status: Open to recruitment
HDACi
PI: Prof Tim Meyer
Status: Open to recruitment
6
Phase I clinical study with RNA oligonucleotide drug MTLCEBPA to investigate its safety and tolerability and to ascertain
whether MTL-CEBPA mediated up-regulation of CEBPA gene
expression is associated with increase in serum albumin in
patients with advanced hepatocellular carcinoma or patients
presenting with secondary liver tumours derived from extra
hepatic primary cancer types.
A phase I/II dose escalation trial of HDAC inhibitor Tefinostat
(CHR- 2845) for cancer associated inflammation in
hepatocellular carcinoma
Breast
Drug Class / PI / Status
Description
Fulvestrant, Neratinib + Fulvestrant,
AZD5363 + Fulvestrant or AZD5363
A multiple parallel cohort, open-label, multi-centre phase IIa
clinical trial aiming to provide proof of principle efficacy for
designated targeted therapies in patients with advanced breast
cancer where the targetable mutation is identified through
ctDNA screening
PI: Dr Rebecca Roylance
Status: In set-up
BET inhibitor + Fulvestrant
PI: Dr Rebecca Roylance
Status: In set-up
A phase I/II dose escalation and expansion study to
investigate the safety, pharmacokinetics, pharmacodynamics
and clinical activity of GSK525762 in combination with
Fulvestrant in subjects with ER+ breast cancer
Head and Neck
Drug Class / PI / Status
Description
PARP-1 inhibitor
A phase I study of Olaparib in addition to Cisplatin-based
concurrent chemoradiotherapy for patients with high risk locally
advanced squamous cell carcinoma of the head and neck
(HNSCC)
PI: Dr Martin Forster
Status: Open to recruitment
Sarcoma
Drug Class / PI / Status
Description
PARP-1 inhibitor
A phase I study of a combination of the PARP inhibitor, Niraparib
and Temozolomide or Irinotecan in patients with previously
treated, incurable Ewing Sarcoma
PI: Dr Sandra Strauss
Status: In set-up (planned opening Nov 16)
Lung
Drug Class / PI / Status
Description
Second Generation Hypo-Methylating
Agent
HyPeR: A phase I, dose escalation study of Guadecitabine (SGI110) a second generation hypo-methylating agent in combination
with Pembrolizumab (MK3475) in patients with refractory solid
tumours
PI: Dr Dionysis Papadatos-Pastos
Status: In set-up
7
Solid Tumours
Drug Class / PI / Status
Description
mAb that specifically binds to LAG3
A phase I/IIa dose escalation and cohort expansion study of
safety, tolerability, and efficacy of anti-LAG-3 monoclonal
antibody in advanced solid tumours.
PI: Dr Martin Forster
Status: In Set-Up
mAb that specifically binds OX40
PI: Dr Martin Forster
Status: In set-up
Anti-PD-L1
PI: Dr Martin Forster
Status: In set-up
Autologous γδ T Lymphocyte Therapy
PI: Dr Rebecca Kristeleit
Status: In set-up (planned opening Nov 16)
Small molecule
PI: Dr Rebecca Kristeleit
A phase I study to evaluate the safety, tolerability,
pharmacokinetics, pharmacodynamics and preliminary clinical
activity of mAb that specifically binds OX40 in adult subjects
with selected advanced solids tumours
A phase I, open-label, multiple-ascending dose trial to
investigate the safety, tolerability, pharmacokinetics, biological
and clinical activity of anti-PD-L1 in subjects with metastatic or
locally advanced solid tumours and expansion to selected
indications
An adaptive study of the safety, tolerability and efficacy of
autologous γδ T Lymphocyte therapy in patients with
advanced cancers which are refractory to current treatment or
who have indolent disease for which immunotherapy may be
beneficial
A multicentre phase II clinical trial of Lurbinectedin in selected
advanced solid tumours.
Status: Open to recruitment
PI3K Inhibitor
PI: Dr Mark Linch
Status: Open to recruitment
8
A phase I, open-label, multicentre study to assess the safety,
tolerability, pharmacokinetics, pharmacodynamics and
preliminary anti-tumour activity of AZD8186 in patients with
advanced castration-resistant prostate cancer (CRPC),
squamous non-small cell lung cancer (sqNSCLC), triple
negative breast cancer (TNBC) and patients with known PTEN
-deficient/mutated or PIK3CB mutated/amplified advanced
solid malignancies, as monotherapy and in combination with
Abiraterone Acetate or AZD2014
Solid Tumours continued
Drug Class / PI / Status
Description
BET Inhibitor
A phase I//IIa trial with BMS986158, a small molecule inhibitor
of the Bromodomain and Extra-Terminal (BET) proteins in
subjects with selected advanced solid tumours.
PI: Dr Rebecca Roylance
Status In-Set Up
IDH1 Inhibitor
PI: Dr Sandra Strauss
Status: In Set-Up
Anti-PD-L1 Ab in combination with antiCTLA-4
PI: Dr Rebecca Kristeleit
An open-label, non-randomised, multicentre phase I study to
determine the maximum tolerated or recommended phase II
dose of oral mutant IDH1 inhibitor and to characterise its
safety, tolerability, pharmacokinetics and preliminary
pharmacodynamic and anti-tumour activity in patients with
IDH1-R132X-mutant advanced solid tumours
A Phase I Study of Anti-PD-L1 antibody in combination with
Tremelimumab (Anti-CTLA-4 Antibody) in subjects with
advanced solid tumours
Status: open to recruitment
Biologic Drug Conjugate
PI: Prof Tim Meyer
Status: In set-up
Inhibitor of FGFR-1, 2 and 3
PI: Dr John Bridgewater
A phase I/IIa, open-label multicentre study to assess the
safety, tolerability, pharmacokinetics, and preliminary
antitumor activity of a biologic drug conjugate in patients with
somatostatin receptor 2 expressing advanced cancers,
including gastroenteropancreatic or lung or thymus or other
neuroendocrine tumours or small cell lung cancer or large cell
neuroendocrine carcinoma of the lung
Proof-of-concept biomarker study of AZD4547 in patients with
FGFR dysregulated tumours
Status: Open to recruitment
ATR kinase inhibitor
PI: Dr Martin Forster
Status: Open to recruitment
PI3K and mTOR inhibitor + chemotherapy
PI: Dr Rebecca Kristeleit
Status: Open to recruitment (Triple negative
breast, NSCLC and Bladder only)
9
A phase I study to assess the tolerability, safety and biological
effects of a specific Ataxia Telangiectasia and Rad3-related
(ATR) inhibitor (AZD6738) as a single agent and in
combination with palliative radiation therapy in patients with
solid tumours
A multi-arm safety and tolerability study of investigational
medication in combination with other anti-tumour agents
Solid Tumours continued
Drug Class / PI / Status
Description
Receptor tyrosine kinase
An open-label, phase II study of Neratinib in patients with solid
tumours with somatic human epidermal growth factor receptor
(EGFR, HER2, HER3) mutations or EGFR gene amplification
PI: Prof Tim Meyer
Status: Open to recruitment
MEK and mTOR kinase inhibitor
PI: Dr Martin Forster
A Phase Ib/IIa study of AZD2014 in combination with
Selumetinib in patients with advanced cancers
Status: Open to recruitment
Anti-PD-1
PI: Prof Tim Meyer
Status: Open to recruitment
Immunotherapeutic peptide
PI: Dr Rebecca Kristeleit
Status: Open to recruitment
PARP inhibitor (PARP-1, -2, -3)
PI: Dr Rebecca Kristeleit
Status: Open to recruitment
AR or ER inhibitor
PI: Dr Rebecca Kristeleit
Status: Open to recruitment
ADC targeting HuMax-TF
PI: Dr Martin Forster
Status: Open to recruitment
FGFR/VEGFR inhibitor
PI: Dr Rebecca Kristeleit
Status: In set-up
10
Non-comparative, two-cohort, single-arm, open-label, phase I/
II study of Nivolumab (BMS-936558) in subjects with viruspositive and virus-negative solid tumours
A phase I, open-label, multi-centre, multi-dose, dose
escalation study of LTX-315 in patients with transdermally
accessible tumours
A phase I multi-centre trial of the combination of Olaparib
(PARP inhibitor) and AZD5363 (AKT inhibitor) in patients with
advanced solid tumours
A phase I/II, dose escalation study to assess the safety and
tolerability of VAL201 in patients with locally advanced or
metastatic prostate cancer and other advanced solid tumours
First-in-human, dose-escalating safety study of tissue factor
specific antibody drug conjugate (HuMax®-TF-ADC) in
patients with locally advanced and/or metastatic solid tumours
known to express tissue factor
Safety and tolerability of single and repeated doses of an
FGFR/VEGFR inhibitor, open-label, non-randomized,
uncontrolled, dose escalation, multicentre, first-in-human study
in subjects with advanced solid tumours
Solid Tumours continued
Drug Class / PI / Status
Description
TRK Inhibitor
A phase II basket study of the oral TRK inhibitor LOXO-101 in
subjects with NTRK fusion-positive tumours
PI: Martin Forster
Status: In set-up
Anti folate receptor-α Ab
PI: Rebecca Kristeleit
Phase I study of MOv18 IgE, a first in class chimeric IgE
antibody against folate receptor-α, in patients with advanced
solid tumours
Status: In set-up
Anti PD-L1
PI: Rebecca Kristeleit
Status: In set-up
A phase I dose escalation and cohort expansion study of an
anti-PD-1 monoclonal antibody, in patients with advanced solid
tumours
Urology
Drug Class / PI / Status
Description
n/a
FORECAST
PI: Mr Hashim Ahmed
FOcal RECurrent Assessment and Salvage Treatment
Status: Open to recruitment
An evaluation of a novel imaging based complex diagnostic
and therapeutic pathway intervention for men who fail
radiotherapy for prostate cancer
n/a
A multicentre prospective single arm intervention trial
evaluating focal therapy using high intensity focused
ultrasound (Sonablate 500) for localised prostate cancer
PI: Prof Mark Emberton
Status: Open to recruitment
Anti-androgen 10-amino acid peptide
PI: Dr Rebecca Kristeleit
Status: Open to recruitment (Prostate only)
11
A phase I/II, dose escalation study to assess the safety and
tolerability of VAL201 in patients with locally advanced or
metastatic prostate cancer and other advanced solid tumours
NIHR UCLH Clinical Research Facility,
University College London Hospitals NHS Foundation Trust,
UCLH, 4th Floor, 170 Tottenham Court Road,
London, W1T 7HA
Reception Number: 020344 72929/72930
Reception Fax Number : 020344 72994
Email: [email protected]
www.uclhospitals.brc.nihr.ac.uk/crf