Phase 1 study of CB-839, a first-in-class, glutaminase inhibitor in patients with multiple myeloma and lymphoma
Dan T. Vogl, MD1, Jonathan L. Kauffman, MD2, Anas Younes, MD3, Keith Stewart, MD4, Keith W. Orford, MD, PhD5, Mark Bennett, PhD5, David S Siegel, MD, PhD6 and Jesus G. Berdeja, MD7
Cancer Center of the University of Pennsylvania, Philadelphia, PA; 2Winship Cancer Institute, Emory University, Atlanta, GA 3Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY; 4Mayo Clinic Arizona, Scottsdale, AZ;
5Calithera Biosciences, South San Francisco, CA; 6Hackensack University Medical Center, John Theurer Cancer Center, Hackensack, NJ; 7Sarah Cannon Research Institute, Nashville, TN
METHODS (continued)
Pyruvate
Lactate
Lactate
Mitochondrion
TCA
Cycle
Mitochondrion
TCA
Cycle
α-KG
Glutamate
α-KG
Glutamate
Glutaminase
Glutaminase
Glutathione
Biosynthetic
intermediates
CB-839
GLUTAMINE
GLUTAMINE
METHODS
Study Design
• Phase 1 dose escalation study of CB-839 in patients with multiple myeloma and other
hematological tumors.
• Monotherapy: Accelerated titration dose escalation design with 3 week cycle length
• Combinations: standard 3+3 design with low-dose dexamethasone (see below) with or
without standard pomalidomide regimen (4mg QD on 21 of 28 days)
• Expansion Cohorts planned in defined patient populations
CX-839-003 Study Design
Monotherapy
dose escalation
Combination
dose escalations
+ Pom/Dex
Patients:
• R/R multiple
myeloma
• B-cell NHL
Doses: 100-600
mg po
Regimens:
• TID
• BID fed
+ Dex
Combination
expansion cohorts
Pom/Dex combo
Patients: R/R after prior pom/dex
with low chance of
response to pom/dex alone
• Currently progressing on pom/dex
(“add-on”)
OR
• No better than SD to prior pom/dex
STUDY STATUS
• 23 patients (14 monotherapy, 9 combinations) had data in the clinical database (as of
Nov 9, 2015)
• Cohort Status
– Monotherapy cohort – COMPLETE
– Dex alone combo cohort – ONGOING
– Pom/Dex combo cohort – ONGOING
• An MTD has not been established for monotherapy or combinations
– Monotherapy dose levels up to 800mg QD have been demonstrated to be safe and well
tolerated
Dosing
Regimen
Study
TID: N=11 (6 MM, 4 FL, 1 DLBCL)
CB-839 + Pom/ Dex
Dose level
100 mg
1
CB-839 Dose
200 mg
1
400 mg BID
250 mg
3
400 mg
6
Dose Level
600 mg
#
4
CB-839 + Dex
BID fed: N=3 (MM only)
CB-839 Dose
#
400 mg BID
5
#
3
CX-839001
CX-839002
C1D15 PK Parameter:
Mean (±SD)
Daily dose
Dosing
(mg)
interval (hr)
Cmin
Cmax
AUC0-8h
(ng/mL)
(ng/mL)
(ng*hr/mL)
1800
~8
495
(±390)
1565
(±922)
7344
(±4058)
600 mg BID fed
(N=23)
1200
~12
457
(±335)
1476
(±676)
7416
(±3757)
600 mg BID fed
(N=3)
1200
~12
725
(±590)
1559
(±960)
9970
(±6748)
PHARMACODYNAMICS
• Strong GLS inhibition was demonstrated in platelets in data from myeloma/lymphoma
patients (CX-839-002) and solid tumor patents (CX-839-0017,8)
– GLS inhibition was measured in platelets 4 hr after dosing on C1D1
– Cmin concentrations with 600 mg BID fed regimen maintain exposures (≥ 200 ng/mL)
that should provide ≥90% inhibition of GLS in most patients
Characteristic
+Pom/Dex
N=4
+Dex
N=5
Age: median
(range)
62
(45 — 84)
69
(32—72)
71
(64—74)
2 (50%)/
2 (50%)
3 (60%)/
2 (40%)
Design: Single arm Simon 2-stage
Endpoint: Overall response rate
Female/Male: N (%)
Doses: 400-600
mg po
Dex only combo
Patients: R/R following at least 2
prior lines
Design: As for pom/dex cohort
Endpoint: Overall response rate
Median (range)
Number of lines of
prior systemic
4-10 regimens: N (%)
therapy
>10 regimens: N (%)
7 (2 — 16)
8 (2 — 15)
4 (3 — 8)
6 (43%)
4 (29%)
1 (25%)
2 (50%)
1 (20%)
2 (40%)
ECOG >1: N (%)
8 (57%)
4 (100%)
4 (80%)
M M _4 0 0 _B ID
M M _4 0 0 _B ID
M M _4 0 0 _B ID
M M _4 0 0 _B ID
M M _4 0 0 _B ID
M M _6 0 0 _B ID
M M _2 0 0 _TID
M M _1 0 0 _TID
F L_2 5 0 _TID
F L_2 5 0 _TID
F L_4 0 0 _TID
M M _6 0 0 _B ID
M M _4 0 0 _TID
M M _4 0 0 _TID
M M _6 0 0 _B ID
M M _4 0 0 _TID
F L_4 0 0 _TID
M M _2 5 0 _TID
D LB C L_4 0 0 _TID
P o m / D e x - o n stu d y
P o m /D e x - o ff stu d y
D e x - o n stu d y
D e x - o ff stu d y
M o n o th e ra p y - o n stu d y
M o n o th e ra p y - o ff stu d y
0
1
2
3
4
5
U r in e M - S p ik e
p la t e le t s fr o m C X -8 3 9 -0 0 2 s t u d y
60
p la t e le t s f r o m ( C X - 8 3 9 - 0 0 1 ) s o lid t u m o r s t u d y
40
e x v iv o p la t e le t d o s e r e s p o n s e
8000
6000
4000
2000
0
-1 5 0 -1 0 0 -5 0
20
10
100
1000
W eek 20
[C B - 8 3 9 @ 4 h ] ( n g / m L )
• Most AE’s have been Gr1 events, including cytopenias, GI events, and fatigue.
• 21.4% (3/14) of pts experienced a total of 5 Gr3 AEs suspected to be related to CB-839
– 4 of 5 Gr3/4 events were hematologic cytopenias (3 thrombocytopenia and 1
anemia), events that were not observed in the CX-839-001 solid tumor Ph1 study
• No patients discontinued due to an AE
• Development of Pom/Dex and Dex-only combinations are underway
– One DLT of Gr4 neutropenia, which was considered possibly related to CB-839, has
occurred in the Pom/Dex combination
MedDRA Preferred Term
Patients with any AE
Anemia
Fatigue
Nausea
Thrombocytopenia
Vomiting
Constipation
Epistaxis
Headache
All AEs (N=14)
Total
Drug Related
14 (100)
10 (71)
5 (36)
2 (14)
5 (36)
4 (29)
5 (36)
4 (29)
5 (36)
3 (21)
4 (29)
2 (14)
3 (21)
1 (7.1)
Myalgia
57th American Society of Hematology Annual Meeting & Exposition, December 5-8, 2015, Orlando, Florida
3 (21)
3 (21)
3 (21)
0
1 (7.1)
1 (7.1)
≥Gr3 AEs (N=14)
Total
Drug Related
6 (43)
3 (21)
3 (21)
1 (7.1)
1 (7.1)
0
0
0
5 (36)
3 (21)
0
0
0
0
0
0
0
0
50
3000
2000
1000
0
-1 5 0 -1 0 0 -5 0
100 150
S tu d y D a y
T im e p o in t : 4 h a f t e r f ir s t d o s e o n C 1 D 1
LLOQ
7
K a p p a L ig h t C h a in
10000
80
6
T im e o n S t u d y (M o n t h s )
100
All Adverse Events in ≥ 3 Patients on Monotherapy
Monotherapy
N=14
M M _4 0 0 _B ID
M M _4 0 0 _B ID
M M _4 0 0 _B ID
M M _4 0 0 _B ID
Serum and Urine Markers Decrease in Patient Receiving Pom/Dex Combo
Platelet and PBMC Pharmacodynamics
Baseline Characteristics
6 (43%)/
8 (57%)
(N = 5 ) (N = 2 8 )
SAFETY AND TOLERABILITY
#
Treatment Duration
Fed
600 mg TID (N=5)
1
Patients: Multiple
myeloma
Regimen: BID fed
PK Parameters on Fed vs Fasted
Schedules
0
002 MM Combination Cohorts (N=9)
F a ste d
D is e a s e _ D o s e (m g )_ S c h e d u le
Enrollment Summary
002 Single Agent Cohorts (N=14)
0
K a p p a L C (m g / d L )
Pyruvate
5000
Dex
Cancer
Cell
10000
(m g / 2 4 h r s )
Normal
Cell
First dose at 600 mg
fed vs. fasted (from solid
tumor study CX-839-0017,8)
• In the monotherapy cohorts (n=14), best response was SD for 7 patients and PD for 6
patients.
• 3 of 14 monotherapy patients remained on study >3 months.
• One patient on the 600mg BID fed regimen has remained on study for >7 months
with stable disease.
• First patient to receive the Pom/Dex combination had a clinically significant reduction
in myeloma markers, including serum free light chain and urine M-protein
+D ex
GLUCOSE
Study Treatment
• Oral CB-839 administered in 21-day cycles using one of two regimens:
– TID: Three times daily (upon waking, at ~3 pm and at bedtime)
– BID fed: Two times daily with meals
• Combinations
– Oral Dex dosed weekly (40mg for <75yo; 20mg for >75 yo) in 4 week cycle
– Oral Pom (4mg) dosed daily for 3 weeks of each 4 week cycle
Pharmacokinetics (PK), Pharmacodynamics (PDn) and Efficacy Assessments
• PK: Serum CB-839 measured on Cycle 1/Day 1 (C1D1) and C1D15
• PDn: Blood draws for collection of platelets on C1D1 predose and at 4 hr
– PDn data were analyzed together with PDn data from concurrent solid tumor Ph1
study (CX-839-0017)
• Efficacy: Serum/urine M-protein and serum free light chain measured with each cycle.
Bone marrow evaluated as clinically indicated
Exposure with Food
M o n o th e ra p y
GLUCOSE
• CB-839 PK was evaluated most extensively in parallel Ph1
study (CX-839-0017,8)
• CB-839 has good PK properties in cancer patients
⁻ Half-life ~4 hr
⁻ Exposure generally increases with dose
• Dosing with food enabled switch to BID dosing regimen
⁻ Increased exposure with fed regimen8
⁻ Similar Cmax and Cmin with BID fed vs. TID regimen
• Similar exposure was achieved in myeloma pts receiving
600mg BID fed (n=3)
Key Inclusion Criteria
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
• Measurable disease
Key Exclusion Criteria
• Active GVHD, prior auto-SCT within 60 days or allo-SCT/DLI within 90 days
• Adequate renal function
̶ NHL patients: CrCl >60 mL/min or serum creatinine <1.5x ULN
̶ MM patients: CrCl >30 mL/min or serum creatinine <3x ULN
• Adequate hematological function
̶ NHL patients: ANC > 1000/mm3, Hb > 8g/dL, platelets > 100,000/mm3
̶ MM patients: ANC > 1000/mm3, platelets > 50,000/mm3
+Pom /
Altered Glucose and Glutamine Metabolism of Cancer Cells
CLINICAL OUTCOMES
U r in e M - S p ik e
• Glutamine is required for the growth and survival of many tumor
• Glutaminase (GLS) controls the formation of glutamate , which is used to generate TCA
cycle intermediates, synthesize glutathione, generate NADPH and maintain redox
balance, and synthesize anabolic building blocks, including nucleotides and fatty acids
• CB-839 is a highly selective, reversible, allosteric inhibitor of glutaminase3
• CB-839 has broad preclinical in vitro and in vivo anti-tumor activity in solid and
hematologic malignancies3,4,5,6 preclinical studies demonstrate significant activity
against multiple myeloma (MM) models as a monotherapy and in combination with
pomalidomide
• CX-839-002 (ClinicalTrials.gov: NCT02071888) is a Phase 1 clinical trial of CB-839 in
patients with multiple myeloma and other hematological tumors.
types1,2
PHARMACOKINETICS
A U C 0 - 8 h (n g * h r / m L )
BACKGROUND AND RATIONALE
% G lu t a m in a s e A c t iv it y
1Abramson
0
0
0
0
50
100 150
S tu d y D a y
8 6 % R e d u c t io n
9 0 % R e d u c t io n
in U r in e M - S p ik e
in K a p p a L ig h t C h a in
Myeloma labs in heavily pretreated patient with receiving CB-839 combined with
Pom/Dex. 67 year-old male with long-standing IgG kappa light chain myeloma.
Since diagnosis in 2008, the patient received 10 prior lines of therapy, including 3
proteasome inhibitor-containing lines and 2 “IMID”-containing lines. The disease
became refractory to both lines of Imid-containing therapy. The patient had not
received a prior pomalidomide-containing regimen.
SUMMARY AND CONCLUSIONS
• Single agent CB-839 is well tolerated in advanced multiple myeloma and lymphoma
patients
– Evaluation of safety and clinical efficacy in combination with
pomalidomide/dexamethasone is ongoing
• Robust inhibition of GLS is demonstrated in platelets
• BID dosing with meals provides optimal PK and safety profile
• Preliminary evidence of clinical activity was demonstrated in combination with
pomalidomide/dexamethasone in a heavily pre-treated myeloma patient.
REFERENCES
1. Wise and Thompson (2010) Trends Biochem Sci
35:427
2. DeBerardinis and Cheng (2010) Oncogene 29:313
3. Gross et al. (2014) Mol Cancer Ther 13:890
4. Parlati et al. (2014) Blood 124:4720
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8.
MacKinnon et al. (2014) Blood 124:3429
Matre et al. (2014) Blood 124:3763
Harding et al. (2015) JCO 33 (suppl):abstr 2512
Meric-Bernstam et al. (2015) AACR-NCI-EORTC
Conference; abstr: C49