A Multi-Center Phase I/II Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory

Multiple Myeloma

Jatin J. Shah, MD1, Edward A. Stadtmauer, MD2, Rafat Abonour, MD3, Adam D. Cohen, MD4, William I. Bensinger, MD5, Cristina Gasparetto, MD6, Jonathan L. Kaufman, MD7,

Suzanne Lentzsch, MD8, Dan T. Vogl, MD2, Robert Z. Orlowski, MD, PhD1, Erica L. Kim, MPH9, Natalia Bialas10, David D. Smith, PhD10, Brian G.M. Durie, MD11

1MD Anderson Cancer Center, Houston, TX, USA

2University of Pennsylvania Abramson Cancer Center, Philadelphia, PA, USA 3Indiana University Simon Cancer Center, Indianapolis, IN, USA

4Fox Chase Cancer Center, Philadelphia, PA, USA 5Fred Hutchinson Cancer Research Center, Seattle, WA, USA

6Duke University Medical Center, Durham, NC, USA 7Winship Cancer Institute of Emory University, Atlanta, GA, USA

8Columbia University Herbert Irving Comprehensive Cancer Center, NY, NY, USA 9Academic Myeloma Consortium, Criterium, Inc., Culver City, CA & Saratoga Springs, NY, USA

10Cedars Sinai Samuel Oschin Cancer Center, Los Angeles, CA, USA

Academic Myeloma Consortium (AMyC)

PI Disclosures

Research Funding: Onyx, Celgene, Novartis, Array Biopharma, Millennium Speaking : None Advisory Board: Onyx, Celgene, Array

Background • Carfilzomib, a novel irreversible proteasome inhibitor, has demonstrated

single-agent activity in relapsed and refractory multiple myeloma (RRMM), and has received FDA regulatory approval for this indication1

– In the pivotal phase II study, single-agent carfilzomib resulted in an ORR of 23.7%, a median DOR of 7.8 months, a median PFS of 3.7 months, and a median OS of 15.6 months1,2

• Pomalidomide is the third drug in the immunomodulatory agent (IMiD®) class, also with single-agent activity that has recently received FDA regulatory approval for patients with RRMM3

– In the pivotal phase II study, treatment with pomalidomide/low-dose dexamethasone resulted in an ORR of 29.2%, a median DOR of 7.4 months, a median PFS of 4.6 months, and a median OS of 14.9 months3,4

1. Kyprolis® [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2013.

2. Siegel, et al. Blood. 2012 Oct 4;120(14):2817-25. 3. Pomylast®[package insert]. Summit, NJ: Celgene Corporation; 2013. 4. Lelev, et al. Blood. 2013 121:1968-75.

Background (continued)

• Preclinical and clinical data demonstrate that the combination of proteasome inhibitors and IMiDs can overcome resistance and improve response rates1−5

• The hypothesis is that the combination of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) would be highly active in RRMM

• Phase I data presented at ASH 2012 identified the maximum tolerated dose (MTD) of carfilzomib (27 mg/m2), pomalidomide (4 mg), and dexamethasone (40 mg) in heavily treated RRMM with a median of 6 lines of prior therapy6

1. Mitsiades N, et al. Blood. 2002;99:4525-30. 2. Hideshima T, et al. Blood 2002:96:2943–2950. 3. Richardson PG, et al. Blood. 2010;116:679-86. 4. Richardson PG, et al. J Clin Oncol. 2009;27:5713-9. 5. Wang M, et al. Blood. 2013;122:3122-8. 6. Shah, J, et al. 2012. ASH Annual Meeting Abstracts 120(21): 74-.

Phase I MTD

• Cohort level 1 (carfilzomib 27 mg/m2, pomalidomide 4 mg, dexamethasone 40 mg): 1 of 6 patients experienced a dose-limiting toxicity (DLT) of febrile neutropenia

• Cohort level 2 (carfilzomib 36 mg/m2, pomalidomide 4 mg, dexamethasone 40 mg): 2 of 6 patients experienced DLTs consisting of grade 4 thrombocytopenia and grade 3 rash

• The MTD was established as carfilzomib 27 mg/m2, pomalidomide 4 mg, dexamethasone 40 mg

Primary Objectives: • To evaluate the overall response rate (ORR) of

Car-Pom-d • Safety

Secondary Objectives: • Duration of response (DOR) • Time to progression • Progression-free survival (PFS) • Time to next therapy • Overall survival

Phase II Study Objectives

Study Design • Phase II portion: planned enrollment of 82 efficacy-

evaluable patients – The study was designed to detect an improvement in

response rate from 35% to 50% with 81% power and a Type I error rate of 0.05

– Simon’s optimal two-stage design: • First stage: 27 patients enrolled (11/27 responses

needed) • Second stage: 55 additional patients enrolled for a

total of 82 efficacy-evaluable patients

Treatment Schema

1 2 8 9 15 16

1 8 15 22

1 21

Carfilzomib

Pomalidomide

Dexamethasone

Cycles 1–6: 28-day cycle

• Concomitant medications: − Anti-viral therapy − Anticoagulation: aspirin 81 mg; LMWH in aspirin-intolerant patients

• Cycles 7+ : maintenance cycles

− Carfilzomib dosed on days 1, 2, 15, 16 − Pomalidomide/dexamethasone were unchanged

• Patients treated until progressive disease or unacceptable toxicity

• Carfilzomib dose on days 1 and 2 of cycle 1 was 20 mg/m2; escalated to 27 mg/m2

starting on day 8 of cycle 1 • Carfilzomib was infused over 30 minutes

Key Inclusion Criteria • Relapsed and/or refractory multiple myeloma

• All patients must have received prior lenalidomide therapy and have been determined to be refractory

– Refractory defined as ≤ 25% response or progression during therapy or within 60 days after completion of a regimen

– Patients must have had full or maximally tolerated dose of lenalidomide administered for a minimum of at least two completed cycles of therapy

• Measurable disease

• ECOG 0−2

• Adequate hematologic, renal, liver, and cardiac function

Patient Demographics

Characteristic N=79 Sex, n (%)

Male Female

50 (63%) 29 (37%)

ECOG performance status, n (%) 0 1 2

35 (44%) 39 (49%) 5 (6%)

Median age, years (range) 64 years (41–78)

Number of prior regimens, median (range) 5 (1–12)

Median time since initial diagnosis, years (range) 4.9 years (1.2 –23)

Prior Therapies Received

* Five patients did not have complete prior therapy data available ** Includes multiple bortezomib combinations **29 of 32 (91%) patients in the phase I portion were bortezomib-refractory

Therapy, n (%)

Prior stem cell transplant 44/74* (59%)

Prior bortezomib** 66/74* (89%)

Prior lenalidomide Lenalidomide-refractory

79/79 (100%) 79/79 (100%)

Baseline FISH/Cytogenetics

FISH/Cytogenetics, n (%) N=79*

Del(13) by FISH 34%

Hyperdiploid 32%

Del(17p) / p53 22%

t(11;14) 21%

Hypodiploid 11%

t(4;14) 10%

Del(1) 9%

t(14;16) 7%

Del(13) / RB locus 6%

*Up to N=79, or as many cytogenetics tests that were reported

mSMART risk

stratification, n (%) N=75**

High risk 18 (24%)

Intermediate risk 19 (25%)

Low risk 38 (51%)

**4 patients did not have complete FISH/cytogenetics data

Treatment-Related Hematologic Adverse Events (N=79)

• Toxicities were generally reversible and manageable

Adverse event Grade 1,

n Grade 2,

n Grade 3,

n Grade 4,

n All grades,

n (%)

Neutropenia 0 4 17 6 27 (34%)

Anemia 1 10 13 1 25 (32%)

Thrombocytopenia 4 7 6 5 22 (28%)

Febrile neutropenia 0 0 3 0 3 (4%)

Treatment-Related Non-Hematologic Adverse Events (N=79)

Adverse event, n Grade 1, n

Grade 2, n

Grade 3, n

Grade 4, n

All grades, n (%)

Fatigue 10 20 3 0 33 (42%) Dyspnea 12 9 1 0 22 (28%) Muscle spasms 11 3 0 0 14 (18%) Diarrhea 6 5 2 0 13 (16%) Skin, rash, pruritis 7 1 2 0 10 (13%)

Pneumonia* 0 2 6 0 9 (11%)

Hypocalcemia 5 3 0 0 8 (10%)

Creatinine elevated 3 2 0 1 6 (8%)

Peripheral sensory neuropathy

2 2 1 0 5 (6%)

DVT/PE/VTE* 0 4 0 0 5 (6%)

Cardiac failure, congestive 0 0 2 0 2 (3%)

*1 grade 5 pneumonia event and 1 grade 5 pulmonary embolism event; both treatment-related

Clinical Activity: Response Rates

Best overall response N=79

VGPR 21 (27%) PR 34 (43%) MR 10 (13%) SD 13 (16%) PD 1 (1%)

Clinical Activity: Response Rates

Best overall response N=79

VGPR 21 (27%) PR 34 (43%) MR 10 (13%) SD 13 (16%) PD 1 (1%)

ORR = 70%

Clinical Activity: Response Rates

ORR = 70%

CBR = 83%

Best overall response N=79

VGPR 21 (27%) PR 34 (43%) MR 10 (13%) SD 13 (16%) PD 1 (1%)

Duration of Response

Median DOR = 17.7 months

Progression-Free Survival Median PFS = 9.7 months

Median 6 cycles of therapy (range, 1–23)

Median Overall Survival Not Reached at 18 Months

Responses by Risk Status*

Responses are preserved in patients with high risk FISH/cytogenetics

* mSmart risk classification; 4 patients did not have complete FISH/cytogenetics data

Best overall response, n

High n=18 (24%)

Intermediate n=19 (25%)

Standard n=38 (51%)

VGPR 4 5 12 PR 10 5 16 MR 3 4 3 SD 1 5 6 PD 0 0 1 ORR 14/18 (78%) 10/19 (53%) 28/38 (74%)

Survival and Risk Status

PFS and OS are sustained independent of risk status

Progression-Free Survival Overall Survival

Outcomes for Patients with Deletion 17p

Conclusions • The combination of Car-Pom-d is highly active in this heavily pretreated,

lenalidomide-refractory patient population – Patients had received a median of 5 prior lines of therapy; 49% of patients

had high/intermediate risk cytogenetics at baseline

• Response rates, PFS, and OS were preserved independent of

FISH/cytogenetic risk status • The regimen was well tolerated with no unexpected toxicities • Enrollment is nearly complete in this phase II trial; subsequent dose

escalation of carfilzomib in less heavily treated patients with 1−3 lines of prior therapy is planned

≥ VGPR 27% ORR 70% CBR 83% DOR (median) 17.7 months PFS (median) 9.7 months OS (median) > 18 months

Acknowledgment

• Academic Myeloma Consortium: Dr. Brian Durie – Unique collaboration of Academic Myeloma

Centers of Excellence

• Onyx and Celgene: – Collaboration between two pharmaceutical

companies

• Patients/Caregivers/Families

• Research staff

Columbia University Department of Medicine

Division of Hematology/Oncology