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, Marti McKinley, BSN, MBA9, Brian G.M. Durie, MD10

1 MD 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 9 Academic Myeloma Consortium (AMyC), CORE Science Solutions, A Criterium Company, Culver

City, CA, 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 • Carfilzomib1, a novel irreversible proteasome inhibitor (PI), has

demonstrated single agent activity in relapsed and refractory MM, and recently received FDA regulatory approval for this indication

• Pomalidomide2 is the third drug in the Immunomodulatory Drug (IMiD) class in clinical development with single agent activity in Lenalidomide refractory patients.

• Preclinical data3 support the combination of proteasome inhibitors and Imids to overcome resistance and improve response rates

• Combination of Bortezomib and Lenalidomide/dex4 and early data with Carfilzomib and Lenalidomide/Dex result in encouraging high response rates in newly diagnosed and relapsed MM

• The hypothesis is that the combination of Carfilzomib and Pomalidomide with dexamethasone (Car-Pom-d) is highly active in RRMM

1 Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8. doi: 10.1016/j.clml.2012.08.003. 1 Vij R, et al. Br J Haematol. 2012 Sep;158(6):739-48. doi: 10.1111/j.1365-2141.2012.09232.x. Epub 2012 Jul 30. 1 Siegel, et al. Blood. 2012 Oct 4;120(14):2817-25. doi: 10.1182/blood-2012-05-425934. Epub 2012 Jul 25 2 Lacy MG, et al. Leukemia. 2010 November; 24 (11): 1934-1939. 3 Mitsiades N, et al. Blood 99:4525–4530. (2002). 3 Hideshima T, et al. Blood 96:2943–2950. (2002). 4 Richardson PG, et al. Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12. 4 Richardson PG, et al. J Clin Oncol. 2009 Dec 1;27(34):5713-9. Epub 2009 Sep 28. 4 Niesvizky R, et al. Blood (ASH Annual Meeting Abstracts). Nov 2009; 114: 304.

Primary Objectives: • To evaluate the safety and determine the maximum

tolerated dose (MTD) of the combination of Carfilzomib and Pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma (RRMM)

Secondary Objectives: • To perform a preliminary evaluation of the efficacy of

Car-Pom-d including: – Overall response (SD, MR, PR, VGPR, CR, sCR) – Time to progression (TTP) – Progression free survival (PFS) – Time to next therapy – Overall survival (OS)

Study Objectives

Study Design

• Phase 1 Dose Escalation Study with dose expansion at Maximum Tolerated Dose (MTD)

• 3+3 Dose Escalation

Carfilzomib Pomalidomide Dexamethasone

Cohort -1 27 mg/m2* 3 mg 40 mg**

Cohort 1 (initial dose level)

27 mg/m2* 4 mg 40 mg**

Cohort 2 36 mg/m2* 4 mg 40 mg**

Cohort 3 45 mg/m2* 4 mg 40 mg**

Cohort 4 56 mg/m2* 4 mg 40 mg**

Start Dose Level

* Carfilzomib doses on days 1 and 2 of Cycle 1 for all cohorts was 20 mg/m2; all subsequent dosing will be as shown in the table above. ** Dexamethasone reduced to 20 mg after cycle 4

Study Schema

1 2 8 9 15 16

1 8 15 22

1 21

Carfilzomib

Pomalidomide

Dexamethasone

• Cycle 1-6: 28 day cycle

• Cycle 7 + : Maintenance Cycles Carfilzomib dosed on days 1, 2, 15, 16; Pomalidomide/dex unchanged • Patients treated until Progressive Disease / Unacceptable toxicity • Concomitant Medications: Anti-viral therapy Anticoagulation: Aspirin 81 mg; LMWH in ASA intolerant

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 containing 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, cardiac function

Patient Demographics

N = 32 Gender Male: 20 (62.5%)

Female:12 (37.5%)

ECOG PS

0 : 16 (50%) 1 : 14 (44%) 2 : 2 (6%)

Age, Median (Range) 63.5 yrs (44 to 78) N prior regimens, Median (Range) 6 regimens (1 to 15)

Yrs since initial Dx Median (Range) 5.0 yrs (1.2 to 9.1)

Prior Therapies

Prior stem cell transplant

21 (65.6%)

Prior bortezomib

31 (97%) All but 2 refractory*

Prior lenalidomide

32 (100%) All refractory

* Includes multiple bortezomib combos

FISH / Cytogenetics (n=31*)

Hyperdiploid 9 (33%) del(1) 2 (7%) del(13) 10 (33%) del(17p) / p53 6 (19%) t(11;14) 6 (21%) t(14;16) 1 (4%) t(4;14) 3 (10%)

* FISH/cytogenetics missing in 1 patient

Phase I MTD • Cohort level 1: 1 of 6 patients experienced a protocol-defined

DLT of febrile neutropenia

• Cohort level 2 (carfilzomib 20/36 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 the starting dose level (carfilzomib 20/27 mg/m2, pomalidomide 4mg, dexamethasone 40 mg)

• 12 patients enrolled in phase I + 20 additional patients enrolled at MTD

Hematologic Adverse Events (Grade 1 -4) n=32

G 1 G 2 G 3 G 4 Total Anemia 1 7 11 1 20

Thrombocytopenia 5 4 7 2 18

Neutropenia 1 8 13 5 27

Febrile neutropenia 0 0 2 0 2

• Low Incidence of Febrile Neutropenia of 6% • Toxicities reversible and manageable

Non-hematologic Adverse Event (≥ 20% patients)

G 1 G 2 G 3 G 4 total

Diarrhea 8 2 0 0 10 (31%)

Fatigue 9 8 1 0 18 (56%)

Dyspnea 9 0 0 0 9 (28%)

Skin, Rash, Pruritis 5 1 1 0 7 (21%)

Creatinine elevated 5 2 1 0 8 (26%)

Hypocalcemia 7 4 0 0 11 (34%)

Notable SAE: G3 Pnuemonia ( n=3) ; Pulmonary Emboli ( n=1); Congestive Heart Failure (n=1)

Numbers (%)

No Grade 3/4 Peripheral Neuropathy

Response Rates

N = 30

Overall Response Rate ( ≥ PR) 15 (50%)

VGPR 4 (13%)

PR 11 (37%)

MR 5 (17%)

SD 7 (23%)

PD 3 (10%)

Clinical Benefit Rate (≥ MR) of 67%

Progression Free Survival P

rogr

essi

on-F

ree

Sur

viva

l Per

cent

age

Time in Study (Months)

Car-Pom-Dex PFS (N = 32) 95% Confidence Interval Median PFS = 7.4 months

0 3 6 9 12

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

Overall Survival (months)

Ove

rall

Sur

viva

l Per

cent

age

Time in Study (Months)

Car-Pom-Dex OS (N = 32) 95% Confidence Interval

0 3 6 9 12

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

Responses by Risk Status*

VGPR PR

MR SD PD

High (n=5) 17p- positive / t(14:16)

0 4 1 0 0

Intermediate (n=6) t(4;14) positive / hypodiploid

0 2 1 2 1

Standard (n=18) Hyperdiploid / t(11;14)

4 6 3 3 2

Total Patients (n=29) 4 12 5 5 3

Responses are preserved in patients with high risk FISH/cytogenetics

* mSmart Risk Classification ** 1 pt did not have FISH/cytogenetics data

Survival and Risk Status

Responses and survival are sustained and durable independent of risk status

Standard Risk (N = 18) Intermediate + High Risk (N = 13) P

rogr

essi

on-F

ree

Sur

viva

l Per

cent

age

Time in Study (Months) 0 3 6 9 12

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

Ove

rall

Surv

ival

Per

cent

age

Time in Study (Months)

Standard Risk (N = 18) Intermediate + High Risk (N = 13)

0 3 6 9 12

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

High & Intermediate

Standard

High & Intermediate

Standard

Progression Free Survival Overall Survival

Conclusions • The maximum tolerated dose was Carfilzomib 20/27 mg/m2,

Pomalidomide 4 mg, and dexamethasone 40 mg in relapsed/refractory myeloma

• There are limited G 3 and 4 non hematologic toxicities; the regimen was tolerated well with no unexpected toxicity

• The combination of Car-Pom–d is highly active in this heavily pretreated, refractory patient population

• The combination has encouraging preserved response rate and survival independent of FISH/cytogenetic risk status

• Enrollment is ongoing in an 82 patient phase II trial within AMyC

≥ VGPR 13% ≥ ORR 50% ≥ CBR 67% PFS (median) 7.4 months OS 90% @ 1 year

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