A Phase 1 Trial of Lenalidomide (REVLIMID ) With Bortezomib (VELCADE ) in Relapsed and Refractory Multiple Myeloma

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1 A Phase 1 Trial of Lenalidomide (REVLIMID ) With Bortezomib (VELCADE ) in Relapsed and Refractory Multiple Myeloma P.G. Richardson, 1 R. Schlossman, 1 N. Munshi, 1 D. Avigan, 2 S. Jagannath, 3 M. Alsina, 4 D. Doss, 1 M. McKenney, 1 K. Hande, 1 M. Farrell, 1 S. Gorelik, 1 K. Colson, 1 D. Warren, 1 L. Lunde, 1 R. Michelle, 1 G. Cole, 2 C. Mitsiades, 1 T. Hideshima, 1 T. Myers, 5 R. Knight, 6 and K. Anderson 1 1 Dana-Farber Cancer Institute, MA; 2 Beth Israel Deaconess Medical Center, MA; 3 St. Vincent s Cancer Center, NY; 4 Moffitt Cancer Center, FL; 5 Millennium Pharmaceuticals Inc., MA; 6 Celgene Corporation, NJ

2 Author Disclosure Statement Research Support/P.I. Employee Millennium Pharmaceuticals, Inc. Celgene,, Inc. N/A Consultant N/A Major Stockholder Speakers Bureau/Advisory Board N/A Millennium Pharmaceuticals, Inc. Celgene,, Inc. Presentation includes discussion of the following off-label use of a drug: Lenalidomide in multiple myeloma

3 Bortezomib Potent preclinical activity against multiple myeloma (MM) via inhibition of NF-κB, activation of caspases 3, 8, 9 1 Maximum tolerated dose (MTD) 1.3 mg/m 2 twice wkly for 2 wks followed by 1 wk of rest 2-4 Efficacious in phase 2 trials of relapsed and/or refractory MM: SUMMIT, 5 CREST 6 Pivotal phase 3 randomized trial (APEX, 7 n = 669) Significant improvements in response rate (RR), time to progression (TTP), survival compared with high-dose dexamethasone (dex) in relapsed MM pts with 1 3 prior therapies In frontline trials in MM, RR 75% 95%, complete response (CR)/near CR (ncr) 25% 31% Hideshima et al. Cancer Res Orlowski et al. J Clin Oncol Aghajanian et al. Clin Cancer Res Papandreou et al. J Clin Oncol Richardson et al. N Engl J Med Jagannath et al. Br J Haematol Richardson et al. N Engl J Med Harousseau et al. J Clin Oncol Jagannath et al. Br J Haematol Oakervee et al. Br J Haematol

4 Lenalidomide Potent preclinical activity against MM via caspase 8-dependent apoptosis; T cell proliferation/stimulation, IL-2, IFN-γ production; TNFα & IL-1β inhibition 1-4 Active, well tolerated in MM: responses with 50% M-protein reduction in 24% 40% of pts receiving lenalidomide ± dex, with relapsed and relapsed/refractory MM, including prior thal and bortezomib pivotal phase 3 randomized trials with HD dex (MM-009, n=354, 010, n=351) Significant improvement in RR (CR, PR),TTP vs HD dex alone in relapsed MM pts with 1-3 prior therapies 8 In frontline with high dose dex, RR 91%, CR / ncr 38% 9 1. Hideshima et al. Blood Davies et al. Blood Mitsiades et al. Blood Lentzsch et al. Cancer Res Richardson et al. Blood Zangari et al. Blood Richardson et al. Blood Weber et al. Haematologica Rajkumar et al. Blood

5 Combination of Lenalidomide + Bortezomib 50 Pt Cells (bortezomib-resistant) Cell Death, % Growth, % Lenalidomide 0 μm 5 μm Len 1μM Bz 3 nm Len 1μM + Bz 3 nm Len = lenalidomide; Bz = bortezomib Bortezomib, nm Mitsiades et al. Blood Hideshima et al, unpublished data

6 Rationale Lenalidomide sensitizes MM cells to bortezomib and dex in preclinical studies 1 Expected overlapping toxicities manageable (primarily hematologic) 2 In phase 1 MTD of lenalidomide 25 mg (PO daily, 28-day cycle) 2,3 MTD of bortezomib 1.3 mg/m 2 (IV twice weekly, 21-day cycle) Mitsiades et al. Blood Richardson et al. Blood Zangari et al. Blood Orlowski et al. J Clin Oncol Aghajanian et al. Clin Cancer Res Papandreou et al. J Clin Oncol

7 Objectives Primary Evaluate safety of combination in pts with relapsed or relapsed/refractory MM Identify MTD and recommended dose for phase 2 study Secondary Evaluate response Assess PK Explore pharmacogenomics/surrogate markers

8 Schema Bortezomib, mg/m 2 Lenalidomide, mg Cohort 1 Cohort 3 Cohort 5 Cohort Cohort 2 Cohort 4 Cohort 6 Cohort 8 8 cohorts of 3 6 pts, with additional 10 pts enrolled at the MTD 21-day cycle* B B B B Lenalidomide daily *For a maximum of 8 cycles; dex added (20 mg day of and day following bortezomib) for pts with progressive disease (PD): extension phase for pts in response

9 Eligibility Inclusion criteria Relapsed or relapsed/refractory MM (at least 1 prior therapy) Age 18 years ECOG performance status 0 2 Prior thalidomide, lenalidomide, bortezomib permitted Women of childbearing potential: negative pregnancy test

10 Eligibility Exclusion criteria Creatinine > 2 mg/dl Concomitant corticosteroids, chemotherapy, or radiation Peripheral neuropathy (PN) grade 3 or grade 2 with pain Platelets < 50,000 cells/mm 3 ANC < 1,000 cells/mm 3 Hgb < 8.0 g/dl AST 2 ULN Intolerance to bortezomib or lenalidomide or hypersensitivity to thalidomide

11 Evaluation Response using EBMT criteria 1 (after 2 cycles and after every subsequent cycle) Adverse events assessed using NCI CTC version 3.0 Dose-limiting toxicity (DLT) Non-hematologic toxicity G 3 Thrombocytopenia with platelets < 10,000/mm 3 on more than 1 occasion despite transfusion support Neutropenia occurring for more than 5 days and/or resulting in neutropenic fever MTD: dose level prior to that resulting in 2 DLTs EBMT = European Group For Blood and Marrow Transplantation; NCI CTC = National Cancer Institute Common Toxicity Criteria. 1. Bladé et al. Br J Haematol

12 Results Baseline Characteristics (N = 24) Characteristic Median age, y (range) Male, % Myeloma type, % IgG IgA Durie-Salmon stage III, % Disease status Relapsed, n Relapsed/refractory, n Median no. of prior therapies (range) Prior SCT, n (%) Prior bortezomib, n (%) Prior lenalidomide, n (%) Prior thalidomide, n (%) 58 (37 79) (1 8) 16 (67) 12 (50) 2 (8) 20 (83)

13 Disposition Enrollment Evaluable for response* Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Cohort 6 Cohort 7 8 N = *Confirmed at cycle 2 and at each subsequent cycle.

14 Adverse Events: Hematologic Cohort Dose Bz (mg/m 2 )/ Len (mg) Cycle Adverse Event 1 1.0/5 3 G4 neutropenia* (ANC 420 in 1 pt) 2 1.3/5 2, 4 G3 thrombocytopenia (plats 32,000 in 2 pts) 3 1.0/10 1 G4 neutropenia* (ANC 300 in 1 pt) 4 1.3/10 1, 4 G3 hyponatremia (Na 129 mmol/l in 1 pt) G4 thrombocytopenia (plats 19,000 in 1 pt) 5 1.0/15 2, 6 G3 thrombocytopenia (plats 38,000 in 1 pt) G3 neutropenia (ANC 890 in 1 pt) 6 1.3/15 NA NA *Less than 5 days (not DLT). Determined to be drug related (DLT). NA = not available

15 Toxicity No discontinuations No significant PN or fatigue (> G3) No thrombotic events No DLT through first 3 cohorts One DLT in cohort 4 G3 hyponatremia; G1 hyponatremia present at baseline No DLT in cohort 5 One DLT in cohort 6 Delay in treatment 2ary to G2 HZV infection MTD not yet reached, cohort 7 to open in January 06

16 Dose Reductions Dose reductions in cohorts pts for bortezomib only (cycles 2-5) 3 pts for both bortezomib (cycles 3-6) and lenalidomide (cycles 6-7) Bortezomib dose reductions mg/m 2 : thrombocytopenia (n = 1), neutropenia and thrombocytopenia (n = 1), angioedema (n = 1), hyponatremia (n = 1) mg/m 2 : hypotension (n = 1), fatigue (n = 1) mg/m 2 : thrombocytopenia (n = 3) Lenalidomide dose reductions mg: thrombocytopenia (n = 1) 10 5 mg: neutropenia (n = 1) and fatigue (n = 1)

17 Best Response (n=21)* Cohort Bortezomib, Lenalidomide (mg/m 2 :mg) # of Cycles CR Response (n = 21)* ncr PR MR SD PD CR + ncr + PR + MR: 67% CR=complete response, PR=partial response, MR = minor response; PD = progressive disease * Evaluable patients, EBMT criteria 1 pt not evaluable Dex added

18 Summary Combination of lenalidomide and bortezomib well tolerated One DLT in cohort 4, cohort 6 No DVT No significant PN or fatigue Active in heavily pretreated pts, including pts who received either agent alone 67% RR (CR + ncr + PR + MR) Dex added in 3 pts no added toxicity; PD in 1 pt, SD in 2 pts Study ongoing to determine MTD Additional 10 pts to be enrolled at MTD

19 Future Directions Completion of PK, surrogate marker analysis Phase 2 studies in relapsed and relapsed refractory MM Phase 2 study in newly diagnosed pts Steroid sparing approach (lower dose dex) Potential oral/iv regimens using lenalidomide and bortezomib in combination with other novel agents

20 Acknowledgments Dana-Farber Cancer Institute CRC nursing team Research pharmacy BIDMC, HCC St. Vincent s Comprehensive Cancer Center Moffitt Cancer Center Millennium Pharmaceuticals, Inc. Celgene Corporation MMRF and IMF The Patients and Their Families