Millennium Pharmaceuticals, Inc., Cambridge, MA; 11 Dana-Farber Cancer Institute, Boston, MA

Transcription

1 Phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma Shaji K. Kumar, 1 Jesus G. Berdeja, 2 Ruben Niesvizky, 3 Sagar Lonial, 4 Mehdi Hamadani, 5 A. Keith Stewart, 6 Vivek Roy, 7 Parameswaran Hari, 8 Robert Vescio, 9 Deborah Berg, 10 Jianchang Lin, 10 Alessandra Di Bacco, 10 Jose Estevam, 10 Neeraj Gupta, 10 Ai-Min Hui, 10 Paul G. Richardson 11 1 Division of Hematology, Mayo Clinic, Rochester, MN; 2 Sarah Cannon Research Institute, Nashville, TN; 3 Center of Excellence for Lymphoma and Myeloma, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, NY; 4 Winship Cancer Institute of Emory University, Atlanta, GA; 5 West Virginia University, Mary Babb Randolph Cancer Center, Morgantown, WV; 6 Mayo Clinic College of Medicine, Scottsdale, AZ; 7 Mayo Clinic, Jacksonville, FL; 8 Division of Hematology Oncology, Medical College of Wisconsin, Milwaukee, WI; 9 Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA; 10 Millennium Pharmaceuticals, Inc., Cambridge, MA; 11 Dana-Farber Cancer Institute, Boston, MA

2 Background High response rates have been seen with the bortezomib, lenalidomide, dexamethasone (VRD/RVD) regimen 1,2 Highlights the feasibility of combining a proteasome inhibitor with an immunomodulatory agent and a steroid in patients with previously untreated multiple myeloma (MM) MLN9708 is an investigational oral, reversible, and specific 20S proteasome inhibitor The first oral proteasome inhibitor in clinical development Physiochemical properties distinct from bortezomib 3 Activity in preclinical models of MM 4 1. Kumar S, et al. Blood 2012;119: Richardson PG, et al. Blood 2010;116: Kupperman E, et al. Cancer Res 2010;70: Chauhan D, et al. Clin Cancer Res 2011;17:

3 MLN9708 studies Weekly and twice-weekly schedules of MLN9708 are being evaluated in single-agent studies in MM Recent preliminary data suggest clinical activity of single-agent MLN9708 in heavily pretreated patients with MM 1,2 Data suggest a generally tolerable toxicity profile with low rates of peripheral neuropathy (PN) observed to date 1, % drug-related PN, with no grade 3 PN reported, with singleagent MLN9708 Here, we report results of the first study of weekly oral MLN9708 in combination with lenalidomide and dexamethasone (triplet oral combination) in patients with previously untreated MM ClinicalTrials.gov: NCT Lonial S, et al. J Clin Oncol 2012;30(suppl):abstract Kumar S, et al. J Clin Oncol 2012;30(suppl):abstract 8034.

4 Key objectives Phase 1: Primary: safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) Phase 2: Primary: combined complete and very good partial response (CR+VGPR) rate, safety, and tolerability Null hypothesis: CR+VGPR rate = 35%; alternative hypothesis: CR+VGPR rate = 50% With 48 response-evaluable patients, 80% power at 1-sided significance level of α = 0.10 Secondary: overall response rate (ORR), time to response, duration of response, and progression-free survival Exploratory: ORR in patients with high-risk cytogenetics, and minimal residual disease (MRD) status in patients achieving CR

5 Patient eligibility Key inclusion criteria: Age 18 years ECOG performance status 0 2 Adequate hepatic, renal, and hematologic function Previously untreated MM Measurable disease: Serum M-protein 1 g/dl Urine M-protein 200 mg/24 hours Involved free light chain 10 mg/dl Key exclusion criteria: Grade 2 PN Prior/concurrent deep vein thrombosis/pulmonary embolism Prior systemic MM therapy

6 Study design Induction: up to 12 x 28-day treatment cycles Maintenance MLN9708 MLN9708 MLN9708 Dex 40 mg Dex 40 mg Dex 40 mg Dex 40 mg Lenalidomide 25 mg, days 1 21 MLN9708 maintenance Days 1, 8, day cycles Phase 1: oral MLN9708 dose-escalation Standard 3+3 schema, 33% dose increments, based on cycle 1 dose-limiting toxicities (DLTs) Phase 2: oral MLN9708 at the RP2D from phase 1 Stem cell collection allowed after 3 cycles, with autologous stem cell transplantation (ASCT) deferred until after 6 cycles MLN9708 maintenance continued until progression or unacceptable toxicity Mandatory thromboprophylaxis with aspirin or low-molecular-weight heparin

7 Enrollment Between November 2010 and February 2012, 65 patients in total enrolled Phase 1 (November 2010 October 2011) 15 patients MLN9708 dose cohorts: 1.68 mg/m 2 (n=3) 2.23 mg/m 2 (n=3) 2.97 mg/m 2 (n=6) 3.95 mg/m 2 (n=3) Phase 2 (October 2011 February 2012) 50 patients Upon establishment of the RP2D, dosing switched to fixed dose, based on population pharmacokinetic analysis, 1 for phase 2 53 patients in total treated at the RP2D 3 from dose-escalation cohort, 50 from phase 2 1. Gupta N, et al. Blood 2011;118:abstract 1433.

8 Patient characteristics Phase 1, n=15 Phase 2, n=50 Total, N=65 Median age, years (range) 67 (40 77) 65 (34 86) 66 (34 86) Age 65 years, n (%) 9 (60) 25 (50) 34 (52) Age 75 years, n (%) 3 (20) 9 (18) 12 (18) Male, n (%) 6 (40) 30 (60) 36 (55) ISS stage at diagnosis, n (%) I 4 (27) 26 (52) 30 (46) II 8 (53) 17 (34) 25 (38) III 3 (20) 7 (14) 10 (15) *In the 30 ISS stage I patients, symptomatic MM (CRAB criteria) demonstrated by presence of lytic bone lesions (n=17), anemia (n=12), and hypercalcemia (n=1).

9 Patients with cytogenetic assessment, N Cytogenetics Phase 1, n=15 Phase 2, n=50 Total, N= Conventional/karyotype 4 (33) 13 (34) 17 (34) Molecular/FISH 5 (42) 23 (61) 28 (56) Both 3 (25) 2 (5) 5 (10) Unfavorable cytogenetics *, n/n (%) 2/5 (40) 5/23 (22) 7/28 (25) Unfavorable abnormalities, n (%) del (9) 2 (7) t(14;16) 0 1 (4) 1 (4) 1q amplification 2 (40) 2 (9) 4 (14) *Indeterminate for 4 patients (1 patient in phase 1, and 3 patients in phase 2). Unfavorable cytogenetics were assessed by FISH and included del 17, t(14;16), or 1q amplification.

10 Phase 1: DLTs, MTD, and RP2D DLTs: One patient with DLT at 2.97 mg/m 2 Grade 3 urticarial rash Three patients with DLTs at 3.95 mg/m 2 Grade 3 nausea, grade 3 vomiting, grade 2 dizziness, grade 2 orthostatic hypotension Grade 3 diarrhea, grade 3 vomiting Grade 3 nausea, grade 3 vomiting, grade 3 syncope, grade 2 PN MTD: 2.97 mg/m 2 RP2D: 2.23 mg/m 2 Determined based on consideration of the balance between toxicity and efficacy across multiple cycles RP2D converted to 4.0 mg fixed dose based on population pharmacokinetic analysis 1 1. Gupta N, et al. Blood 2011;118:abstract 1433.

11 Treatment exposure Phase 1, n=15 RP2D, n=53 Total, N=65 Median cycles of MLN9708 received, n (range) 6 (1 19) 7 (1 19) 6 (1 19) Patients treated with cycles of MLN9708, n (%) 4 12 (80) 49 (92) 58 (89) 8 4 (27) 24 (45) 25 (38) 12 4 (27) 3 (6) 4 (6) Median relative dose intensity*, % MLN Lenalidomide Dexamethasone *Dose taken/dose prescribed.

12 Patient follow up Phase 1, n=15 RP2D, n=53 Total, N=65 Patients remaining on treatment, n (%) 4 (27) 26 (49) 27 (42) Reasons for going off treatment, n (%) Proceeding to ASCT 9 (60) 11 (21) 20 (31) AE 2 (13) 6 (11) 8 (12) Progressive disease 0 3 (6) 3 (5) Other 0 7 (13) 7 (11) At data cut-off of October 17, 2012.

13 Stem cell mobilization Median cycle of first stem cell mobilization: 4 (range 3 7) Sites used institutional standard mobilization regimen, which included: G-CSF (n=3) Cyclophosphamide + G-CSF (n=3) Plerixafor + G-CSF (n=2) Cyclophosphamide (n=1) Bortezomib (n=1) Median number of apheresis procedures: 2 (range 1 4) Median number of harvested CD34+ cells: 11.3 x 10 6 /L (range 5 28 x 10 6 /L) MLN9708 plus lenalidomide and dexamethasone did not appear to have an adverse impact on stem cell mobilization

14 Summary of safety profile AE, n (%) Phase 1, n=15 RP2D, n=53 Total, N=65 Any AE* 15 (100) 53 (100) 65 (100) Any drug-related AE 15 (100) 51 (96) 63 (97) Any grade 3 AE 11 (73) 34 (64) 43 (66) Any drug-related grade 3 AE 9 (60) 27 (51) 34 (52) Any serious AE (SAE) 8 (53) 19 (36) 24 (37) Any drug-related SAE 4 (27) 11 (21) 13 (20) Dose reduction due to AE 8 (53) 21 (40) 28 (43) On-study death 0 1 (2) 1 (2) *AEs graded using NCI-CTCAE v4.02. Drug-related defined as related to any drug in the combination

15 On-study death and treatment discontinuations due to AEs One patient died on study Treated at RP2D (4.0 mg) Pneumonia, respiratory syncytial virus (RSV) after cycle 4 considered possibly related to treatment; alternatively related to underlying disease state Seven additional patients discontinued study treatment due to AEs, including four due to treatment-related AEs Five patients treated at the RP2D (4.0 mg) discontinued, including three due to treatment-related AEs

16 Most common AEs (all cause, all grade; 20% of patients in total) AE, n (%) Phase 1, n=15 RP2D, n=53 Total, N=65 Rash* 11 (73) 34 (63) 44 (68) Fatigue 6 (40) 27 (51) 31 (48) Nausea 7 (47) 22 (42) 27 (42) Diarrhea 8 (53) 18 (34) 25 (38) Constipation 5 (33) 20 (38) 24 (37) PN 6 (40) 16 (30) 21 (32) Vomiting 9 (60) 13 (25) 21 (32) Back pain 5 (33) 15 (28) 19 (29) Peripheral edema 4 (27) 17 (32) 19 (29) Anemia 5 (33) 14 (26) 18 (28) Upper respiratory tract infection 4 (27) 16 (30) 18 (28) Thrombocytopenia 4 (27) 13 (25) 17 (26) Dyspnea 5 (33) 9 (17) 14 (22) Insomnia 4 (27) 11 (21) 14 (22) Dizziness 5 (33) 9 (17) 13 (20) Muscle spasms 6 (40) 9 (17) 13 (20) *Pruritic, papular, maculo-papular, erythematous, rash, palmar-plantar erythrodysesthesia. PN and peripheral sensory neuropathy

17 Grade 3 ( 5%) and all grade 4 AEs (N=65) Hematologic * * *Occurred in same patient % Rash includes pruritic, papular, maculo-papular, erythematous, rash, palmar-plantar erythrodysesthesia

18 Peripheral neuropathy (PN) A total of 21 patients (32%) reported treatment-emergent PN Includes the preferred terms of peripheral neuropathy and peripheral sensory neuropathy 2 had PN at baseline PN was grade 1 in the majority (n=13) of patients Grade 2 reported in 6 patients Grade 3 reported in 2 patients (3%) Both patients off study; PN has resolved in one, and has reduced to grade 1 (mild, without impact on activities of daily living) in the other

19 Preliminary response data 64 of 65 patients were evaluable for response (i.e. had measurable disease at baseline, received at least one cycle of treatment, and had a response assessment) Median time to first response ( PR) was 1 cycle Median duration of response not reached Similar responses were seen in patients with favorable and unfavorable cytogenetics Median cycles of MLN9708 received, n (range) Phase 1, n=15 RP2D, n=52 Total, N=64 6 (1 19) 7 (1 19) 6 (1 19) ORR ( PR), % VGPR, % CR+nCR*, % CR, % *ncr required bone marrow confirmation per protocol

20 Preliminary response data over course of treatment patients treated at RP2D (2.23 mg/m 2 / 4.0 mg) % ORR 94% ORR 95% After 4 cycles (n=47) VGPR VGPR 49% 58% VGPR 58% After 8 cycles (n=19) ORR 90% 32 Overall (n=52) CR VGPR PR Of 3 response-evaluable patients who completed 12 cycles, 2 achieved CR and 1 VGPR

21 Best percent change in M-protein from baseline in response-evaluable patients % change from baseline to best M-protein response Phase 1, 1.68 mg/m 2 Phase 1, 2.97 mg/m 2 RP2D, 2.23 mg/m 2 / 4.0 mg Phase 1, 3.95 mg/m 2 48% of patients achieved 100% reduction in M-protein Reductions were seen at multiple dose levels

22 MRD evaluation MRD samples collected from patients achieving CR N=9 MRD-evaluable samples 8/9 (89%) MRD-negative samples 7/8 (88%) (κ:λ light chain ratio 0.3 3)

23 Progression-free survival 1.0 Survival probability of 65 patients have progressed or died Estimated 1-year progression-free survival probability: 93% Progression free survival, months Patients at risk:

24 Conclusions The all-oral combination of weekly MLN9708, lenalidomide, and dexamethasone appears to be generally well tolerated To date, the incidence of PN has been limited with this triplet regimen The primary endpoint of the study was met, suggesting antitumor activity at the RP2D At data cut-off, with a median drug exposure of 6 months, 92% of patients overall had achieved PR or better, including a VGPR rate of 55% and a CR rate of 23% Responses increased with number of cycles and deepened over time 88% of patients achieving CR who were evaluable for MRD status were confirmed as MRD-negative A phase 3 trial of MLN9708 plus lenalidomide dexamethasone versus placebo plus lenalidomide dexamethasone in patients with relapsed and/or refractory MM is currently enrolling (NCT ) A phase 3 trial of MLN9708 plus lenalidomide dexamethasone in previously untreated MM is in the planning stages

25 Acknowledgments We thank all the patients and their families who participated in this study We also thank the physicians, research nurses, study coordinators, and research staff involved in the study We acknowledge Steve Hill of FireKite for writing assistance during the development of this presentation, which was funded by Millennium Pharmaceuticals, Inc.