Proteasome inhibitor (PI) and immunomodulatory drug (IMiD) refractory multiple myeloma is associated with inferior patient outcomes

Transcription

1 Alliance A A phase I/II study of pomalidomide, dexamethasone and ixazomib versus pomalidomide and dexamethasone for patients with multiple myeloma refractory to lenalidomide and proteasome inhibitor based therapy: Phase I results Peter M. Voorhees, Flora Mulkey, Hani Hassoun, Claudia E. Paba- Prada, Yvonne A. Efebera, Eva Hoke, Chelsea Schultz, Guadalupe Aquino, Destin Carlisle, Vera Suman and Paul G. Richardson The American Society of Hematology Annual Meeting, December 6 th, 2015

2 Background Proteasome inhibitor (PI) and immunomodulatory drug (IMiD) refractory multiple myeloma is associated with inferior patient outcomes Pts with disease refractory to an IMiD (thalidomide or lenalidomide) and bortezomib had a median OS of only 9 months 1 The pomalidomide / dexamethasone (Dex) combination has proven benefit in patients with dual lenalidomide / bortezomib refractory disease Improved median PFS compared with high dose dex 2 There remains room for improvement Overall response rate 31%, median PFS 3.7 months, median OS 11.1 months 2 Ixazomib is a boronic acid-based, reversible inhibitor of the β5 subunit of the proteasome with preclinical activity in myeloma 3,4 Faster dissociation rate relative to other PIs may allow for better proteasome inhibition at the tumor level Clinical activity seen as monotherapy in relapsed myeloma and in combination with lenalidomide (Len) and dexamethasone 5-7 FDA approved in combination with Len and Dex for pts receiving 1 prior therapy 1 Kumar S, et al. Leukemia. 2012;26: San Miguel J, et al. Lancet Oncol. 2013;14: Kupperman E, et al. Cancer Res. 2010;70: Kumar S, et al. Blood. 2014;124: Richardson PG, et al. Blood. 2014;124: Kumar S, et al. Lancet Oncol. 2014;15: Chauhan D, et al. Clin Cancer Res. 2011;17:

3 Why Ixazomib in Combination with Pomalidomide and Dexamethasone for Proteasome Inhibitor Refractory Disease? Clonal heterogeneity Subclones with differing drug resistance profiles may predominate at any given time depending on previous treatment applied Preclinical data in PI-resistant disease 1 Anecdotal clinical activity seen in PI resistant disease in Phase I/II studies of ixazomib 2,3 Synergy: myeloma that has become resistant to sequential IMiD- and PI-based therapy may respond to an IMiD / PI combination Preclinical synergy seen and highly promising clinical activity noted with ixazomib in combination with lenalidomide and dexamethasone 1,4 Not all drug resistance is created equal Progression on active treatment is likely worse than progression within 60 days of completing a regimen A drug capable of producing prolonged stabilization of disease may not be an ideal agent as monotherapy but could prolong PFS in the context of a pomalidomide / dexamethasone platform Stable disease or better was seen in 60% of patients with relapsed and relapsed/refractory myeloma on weekly ixazomib monotherapy at the MTD 2 1 Chauhan D, et al. Clin Cancer Res. 2011;17: Kumar S, et al. Blood. 2014;124: Richardson PG, et al. Blood. 2014;124: Kumar S, et al. Lancet Oncol. 2014;15:

4 Phase I Schema Standard 3+3, dose escalation design Treatment until PD, unacceptable toxicity or patient preference Thromboprophylaxis, zoster prophylaxis required = Ixa = Dex Pomalidomide Days 1-21 Day Cohort Pom (mg) Ixazomib (mg) * If the MTD is cohort 2, a cohort 2A will be pursued (Pom 2 mg, Ixazomib 4 mg) If the MTD is cohort 3, a cohort 3A will be pursued (Pom 3 mg, Ixazomib 4 mg) *Starting dose level Dex 40 mg for those 75, 20 mg for those >75

5 Objectives Primary: Establish the maximum tolerated dose (MTD) of the pomalidomide, ixazomib and dexamethasone combination based on dose limiting toxicities (DLTs) occurring in the 1 st cycle of therapy. DLT definition: Therapy related grade 3 non-hematologic toxicity with the following exceptions: Diarrhea, nausea, vomiting or hyperglycemia controlled with optimal supportive care Therapy related grade 4 neutropenia >7 days or grade 4 thrombocytopenia lasting >7 days or associated with a grade 3 bleeding event Secondary: Grade 4 lymphopenia was not considered a DLT Safety (DLTs, adverse events (AEs), serious AEs) Preliminary clinical activity (response rate, time to first response, duration of response, progression-free survival, overall survival)

6 Key Eligibility Criteria Relapsed and relapsed/refractory symptomatic myeloma Lenalidomide and proteasome inhibitor refractory* Refractoriness may develop at any point over the course of therapy 2 prior lines of therapy 14 day washout [21 for investigational agent(s)] ECOG PS 0-2 ANC 1.0x10 9 /L, Plts 50x10 9 /L CrCl 50 ml/min, t. bili<1.5x ULN, AST/ALT <2.5X ULN Grade 2 peripheral neuropathy Pomalidomide naïve or sensitive disease * Disease progression on or within 60 days of the last dose of a lenalidomide- AND proteasome inhibitor-based therapy

7 Patient Disposition Dose Level # Pts Enrolled # Pts Evaluable for DLT N/A Reason for DLT Not Evaluable Status pt inadvertently treated at dose level 1 during cycle #1, 1 pt with MDS on screening marrow who was not treated pt not treated due to rapid deterioration in clinical condition during the lead up to therapy * 1 protocol violation (screening platelet count < 50), 2 therapy disruptions over cycle #1 for AEs not rising to the level of DLTs (1 pt with on-treatment TIAs that were found to be present prior to the start of treatment, 1 pt with grade 2 sinus bradycardia), 1 therapy disruption over cycle #1 due to complications of disease progression. * 1 patient in dose level 4 with cycle 1 treatment ongoing

8 Baseline Patient Characteristics Characteristics Evaluable Patients = 22 Median Age, Years (Range) 65 (47 77) Median Time Since Diagnosis, Years (Range) 5.18 ( ) Female / Male (%) 36 / 64 Race (%) Asian Black / African American Caucasian Missing or Unknown Median Creatinine Clearance, ml/min (Range) 76 (53 143) ECOG Performance Status (%)

9 Baseline Disease Characteristics Characteristics Evaluable Patients = 22 ISS Stage at Study Entry (%) 1 / 2 / 3 73 / 18 / 9 Elevated LDH (%) Yes / No 9 / 91 Known Extramedullary Disease (%) Yes / No / Missing 14 / 82 / 5 Cytogenetic Profile (%) High Risk * / Standard Risk High Risk excluding gain of 1q / Standard Risk Missing or Not Evaluable Len/PI Refractory Status (%) Refractory to a Len / PI Combination Refractory to Sequential Len- / PI-based Therapy 59 / / * High-risk defined as del(1p), gain of 1q, del(17p), t(4;14), t(14;16) or t(14;20) 1 del(17p) only, 6 with gain of 1q only, 6 with gain of 1q and del(17p). No high risk IgH translocations were seen in this patient cohort. ISS=International Staging System, len=lenalidomide, PI=Proteasome Inhibitor

10 Prior Therapy Characteristics Evaluable Patients = 22 Median Prior Lines of Therapy (Range) 3 (2-10) Drug Exposure (%) Bortezomib 100 Carfilzomib 32 Lenalidomide 100 Pomalidomide 5 Corticosteroids 100 Alkylating Agents 45 High Dose Melphalan / ASCT 77 Daratumumab 5

11 Dose Limiting Toxicities and Dose Reductions / Delays Characteristic Evaluable Patients = 22 Dose Limiting Toxicities Dose Reductions (%) Pomalidomide Ixazomib Dexamethasone Dose Delays (%) Pomalidomide Ixazomib Dexamethasone Dose Level 3: Febrile neutropenia (N=1) Dose Level 4: Febrile neutropenia (N=1) 14 patients have come off treatment: 11 for disease progression; 2 due to an adverse event (grade 2 sensorimotor peripheral neuropathy; grade 4 neutropenia); and 1 due to patient preference

12 Adverse Events 1 venous thromboembolic event (pulmonary embolism) has occurred on study

13 Overall Response Evaluable Patients = 20 Overall Response Rate, % VGPR PR MR SD PD Median Time to Response, Months (Range) Response by Cytogenetic Risk, % (18 evaluable) High Risk (N=13) / Standard Risk (N=5) High Risk excluding gain of 1q (N=7) / Standard Risk (N=11) Response by Refractory Status, % Refractory to Combination Len/PI (N=6) Refractory to Sequential Len / PI-based Therapy (N=14) Response ( ) 46 (5 PRs, 1 VGPR) / 100 (5 PRs) 43 (2 PRs, 1 VGPR) / 73 (8 PRs) 50 (3 PRs) 57 (7 PRs, 1 VGPR)

14 Best Response * * 418% increase Responses were seen at all dose levels

15 Response Over Time Many responses have proven durable, even at the lower dose cohorts

16 Conclusions Pomalidomide, ixazomib and dexamethasone can be combined safely Moderate to severe hematologic toxicity is common and requires close monitoring and supportive care Non-hematologic toxicity is less common and typically mild to moderate in severity Dose level 3 (4 mg of pomalidomide and 3 mg of ixazomib) was well tolerated Enrollment into dose level 4 (4 mg of pomalidomide / 4 mg of ixazomib) is ongoing and near complete The preliminary efficacy of the regimen is promising 55% response rate in PI / lenalidomide refractory disease with responses in patients with high risk cytogenetics Durable responses were seen

17 Cross-over at disease progression Next Steps: Phase II R A N D O M I Z E N=54 POM 4 mg D1-21 DEX 20/40 mg D1, 8, 15, 22 N=54 POM TBD D1-21 DEX 20/40 mg D1, 8, 15, 22 IXAZOMIB TBD D1, 8, 15 Primary Objective PFS Secondary Objectives Response, DOR, OS, Safety Correlative Objectives Cereblon / Ikaros / Aiolos / IRF-4 / c-myc pathway markers of clinical efficacy Treatment until disease progression, unacceptable toxicity, patient preference Stratification: 1) Refractory to combination vs. sequential len/pi-based tx; 2) 2-3 vs. 4 prior lines of tx; 3) Prior Pom exposure

18 Acknowledgements The investigators and protocol staff at all participating sites The study personnel at the Alliance for Clinical Trials in Oncology The patients and their families