Randomized Placebo-Controlled Phase III Study Of Perifosine Combined With Bortezomib and Dexamethasone In Relapsed, Refractory Multiple Myeloma Patients Previously Treated With Bortezomib

Perifosine (PERI) is an oral, synthetic alkylphospholipid that inhibits or modifies signal transduction pathways including AKT, NFkB and JNK, with potent anti-myeloma activity pre-clinically. In a phase I/II study, an overall response rate (ORR; defined as PR or better) of 41% was demonstrated with PERI in combination with bortezomib (BTZ) ± dexamethasone (DEX) in 73 evaluable multiple myeloma (MM) patients (pts) with relapsed and refractory disease, including an ORR of 65% in BTZ-relapsed pts and 32% in BTZ-refractory pts. Based on these results, a placebo-controlled Phase III study evaluated the benefit of adding PERI at 50 mg daily to BTZ+DEX in MM pts who had previously relapsed after a BTZ-based regimen and received between 1 and 4 prior lines of therapy.

This was a double-blind, placebo-controlled randomized study. Eligible pts had measurable disease (baseline serum M-protein > 0.5 g/dL and/or > 200 mg/24-hr urinary M-protein excretion), had relapsed more than 60 days after BTZ-based therapies received as either single agent (at least two 21-day cycles) or in combination with other agents. Pts were randomized 1:1 to PERI (50 mg PO QD) + BTZ (1.3 mg/m²on Day 1, 4, 8, 11) + DEX (20 mg on Day 1, 2, 4, 5, 8, 9, 11, 12) or placebo + BTZ + DEX. Randomization was stratified according to prior lines of therapy (1 vs. > 1) and disease status after last therapy (refractory or relapsed with treatment-free interval < vs. > 6 months). Serum/urine protein electrophoresis (SPEP/UPEP) were performed by a central laboratory at the start of each 21-day treatment cycle to assess disease status until confirmed disease progression. Response or progression by non-SPEP/UPEP or by local laboratory SPEP/UPEP were adjudicated by an independent reviewer blinded to treatment arms and all responses were assessed using modified EBMT and Uniform Criteria. Survival status was assessed every 3 months. Progression-free survival (PFS) after randomization was the primary endpoint. Overall survival (OS) and response rate were secondary endpoints. Toxicity was assessed using version CTCAE 3.0 across both arms and for all grades of adverse events encountered, with attribution assessed locally and centrally as part of standard monitoring practice for safety.

Between March 2010 and March 2013 (3 years), 135 pts were randomized (PERI=69, placebo=66) at 48 study sites. At that point, 80 events (progression or death) had been observed and the first planned interim analysis was performed by an independent data safety and monitoring committee. Baseline demographics were reasonably balanced between groups: age < 65 years (PERI=61%, placebo=42%), male (PERI=60%, placebo= 56%), ECOG PS 0 (PERI=57%, placebo=54%), and pts with > 1 line of prior therapy, relapse and treatment-free ≥ 6 months (PERI=39%, placebo=38%). PFS was PERI=22.7 weeks, placebo=39 weeks (HR 1.269 [0.817, 1.969], p=0.287). In contrast, median OS was PERI=141.9 weeks, placebo=83.3 weeks which was actuarially in favor of PERI but did not achieve significance (HR 0.734 [0.380, 1.419], p=0.356). Similarly, clinical benefit rate (CBR=SD or >) was as follows: PERI=46.4%, placebo=43.9%, with best ORR (CR+PR) PERI=20.3%, placebo=27.3%, which was historically low for both arms in this setting, and suggests relatively resistant disease in the pts selected and available for analysis. Encouragingly, no safety concerns were observed between PERI and placebo. Limited study logistics and enrollment challenges resulted in very slow accrual, in particular early on in the conduct of the trial, and as a result substantially constrained the sample size. The study was subsequently discontinued following the recommendation of the monitoring committee.

Although OS was greater by first interim analysis, this Phase III study showed no benefit in PFS or ORR when adding PERI to BTZ and DEX in pts with highly resistant, relapsed and refractory MM previously treated with BTZ at the time of this pre-planned early evaluation of outcome. Tolerability appeared favorable at the dose of PERI selected. Slow accrual and small sample size restrict the ability to definitively interpret these results further. However, other signal tranduction pathway inhibitors of Akt and NFkB continue in development for pts with advanced MM, and are demonstrating promising early results, thus supporting additional study for this potentially important class of anti-MM agents.

Richardson:Aeterna Zentaris: Advisory Committee Other; Celgene: Advisory Committee, Advisory Committee Other; Millennium: Advisory Committee, Advisory Committee Other; J & J: Advisory Committee, Advisory Committee Other. Hari:Celgene: Consultancy; Onyx: Consultancy. Martinez-Lopez:Celgene: Honoraria, Research Funding. Ghobrial:Onyx: Advisoryboard Other; BMS: Advisory board, Advisory board Other, Research Funding; Noxxon: Research Funding; Sanofi: Research Funding. Sportelli:Keryx Biopharmaceuticals, Inc.: Employment, Equity Ownership. Chen:Aeterna Zentaris: Consultancy; Keryx Biopharmaceuticals, Inc.: Consultancy. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership.