Perifosine in Combination with Bortezomib and Dexamethasone Extends Progression-Free Survival and Overall Survival in Relapsed/Refractory Multiple Myeloma Patients Previously Treated with Bortezombib: Updated Phase I/II Trial Results.

INTRODUCTION: Perifosine is an orally -bioavailable, novel signal transduction modulator with multiple pathway effects including inhibition of Akt and activation of JNK. We conducted a phase I/II study of perifosine + bortezomib (Vel) +/− dexamethasone (Dex) which demonstrated encouraging safety and clinical activity in 73 evaluable Vel relapsed and Vel refractory patients (pts) (ASH 2008 # 870). Herein, we report on the updated safety, overall response rate (ORR), time to progression (TTP) and overall survival (OS) results of perifosine + Vel (+/− Dex), in multiple myeloma (MM) pts with advanced disease and who were previously relapsed from and/or refractory to Vel. METHODS: The phase I stage of the study enrolled a total of 18 pts with a selected phase II dose of perifosine 50 mg qd + Vel 1.3 mg/m² (d 1, 4, 8, 11) in 21-d cycles. The phase II enrolled 66 pts. Dex 20mg (on day of and after each Vel dose) could be added in pts with progressive disease (PD). NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by modified EBMT and Uniform criteria. RESULTS: A total of 84 pts have been enrolled comprised of 51 men and 33 women, median age 63 y (range 35 – 89): 83% of pts had relapsed/refractory MM, with a median of 5 lines of prior treatment (range 1–13). Prior therapy included Vel (100%), dex (98%), lenalidomide (75%), thalidomide (74%) and SCT (57%), with pts receiving a median of 2 prior Vel-based treatments. Seventy three pts were evaluable for response (having completed at least two or more cycles of therapy), and all 84 were assessed for safety. Most common (≥ 10%) grade 1 / 2 events included nausea, diarrhea, vomiting, fatigue and anorexia, which were manageable with supportive care and dose reductions. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia, neutropenia, anemia, hyponatremia and diarrhea. No DVT has been seen, and only 1 worsening peripheral neuropathy from grade 1 to 3 was reported, which proved reversible after treatment discontinuation. Two pts had perifosine reduced to 50 mg (GI related) in the phase 1 and 5 pts reduced to qod dosing in the phase II: 15 pts had Vel dose reductions primarily due to hematologic toxicity. No treatment related mortality was seen. Of the 11 pts who were inevaluable for efficacy, 6 were due to toxicity resulting in failure to complete two cycles or more of therapy; 3 for withdrawal of consent/ non-compliance, and 2 due to rapid disease progression within 1 cycle. ORR, TTP, and OS are as follows: As of August 2009, the median OS for all evaluable study pts and Vel relapsed pts has not been reached with 40/73 (55%) pts and 14/20 (70%) pts alive, respectively. 26/53 (49%) Vel refractory pts remain alive (range 9 mos to 3 years). The median OS for the 60/73 pts (82%) with stable disease or better is currently 33.4 mos.

Perifosine in combination with Vel (+/− dex) has been generally well tolerated and continues to demonstrate impressive activity in both heavily pre-treated, Vel-refractory pts, with an ORR of 38% and OS of 16 mos, and in Vel-relapsed pts with an ORR of 55%, a median TTP of 8.8 months and a median OS of 25 mos, to date. Moreover, 80% of pts achieved stable disease or better, with a median OS of 33.4 mos. A phase III randomized, trial evaluating perifosine vs. placebo when combined with Vel and Dex in Vel-exposed pts with relapsed and refractory MM has been granted special protocol assessment (SPA) and is expected to commence by the end of the year.

Richardson:Keryx Biopharmaceuticals: Honoraria. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Keryx Biopharmaceuticals: Consultancy.