Phase I/II Report from a Multicenter Trial of Perifosine (KRX-0401) + Bortezomib in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma Previously Treated with Bortezomib.

INTRODUCTION: Perifosine (peri) is an oral, signal transduction modulator with multiple pathway effects including inhibition of Akt and activation of JNK. In vitro, peri + bortezomib (Velcade®, Vel) shows additive cytotoxicity against MM cells with peri inhibiting Vel induced Akt activation. Peri with dexamethasone (dex) has activity in patients (pts) with advanced, relapsed/refractory MM (ASH 2006 #3582). This phase I/II study sought to determine MTD and evaluate the activity of peri plus Vel +/− dex in pts with relapsed and relapsed/refractory MM, who were either previously treated or refractory to Vel.

METHODS: 4 cohorts (at least 3 pts each) were planned, with dosing of peri 50 mg or 100 mg (daily) and Vel 1.0 or 1.3 mg/m² (d 1, 4, 8, 11) in 21-d cycles. 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; DLT was defined as any grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <10,000/mm³ on >1 occasion despite transfusion. Response was assessed by modified EBMT and Uniform criteria.

RESULTS: 18 pts (11 M/ 7 F, median age 64 y, range 42 – 87) have been enrolled; 3 pts in cohort 1 (peri 50mg, Vel 1.0mg/m²), 3 pts in cohort 2 (peri 100mg, Vel 1.0mg/m²), 6 pts in cohort 3 (peri 50mg, Vel 1.3mg/m²) and 6 pts in cohort 4 (peri 100mg, Vel 1.3mg/m²). 14 pts (78%) had relapsed/refractory MM, with a median of 5 lines of prior treatment (range 2–7). Prior therapy included Vel (100%), dex (89%), thalidomide (67%), lenalidomide (33%) and SCT (56%). 16/18 pts were evaluable for toxicity with most common AE’s as follows:

No DVT and no G3 peripheral neuropathy have been reported. 1 pt had peri reduced to 50mg due to persistent G2 nausea and 3 pts had Vel reduced from 1.3 to 1.0mg/m² secondary to hematologic toxicity (n=2) and rash (n=1). 15/18 pts are evaluable for response, with best response to peri + Vel, or peri + Vel + dex after ≥ 2 cycles as follows:

Dex was added in 6/18 pts with PD, with 5 pts evaluable for response to date on the dex combination. 10 pts remain on study.

CONCLUSIONS: Peri in combination with Vel (+/− dex) was generally well tolerated and active in a heavily pre-treated pt population (78% had relapsed/refractory MM and 100% prior Vel). Responses seen in every cohort with greater toxicity reported in cohorts with 100 mg/d of peri. The phase II portion has now been initiated with peri 50 mg qhs and Vel 1.3mg/m² days 1, 4, 8 and 11 every 21 days.