Phase I Results of Perifosine (KRX-0401) in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma (MM)

INTRODUCTION: Perifosine (Peri) a novel, oral signal transduction modulator with multiple effects including inhibition of Akt and activation of JNK, has demonstrated clinical activity when combined with dexamethasone (Dex) in patients (pts) with relapsed/refractory MM (ASH 2007 #1164). Lenalidomide (Revlimid^®, Rev) a novel, oral immunomodulatory drug has single-agent activity against MM and additive effects when combined with Dex. We previously reported encouraging safety data and observed clinical activity of the oral triplet combination in the first 12 pts (ASH 2007 # 1169). We now report the phase I results of this study which aimed to determine the MTD and activity of Peri + Rev + Dex, as an oral combination in pts with relapsed or refractory MM.

METHODS: Four cohorts (≥6 pts each) were planned, dosing Peri at 50 or 100mg (daily), Rev 15 or 25mg (d 1–21) and Dex 20mg (d 1–4, 9–12 and 17–20 for 4 cycles, then 20 mg d 1–4) in 28-d cycles. To limit dex-related toxicities, the protocol was amended to use weekly dex (40 mg), applying to cohorts 3, 4, and the MTD cohort. Toxicity was assessed using NCI CTCAE v3.0; DLT was defined as grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <25,000/mm³ on >1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Pts had to have received at least 1 prior therapy and no more than 4. Pts refractory to Rev/Dex were excluded.

RESULTS: 32 pts (17 men and 15 women, median age 61 y, range 37 – 80) were enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg); 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg); 8 pts in cohort 3 (Peri 100mg, Rev 15mg, Dex 40mg/wk); 6 pts in cohort 4 (Peri 100mg, Rev 25mg, Dex 40mg/wk) and 6 pts at MTD (Cohort 4). Median prior lines of treatment was 2 (range 1–4). Prior therapy included dex (94%), thalidomide (83%), bortezomib (47%), and stem cell transplant (47%). 37% of pts had progressed on prior Thal/Dex. Two pts did not complete one full cycle (noncompliance and adverse event not related to study drugs – both in cohort 3) and were not included in the safety and efficacy analysis. Of the 30 pts evaluable for safety, the most common (≥ 10%) grade 1/2 events included nausea (13%); diarrhea (17%); weight loss (17%); upper respiratory infection (23%); fatigue (30%); thrombocytopenia (20%); neutropenia (20%); hypophosphatemia (23%); increased creatinine (23%); anemia (36%); hypercalcemia (47%). Grade 3/4 adverse events ≥ 5% included neutropenia (20%); hypophosphatemia (17%); thrombocytopenia (13%); anemia (10%), fatigue (7%). There was one reported DLT in cohort 3 (Nausea). Rev was reduced in 8 pts, Peri reduced in 8 pts and Dex reduced in 6 pts. All 30 pts in the analysis are evaluable for response, with best response as follows:

As of August 2008, the median time to progression (TTP) for pts achieving ≥ PR is 31 wks (range 11–79), and the median TTP for all 30 pts is 23 wks (range 4 – 79). The median TTP has not been met with 11/30 pts continuing on active treatment. Survival for all study pts remains at 90%.

CONCLUSIONS: Patients have tolerated Peri + Rev + Dex well with manageable toxicity, and with encouraging clinical activity demonstrated by an ORR (≥ PR) of 50%. Accrual is complete and the final analysis for all pts will be presented at the meeting.