A Multiple Myeloma Research Consortium (MMRC) Multicenter Phase I Trial of Perifosine (KRX-0401) in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (MM): Updated Results. (2007)

Abstract 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 2006 #3582). Lenalidomide (Revlimid, Rev) a novel, oral immunomodulatory drug has additive effects when combined with Dex. Pre-clinical studies demonstrate increased cytotoxicity against MM cells when Peri is combined with Rev/Dex compared to each drug alone or in combination (Hideshima, T.et al Data on File). The addition of Peri to Rev/Dex may therefore enhance its clinical activity. This phase 1 study aimed to determine MTD and activity of Peri + Rev + Dex, in pts with 2nd or 3rd line MM. METHODS: Four cohorts (6 pts each) are 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. Toxicity assessment uses NCI CTCAE v3.0; DLT is defined as grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets &lt;25,000/mm3 on &gt;1 occasion despite transfusion. Response is assessed by modified EBMT criteria. RESULTS: 12 pts (6 M / 6 F, median age 62 y, range 40 – 78) have been enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg) and 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg). 7 pts (58%) had relapsed/refractory MM, with a median of 2 lines of prior treatment (range 1–3). Prior therapy included dex (100%), thalidomide (83%), bortezomib (58%), stem cell transplant (67%) and one patient who had relapsed on prior Rev/Dex. 10 pts have completed one full cycle of treatment and the most common adverse events (≥ 10%) have been as follows: Adverse Event Grade 1 Grade 2 Grade 3 Nausea 10% 0% 0% Vomiting 10% 0% 0% Diarrhea 30% 10% 10% Fatigue 20% 20% 10% Thrombocytopenia 10% 10% 20% Increase Creatinine 10% 10% 0% Neutropenia 0% 0% 20% Leukopenia 0% 0% 20% No DLT’s or G 4 events have been reported. Rev was reduced in 1 patient and dex was reduced in 3 pts. 9 of 12 pts are evaluable for response, with best response (EBMT and Uniform criteria) after ≥ 2 cycles was as follows: Response N (%) Duration (wks) Near Complete Response (nCR) 1 (11%) 28+ Very Good Partial Response (VGPR) 1 (11%) 21+ Partial Response (PR) 3 (33%) 31+, 12+, 8+ Minimal Response (MR) 1 (11%) 21+ Stable Disease (SD) &lt; 25% reduction in M-protein 1 (11%) 16 Progressive Disease (PD) 2 (22%) 8, 4 7/10 pts remain on study. CONCLUSIONS: Pts to date have tolerated Peri + Rev + Dex well with no unexpected toxicities and clinical activity has been noted within the first 2 cohorts with 5 of 9 (56%) of pts achieving at least PR. To limit dex-related toxicities, the protocol will be amended to use weekly Dex as per Rajkumar et al. (ASCO 2007), which will apply to cohorts 3 and 4. Accrual is ongoing and additional results will be updated at the meeting.