A Multiple Myeloma Research Consortium (MMRC) Multicenter Phase I Trial of Perifosine (KRX-0401) in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma (MM): Updated Results
A. Jakubowiak, T. Zimmerman, M. Alsina, PG. Richardson, J. Kaufman, C. Brozo, T. Kendall, A. McAllister, C. Leister, T. Hideshima, P. Sportelli, R. Birch, I.C. Henderson, K. Giusti, K. Anderson. Univ. of Michigan Cancer Ctr., MI; Univ. of Chicago Cancer Ctr. IL; H. Lee Moffitt Cancer Ctr.; Dana-Farber Cancer Inst., MA; Emory Winship Cancer Inst., GA: Keryx Biopharmaceuticals, Inc.,NY: Multiple Myeloma Research Foundation, CT
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 single-agent activity against MM and 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 perifosine to Rev/Dex may therefore enhance its clinical activity. This phase 1 study aimed to determine MTD and activity of Peri + Rev + Dex, as an oral combination in pts with relapsed or refractory (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 <25,000/mm3 on >1 occasion despite transfusion. Response is assessed by modified EBMT criteria.
Results:
12 pts (6 men and 6 women, 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 and 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 Creatine | 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) to Peri + Rev + Dex 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) | 1* (11%) | 16 |
| Progression (PD) | 2 (22%) | 8, 4 |
|
stable disease (SD): < 25% reduction in M-protein *1 pt off treatment in cycle 5 due to symptomatic PD with SD of M-protein at end of study |
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7/10 pts remain on study. Conclusions: Although early, 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 pts results in this phase I will be updated at the meeting.
