Final Results of a Phase II Trial of the Novel Oral Akt Inhibitor Perifosine in Relapsed and/or Refractory Waldenstrom Macroglobulinemia (WM).
Authors: Ghobrial Irene M. , Leleu Xavier , Rubin Nancy , Xie Wanling , Hong Fangxin , Chuma Stacey , Leduc Renee , Nelson Marybeth , O’Connor Kelly , Sam Amy , Harris Brianna , Warren Diane , Sportelli Peter , Treon Steven P. , Weller Edie , Anderson Kenneth C. , Richardson Paul G. 
Published: April 2020

Abstract
INTRODUCTION: Perifosine is an oral, novel synthetic alkylphospholipid, with multiple effects on signal transduction pathways, including inhibition of Akt. We previously demonstrated that Akt is upregulated in samples of patients (pts) with WM, and the Akt inhibitor perifosine induces significant growth inhibition in vitro and in vivo in xenograft models in WM. This phase II study aimed to determine the activity and safety of perifosine at a dose of 150mg in pts with relapsed/refractory WM.
METHODS: Pts who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM, and included minimal response (MR), partial response (PR) and complete response (CR). All pts received 150 mg perifosine daily for 28 days per cycle until progression or excessive toxicity.
RESULTS: The trial accrued from 10/06 to 11/07, with 37 pts (27 men and 10 women, median age 65 years, range 44 – 82) treated. Of these patients 65% were relapsed and 35% were relapsed and refractory to prior therapy. The median number of lines of prior treatment was 3 (range 1 – 5) with 35% of the patients having more than 3 lines of prior therapy. Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g. CHOP, CVP), chlorambucil, and bortezomib. Thirty-six patients are evaluable for response after at least 2 cycles of therapy. The overall response rate (PR+MR) was 36%. PR occurred in 2 (6%) patients, with a median duration of response of 9+ and 18+ months, MR occurred in 11 (30%) patients, with a median duration of response of 7 months (2–21+ months). Stable disease occurred in 21 (58%) patients, and progressive disease in 2 (6%) patients at 2 and 4 months. The most common adverse events were GI toxicities (nausea, vomiting and diarrhea) with grade 1 and 2 in 36% of the patients. Grade 3 and 4 events included anemia (9%) and leucopenia (9%). Grade 3 arthritis occurred in 9% of the pts; was considered likely related to therapy, (especially in rapidly responding pts), and reversed with symptomatic treatment as well as dose reduction. Dose reductions to 100 mg occurred in a total of 36% of the pts and were otherwise due to GI toxicity or cytopenias. As of August 2008, the progression free survival (PFS) and time to progression (TTP) are similar at a median of 10.7 months (7.2-not reached).
CONCLUSION: Perifosine monotherapy induces a prolonged time to progression in relapsed or refractory WM, with a promising response rate of 36%, stabilization of disease in 58% of pts, and manageable toxicity, as well as the convenience of oral administration. Future clinical trials in combination with rituximab are planned.