Phase II Trial of Perifosine (KRX-0401) in Relapsed and/or Refractory Waldenström Macroglobulinemia: Preliminary Results.
Authors: Ghobrial Irene M. , Leleu Xavier , Rubin Nancy , Nelson Marybeth , Leduc Renee , Warren Diane , Allen Jana , Lovecchio Sue , Soumerai Jacob , Sportelli Peter , Birch Robert , Henderson Craig , Treon Steven P. , Richardson Paul , Anderson Kenneth C. 
Published: October 2019

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 with WM and that the AKT inhibitor perifosine induces significant growth inhibition in vitro and in vivo in xenograft models in WM. Phase I trials with perifosine have demonstrated a favorable side effect profile. This phase II study aimed to determine safety and activity of the oral AKT inhibitor perifosine in patients with relapsed/refractory WM.
METHODS: Patients 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. All patients received 150 mg perifosine daily for 28 days per cycle for 6 cycles; response was assessed after 2 cycles.
RESULTS: 28 pts (20 men and 8 women, median age 64.8 years, range 51 – 80) have been treated to date. The median number of lines of prior treatment was 2 (range 1 – 5). The median IgM at baseline was 3245 mg/dL (range 972– 8480); median M-spike at baseline was 1.9 g/dL (range 0.5 – 4.85); and median hemoglobin was 11.3 g.dL (7.0–14.0). The median follow up was 5 months (range 1 – 8 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil. and bortezomib. 21 pts are currently evaluable for response, best response to single agent perifosine after 2 cycles are presented in Table 1. Median duration of response has not been reached. None of the patients progressed while on therapy with perifosine. The median M spike reduction was 20% (0 – 76). Patients tolerated perifosine well without significant toxicities: grade 3 nausea/vomiting in 1 patient resolved with dose reduction to 100 mg; grade 3 anemia in one patient was related to cold-agglutinin hemolytic anemia; and 2 patients had GI bleeding unrelated to therapy. Dose reduction (to 100 mg/d) was required in 4 patients; 2 for nausea and loss of weight, 1 for non-specific bone pain and 1 for an episode of fever and fatigue. Four patients discontinued therapy, one for cold-aggutinin related hemolytic anemia related to WM, one due to corneal ulceration that was possibly related to perifosine and corneal infection, and 2 for patient decision. Attributable toxicities otherwise proved manageable with appropriate supportive care and perifosine was generally well tolerated, with no peripheral neuropathy.
CONCLUSIONS: Oral perifosine as monotherapy has been well tolerated and demonstrates encouraging activity achieving PR + MR in 34%, and/or stabilization of disease in 66% of evaluable patients with relapsed WM. Updated data will be presented at the meeting.
Table 1 Response N=21; ORR (CR+PR+MR)=34% Median time to best response (months) Partial response 2(10%) 5 Minimal response 5 (24%) 4 (3–6) Stable Disease (SD) 14 (66%) NA Progressive Disease 0