Phase I study of single-agent perifosine for recurrent pediatric solid tumors.

Abstract

9540 Background: Perifosine is a synthetic alkylphospholipid which inhibits Akt activity and also has been reported to affect the JNK and MAPK signaling pathways. Single agent trials of perifosine in adults have demonstrated responses in patients with renal cell carcinoma, advanced brain tumors, soft-tissue sarcomas, hepatocellular carcinoma, as well as in hematologic malignancies including multiple myeloma and Waldenstrom's macroglobulinemia. We sought to determine the safety of perifosine in children with recurrent solid tumors Methods: Pediatric patients with recurrent solid tumors were enrolled in a phase I, open-label, dose-escalating study to assess pharmacokinetics (PK), and to identify the maximally tolerated dose (MTD). Cohorts of 3 pts were treated at three dose levels: 25mg/m2/day, 50mg/m2/day and 75mg/m2/day using 50mg tablets of perifosine after a loading dose on D#1 Results: 9 pts (4 male, 5 female) with high-grade glioma (n=5), medulloblastoma (n=2) or neuroblastoma (n=2) have been treated to date. Their median age was 13 years (range 5-18), most were heavily pretreated, with a median of 3 prior treatment regimens (range 1-10). No DLTs were observed. No ≥ grade 3 toxicities or adverse events have been encountered. Grade 2 toxicities that were possibly related to perifosine include asthenia (22%), asymptomatic transaminase elevation (22%), neutropenia (33%), leukopenia (11%), hyperglycemia (22%), hypomagnesemia (22%), hypophosphatemia (11%), and colitis which resolved despite drug continuation (11%). Preliminary PK data resulted in the following steady state serum levels: 14.1±4μ M for dose level 1, 32.8±8.1 μ M for dose level 2, and 31.6 ±7.8μ M for dose level 3. Conclusions: Perifosine is well tolerated in children with advanced solid tumors. No significant financial relationships to disclose.