Background: Perifosine is a synthetic alkylphospholipid which inhibits Akt phosphorylation and affects JNK and MAPK signaling pathways. A phase I/Ib trial on neuroblastoma (NB) suggested the efficacy of perifosine monotherapy (Kushner, BH; ANR 2012). Therefore, we conducted a phase I trial to evaluate the tolerability, safety, efficacy, and pharmacokinetics of perifosine in Japanese patients (pts) with NB.
Methods: Pts with relapsed or refractory NB after receiving standard chemotherapies were eligible. Pts received 100-300 mg/body on day 1, followed by daily maintenance doses (50-150 mg/body) until progressive disease. We assessed dose-limiting toxicities (DLTs) and pharmacokinetics in the first 10 pts, as well as safety and efficacy in all pts.
Results: A total of 19 pts were enrolled between June 2013 and March 2014. Median age was 6 years (2-22) and the median number of prior chemotherapy regimens was 3 (1-10). No DLTs were observed. The most common adverse drug reactions were vomiting (63.2%), nausea (52.6%), and diarrhea (36.8%). The frequent grade 3 or 4 adverse drug reaction was ALT increased (10.5%). According to INRC, the response rate (RR) and disease control rate (DCR) were 0% and 55.6%, respectively, and median progression-free survival (PFS) was 122 days (1-344+). According to RECIST, RR and DCR were 9.0% and 54.5%, respectively, and median PFS was not reached. The median overall survival was not also reached at 12 months after the last patient was enrolled. Plasma concentrations of perifosine on day 15 and day 29 were 27.5±9.8 μM and 27.3±11.5 μM, respectively.
Conclusion: Perifosine monotherapy was tolerable in Japanese NB pts. Although DCR was more than 50% and some pts achieved long PFS, RR did not show encouraging efficacy. Further investigation of combination therapy with other drugs is warranted.