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Published on: July 31, 2016
Phase I study of perifosine monotherapy in patients with recurrent or refractory neuroblastoma
Kimikazu Matsumoto1, Hiroyuki Shichino2, Hiroshi Kawamoto3
1Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
Purpose:
Perifosine is an alkylphospholipid analog that inhibits or modulates signaling through signal transduction pathways such as Akt, which is enhanced in neuroblastoma (NB) by activation of tyrosine kinase receptors. We conducted a phase I study of perifosine in Japanese patients with recurrent or refractory NB.
Experimental Design:
All patients enrolled were over 2 years of age; all had refractory or relapsed NB and a performance status of greater than 50%. Perifosine was orally administered at a loading dose (100-300 mg) on day 1 and at a maintenance dose (50-150 mg) from day 2 onward. Dose-limiting toxicity (DLT) and pharmacokinetics were assessed in Step 1 and safety and efficacy in Step 2.
Results:
Nineteen patients were recruited. No DLT was observed. Adverse reactions occurring in more than 30% of the patients were vomiting (63%), nausea (53%), and diarrhea (37%). The mean plasma concentration of perifosine was 27.5 ± 9.8 μM on day 15 and 27.3 ± 11.5 μM on day 29. The response rate (RR) in 18 patients evaluable according to modified International Neuroblastoma Response Criteria was 0%; the disease control rate (DCR) was 56%. Median progression-free survival (PFS) was 122 days. In 11 patients evaluable according to the Response Evaluation Criteria in Solid Tumors, the RR and DCR were 9% and 55%, respectively. The median PFS was not reached.
Conclusions:
Perifosine monotherapy was well tolerated in Japanese patients with recurrent/refractory NB. Further investigations in combination with other anticancer or molecular targeted agents are warranted.
Insights
Perifosine, an Akt pathway inhibitor, was evaluated in Japanese patients with neuroblastoma (NB). The drug was well-tolerated, showing manageable side effects and warrants further investigation in combination therapies for NB.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Neuroblastoma (NB) often exhibits enhanced Akt signaling due to tyrosine kinase receptor activation.
- Perifosine, an alkylphospholipid analog, targets signaling pathways including Akt.
Purpose of the Study:
- To assess the safety and efficacy of perifosine in Japanese patients with recurrent or refractory neuroblastoma.
- To determine dose-limiting toxicity (DLT) and pharmacokinetics of perifosine in this patient population.
Main Methods:
- A phase I study involving oral administration of perifosine to Japanese patients with relapsed/refractory NB.
- Dose escalation and safety assessments were conducted, with efficacy evaluated using modified International Neuroblastoma Response Criteria and Response Evaluation Criteria in Solid Tumors.
Main Results:
- Nineteen patients were enrolled; no dose-limiting toxicity was observed.
- Common adverse reactions included vomiting (63%), nausea (53%), and diarrhea (37%).
- The overall response rate was low (0-9%), but the disease control rate was 55-56%, with a median progression-free survival of 122 days in one cohort.
Conclusions:
- Perifosine monotherapy demonstrated good tolerability in Japanese patients with recurrent/refractory NB.
- Further research is recommended to explore perifosine in combination with other anticancer or molecular targeted agents for neuroblastoma treatment.
