Matsumoto Kimikazu, Shichino Hiroyuki, Kawamoto Hiroshi, Kosaka Yoshiyuki, Chin Motoaki, Kato Koji, Mugishima Hideo
Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.
Department of Pediatrics, National Center For Global Health and Medicine, Tokyo, Japan.
Pediatr Blood Cancer. 2017 Nov;64(11). doi: 10.1002/pbc.26623. Epub 2017 May 18.
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.
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.
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.
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.
哌立福新是一种烷基磷脂类似物，可通过Akt等信号转导途径抑制或调节信号传导，酪氨酸激酶受体激活会使神经母细胞瘤（NB）中的Akt信号增强。我们对日本复发性或难治性NB患者进行了哌立福新的I期研究。
所有入组患者年龄均超过2岁；均患有难治性或复发性NB，且体能状态大于50%。第1天给予哌立福新负荷剂量（100 - 300mg）口服，从第2天起给予维持剂量（50 - 150mg）。在第1阶段评估剂量限制性毒性（DLT）和药代动力学，在第2阶段评估安全性和疗效。
招募了19名患者。未观察到DLT。超过30%的患者出现的不良反应为呕吐（63%）、恶心（53%）和腹泻（37%）。第15天时哌立福新的平均血浆浓度为27.5±9.8μM，第29天时为27.3±11.5μM。根据改良国际神经母细胞瘤反应标准可评估的18例患者的缓解率（RR）为0%；疾病控制率（DCR）为56%。无进展生存期（PFS）中位数为122天。根据实体瘤疗效评价标准可评估的11例患者中，RR和DCR分别为9%和55%。未达到PFS中位数。
哌立福新单药治疗在日本复发性/难治性NB患者中耐受性良好。有必要进一步开展与其他抗癌或分子靶向药物联合使用的研究。
