A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma - A children's oncology group study
A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma - A children's oncology group study
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DOI：
10.1002/cncr.23078
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发表时间：
2007-12-01
期刊：
影响因子：
6.2
通讯作者：
Pollack, Ian F.
中科院分区：
文献类型：
--
作者：
Fouladi, Maryam;Nicholson, H. Stacy;Pollack, Ian F.
背景进行了一项替吡法尼的开放标签II期研究，以评估其在复发或难治性髓母细胞瘤（MB）/原始神经外胚层肿瘤（PNET）、高级别胶质瘤（HGG）和弥漫性脑干胶质瘤（BSG）儿童中的安全性和有效性。在2004年1月至2005年7月期间，患者入组并分层如下：分层1，复发性或难治性MB/PNET;分层2，复发性或难治性HGG;分层3，复发性或难治性BSG。患者接受tipifarnib 200 mg/m2/剂，每日两次，共21天，每28天重复一次。排除接受酶诱导抗惊厥药和其他CYP 3A 4/5诱导剂或抑制剂的患者。主要目的是估计所有分层的持续缓解率。97例患者入组研究，中位年龄为11.2岁（范围：3.2-21.9岁），81例患者可评价缓解。35例BSG患者和31例HGG患者中各有1例持续部分缓解。在15例MB/PNET患者中未观察到缓解。8例患者（3例HGG，1例MB和4例BSG）在>= 4个疗程（范围，4-25个疗程）内保持稳定。接受的疗程中位数为2个（范围：1-25个疗程）。最常见的3级和4级毒性包括中性粒细胞减少症（18.7%）、血小板减少症（14.3%）和白细胞减少症（14.3%）。HGG的6个月无进展生存率（+/-标准差）为14% +/- 6%，MB/PNET为6% +/- 6%，BSG为3% +/- 3%。结论。替吡法尼耐受性良好，但作为一种单一药物在儿童复发性中枢神经系统恶性肿瘤中几乎没有活性。
BACKGROUND. An open-label Phase II study of tipifarnib was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB)/primitive neuroectodermal tumor (PNET), high-grade glioma (HGG), and diffuse intrinsic brainstem glioma (BSG).METHODS. Between January 2004 and July 2005, patients were enrolled and stratified as follows: Stratum 1, recurrent or refractory MB/PNET; Stratum 2, recurrent or refractory HGG; and Stratum 3, recurrent or refractory BSG. Patients received tipifarnib 200 mg/m(2) per dose twice daily for 21 days repeated every 28 days. Patients who received enzyme-inducing anticonvulsants and other CYP3A4/5 inducers or inhibitors were excluded. The primary objective was to estimate the sustained response rate in all strata.RESULTS. Ninety-seven patients with a median age of 11.2 years (range, 3.2-21.9 years) were enrolled on the study, and 81 patients were evaluable for response. One of 35 patients with BSG and 1 of 31 patients with HGG had a sustained partial response. No responses were observed in 15 patients with MB/PNET. Eight patients (3 HGG, 1 MB, and 4 BSG) remained stable for >= 4 courses (range, 4-25 courses). The median number of courses received was 2 (range, 1-25 courses). The most frequent grade 3 and 4 toxicities included neutropenia (18.7%), thrombocytopenia (14.3%), and leukopenia (14.3%). The 6-month progression-free survival rate (+/- standard deviation) was 14% +/- 6% for HGG, 6% +/- 6% for MB/PNET and 3% +/- 3% for BSG.CONCLUSIONS. Tipifarnib tolerated well but had little activity as a single agent in children with recurrent central nervous system malignancies.