Chheda Milan G, Wen Patrick Y, Hochberg Fred H, Chi Andrew S, Drappatz Jan, Eichler April F, Yang Daniel, Beroukhim Rameen, Norden Andrew D, Gerstner Elizabeth R, Betensky Rebecca A, Batchelor Tracy T
Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Yawkey 9 East, 55 Fruit Street, Boston, MA, 02114, USA,
J Neurooncol. 2015 Feb;121(3):627-34. doi: 10.1007/s11060-014-1680-2. Epub 2014 Dec 13.
Targeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule.
针对胶质母细胞瘤（GBM）的特定分子改变可能更有效地杀死肿瘤细胞并延长生存期。凡德他尼可抑制表皮生长因子受体和血管内皮生长因子受体2。西罗莫司可抑制雷帕霉素靶蛋白（mTOR），它是磷脂酰肌醇3-激酶信号通路的成员之一。我们试图确定凡德他尼联合西罗莫司的最大耐受剂量（MTD）和剂量限制性毒性（DLT）。招募了22例复发性GBM患者（14例男性；8例女性）。中位年龄和KPS分别为52.5岁和90%。患者未接受过抗VEGF和抗EGF治疗以及mTOR抑制剂治疗，且未服用诱导CYP3A4的药物。凡德他尼和西罗莫司按照连续每日给药方案在剂量递增队列中口服给药。10例患者进入剂量递增阶段。另外12例在MTD剂量水平入组，采用单臂、单阶段II期设计探索6个月无进展生存期（PFS6）。总共有19例患者在MTD剂量水平接受了至少一剂治疗，15例患者在MTD剂量水平完成了至少1个周期的治疗。MTD为200mg凡德他尼加2mg西罗莫司。DLT为AST/SGOT升高。最常见的毒性反应为淋巴细胞减少、疲劳、皮疹和低磷血症。对于19例在MTD剂量水平接受了至少一剂治疗的患者，包括I期组的7例患者，2例出现部分缓解[10.5%；95%CI（1，33%）]，PFS6为15.8%[95%CI（3.9，34.9%）]。凡德他尼和西罗莫司可以按照连续每日给药方案安全地联合使用。
