Becher Oren J, Gilheeney Stephen W, Khakoo Yasmin, Lyden David C, Haque Sofia, De Braganca Kevin C, Kolesar Jill M, Huse Jason T, Modak Shakeel, Wexler Leonard H, Kramer Kim, Spasojevic Ivan, Dunkel Ira J
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina.
Pediatr Blood Cancer. 2017 Jul;64(7). doi: 10.1002/pbc.26409. Epub 2016 Dec 30.
The PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.
We performed a standard 3+3 phase I, open-label, dose-escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25-75 mg/m /day) and temsirolimus (25-75 mg/m IV weekly) were investigated.
Twenty-three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high-grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose-limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single-agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high-grade glioma; no partial or complete responses were achieved.
The combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.
PI3K/AKT/mTOR通路在包括胶质瘤和髓母细胞瘤在内的许多小儿实体瘤中异常激活。小儿胶质瘤模型的临床前数据表明，哌立福新（AKT抑制剂）和替西罗莫司（mTOR抑制剂）联合使用在抑制该信号轴方面比单独使用任何一种药物更有效。我们开展本研究以评估联合用药的药代动力学并确定最大耐受剂量。
我们对复发/难治性小儿实体瘤患者进行了一项标准的3+3期I期开放标签剂量递增研究。研究了四个剂量水平的哌立福新（25 - 75 mg/m²/天）和替西罗莫司（25 - 75 mg/m²静脉注射，每周一次）。
23例患者（中位年龄8.5岁）接受了治疗，其中脑肿瘤患者（弥漫性脑桥内生性胶质瘤[DIPG]8例、高级别胶质瘤6例、髓母细胞瘤2例、室管膜瘤1例）、神经母细胞瘤（4例）或横纹肌肉瘤（2例）。联合用药总体耐受性良好，未出现剂量限制性毒性。最常见的3级或4级毒性（至少可能相关）为血小板减少（38.1%）、中性粒细胞减少（23.8%）、淋巴细胞减少（23.8%）和高胆固醇血症（19.0%）。替西罗莫司的药代动力学结果与替西罗莫司单药II期小儿研究中观察到的结果相似，哌立福新的药代动力学结果与成人中的结果相似。11例DIPG或高级别胶质瘤患者中有9例病情稳定；未实现部分或完全缓解。
这些AKT和mTOR抑制剂联合使用对复发/难治性小儿实体瘤患者是安全可行的。
