Phase 1 Trial of Temsirolimus in Combination with Irinotecan and Temozolomide in Children, Adolescents and Young Adults with Relapsed or Refractory Solid Tumors: A Children's Oncology Group Study
Phase 1 Trial of Temsirolimus in Combination with Irinotecan and Temozolomide in Children, Adolescents and Young Adults with Relapsed or Refractory Solid Tumors: A Children's Oncology Group Study
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DOI：
10.1002/pbc.24874
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发表时间：
2014-05-01
影响因子：
3.2
通讯作者：
Blaney, Susan
中科院分区：
文献类型：
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作者：
Bagatell, Rochelle;Norris, Robin;Blaney, Susan
背景mTOR抑制剂在儿科肿瘤模型中具有活性。在患有复发性/难治性实体瘤（包括中枢神经系统（CNS）肿瘤）的儿童中进行了mTOR抑制剂替西罗莫司（TEM）与伊立替康（IRN）和替莫唑胺（TMZ）的I期试验，在21天周期的第1天和第8天施用递增剂量的静脉内（IV）TEM。第1-5天口服（PO）IRN（50 mg/m2/剂，递增至最大90 mg/m2/剂）和TMZ（100 mg/m2/剂，递增至最大150 mg/m2/剂）。当确定最大耐受剂量（MTD），TEM频率增加到weekly.ResultsSeventy-one合格的患者（中位年龄10.9岁，范围1.0-21.5）与神经母细胞瘤（16），骨肉瘤（7），尤文肉瘤（7），横纹肌肉瘤（4），中枢神经系统（22）或其他（15）肿瘤入组。两名接受口服皮质类固醇的患者发生剂量限制性高脂血症。随后对方案进行了修订，以排除长期使用类固醇。MTD确定为TEM 35 mg/m2 IV每周一次，IRN 90 mg/m2和TMZ 125 mg/m2 PO第1-5天。在较高剂量水平下，血清丙氨酸氨基转移酶和甘油三酯升高、厌食和血小板减少是剂量限制性的。其他3级方案相关毒性包括白细胞减少症、中性粒细胞减少症、淋巴细胞减少症、贫血和恶心/呕吐。6例患者的客观反应证实了中央审查，其中三个有持续的反应，通过14 cyclesoftherapy.ConclusionThe组合TEM（35 mg/m2/剂量IV每周），IRN（90 mg/m2/剂量第1-5天）和TMZ（125 mg/m2/剂量第1-5天）PO每21天给药的儿童耐受性良好。该组合的II期试验正在进行中。儿科血液癌症2014;61：833-839。(c)2013 Wiley Periodicals，Inc.
BackgroundmTOR inhibitors have activity in pediatric tumor models. A phase I trial of the mTOR inhibitor temsirolimus (TEM) with irinotecan (IRN) and temozolomide (TMZ) was conducted in children with recurrent/refractory solid tumors, including central nervous system (CNS) tumors.MethodsEscalating doses of intravenous (IV) TEM were administered on days 1 and 8 of 21-day cycles. IRN (50mg/m(2)/dose escalated to a maximum of 90mg/m(2)/dose) and TMZ (100mg/m(2)/dose escalated to a maximum of 150mg/m(2)/dose) were administered orally (PO) on days 1-5. When maximum tolerated doses (MTD) were identified, TEM frequency was increased to weekly.ResultsSeventy-one eligible pts (median age 10.9 years, range 1.0-21.5) with neuroblastoma (16), osteosarcoma (7), Ewing sarcoma (7), rhabdomyosarcoma (4), CNS (22) or other (15) tumors were enrolled. Dose-limiting hyperlipidemia occurred in two patients receiving oral corticosteroids. The protocol was subsequently amended to preclude chronic steroid use. The MTD was identified as TEM 35mg/m(2) IV weekly, with IRN 90mg/m(2) and TMZ 125mg/m(2) PO on days 1-5. At higher dose levels, elevated serum alanine aminotransferase and triglycerides, anorexia, and thrombocytopenia were dose limiting. Additional grade 3 regimen-related toxicities included leukopenia, neutropenia, lymphopenia, anemia, and nausea/vomiting. Six patients had objective responses confirmed by central review; three of these had sustained responses through 14 cycles of therapy.ConclusionThe combination of TEM (35mg/m(2)/dose IV weekly), IRN (90mg/m(2)/dose days 1-5) and TMZ (125mg/m(2)/dose days 1-5) administered PO every 21 days is well tolerated in children. Phase 2 trials of this combination are ongoing. Pediatr Blood Cancer 2014;61:833-839. (c) 2013 Wiley Periodicals, Inc.