Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California, USA.
PLoS One. 2013 Jul 22;8(7):e68416. doi: 10.1371/journal.pone.0068416. Print 2013.
To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of irinotecan administered in combination with vincristine, temozolomide and bevacizumab in children with refractory solid tumors.
The study design included two dose levels (DL) of irinotecan given intravenously once daily for 5 consecutive days (DL1: 30 mg/m(2), and DL2: 50 mg/m(2)), combined with vincristine 1.5 mg/m(2) on days 1 and 8, temozolomide 100 mg/m(2) on days 1-5, and bevacizumab 15mg/kg on day 1, administered every 21 days for a maximum of 12 cycles.
Thirteen patients were enrolled and 12 were evaluable for toxicity Dose limiting toxicity observed included grade 3 hyperbilirubinemia in 1 of 6 patients on DL1, and grade 3 colitis in 1 of 6 patients on DL2. DL 2 was the determined MTD. A total of 87 cycles were administered. Myelosuppression was mild. Grade 1-2 diarrhea occurred in the majority of cycles with grade 3 diarrhea occurring in only one cycle. Grade 2 hypertension developed in two patients. Severe hemorrhage, intestinal perforation, posterior leukoencephalopathy or growth plate abnormalities were not observed. Objective responses were noted in three Wilms tumor patients and one each of medulloblastoma and hepatocellular carcinoma. Five patients completed all 12 cycles of protocol therapy.
Irinotecan 50 mg/m(2)/day for 5 days was the MTD when combined with vincristine, temozolomide and bevacizumab administered on a 21 day schedule. Encouraging anti-tumor activity was noted.
ClinicalTrials.gov; NCT00993044; http://clinicaltrials.gov/show/NCT00993044.
为了确定在难治性实体瘤患儿中联合应用伊立替康、长春新碱、替莫唑胺和贝伐单抗时的最大耐受剂量（MTD）和剂量限制毒性（DLT）。
该研究设计包括两个伊立替康静脉滴注剂量水平（DL），连续 5 天，每天 1 次（DL1：30mg/m²，DL2：50mg/m²），联合长春新碱 1.5mg/m²，第 1 和第 8 天；替莫唑胺 100mg/m²，第 1-5 天；贝伐单抗 15mg/kg，第 1 天，每 21 天 1 个周期，最多 12 个周期。
共纳入 13 例患儿，12 例可评价毒性。DL1 组 6 例中有 1 例发生 3 级高胆红素血症，DL2 组 6 例中有 1 例发生 3 级结肠炎，为剂量限制毒性。DL2 为确定的 MTD。共进行了 87 个周期的治疗。骨髓抑制较轻。大多数周期出现 1-2 级腹泻，仅有 1 个周期出现 3 级腹泻。2 例发生 2 级高血压。未发生严重出血、肠穿孔、后部白质脑病或生长板异常。3 例 Wilms 瘤患儿、1 例髓母细胞瘤和 1 例肝细胞癌患儿有客观缓解。5 例患儿完成了方案治疗的所有 12 个周期。
当伊立替康 50mg/m²/天连用 5 天，与长春新碱、替莫唑胺和贝伐单抗联合应用，21 天 1 个周期时，其 MTD 为 50mg/m²/天。观察到有令人鼓舞的抗肿瘤活性。
ClinicalTrials.gov；NCT00993044；http://clinicaltrials.gov/show/NCT00993044。
