Jannier Sarah, Kemmel Véronique, Sebastia Sancho Consuelo, Chammas Agathe, Sabo Amelia-Naomie, Pencreach Erwan, Farace Françoise, Chenard Marie Pierre, Lhermitte Benoit, Geoerger Birgit, Aerts Isabelle, Frappaz Didier, Leblond Pierre, André Nicolas, Ducassou Stephane, Corradini Nadège, Bertozzi Anne Isabelle, Guérin Eric, Vincent Florence, Velten Michel, Entz-Werle Natacha
Pediatric Onco-Hematology Unit, University Hospital of Strasbourg, 67098 Strasbourg, France.
Laboratory of Biochemistry, University Hospital of Strasbourg, 67098 Strasbourg, France.
Cancers (Basel). 2020 Oct 20;12(10):3051. doi: 10.3390/cancers12103051.
Hypoxic environment is a prognostic factor linked in pediatric cancers to a worse outcome, favoring tumor progression and resistance to treatments. The activation of mechanistic Target Of Rapamycin (mTor)/hypoxia inducible factor (HIF)-1 pathway can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a phase I trial associating both drugs in pediatric refractory/relapsing solid tumors. Patients were enrolled according to a 3 + 3 escalation design with ten levels, aiming to determine the MTD (maximum tolerated dose) of rapamycin plus irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m/day), associating biweekly intravenous irinotecan (125 to 240 mg/m/dose). Toxicities, pharmacokinetics, efficacy analyses, and pharmacodynamics were evaluated. Forty-two patients, aged from 2 to 18 years, were included. No MTD was reached. Adverse events were mild to moderate. Only rapamycin doses of 1.5 mg/m/day reached over time clinically active plasma concentrations. Tumor responses and prolonged stable disease were associated with a mean irinotecan area under the curve of more than 400 min.mg/L. Fourteen out of 31 (45.1%) patients had a non-progressive disease at 8 weeks. Most of them were sarcomas and brain tumors. For the phase II trial, we can then propose biweekly 125 mg/m irinotecan dose with a pharmacokinetic (PK) follow-up and a rapamycin dose of 1.5 mg/m/day, reaching a blood concentration above 10 g/L.
缺氧环境是与儿童癌症预后较差相关的一个因素，它有利于肿瘤进展和对治疗产生抗性。雷帕霉素和伊立替康可分别作用于机制性雷帕霉素靶蛋白（mTor）/缺氧诱导因子（HIF）-1通路的激活。因此，我们设计了一项I期试验，将这两种药物联合用于儿童难治性/复发性实体瘤。患者按照3 + 3剂量递增设计入组，共十个剂量水平，旨在确定雷帕霉素加伊立替康的最大耐受剂量（MTD）。雷帕霉素在28天周期内每日口服一次（1至2.5mg/m²/天），每两周联合静脉注射伊立替康（125至240mg/m²/剂量）。对毒性、药代动力学、疗效分析和药效学进行了评估。纳入了42名年龄在2至18岁之间的患者。未达到MTD。不良事件为轻至中度。随着时间推移，只有1.5mg/m²/天的雷帕霉素剂量达到了临床活性血浆浓度。肿瘤反应和疾病长期稳定与伊立替康曲线下平均面积超过400min.mg/L相关。31名患者中有14名（45.1%）在8周时疾病无进展。其中大多数是肉瘤和脑肿瘤。对于II期试验，我们随后可以建议每两周使用125mg/m²的伊立替康剂量并进行药代动力学（PK）随访，雷帕霉素剂量为1.5mg/m²/天，使血药浓度达到10μg/L以上。
