A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group
A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group
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DOI：
10.1002/pbc.27077
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发表时间：
2018-08-01
影响因子：
3.2
通讯作者：
Weigel, Brenda J.
中科院分区：
文献类型：
--
作者：
Chuk, Meredith K.;Widemann, Brigitte C.;Weigel, Brenda J.
BackgroundWe进行了一项1期试验，以确定最大耐受剂量（MTD），毒性特征，药代动力学（PK），药效学（PD），和卡博替尼在儿童难治性或复发性实体瘤的初步活性。结果41例患者，中位（范围）年龄13（4-18）岁，接受卡博替尼达到每周累积剂量相当于30（n=6），40（n=23）。或55（n=12）mg/m2/天。在40 mg/m2/d剂量下，剂量限制性毒性（DLT）为掌跖红斑综合征、粘膜炎、丙氨酸氨基转移酶、脂肪酶和胆红素升高。剂量为55 mg/m2/d时，高血压、可逆性后部白质脑病综合征、头痛、疲劳和蛋白尿为DLT。常见的非DLT包括腹泻、甲状腺功能减退、疲乏、恶心、呕吐、肝转氨酶升高和蛋白尿。在后续周期中，所有剂量水平均发生DLT。在所有剂量水平中，稳态暴露和峰值卡博替尼浓度相似。4例患者出现了确认的部分缓解：甲状腺髓样癌（MTC; n=2）、肾母细胞瘤和透明细胞肉瘤。7例患者（MTC [n=2]、尤文肉瘤、滑膜肉瘤、腺泡状软组织肉瘤、副神经节瘤和室管膜瘤）病情稳定（>6个周期），未达到方案定义的MTD;在所有剂量水平的第一个和随后的周期中发生DLT和毒性剂量降低。基于毒性特征、药代动力学和反应，卡博替尼在患有难治性实体瘤的儿科患者中的推荐剂量为40 mg/m2/天。正在进行卡博替尼的2期研究。
BackgroundWe conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors.MethodsPatients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed.ResultsForty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n=6), 40 (n=23). or 55 (n=12) mg/m(2)/day. At 40mg/m(2)/d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55mg/m(2)/d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n=2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n=2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma).ConclusionsA protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40mg/m(2)/day. A phase 2 study of cabozantinib is being conducted.