Geller James I, Perentesis John P, Liu Xiaowei, Minard Charles G, Kudgus Rachel A, Reid Joel M, Fox Elizabeth, Blaney Susan M, Weigel Brenda J
Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH.
Children's Oncology Group, Monrovia, CA.
Pediatr Blood Cancer. 2017 Nov;64(11). doi: 10.1002/pbc.26565. Epub 2017 Apr 27.
The c-Met receptor tyrosine kinase is dysregulated in many pediatric cancers. Tivantinib is an oral small molecule that inhibits the c-Met receptor tyrosine kinase. A phase 1 and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with relapsed/refractory solid tumors.
Oral tivantinib capsules were administered twice daily with food, continuously in 28-day cycles. Dose levels 170, 200, and 240 mg/m /dose were evaluated using a rolling-six design (Part A). In Part B, subjects received tivantinib powder sprinkled on food at the recommended phase 2 dose (RP2D) from Part A. PK, CYP2C19 genotyping, and baseline tumor tissue c-Met expression were analyzed.
Thirty-six patients were enrolled: 20 in Part A, 6 in a PK expansion cohort, and 10 in Part B. Fifteen patients had primary central nervous system tumors and 21 had solid tumors. In Part A, there were no dose-limiting toxicities. One grade 4 intracranial hemorrhage occurred in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m ). PK analysis showed marked interpatient variability (20-fold) in the C and AUC across all dose levels. Sprinkling tivantinib powder over food did not alter exposure. Membranous and total c-Met expression was moderate (2), low (4), or not detected (26). Two patients had stable disease as the best response.
The RP2D of tivantinib given with food in children with refractory solid tumors is 240 mg/m /dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase 1 trial.
c-Met受体酪氨酸激酶在许多儿童癌症中存在失调。替万替尼是一种口服小分子，可抑制c-Met受体酪氨酸激酶。在复发/难治性实体瘤患儿中进行了一项评估替万替尼的1期和药代动力学（PK）试验。
口服替万替尼胶囊，每日两次，与食物同服，以28天为周期持续给药。采用滚动6例设计评估170、200和240mg/m²/剂量的剂量水平（A部分）。在B部分，受试者接受A部分推荐的2期剂量（RP2D）的替万替尼粉末撒在食物上。分析了PK、CYP2C19基因分型和基线肿瘤组织c-Met表达。
共纳入36例患者：A部分20例，PK扩展队列6例，B部分10例。15例患者患有原发性中枢神经系统肿瘤，21例患有实体瘤。在A部分，没有剂量限制毒性。在扩展的PK队列（240mg/m²）中，一名患有进行性脑肿瘤的患者发生了1例4级颅内出血。PK分析显示，所有剂量水平下，患者间的Cmax和AUC存在显著差异（20倍）。将替万替尼粉末撒在食物上不会改变药物暴露。膜性和总c-Met表达为中度（2例）、低度（4例）或未检测到（26例）。2例患者的最佳反应为病情稳定。
难治性实体瘤患儿与食物同服替万替尼的RP2D为240mg/m²/剂量。替万替尼在儿童中的PK显示出高度变异性。在这项1期试验中未观察到客观反应。
