Background
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 I and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with relapsed/refractory solid tumors.
Methods
Oral tivantinib capsules were administered bid with food, continuously in 28-day cycles. Dose levels 170, 200 and 240 mg/m2/dose were evaluated using a rolling 6 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.
Results
Thirty-six patients were enrolled: 20 in Part A, 6 to a PK expansion cohort, and 10 to Part B. Fifteen patients had primary CNS tumors and 21 had solid tumors. In Part A, there were no DLTs. One grade 4 intracranial hemorrhage occurred in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m2). PK analysis showed marked inter-patient variability (20-fold) in the Cmax and AUC0–8h 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 best response.
Conclusions
The RP2D of tivantinib given with food in children with refractory solid tumors is 240 mg/m2/dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase I trial.