Background: Tivantinib is an oral small molecule that inhibits the c-Met receptor tyrosine kinase (RTK), which is dysregulated in many pediatric cancers. A phase I and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with refractory solid and CNS tumors. Methods: Oral tivantib capsules were administered bid, continuously in 28-day cycles. Three dose levels (170, 200 or 240mg/m²/dose) were evaluated using a rolling 6 design (Part A). In Part B, patients received tivantinib powder sprinkled on food at the RP2D from Part A. Serial PK (day 1) and trough samples (day 28) were obtained in Cycle 1. CYP450 genotyping was performed in all participants. Results: Thirty-six patients were enrolled (24 male, median age 12.1 years (range, 3.8-21): 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. Twenty-six patients were evaluable for toxicity assessment and 32 for response. In Part A there were 0/5, 0/6 and 0/5 pts with DLT at dose levels 1-3. There was 1 grade (GR) 4 intracranial hemorrhage in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m²). Non dose-limiting toxicities at least possibly attributable to tivantinib included grade 3 or 4 myelosuppression [lymphopenia (3), neutropenia (2), anemia (2), and thrombocytopenia (1)]; Gr 1 or 2 toxicities occurring in > 10% of evaluable patients included fatigue (9), leukopenia (7), vomiting (5), nausea (5), anemia (12), neutropenia (5), lymphopenia (3), hypoalbuminemia (4), and thrombocytopenia (3). PK analysis showed marked inter-patient variability (20-fold) in the C_max and AUC_last across all dose levels. Sprinkling tivantinib powder over food did not appear to alter exposure. The average terminal elimination t_1/2 was 2.5 hours. Conclusions: The RP2D of tivantinib given with food is 240 mg/m²/dose. PK of tivantinib in children demonstrated high variability. Clinical trial information: NCT01725191.