Background: Cabozantinib, an oral inhibitor of tyrosine kinases including MET, VEGFR2 and RET, is approved for adults with progressive, metastatic medullary thyroid carcinoma (MTC). We conducted a phase I and pharmacokinetic (PK) trial of cabozantinib in children with refractory solid tumors. Methods: Cabozantinib was administered daily (28 day cycles) using the rolling 6 design; 3 dose levels were evaluated. If a cohort was filled, patients (pts) with MTC could be enrolled at the previous lower dose. PK and pharmacodynamic (PD) studies were conducted in all patients, including an expanded cohort at the recommended phase 2 dose (RP2D). Results: 29 eligible (25 evaluable) pts, median age 14 yr (range, 4-18) [CNS tumor (n=6), MTC (n=3), hepatocellular carcinoma (HCC, n=2), Ewing sarcoma (EWS, n=2), other sarcomas (n=8), or other (n=8)] have received a median of 3 (range, 1-10) cycles, with 6 pts still on study. During the dose escalation phase dose-limiting toxicities (DLT) occurred in 0/6 pts at 30 and 40 mg/m² and 1/6 pts at 55 mg/m² [Gr3 fatigue and headache]. Other first cycle DLTs in expansion cohorts included: Gr 2 palmar plantar erythrodysesthesia (PPE) and oral mucositis (n=1; 40 mg/m²); Gr3 proteinuria and Gr2 hypertension (HTN) (n=1; 55 mg/m²); and Gr3 HTN and reversible posterior leukoencephalopathy syndrome (n=1; 55mg/m²). Later cycle DLTs in 10 pts include: Gr3 weight loss (n=2), Gr3 PPE (n=2), Gr3 and 4 lipase increase (n=1 each), Gr4 neutropenia (n=1), Gr2 fatigue (n=1), Gr2 arthralgia (n=1) and Gr3 anorexia, dyspnea, skin ulcer (n=1). Cabozantinib exposure was not dose proportional. The mean ± SD steady state AUC_0-24h at 30 mg/m² (n=6), 40 mg/m² (n=6) and 55 mg/m²(n=6) was 31.9 ± 7.8, 33.3 ± 11.3 and 33.7 ± 15 µg·h/mL, respectively. The median accumulation index was 3.0 (0.5-8.7). Responses will be reported. Conclusions: Based on DLTs observed in later cycles, the recommended dose of cabozantinib in children with solid tumors is 40 mg/m² (adult fixed dose ≈72 mg). Enrollment is ongoing to further assess PK and PD at the RP2D. A phase II trial is planned. Clinical trial information: NCT01709435.