Phase I dose-escalation and pharmacokinetic (PK) study of regorafenib in pediatric patients with recurrent or refractory solid malignancies.

10542 Background: Regorafenib, a multikinase inhibitor targeting VEGFR1-3, PDGFR, TIE-2, RET, c-KIT, is approved for the treatment of adults with advanced CRC and GIST. This study assessed its safety, PK, maximum tolerated/recommended phase 2 dose (MTD/RP2D) in pediatric patients. The study was run in ITCC sites. Methods: Patients 6 months to < 18 years with histologically confirmed recurrent/refractory solid tumors received tablets or granulates QD for the first 21 days of each 28-day cycle. Starting dose of 60 mg/m2 was based on a physiology-based PK (PBPK) model developed in adults and scaled to children 2–18 years, and estimated to 80% of the adult exposure of total regorafenib after multiple dosing. Doses of 60, 72, 82, and 93 mg/m2/day were assessed by a rolling-6 design. The PBPK model was updated in real time to support dose escalation decisions. Results: 41 patients, median 13 years (3–17), 20 with central nervous system tumors, 11 with sarcomas, received a median of 2 cycles (1–16). Dose-limiting toxicities were thrombocytopenia at 60 mg/m2, rash at 72 mg/m2, pyrexia at 82 mg/m2, hypertension and exfoliative dermatitis at 93 mg/m2. MTD was defined as 82 mg/m2 but due to a higher rate of grade 3/4 hematologic events in heavily pretreated patients than in adults, RP2D was determined as 72 mg/m2. 98% of patients had at least one adverse event considered drug related, the majority grades 1 or 2, most frequent being skin and subcutaneous disorders (76%), hyperbilirubinemia (42%), thrombocytopenia (37%), AST increase (34%), and fatigue, nausea, ALT increase (32% each). The observed exposure of regorafenib and its metabolites at all dose levels was similar to the adult exposure in 80–160 mg dose range. One partial response was seen in a patient with rhabdomyosarcoma, with stable disease of at least 15 weeks in 8 patients, including 31 and 56+ weeks in 2 anaplastic ependymomas. Conclusions: The toxicity of regorafenib in pediatric patients was tolerable and consistent with the known adult profile, although increased hematologic toxicity was observed in heavily pretreated patients. The RP2D was 72 mg/m2, estimated to be 100% of adult exposure after multiple dosing based on the PBPK model. Clinical trial information: NCT02085148.