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Background: Regorafenib, a multikinase inhibitor targeting VEGFR1-3, PDGFR, TIE-2, RET, c-KIT, is approved for the treatment of adults ith advanced CRC and GIST. This study assessed its safety, PK, maximum toleratedrecommended phase 2 dose MTDRP2D in pediatric patients. The study as run in ITCC sites. Methods: Patients 6 months to lt 18 years ith histologically confirmed recurrentrefractory solid tumors received tablets or granulates QD for the first 21 days of each 28-day cycle. Starting dose of 60 mgm2 as based on a physiology-based PK PBPK model developed in adults and scaled to children 218 years, and estimated to 80 percent of the adult exposure of total regorafenib after multiple dosing. Doses of 60,72,82, and 93 mgm2day ere assessed by a rolling-6 design. The PBPK model as updated in real time to support dose escalation decisions. Results: 41 patients, median 13 years 317 , 20 ith central nervous system tumors, 11 ith sarcomas, received a median of 2 cycles 116 . Dose-limiting toxicities ere thrombocytopenia at 60 mgm2, rash at 72 mgm2, pyrexia at 82 mgm2, hypertension and exfoliative dermatitis at 93 mgm2. MTD as defined as 82 mgm2 but due to a higher rate of grade 34 hematologic events in heavily pretreated patients than in adults, RP2D as determined as 72 mgm2. 98 percent 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 percent , hyperbilirubinemia 42 percent , thrombocytopenia 37 percent , AST increase 34 percent , and fatigue, nausea, ALT increase 32 percent each . The observed exposure of regorafenib and its metabolites at all dose levels as similar to the adult exposure in 80160 mg dose range. One partial response as seen in a patient ith rhabdomyosarcoma, ith stable disease of at least 15 eeks in 8 patients, including 31 and 56+ eeks in 2 anaplastic ependymomas. Conclusions: The toxicity of regorafenib in pediatric patients as tolerable and consistent ith the knon adult profile, although increased hematologic toxicity as observed in heavily pretreated patients. The RP2D as 72 mgm2, estimated to be 100 percent of adult exposure after multiple dosing based on the PBPK model. Clinical trial information: lta href=http:clinicaltrials.govshoNCT02085148 NCT02085148,J Clin Oncol 34, 2016 suppl; abstr 10542 ,NCT02085148,00:00.0,Pediatric Oncology