Phase I Trial of Selinexor in Pediatric Recurrent/Refractory Solid and CNS Tumors (ADVL1414): A Children's Oncology Group Phase I Consortium Trial.

Purpose: Selinexor is a first-in-class, central nervous system (CNS)-penetrant, oral inhibitor of exportin 1 (XPO1), the main nuclear exporter of many key tumor suppressors. We report a phase I trial of selinexor in children and adolescents with recurrent CNS and solid tumors (NCT02323880).

Patients and methods: A rolling six design was used to evaluate the maximum tolerated dose (MTD) and first dose pharmacokinetics of selinexor administered once (35-45 mg/m2) or twice (20-35 mg/m2) weekly during a 28-day cycle (part A). Ten additional patients with high-grade glioma (HGG) were treated at the MTD administered once weekly (part B).

Results: In part A, 49 patients were enrolled. Continuous twice weekly dosing was limited by extended hematologic toxicity. The MTD on a twice weekly schedule for 3 weeks on/1 week off (twice weekly 3/1) was 20 mg/m2/dose. Dose-limiting toxicities (DLTs) on this schedule included fatigue, acute reversible neurologic changes, neutropenia, thrombocytopenia, and aspartate aminotransferase/alanine aminotransferase increase. On a continuous once weekly schedule, the MTD was 35 mg/m2/dose; DLTs included seizure and thrombocytopenia. In part B (HGG expansion), there were no additional DLTs observed. Non-DLTs included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. There were no objective responses. The median number of cycles received was 1 (range, 1-9); eight of 59 patients (13.5%) received 5 to 9 cycles, five of whom had HGG.

Conclusions: Selinexor-related toxicities were primarily hematologic and neurologic, requiring dose or dose-frequency reduction. The MTD and recommended initial phase II dose of selinexor in children and adolescents with recurrent solid and CNS tumors is 35 mg/m2/dose once weekly.