Clinical experience of ONC201 in patients with recurrent H3 K27M-mutant spinal cord glioma.

Abstract

2563 Background: High-grade gliomas of the spinal cord are a rare and understudied entity, representing < 5% of all spinal cord tumors. Reported median survival times range from 10-16 months. Up to 53% of tumors harbor the H3 K27M mutation, which is associated with an unfavorable prognosis. Postsurgical treatment often includes radiation ± temozolomide, although the role of chemotherapy has not been conclusively established. At recurrence, there are no effective therapies and most clinical studies exclude patients with spinal cord tumors. We report our clinical experience with ONC201, a small molecule DRD2 antagonist and caseinolytic protease P agonist, in patients with recurrent H3 K27M-mutant diffuse gliomas of the spinal cord (scDG). Methods: Adults and children with recurrent H3 K27M-mutant scDG received ONC201 in two Phase II clinical trials enrolling adult recurrent H3 K27M-mutant glioma patients (NCT02525692; NCT03295396) and in one Phase I clinical trial enrolling pediatric patients (NCT03416530). Adult patients received ONC201 at the RP2D dose of 625 mg weekly and pediatric patients received the RP2D of 625 mg weekly, scaled by body weight. All patients began ONC201 as a single agent until disease progression. Five patients continued ONC201 combined with bevacizumab beyond progression. Results: As of January 15, 2020, 12 evaluable patients (adult n = 8, pediatric n = 4) received ONC201. The median age was 20.9 (range: 7-72) years. The median follow-up time for the single agent ONC201 group was 5.4 (range 1.3-9.7) months while that of the combination group is 7.4 (range 6.2-25.1) months. The median number of ONC201 doses was 10 (range: 5-39) for the ONC201 single agent group and 34 (range: 21-100) for the combination group. Five of 7 patients remain alive in the ONC201 single agent group while 3 of 5 patients remain alive in the combination group. Three patients in the ONC201 single agent group and 2 patients in the combination group continue on treatment. There were no drug-related toxicities requiring dose reduction or discontinuation. Conclusions: Treatment with ONC201 alone or combined with bevacizumab is well tolerated in patients with recurrent H3 K27M-mutant scDG and a subset of patients experiences prolonged survival that exceeds historical outcomes. Clinical trial information: NCT02525692; NCT03295396; NCT03416530 .