ONC201 in Pediatric H3 K27M Gliomas

This is a multicenter, open-label, seven arm, dose escalation, phase I study of oral ONC201
in pediatric patients with newly diagnosed Diffuse Intrinsic Pontine Glioma (DIPG) and
recurrent/refractory H3 K27M gliomas. Arm A will define the RP2D for single agent ONC201 in
pediatric patients with glioma who are positive for the H3 K27M mutation (positive testing in
CLIA laboratory) and have completed at least one line of prior therapy. This will allow for
recurrent patients and also patients who have not yet recurred, but have completed radiation
and will inevitably recur based on prior clinical experience and the literature. Arm B will
define the RP2D for ONC201 in combination with radiation in pediatric patients with newly
diagnosed DIPG. Arm C will determine intratumoral drug concentrations and biomarker
expression in pediatric patients with midline gliomas. Arm D will determine H3 K27M DNA
levels and drug concentrations in the CSF of pediatric H3 K27M-mutant glioma patients. Arm E
will determine the RP2D for single agent ONC201 administered as a liquid formulation in
Ora-Sweet to patients with DIPG and/or H3 K27M glioma. Arm F is a dose expansion cohort to
confirm the safety and estimate the efficacy in recurrent H3 K27M-mutant glioma population at
the RP2D. Arm G will define the RP2D for single agent ONC201 given on two consecutive days of
each week in pediatric patients with glioma who are positive for the H3 K27M mutation and
have completed at least one line of prior therapy.

Treatment Sites in Georgia