This is a multicenter, open-label, five 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. All patients must be 2-12 weeks from completion of first-line radiation.
Name: ONC201
Description: ONC201 is a orally active, small molecule DRD2 antagonist that kills cancer cells but not normal cells.Type: DrugONC201 in relapsed/refractory H3 K27M glioma ONC201 in newly diagnosed DIPG Midline Glioma Biopsy H3 K27M CSF Biopsy Liquid ONC201 in relapsed/refractory H3 K27M glioma
Description: Determination of recommended Phase 2 dose (RP2D) as a single agent or in combination with radiation
Measure: RP2D Time: 28 daysAllocation: Non-Randomized
Parallel Assignment
There is one SNP
ONC201 in Newly Diagnosed Diffuse Intrinsic Pontine Glioma and Recurrent/Refractory Pediatric H3 K27M Gliomas. --- K27M ---
ONC201 in Pediatric H3 K27M Gliomas This is a multicenter, open-label, five 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. --- K27M ---
ONC201 in Pediatric H3 K27M Gliomas This is a multicenter, open-label, five 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. --- K27M --- --- K27M ---
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. --- K27M ---
Arm D will determine H3 K27M DNA levels and drug concentrations in the CSF of pediatric H3 K27M-mutant glioma patients. --- K27M ---
Arm D will determine H3 K27M DNA levels and drug concentrations in the CSF of pediatric H3 K27M-mutant glioma patients. --- K27M --- --- K27M ---
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. --- K27M ---
3. Arm A: 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. --- K27M ---
Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available. --- K27M ---
Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available. --- K27M ---
Arm D: Pediatric patients with recurrent glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory), have completed at least one line of prior therapy, must be willing to undergo serial lumbar puncture to obtain cerebrospinal fluid (CSF), and must be scheduled to undergo sedated MRIs. --- K27M ---
Arm E: Patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) or have diagnosed diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible with or without histologic confirmation. --- K27M ---
Archival tumor specimen: All subjects in all arms submit at least 5 unstained slides from a tumor specimen that harbors H3 K27M mutation if archival tissue is available. --- K27M ---
For subjects in Arms A, B or E, if no archival tumor tissue is available, or if H3 K27M status of tumor is unknown, then subjects must agree to submit a post-mortem biopsy specimen. --- K27M ---
Subjects in Arm C do not require prior tumor biopsy or confirmation of the presence of the H3 K27M mutation. --- K27M ---
Subjects in Arm D must have confirmation of the presence of the H3 K27M mutation in any glioma sample prior to enrollment. --- K27M ---