NCT03416530

ONC201 in Pediatric H3 K27M Gliomas

ONC201 in Newly Diagnosed Diffuse Intrinsic Pontine Glioma and Recurrent/Refractory Pediatric H3 K27M Gliomas

• Status: Terminated
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 134 (actual)
• Sponsor: Jazz Pharmaceuticals · Industry
• Sex: All
• Age: 2 Years – 18 Years
• Healthy volunteers: Not accepted

Summary

This was a Phase 1, open label, multicenter, 8-arm, dose escalation study of dordaviprone (ONC201) in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and recurrent/refractory H3 K27M-mutant gliomas. The primary endpoint of this study was to determine the recommended Phase 2 dose (RP2D) of dordaviprone (ONC201) in pediatric glioma patients as a single agent in combination with radiation.

Detailed description

This study was to include 8 arms; the intention for each arm is summarized below: * Arm A: To define the RP2D for single agent dordaviprone (ONC201) in pediatric patients with glioma who are positive for the H3 K27M mutation and have completed at least 1 line of prior therapy. * Arm B: To define the RP2D for dordaviprone (ONC201) in combination with radiation in pediatric patients with newly diagnosed DIPG. * Arm C: To determine intratumoral drug concentrations and biomarker expression in pediatric patients with midline gliomas. * Arm D: To determine H3 K27M DNA levels and drug concentrations in the cerebral spinal fluid (CSF) of pediatric patients with H3 K27M-mutant glioma. * Arm E: To define the RP2D for single agent dordaviprone (ONC201) when administered as a liquid formulation in Ora-Sweet to pediatric patients with DIPG and/or H3 K27M-mutant glioma. * Arm F: A dose expansion cohort to confirm the safety and estimate the efficacy of dordaviprone (ONC201) in recurrent H3 K27M-mutant glioma at the RP2D. * Arm G: To define the RP2D for single agent dordaviprone (ONC201) when administered on 2 consecutive days of each week in pediatric patients with H3 K27M-mutant glioma who have completed at least 1 line of prior therapy. * Arm H: To assess intra-tumoral concentrations following twice weekly dosing of dordaviprone (ONC201) in 2 cohorts: pediatric patients with DIPG and pediatric patients with thalamic gliomas. \*Note: This arm did not enroll any patients. Pediatric patients in Arms A through F received dordaviprone (ONC201) once weekly. Patients in Arms C, D, E, and F received dordaviprone (ONC201) at the RP2D determined in either Arm A or Arm B. Pediatric patients in Arm G received dordaviprone (ONC201) twice weekly on 2 consecutive days. Safety was also assessed, with evaluations including the reporting of adverse events, as well as measurements of vital signs, electrocardiograms, and clinical laboratory results. This study was terminated by an administrative protocol amendment (17 January 2023). The decision to terminate the study was not related to any safety concerns with dordaviprone (ONC201). Before the study was terminated a total of 134 patients were enrolled and had received at least 1 dose of dordaviprone (ONC201). At the time of the administrative protocol amendment, patient enrollment was completed in Arms A, B, C, D, E, and G, and patient enrollment was stopped prior to reaching the targeted enrollment in Arms F and H.

Conditions

• Diffuse Intrinsic Pontine Glioma
• Glioma, Malignant

Interventions

Type	Name	Description
DRUG	Dordaviprone (ONC201)	Dordaviprone is a brain-penetrant, small-molecule imipridone that acts as a mitochondrial caseinolytic protease P (ClpP) agonist and a dopamine receptor D2 (DRD2) antagonist.

Timeline

• Start date: 2018-01-25
• Primary completion: 2022-12-31
• Completion: 2023-05-24
• First posted: 2018-01-31
• Last updated: 2025-02-14

Locations

8 sites across 1 country: United States

Regulatory

• FDA-regulated drug study