This phase II trial determines if the combination of ONC201 with different drugs is effective for treating participants with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for participants with DMGs, and there are few treatment options. This trial will utilize an adaptive platform design in that the different treatment arms for each cohort will be opened and closed based on ongoing preclinical investigation as well as evolving outcome data from the trial.
Novel agents will be continuously added to this study as pre-clinical data emerge to suggest additive or synergistic activity when combined ONC201. Should a novel agent not have an RP2D at the time of incorporation into this study, a phase 1 lead-in will be performed prior to initiation of combination therapy (via study amendment).
New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 1B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma Histone 3 lysine 27 - mutant (H3K27M); World Health Organization (WHO) grade III and IV H3 wildtype gliomas.
Must be within 6 weeks of diagnosis to begin standard of care radiation therapy on study.
Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In Cohort 2B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas.
Participants must be within 4-14 weeks of completion of radiation. Radiation should have started within 6 weeks of diagnosis.
Prior exposure to radiation therapy.
Thalamic and Cerebellar H3K27M DMG.
Thalamic and Cerebellar H3K27M DMG that has undergone standard radiation without concurrent therapy (other than temozolomide).
Prior exposure to re-irradiation for tumor progression.
Parallel
ONC201
DrugGiven orally (PO)
Radiation Therapy
RadiationUndergo radiation therapy
Paxalisib
DrugGiven PO
DNX-2401
DrugDNX-2401 is an oncolytic adenovirus that will be administered through direct intratumoral infusion of DNX-2401 via a specialized Neuro Ventricular Cannula.
6
Treatment groupsSee each treatment group below.
Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only
Percentage of participants alive and free from progression at 6 months after the diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.
Progression-free survival at 6 months (PFS6) - Cohorts 2A, 2B Only
Percentage of participants alive and free from progression at 6 months after diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.
Overall survival at 7 months (OS7) - Cohort 3A & 3B Only
OS7 is defined as the percentage of participants alive at 7 months after the initiation of the combination of the backbone (i.e., ONC201) with a novel agent given in the maintenance phase of therapy. The primary analysis for OS7 is based on the ITT population, according to treatment arm assignment. OS7 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown survival status at 7 months are considered failures (i.e., dead) for the OS7 analysis.
Proportion of participants reporting dose-limiting toxicities (DLTs) (Cohort 4)
The safety and tolerability of ONC201 at a previously untested dose will be measured by the proportion of participants reporting a DLT within the first cycle of treatment.
Click on the lead sponsor to view all of their trials.
University of California, San Francisco
Lead sponsor
The Chad-Tough Defeat DIPG Foundation
Collaborator
Mithil Prasad Foundation
Collaborator
Storm the Heavens Fund
Collaborator
National Institute of Neurological Disorders and Stroke (NINDS)
Collaborator
Jazz Pharmaceuticals
Collaborator
Neeve Kolte and Brave Ronil Foundation
Collaborator
Will Meeker Foundation
Collaborator
CV Biomanufacturing
Collaborator
Tough2gether Foundation
Collaborator
