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).
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Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only
Timeframe: 6 months after diagnosis
Progression-free survival at 6 months (PFS6) - Cohorts 2A, 2B Only
Timeframe: 6 months after diagnosis
Overall survival at 7 months (OS7) - Cohort 3A & 3B Only
Timeframe: 7 months after administration of ONC201 in the maintenance phase
Proportion of participants reporting dose-limiting toxicities (DLTs) (Cohort 4)
Timeframe: Up through the first cycle of maintenance therapy, approximately 8 months
Number of participants requiring dose modification through first cycle of maintenance (Cohort 5)
Timeframe: Up through the first cycle of maintenance therapy, approximately 8 months
Maximum tolerated number of intratumor infusions of DNX-2401, with a maximum of 6, in participants with thalamic or pontine DMG who have completed radiotherapy (Cohort 6)
Timeframe: A maximum of 6 infusions will be administered every 30 days - approximately 8 months