Combination Therapy for the Treatment of Diffuse Midline Gliomas
brief summary
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).
detailed description
OUTLINE:
This is a multi-arm/cohort, multi-institutional, open-label trial. The study is divided into cohorts based on stage of disease (newly-diagnosed, post-radiation therapy without disease progression, and at disease progression).
---THIS STUDY IS NOT ENROLLING ON COHORTS 1, 2, AND 3 --
ENROLLING:
* Cohort 4: Participants in Cohort 4 will be treated with escalating doses of ONC201 based on evolving pharmacokinetic (PK) data available for ONC201. * Cohort 5: Participants in Cohort 5 will be treated with escalating doses of ONC201 based on evolving PK data and in combination with targeted therapy (or therapies determined by tumor molecular sequencing). * Cohort 6: Participants in cohort 6 will be treated with repeated intratumoral injections of DNX-2401.
PRIMARY OBJECTIVES:
I. To assess efficacy of combination therapy with ONC201 (ONC201) and novel agent in participants with DMG based on median progression-free survival at 6 months (PFS6) (Cohorts 1 and 2).
II. To assess efficacy of combination therapy with ONC201 and novel agent in participants with recurrent DMG based on overall survival at 7 months (OS7) (Cohort 3).
III. To assess the safety and toxicity of a revised ONC201 dose and dosing schedule in participants with DMG. (Cohort 4).
IV. To assess the safety and toxicity of a revised ONC201 dosing schedule in combination with radiation or re-irradiation in participants with DMG. (Cohort 4).
V. To evaluate the pharmacokinetic profile of a revised ONC201 dose and dosing schedule in participants with DMG. (Cohort 4).
VI. To assess the safety and toxicity of ONC201 with agent(s) that will be determined by a specialized tumor board recommendation that is based on molecular assessments of tumor tissue or cerebrospinal fluid (CSF). (Cohort 5).
VII. To determine the maximum tolerated number of intratumor infusions of DNX-2401, with a maximum of 6, in participants with thalamic or pontine DMG who completed radiotherapy. (Cohort 6, Phase 1) VIII. To assess efficacy of repeated intratumor infusions with DNX-2401 in participants with DMG based on overall survival at 15 months. (Cohort 6, expansion cohort)
official title
A Combination Therapy Trial Using an Adaptive Platform Design for Children and Young Adults With Diffuse Midline Gliomas (DMGs) Including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression