Combination Therapy for the Treatment of Diffuse Midline Gliomas

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, 3, and 4 -- COHORT DESCRIPTIONS: --ENROLLING-- COHORT 5: Includes participants whose tumor demonstrates specific molecular alterations of interest considered targetable by an approved/available agent(s) and recommended by the PNOC022 tumor board. Participants are also allowed to receive ONC201 monotherapy with radiation or re-irradiation therapy. Cohort 5\^1: Includes newly diagnosed participants who have already undergone tumor tissue collection and have not yet completed radiation therapy. Cohort 5\^2: Includes newly diagnosed participants who have already undergone tumor tissue collection and have completed radiation therapy. Cohort 5\^3: Includes participants with progressive DMG who are not planned for SOC tumor collection and will undergo re-irradiation. --ENROLLING-- COHORT 6: Includes participants with DMGs who have completed focal radiation therapy and are within 4-14 weeks from completion of radiation therapy without evidence of progression, who will undergo repeated intratumor DNX-2401 infusions. -NOT CURRENTLY ENROLLING- COHORTS 1A \& 2A (Target Validation cohorts); Includes newly diagnosed participants that have not yet undergone tumor tissue collection. Cohort 1A will include participants with DMG who have not yet completed radiation therapy and Cohort 2A will include participants with DMG who have completed radiation therapy. -NOT CURRENTLY ENROLLING - COHORTS 1B \& 2B: Includes newly-diagnosed participants who have already undergone tumor tissue collection. Cohort 1B will include participants with DMG who have not yet completed radiation therapy and Cohort 2B will include participants with DMG who have completed radiation therapy. -NOT CURRENTLY ENROLLING- COHORTS 3A \& 3B: Includes participants with progressive DMG. Cohort 3A will include participants planned for standard of care (SOC) tumor tissue collection. Cohort 3B will include participants not planned for SOC tumor tissue collection. The nomenclature will delineate participants previously enrolled in Cohorts 1 or 2. -NOT CURRENTLY ENROLLING - COMBINATION COHORTS 1, 2 and 3: Participants are randomized to 1 of 3 arms (Arm 2,4,6) ARM 2: During the trial validation phase, participants without prior biopsy receive ONC201 on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 weekly during radiation therapy. During the maintenance phase, participants receive ONC201 weekly and paxalisib daily. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. ARM 4: During the trial validation phase, participants without prior biopsy receive ONC201 on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants may receive ONC201 weekly during radiation therapy. During the maintenance phase, participants receive ONC201 weekly and paxalisib. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity. ARM 6: During trial validation phase, participants without prior biopsy receive paxalisib on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo radiation therapy five times a week and receive paxalisib during radiation therapy. During the maintenance phase, participants receive ONC201 and paxalisib during each cycle. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. -NOT CURRENTLY ENROLLING - COHORT 4A and 4B: Includes patients who are currently not eligible for defined combination arms of PNOC022 or other clinical trials investigating ONC201, such as ONC201-108 ACTION trial. Cohort 4A\^1: Includes newly diagnosed participants that have not yet undergone tumor tissue collection and have not yet completed radiation therapy. Cohort 4A\^2: Includes newly diagnosed participants that have not yet undergone tumor tissue collection and have completed radiation therapy. Cohort 4A\^3: Includes participants with progressive DMG who are planned for SOC tumor collection and will undergo re-irradiation. Cohort 4B\^1: Includes newly diagnosed participants who have already undergone tumor tissue collection and have not yet completed radiation therapy. Cohort 4B\^2: Includes newly diagnosed participants who have already undergone tumor tissue collection and have completed radiation therapy. Cohort 4B\^3: Includes participants with progressive DMG who are not planned for SOC tumor collection and will undergo re-irradiation. All Cohorts: After completion of study treatment, participants are followed at 30 days and then every 3 months for up to 5 years, until withdrawal of consent, or until death, whichever occurs first. 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) EXPLORATORY OBJECTIVES: I. To confirm blood brain barrier (BBB) penetration of ONC201 in DMGs by measuring the concentration of ONC201 in tumor tissue (All cohorts except Cohort 6; target validation phase). II. To confirm BBB penetration of novel agents in DMGs by measuring the concentration of drug (or metabolite) in tumor tissue All cohorts except Cohort 6; target validation phase). III. To assess changes in immune cell infiltration in DMG tumor tissue after 1 or 2 doses of ONC201 (All cohorts except Cohort 6; target validation phase). IV. To assess correlation of intratumoral concentration of ONC201 with clinical outcome (All cohorts except Cohort 6; target validation phase). V. To assess correlation of intratumoral drug concentration of novel agents with clinical outcome. (All cohorts except Cohort 6; target validation phase). VI. To assess if intratumoral ONC201 concentrations differ in irradiated versus nonirradiated tumor tissue. (All cohorts except Cohort 6; target validation phase). VII. To assess if intratumoral concentrations of novel agents differ in irradiated versus nonirradiated tumor tissue. (All cohorts except Cohort 6; target validation phase). VIII. To assess tumor tissue biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts except Cohort 6; target validation phase). IX. To assess efficacy of combination therapy ONC201 and novel agent based on overall survival at 12 months (OS12). (All cohorts except Cohort 6; maintenance combinations). X. To assess toxicity of combination therapy ONC201 and novel agents. (All cohorts except Cohort 6; maintenance combinations). XI. To assess the toxicity of weekly ONC201 in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase). XII. To assess the toxicity of twice weekly ONC201 in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase). XIII. To assess the toxicity of novel agents in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase). XIV. To assess the toxicity of weekly ONC201 in combination with re-irradiation after progression. (Cohort 3). XV. To assess the toxicity of twice weekly ONC201 in combination with re-irradiation therapy after progression. (Cohort 3). XVI. To assess the toxicity of novel agents in combination with re-irradiation after progression. (Cohort 3). XVII. To assess the toxicity of ONC201 in combination with novel agents in participants after re-irradiation after progression. (Cohort 3). XVIII. To assess efficacy of a revised ONC201 dose and dosing schedule board based on median progression free survival (PFS) and overall survival (OS). (Cohort 4). XIX. To assess efficacy of ONC201 in combination with targeted agent(s) that will be determined by a specialized tumor board based on median OS. (Cohort 5). XX. To assess cerebrospinal fluid (CSF) biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts except Cohort 6) XXI. To assess levels of circulating tumor deoxyribonucleic acid (ctDNA) in the context of imaging response criteria and clinical outcome, such as PFS6 and/or OS12. (All cohorts except Cohort 6) XXII. To assess single cell ribonucleic acid (RNA) sequencing in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts except Cohort 6) XXIII. To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics.(All cohorts except Cohort 6) XXIV. To assess Health-Related Quality of Life (HRQOL) and cognitive measures.(All cohorts except Cohort 6) XXV. To assess participants and/or proxy satisfaction with study participation via participant-reported outcome (PRO) measures. (All cohorts except Cohort 6) XXVI. To assess on therapy toxicity and survival in the context of race, ethnicity and other health related social risks. (All cohorts except Cohort 6) XXVII. To assess volumetric measurements of tumor in correlation with median OS. (All cohorts except Cohort 6) XXVIII. To assess MR spectroscopy of tumor in correlation with radiographic response, ONC201 exposure and median PFS and OS. (All cohorts except Cohort 6) XXIX. To assess the therapeutic benefit including overall survival (OS), progression-free survival (PFS), the tumor objective response rate (ORR) and proportion of pseudoprogression (PSP) (Cohort 6) XXX. To assess the persistence of DNX-2401 antigen, DNA and transcripts in the tumor in the context of imaging response criteria and clinical outcome. (Cohort 6) XXXI. To assess the changes in cellular, molecular, and immunologic variables in the tumor in context of imaging response criteria and clinical outcome. (Cohort 6) XXXII. To assess the microbiome in the context of imaging response and clinical outcome. (Cohort 6) XXXIII. To assess peripheral blood biomarkers and cfDNA studies in the context of imaging and clinical outcome. (Cohort 6) XXXIV. To assess CSF biomarkers and cfDNA studies in the context of imaging and clinical outcomes. (Cohort 6) XXXV. To assess changes in functional status and in quality of life applying the PedsQLTM (Generic Score Scale). (Cohort 6) XXXVI. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures. (Cohort 6) XXXVII. To assess on therapy toxicity in the context of race, ethnicity and other health related social risks. (Cohort 6) XXXVIII. To assess volumetric measurements of tumor in correlation with median OS. (Cohort 6) XXXIX. To assess MR spectroscopy of tumor in correlation with radiographic response. (Cohort 6)