Combination Therapy for the Treatment of Diffuse Midline Gliomas

Diffuse Intrinsic Pontine Glioma Clinical Trial

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

Status Active, not recruiting

Clinical Trial Summary

This phase II trial determines if the combination of ONC201 with different drugs, panobinostat or paxalisib, is effective for treating patients with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for patients with DMGs, and there are few treatment options. ONC201, panobinostat, and paxalisib are all enzyme inhibitors that may stop the growth of tumor cells by clocking some of the enzymes needed for cell growth. This phase II trial assesses different combinations of these drugs for the treatment of DMGs.

Clinical Trial Description

OUTLINE: Participants will be randomized at study entry to one of the three study arms and subsequently will be included in one to three phases, and one of 3 cohorts depending on their stage of disease and prior treatment. 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). 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; 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; target validation phase). III. To assess changes in immune cell infiltration in DMG tumor tissue after 1 or 2 doses of ONC201 (All cohorts; target validation phase). IV. To assess correlation of intratumoral concentration of ONC201 with clinical outcome (All cohorts; target validation phase). V. To assess correlation of intratumoral drug concentration of novel agents with clinical outcome. (All cohorts; target validation phase). VI. To assess if intratumoral ONC201 concentrations differ in irradiated versus nonirradiated tumor tissue. (All cohorts; target validation phase). VII. To assess if intratumoral concentrations of novel agents differ in irradiated versus nonirradiated tumor tissue. (All cohorts; target validation phase). VIII. To assess tumor tissue biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts; target validation phase). IX. To assess efficacy of combination therapy ONC201 and novel agent based on overall survival at 12 months (OS12). (All cohorts; maintenance combinations). X. To assess toxicity of combination therapy ONC201 and novel agents. (All cohorts; 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 cerebrospinal fluid (CSF) biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases). XIX. 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/phases). XX. To assess single cell ribonucleic acid (RNA) sequencing in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases). XXI. To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics. XXII. To assess Health-Related Quality of Life (HRQOL) and cognitive measures. (All cohorts/phases). XXIII. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures. (All cohorts/phases). COHORT DESCRIPTIONS: 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. 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. 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. TREATMENT ARM DESCRIPTIONS: ARM 2: During the trial validation phase, patients without prior biopsy receive ONC201 PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. ARM 4: During the trial validation phase, patients without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity. ARM 6: During trial validation phase, patients without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. After completion of study treatment, patient are followed every 12 months. ;

Related Conditions & MeSH terms

• Diffuse Intrinsic Pontine Glioma
• Diffuse Midline Glioma, H3 K27M-Mutant
• Glioma
• Recurrence
• Recurrent Diffuse Intrinsic Pontine Glioma
• Recurrent WHO Grade III Glioma
• WHO Grade III Glioma

• NCT number: NCT05009992
• Study type: Interventional
• Source: University of California, San Francisco
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 20, 2021
• Completion date: June 30, 2027