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 Recruiting

Clinical Trial Summary

This phase II trial determines if the combination of ONC201 with different drugs, panobinostat or paxalisib, 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. 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

-NOT CURRENTLY ENROLLING COHORTS 1, 2, or 3-

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).

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).

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 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/phases).

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/phases).

XXII. To assess single cell ribonucleic acid (RNA) sequencing in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases).

XXIII. To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics. (All cohorts/phases) XXIV. To assess Health-Related Quality of Life (HRQOL) and cognitive measures. (All cohorts/phases).

XXV. To assess participants and/or proxy satisfaction with study participation via participant-reported outcome (PRO) measures. (All cohorts/phases).

XXVI. To assess on therapy toxicity and survival in the context of race, ethnicity and other health related social risks. (All cohorts/phases).

XXVII. To assess volumetric measurements of tumor in correlation with median OS. (All cohorts/phases).

XXVIII. To assess MR spectroscopy of tumor in correlation with radiographic response, ONC201 exposure and median PFS and OS. (All cohorts/phases).

COHORT DESCRIPTIONS:

-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.

****

Participants who are currently not eligible for defined combination arms are assigned to Cohort 4 and participants whose tumor demonstrates specific molecular alterations considered targetable by an approved/available agent are assigned to Cohort 5.

****

COHORTS 4A & 4B: Includes participants with DMGs who are not otherwise eligible for any alternative clinical trial containing ONC201 such as ONC201-108 ACTION trial, participants who will receive radiation therapy as part of their standard-of-care treatment are also allowed to receive ONC201 with radiation or re-irradiation therapy.

COHORT 5: Includes participants whose tumor demonstrates specific molecular alterations considered targetable by an approved/available agent(s) and recommended by the PNOC022 tumor board.

-NOT CURRENTLY ENROLLING - COMBINATION COHORTS 1, 2 and 3: Participants are randomized to 1 of 3 arms.

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.

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. ;

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
• Contact: Kelly Hitchner
• Phone: (415) 502-1600
• Email: PNOC022@ucsf.edu
• Status: Recruiting
• Phase: Phase 2
• Start date: October 20, 2021
• Completion date: June 30, 2029