Combination Therapy for Treating Diffuse Midline Gliomas

Sponsor: University of California, San Francisco

Sponsor score: 40

ClinicalTrials ID:NCT05009992

This clinical trial is exploring whether combining the drug ONC201 with other medications, like panobinostat or paxalisib, can effectively treat diffuse midline gliomas (DMGs), a type of brain tumor with limited treatment options. The study aims to find out if these drug combinations can stop tumor growth by blocking certain enzymes.

Patient Parameters

Parameter	Options

Program Overview

This phase II study is testing if combining ONC201 with other drugs, such as panobinostat or paxalisib, can help treat diffuse midline gliomas (DMGs). These drugs are enzyme inhibitors that may prevent tumor growth by blocking enzymes needed for cell growth. The trial will assess different combinations of these drugs to see if they can improve outcomes for patients with DMGs, a type of brain tumor that currently has few treatment options.

Description

This study is not currently enrolling participants in Cohorts 1, 2, or 3.

Study Outline:

Participants will be randomly assigned to one of three study groups and may go through one to three phases, depending on their disease stage and previous treatments.

Primary Objectives:

To evaluate the effectiveness of ONC201 combined with other drugs in patients with DMG, focusing on progression-free survival at 6 months (Cohorts 1 and 2).
To assess the effectiveness of ONC201 combined with other drugs in patients with recurrent DMG, focusing on overall survival at 7 months (Cohort 3).
To evaluate the safety and side effects of a new ONC201 dose and schedule in patients with DMG (Cohort 4).
To evaluate the safety and side effects of ONC201 combined with radiation or re-irradiation in patients with DMG (Cohort 4).
To study how the body processes the new ONC201 dose and schedule in patients with DMG (Cohort 4).
To evaluate the safety and side effects of ONC201 combined with other drugs recommended by a specialized tumor board based on tumor or cerebrospinal fluid analysis (Cohort 5).

Exploratory Objectives:

To confirm if ONC201 can penetrate the blood-brain barrier in DMGs by measuring its concentration in tumor tissue.
To confirm if other drugs can penetrate the blood-brain barrier in DMGs by measuring their concentration in tumor tissue.
To assess changes in immune cells in DMG tumor tissue after ONC201 treatment.
To correlate ONC201 concentration in tumors with clinical outcomes.
To correlate other drug concentrations in tumors with clinical outcomes.
To compare ONC201 concentrations in irradiated vs. non-irradiated tumor tissue.
To compare other drug concentrations in irradiated vs. non-irradiated tumor tissue.
To assess tumor biomarkers in relation to clinical outcomes like progression-free survival and overall survival.
To evaluate the effectiveness of ONC201 combined with other drugs based on overall survival at 12 months.
To assess the side effects of ONC201 combined with other drugs.
To assess the side effects of weekly ONC201 combined with initial radiation therapy.
To assess the side effects of twice-weekly ONC201 combined with initial radiation therapy.
To assess the side effects of other drugs combined with initial radiation therapy.
To assess the side effects of weekly ONC201 combined with re-irradiation after disease progression.
To assess the side effects of twice-weekly ONC201 combined with re-irradiation after disease progression.
To assess the side effects of other drugs combined with re-irradiation after disease progression.
To assess the side effects of ONC201 combined with other drugs after re-irradiation after disease progression.
To evaluate the effectiveness of a new ONC201 dose and schedule based on progression-free survival and overall survival.
To evaluate the effectiveness of ONC201 combined with targeted drugs recommended by a specialized tumor board based on overall survival.
To assess cerebrospinal fluid biomarkers in relation to clinical outcomes like progression-free survival and overall survival.
To assess levels of circulating tumor DNA in relation to imaging response criteria and clinical outcomes.
To assess single-cell RNA sequencing in relation to clinical outcomes.
To assess microbiome and flow cytometry studies in relation to imaging and clinical outcomes.
To assess health-related quality of life and cognitive measures.
To assess participant satisfaction with study participation through participant-reported outcome measures.
To assess treatment toxicity and survival in relation to race, ethnicity, and other health-related social risks.
To assess tumor volume measurements in relation to overall survival.
To assess MR spectroscopy of tumors in relation to radiographic response, ONC201 exposure, and progression-free survival and overall survival.

Cohort Descriptions:

Not Currently Enrolling: Cohorts 1A & 2A (Target Validation cohorts) include newly diagnosed participants who have not yet undergone tumor tissue collection. Cohort 1A includes participants with DMG who have not completed radiation therapy, and Cohort 2A includes participants with DMG who have completed radiation therapy.
Not Currently Enrolling: Cohorts 1B & 2B include newly diagnosed participants who have already undergone tumor tissue collection. Cohort 1B includes participants with DMG who have not completed radiation therapy, and Cohort 2B includes participants with DMG who have completed radiation therapy.
Not Currently Enrolling: Cohorts 3A & 3B include participants with progressive DMG. Cohort 3A includes participants planned for standard tumor tissue collection, and Cohort 3B includes participants not planned for standard tumor tissue collection.

Participants not eligible for defined combination arms are assigned to Cohort 4, and those with specific molecular alterations in their tumors are assigned to Cohort 5.

Cohorts 4A & 4B: Include participants with DMGs not eligible for other clinical trials involving ONC201, such as the ONC201-108 ACTION trial. Participants receiving radiation therapy as part of standard care may also receive ONC201 with radiation or re-irradiation therapy.
Cohort 5: Includes participants with tumors showing specific molecular alterations targetable by approved agents, as recommended by the PNOC022 tumor board.

Not Currently Enrolling - Combination Cohorts 1, 2, and 3: Participants are randomized to one of three arms.

Arm 2: During the trial validation phase, participants without prior biopsy receive ONC201 before standard biopsy. During the radiation/re-irradiation phase, participants without prior radiation or with disease progression after radiation receive weekly radiation and ONC201. During the maintenance phase, participants receive ONC201 weekly and paxalisib daily, repeating every 28 days unless there are adverse effects.
Arm 4: During the trial validation phase, participants without prior biopsy receive ONC201 before standard biopsy. During the radiation/re-irradiation phase, participants may receive ONC201 weekly during radiation. During the maintenance phase, participants receive ONC201 weekly and paxalisib, repeating every 28 days unless there are adverse effects.
Arm 6: During the trial validation phase, participants without prior biopsy receive paxalisib before standard biopsy. During the radiation/re-irradiation phase, participants without prior radiation or with disease progression after radiation receive radiation five times a week and paxalisib. During the maintenance phase, participants receive ONC201 and paxalisib, repeating every 28 days unless there are adverse effects.

After completing the study treatment, participants are followed up at 30 days and then every 3 months for up to 5 years, until they withdraw consent or pass away, whichever comes first.

Eligibility Criteria

Inclusion Criteria

Cohort 1A and 1B:
- Newly diagnosed with DMG, including spinal cord tumors, confirmed by imaging or pathology.
- Must start standard radiation therapy within 6 weeks of diagnosis.
Cohort 2A and 2B:
- Diagnosed with DMG, including spinal cord tumors, and completed standard radiation therapy.
- Must be 4-14 weeks post-radiation.
Cohort 3A and 3B:
- Diagnosed with recurrent DMG, including spinal cord tumors, and completed standard radiation therapy.
- Must show disease progression without prior treatment for this progression or re-irradiation.
Cohort 4A and 4B:
- Diagnosed with DMG or recurrent DMG, including spinal cord tumors.
- Not eligible for other ONC201 clinical trials.
Cohort 5:
- Diagnosed with DMG or recurrent DMG, including spinal cord tumors.
- Not eligible for other ONC201 clinical trials.
- Tumor must have specific molecular changes targetable by approved agents, such as BRAFV600E, PDGFRA, FGFR1, or NF1.

All Cohorts:

Age 2 to 39 years.
Must have recovered from prior therapy side effects.
Body weight must be at least 10 kg to receive ONC201.
Must meet specific time requirements after previous treatments.
Use of bevacizumab for radiation-induced swelling is allowed.
Prior use of temozolomide or dexamethasone is allowed.
Must have stable or decreasing corticosteroid dose before MRI.
Must meet specific blood count and organ function criteria.
No breathing difficulties or exercise intolerance.
Must meet specific glucose and cholesterol levels.
No history of heart failure or long QT syndrome.
Must have adequate heart function if at risk for heart disease.
Seizure disorder must be well controlled.
Must agree to use contraception if of childbearing potential.
Must meet specific performance scores.
Must provide adequate tumor tissue samples.
Must understand and sign informed consent.

Exclusion Criteria

Cohort 1A and 1B:
- Prior radiation therapy.
- Thalamic and cerebellar H3K27M DMG.
Cohort 2A and 2B:
- Tumors without pontine or spinal cord epicenter.
- Thalamic and cerebellar H3K27M DMG treated with standard radiation without concurrent therapy.
Cohort 1A and 2A:
- Not suitable for tissue resection/biopsy.
Cohort 3A and 3B:
- Prior re-irradiation for tumor progression.
- Previous ONC201 trial participants in the upfront setting.
- Thalamic and cerebellar H3K27M DMG.
Cohort 4:
- Thalamic and cerebellar H3K27M DMG, except those treated with ONC201/ONC026 before 2024.
Cohort 5:
- Thalamic and cerebellar H3K27M DMG, except those treated with ONC201/ONC026 before 2024.
- Drug-specific exclusion criteria.

All Cohorts:

Previous ONC201 trial participants in the upfront setting.
Diagnosis of histone H3 wildtype grade II diffuse astrocytoma.
Currently receiving another investigational drug.
Currently receiving other anti-cancer agents.
Known immune system disorders or infections like HIV or hepatitis.
Uncontrolled infection or systemic illness.
Female participants must not be pregnant or breastfeeding.
Active drug use or alcoholism.
Allergic reactions to similar study drugs.
Evidence of widespread disease or CSF dissemination.
Additional malignancy requiring treatment within 3 years.
Use of certain enzyme inhibitors or inducers before the study.
Concurrent corticosteroids are allowed.

Locations

FACILITY	ZIP	CITY	STATE
University of Alabama at Birmingham	35233	Birmingham	Alabama
Children's Hospital Los Angeles	90027	Los Angeles	California
University of California, San Diego / Rady Children's Hospital, San Diego	92123	San Diego	California
University of California, San Francisco	94143	San Francisco	California
Children's National Hospital	20010	Washington	District of Columbia
Indiana University Riley Children's Hospital	46202	Indianapolis	Indiana
Johns Hopkins University	21287	Baltimore	Maryland
Dana-Farber Cancer Institute Harvard University	02215-6024	Boston	Massachusetts
University of Michigan	48109	Ann Arbor	Michigan
Children's Minnesota	55404	Minneapolis	Minnesota

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