ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors

NCT04732065 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: 200814NCI-2021-00046R01CA266596
• Study Type: interventional
• Target: 208
• Locations: 3 countries
• Sites: 6

Brief Summary

This phase I trial studies the effects and best dose of ONC206 alone or in combination with radiation therapy in treating patients with diffuse midline gliomas that is newly diagnosed or has come back (recurrent) or other recurrent primary malignant CNS tumors. ONC206 is a recently discovered compound that may stop cancer cells from growing. This drug has been shown in laboratory experiments to kill brain tumor cells by causing a so called "stress response" in tumor cells. This stress response causes cancer cells to die, but without affecting normal cells. ONC206 alone or in combination with radiation therapy may be effective in treating newly diagnosed or recurrent diffuse midline gliomas and other recurrent primary malignant CNS tumors.

Conditions

Glioblastoma; Recurrent Ependymoma; Spinal Cord Glioma; World Health Organization (WHO) Grade III Glioma; CNS Tumor; Central Nervous System Tumor; Diffuse Midline Glioma (DMG); Recurrent Malignant Central Nervous System Neoplasm

Keywords

H3 K27M-Mutant

Outcome Measures

Primary Outcomes (2)

• Proportion of participants with dose-limiting toxicities (DLT)

  A DLT is defined as a treatment-related adverse event (AE) or abnormal laboratory value that occurs in the first cycle of treatment (Cycle 1 for Arm A and D; Cycle 0 for Arm B and C), meets criteria for DLT as outlined below and is assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications, and is judged by the investigator to be related to ONC206 as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0).

  Within 4 weeks after first dose

• Maximum tolerated dose (MTD) of ONC206

  The Bayesian optimal interval (BOIN) design will be used to find the MTD within each arm. MTD is selected based on isotonic regression and this computation is implemented by the shiny app "BOIN" available at http://www.trialdesign.org. Specifically, select as the MTD the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher dose level when the isotonic estimate is lower than the target toxicity rate and select the lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate.

  Within 4 weeks after first dose

Secondary Outcomes (6)

• Mean maximum concentration (Cmax) of ONC206

  Day 1 (pre-dose, 0.5, 1, 2, 4, 8 hours (h) post-dose), Day 2 (24 h post-dose for dose 1-5), Day 3 (0.5, 1, 2, 4, and 8h post fifth treatment for dose 6-10) (up to 3 days in total)

• Mean corresponding time (Tmax) of ONC206

  Day 1 (pre-dose, 0.5, 1, 2, 4, 8 hours (h) post-dose), Day 2 (24 h post-dose for dose 1-5), Day 3 (0.5, 1, 2, 4, and 8h post fifth treatment for dose 6-10) (up to 3 days in total)

• Area under the curve (AUC) of ONC206

  Day 1 (pre-dose, 0.5, 1, 2, 4, 8 hours (h) post-dose), Day 2 (24 h post-dose for dose 1-5), Day 3 (0.5, 1, 2, 4, and 8h post fifth treatment for dose 6-10) (up to 3 days in total)

• Elimination half-life (t1/2) of ONC206

  Day 1 (pre-dose, 0.5, 1, 2, 4, 8 hours (h) post-dose), Day 2 (24 h post-dose for dose 1-5), Day 3 (0.5, 1, 2, 4, and 8h post fifth treatment for dose 6-10) (up to 3 days in total)

• Mean Total body clearance (CL) for ONC206

  Day 1 (pre-dose, 0.5, 1, 2, 4, 8 hours (h) post-dose), Day 2 (24 h post-dose for dose 1-5), Day 3 (0.5, 1, 2, 4, and 8h post fifth treatment for dose 6-10) (up to 3 days in total)

Study Arms (4)

Arm A: ONC206 for participants with diffuse midline gliomas + prior therapy

EXPERIMENTAL

Participants receive ONC206 orally (PO) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment can proceed up to 24 months.

Drug: ONC206; Procedure: Optional Proton (1H) MR spectroscopy (MRS)

Arm B: ONC206 + radiation therapy for newly diagnosed participants

EXPERIMENTAL

Participants undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment can proceed up to 24 months.

Drug: ONC206; Radiation: Standard of Care Radiation Therapy; Procedure: Optional Proton (1H) MR spectroscopy (MRS)

Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreated

EXPERIMENTAL

Participants undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment can proceed up to 24 months.

Drug: ONC206; Radiation: Standard of Care Radiation Therapy; Procedure: Optional Proton (1H) MR spectroscopy (MRS)

Arm D: ONC206 Therapy, Primary malignant CNS tumors with progression

EXPERIMENTAL

Participants receive ONC206 PO once a day (QD) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment can proceed up to 24 months.

Drug: ONC206; Procedure: Optional Proton (1H) MR spectroscopy (MRS)

Interventions

Optional Proton (1H) MR spectroscopy (MRS) PROCEDURE

Optional imaging procedure

Also known as: MRS

Arm A: ONC206 for participants with diffuse midline gliomas + prior therapy; Arm B: ONC206 + radiation therapy for newly diagnosed participants; Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreated; Arm D: ONC206 Therapy, Primary malignant CNS tumors with progression

ONC206 DRUG

Given orally (PO)

Also known as: antagonist of dopamine receptor D2 (DRD2) /human mitochondrial caseinolytic protease P (ClpP)ClpP Agonist, DRD2 antagonist/ClpP agonist

Arm A: ONC206 for participants with diffuse midline gliomas + prior therapy; Arm B: ONC206 + radiation therapy for newly diagnosed participants; Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreated; Arm D: ONC206 Therapy, Primary malignant CNS tumors with progression

Standard of Care Radiation Therapy RADIATION

Undergo RT

Also known as: Radiation Therapy (RT), Cancer Radiotherapy

Arm B: ONC206 + radiation therapy for newly diagnosed participants; Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreated

Eligibility Criteria

• Age: 2 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• ARM A: Children and young adults with DMG, H3K27 altered (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) who completed at least one line of prior therapy. Prior treatment must have included focal radiation therapy and patients must be within 4-14 weeks from completion of radiation therapy to registration (patients must start treatment within 1 week from registration), have not started any other therapies post-radiation, and have no evidence of disease progression.
• ARM A: Tumor tissue confirmation of DMG, H3K27 altered is mandatory and pathology must be consistent with a DMG, H3K27 altered.
• ARM A: Participants must have recovered from all acute side effects of prior therapy.
• ARM A: From the projected start of scheduled study treatment, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team)
• ARM B: Newly diagnosed children and young adults (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) with a diagnosis of DMG, H3K27 altered are eligible, including spinal cord DMGs.
• ARM B: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG, H3K27 altered.
• ARM C: Children and young adults with DMGs (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) who have evidence of progression but have not been treated for this progression and are recommended to get re-irradiation.
• ARM C: Patients must have undergone prior focal radiation therapy as part of their initial therapy and should be at least 6 months from prior radiation therapy. If timing is less than 6 months from prior focal radiation, these patients need to be discussed with the study chair(s).
• ARM C: Tumor tissue confirmation is mandatory and pathology must be consistent with a DMG, H3K27 altered.
• ARM C: Participants must have recovered from all acute side effects of prior therapy
• ARM C: From the projected start of scheduled study treatment, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team)
• ARM D: Children and young adults with recurrent primary malignant CNS tumors, excluding DMGs, (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) who have evidence of progression but have not been treated for this progression. Participants who received a surgical resection for that progression are eligible if surgery has no curative intent. These patients need to be discussed with the study team.
• ARM D: Prior tumor tissue confirmation is mandatory and pathology from the primary tumor must be consistent with malignant CNS tumor (diagnosis of ependymoma is allowed).Tissue at the time of progression is not required.
• ARM D: Participants must have recovered from all acute side effects of prior therapy
• ARM D: From the projected start of scheduled study treatment, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team). Bevacizumab used for pseudoprogression does not require a wash out period.

You may not qualify if:

• Arm C \& D: Patients who participated in trials investigating ONC201 in the upfront setting will not be eligible. Prior ONC201 exposure as part of PNOC022 or expanded access programs will be allowed.
• Participants who are currently receiving another investigational drug are not eligible.
• Participants who are currently receiving other anti-cancer agents are not eligible.
• Participants with a known disorder that affects their immune system, such as human immunodeficiency virus (HIV) or hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy are not eligible. Note: Participants that are currently using inhaled, intranasal, ocular, topical or other non-oral or non-intravenous (IV) steroids are not necessarily excluded from the study but need to be discussed with the study chair.
• Participants with uncontrolled infection.
• Female participants of childbearing potential must not be pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy.
• Active illicit drug use or diagnosis of alcoholism.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC206.
• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant or family.
• Any participants with illnesses that may affect absorption of ONC206.
• Any participants on strong inhibitors or inducers of CYP3A4, 2D6, 1A2, 2C9 and 2C19 at least 14 days prior and throughout the study.

Sponsors & Collaborators

• Jazz Pharmaceuticals: collaborator
• Mithil Prasad Foundation: collaborator
• Storm the Heavens Fund: collaborator
• National Cancer Institute (NCI): collaborator
• Dana-Farber Cancer Institute: collaborator
• Sabine Mueller, MD, PhD: lead
• The ChadTough Defeat DIPG Foundation: collaborator

Study Sites (6)

University of California, San Francisco

San Francisco, California, 94143, United States

RECRUITING

Emory University

Atlanta, Georgia, 30322, United States

RECRUITING

University of Michigan

Ann Arbor, Michigan, 48109, United States

RECRUITING

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

Princess Máxima Center for Pediatric Oncology

Utrecht, 3584, Netherlands

RECRUITING

The University Children's Hospital in Zurich

Zurich, Canton of Zurich, 8032, Switzerland

RECRUITING

Related Publications (2)

• Tzaridis T, Liu J, Chien FL, Malhotra A, Zhu D, Gershon I, Zhang H, Velazquez Vega JE, Schniederjan M, Sposito T, Adams PD, Allen JE, Prabhu VV, Wechsler-Reya RJ, MacDonald TJ. ONC206 demonstrates potent anti-tumorigenic activity and is a potential novel therapeutic strategy for high-risk medulloblastoma. bioRxiv [Preprint]. 2025 Sep 29:2025.09.25.678693. doi: 10.1101/2025.09.25.678693.

  PMID: 41256696 DERIVED

• Przystal JM, Cianciolo Cosentino C, Yadavilli S, Zhang J, Laternser S, Bonner ER, Prasad R, Dawood AA, Lobeto N, Chin Chong W, Biery MC, Myers C, Olson JM, Panditharatna E, Kritzer B, Mourabit S, Vitanza NA, Filbin MG, de Iuliis GN, Dun MD, Koschmann C, Cain JE, Grotzer MA, Waszak SM, Mueller S, Nazarian J. Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas. Neuro Oncol. 2022 Sep 1;24(9):1438-1451. doi: 10.1093/neuonc/noac041.

  PMID: 35157764 DERIVED

MeSH Terms

Conditions

Glioblastoma; Ependymoma; Central Nervous System Neoplasms

Interventions

ONC206; Radiotherapy; Radiation; Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Neoplasms by Site; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Physical Phenomena; Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Sabine Mueller, MD, PhD

  University of California, San Francisco

  STUDY CHAIR

Central Study Contacts

PNOC Operations

CONTACT

(415) 502-1600; PNOC023@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 26, 2021
• First Posted: February 1, 2021
• Study Start: August 23, 2021
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): July 31, 2027
• Last Updated: March 17, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL

Locations

US (4); CH (1); NL (1)