ONC201 in Adults With Recurrent H3 K27M-mutant Glioma

NCT03295396 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: ONC013
• Study Type: interventional
• Target: 73
• Locations: 1 country
• Sites: 9

Brief Summary

This was a Phase 2, open-label, 2-arm study of dordaviprone (ONC201) in patients with recurrent H3 K27M- mutant glioma. The primary assessment of dordaviprone (ONC201) involved evaluating its anti-tumor activity through the overall response rate according to the Response Assessment in Neuro-Oncology (RANO) criteria for high-grade glioma (HGG).

Conditions

Glioma

Outcome Measures

Primary Outcomes (1)

• Number of Patients With Overall Response

  Quantitative thresholds for objective response by Response Assessment in Neuro-Oncology (RANO) criteria for target lesions on radiographic imaging are Complete Response (CR) is the disappearance of all target lesions; Partial Response (PR) requires a ≥50% decrease in the sum of products of perpendicular diameters of target lesions from baseline. Other considerations for RANO response include assessments of non-target lesions, corticosteroids, and performance status. The Overall Response Rate is the proportion of patients who achieve either CR or PR. Tumor assessments were conducted at 8 weeks (±1 week) following the initiation of therapy and every 8 weeks (±1 week) thereafter. All patients who received at least one dose of dordaviprone (ONC201) were included in the analysis, including patients with diffuse intrinsic pontine glioma (DIPG) or primary spinal tumors, which are historically not assessable for response using RANO-HGG criteria due to anatomical or imaging limitations.

  From first dose of study treatment through study completion, an average of 1 year

Secondary Outcomes (1)

• Duration of Response (DOR)

  From objective response (complete response or partial response) per RANO to disease progression or death, up to 40.6 months.

Study Arms (2)

Arm A

EXPERIMENTAL

Patients received 625 mg dordaviprone (ONC201) once weekly. Arm A included patients with recurrent H3 K27M-mutant glioma including those with diffuse intrinsic pontine glioma (DIPG), primary spinal tumors, and some atypical histologies.

Drug: Dordaviprone (ONC201)

Arm B

EXPERIMENTAL

Patients received 625 mg dordaviprone (ONC201) once weekly. Arm B included patients with recurrent H3 K27M-mutant glioma, but excluded patients with the following: * Primary malignant lesion located in the pons or spinal cord. * Atypical non-astrocytic histologies such as ependymoma, ganglioma and pleomorphic xanthoastrocytoma, or pilocytic astrocytoma and subependymal giant cell astrocytoma (SEGA). * Prior bevacizumab treatment of \>4 doses of \>7.5 mg/kg

Drug: Dordaviprone (ONC201)

Interventions

Dordaviprone (ONC201) DRUG

Dordaviprone (ONC201) is a central nervous system (CNS)-penetrant, small-molecule imipridone that acts as a mitochondrial caseinolytic protease P (ClpP) agonist and a dopamine receptor D2 (DRD2) antagonist.

Also known as: Dordaviprone

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Had histologically confirmed diagnosis of high-grade glioma (HGG) in any tumor sample and presence of histone H3 K27M mutation detected in a Clinical Laboratory Improvement Amendment (CLIA) certified laboratory by immunohistochemistry or DNA sequencing test on any glioma tumor sample.
• Had unequivocal evidence of progressive disease on contrast-enhanced brain computed tomography (CT) or magnetic resonance imaging (MRI) as defined by Response Assessment in Neuro-Oncology (RANO)-HGG criteria, or have documented recurrent glioma on diagnostic biopsy.
• Had measurable disease by RANO-HGG criteria.
• Patients must have had previous therapy with at least radiotherapy.
• Had no more than two prior episodes of recurrence from radiotherapy and/or chemotherapy. Use of bevacizumab solely for treatment of radiation necrosis, pseudoprogression, or treatment effect was not considered a recurrence.
• Had an interval of at least 90 days from the completion of radiotherapy to the first dose of dordaviprone (ONC201). If patients were within 90 days of radiotherapy, they may have still been eligible if they met one or more of the following criteria.
• Progressive tumor is outside the original high-dose radiotherapy target volume as determined by the treating investigator, or
• Histologic confirmation of tumor through biopsy or resection, or
• Nuclear medicine imaging, magnetic resonance (MR) spectroscopy, or MR perfusion imaging consistent with true progressive disease, rather than pseudoprogression or radiation necrosis obtained within 28 days of registration.
• From the projected start of scheduled study treatment, the following time periods must have had elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.
• All adverse events Grade \>1 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must have been resolved to Grade 1 or baseline, except for alopecia and sensory neuropathy Grade ≤2, or other Grade ≤2 not constituting a safety risk based on investigator's judgment, are acceptable.
• Were male or female aged ≥18 years.
• Had a Karnofsky Performance Status (KPS) ≥60.
• Had adequate organ and marrow function as defined below, all screening labs should be performed within 14 days of treatment initiation:
• leukocytes ≥ 3,000/mcL

You may not qualify if:

• Arm B: Had a primary malignant lesion located in the pons or spinal cord.
• Arm B: Had atypical non-astrocytic histologies such as ependymoma, ganglioma and pleomorphic xanthoastrocytoma, or pilocytic astrocytoma and subependymal giant cell astrocytoma (SEGA).
• Arm B: Had prior bevacizumab treatment of \>4 doses of \>7.5 mg/kg
• Had a history of allergic reactions attributed to compounds of similar chemical or biologic composition to dordaviprone (ONC201) or its excipients.
• Had current or planned participation in a study of an investigational agent or using an investigational device.
• Had presence of diffuse leptomeningeal disease or evidence of cerebrospinal fluid (CSF) dissemination.
• Had uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
• Had an active infection requiring systemic therapy.
• Were pregnant and/or breastfeeding women or unable to maintain use of contraception while on study and for 30 days after the last dose of study drug. Dordaviprone (ONC201) is a novel agent with unknown potential for teratogenic or abortifacient effects.
• Had known HIV-positive test on combination antiretroviral therapy.
• Had known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias or bradycardia, unless arrhythmia is controlled and after Cardiology has cleared patient to receive dordaviprone (ONC201). Receiving therapeutic agents known to prolong QT interval will be excluded. History of congested heart failure (CHF), or myocardial infarction (MI) or stroke in the last 3 months will be excluded.
• Had active illicit drug use or diagnosis of alcoholism.
• Had tumors with known IDH1 (isocitrate dehydrogenase 1) or known IDH2 mutations as determined by immunohistochemistry for the IDH1 R132H variant or by direct sequencing. IDH1/2-mutant gliomas have a markedly longer overall survival rate compared to those with IDH1/2-wildtype glioma (Parsons et al., 2008; Yan et al., 2009), indicating IDH1/2-mutant gliomas have a distinct natural history.
• Had tumors with known 1p/19q co-deletion.
• Had known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ melanoma, or in situ cervical cancer that has undergone potentially curative therapy.

Sponsors & Collaborators

• Jazz Pharmaceuticals: lead
• Oncoceutics, Inc.: collaborator

Study Sites (9)

University of California, San Francisco

San Francisco, California, 94143-0112, United States

Location

Stanford Cancer Center

Stanford, California, 94305, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

New York University School of Medicine

New York, New York, 10016, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Levine Cancer Institute

Charlotte, North Carolina, 28204, United States

Location

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Arrillaga-Romany I, Gardner SL, Odia Y, Aguilera D, Allen JE, Batchelor T, Butowski N, Chen C, Cloughesy T, Cluster A, de Groot J, Dixit KS, Graber JJ, Haggiagi AM, Harrison RA, Kheradpour A, Kilburn LB, Kurz SC, Lu G, MacDonald TJ, Mehta M, Melemed AS, Nghiemphu PL, Ramage SC, Shonka N, Sumrall A, Tarapore RS, Taylor L, Umemura Y, Wen PY. ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma. J Clin Oncol. 2024 May 1;42(13):1542-1552. doi: 10.1200/JCO.23.01134. Epub 2024 Feb 9.

  PMID: 38335473 DERIVED

MeSH Terms

Conditions

Glioma

Interventions

TIC10 compound

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Limitations and Caveats

The Sponsor terminated this study based on the initiation of a randomized Phase 3 study of dordaviprone (ONC201) in an earlier setting; closing this study ensured enrollment would not compete with the Phase 3 study. The decision was not related to any safety concerns with dordaviprone (ONC201). At the time enrollment was halted, some treatment arms had not completed enrollment. Note: This study did not assess response using RANO 2.0, as these criteria were established after study initiation.

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Chimerix, Inc.

clinicaltrials@chimerix.com

919-806-1074

Study Officials

• Allen Mellemed, MD

  Chimerix, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 1, 2017
• First Posted: September 27, 2017
• Study Start: October 30, 2017
• Primary Completion: December 31, 2022
• Study Completion: July 19, 2023
• Last Updated: July 28, 2025
• Results First Posted: July 28, 2025

Record last verified: 2025-07

Locations

US (9)