Oral ONC201 in Adult Recurrent Glioblastoma

NCT02525692 | Terminated Phase 2 Results

• 1 other identifier: ONC006
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 5

Brief Summary

This was a Phase 2, open-label, 6-arm, multi-center study of dordaviprone (ONC201) in patients with recurrent glioblastoma (Arms A, B, and C), H3 K27M-mutant diffuse glioma (Arm D), or diffuse midline glioma (Arms E and F). The primary objective of this study was the assessment of dordaivprone (ONC201) anti-tumor activity through progression-free survival at 6 months using Response Assessment in Neuro-Oncology (RANO) criteria for high-grade glioma (HGG).

Conditions

Glioblastoma; Diffuse Midline Glioma; H3 K27M Glioma; Thalamic Glioma; Infratentorial Glioma; Basal Ganglia Glioma

Outcome Measures

Primary Outcomes (1)

• Percent of Patients With Probability of Progression-Free Survival at 6 Months

  Progression-free survival rate at 6 months was defined as the percentage of patients who exhibit progression-free survival for \>6 months.

  Progression-free survival assessments were conducted 6 months following treatment initiation.

Study Arms (6)

Arm A

EXPERIMENTAL

Patients had histologically confirmed World Health Organization Grade IV glioblastoma with any number of recurrences. Patients received 625 mg dordaviprone (ONC201) once every 3 weeks.

Drug: Dordaviprone (ONC201)

Arm B

EXPERIMENTAL

Patients had first recurrence histologically confirmed World Health Organization Grade IV glioma. Patients received 625 mg dordaviprone (ONC201) weekly (Days 1, 8, and 15 of each cycle).

Drug: Dordaviprone (ONC201)

Arm C

EXPERIMENTAL

Patients had clinical and/or radiographic evidence of first recurrence of histologically confirmed World Health Organization Grade IV glioblastoma and were eligible for salvage surgical resection. Patients received 625 mg dordaviprone (ONC201) weekly (Days 1, 8, and 15 of each cycle). Surgical resection was performed approximately 24 hours after at least the second dose of ONC201.

Drug: Dordaviprone (ONC201)

Arm D

EXPERIMENTAL

Patients had confirmed World Health Organization Grade IV glioma with H3 K27M mutation (any number of recurrences were allowed). Patients received 625 mg dordaviprone (ONC201) weekly (Days 1, 8, and 15 of each cycle).

Drug: Dordaviprone (ONC201)

Arm E

EXPERIMENTAL

Patients had clinical and/or radiographic evidence of midline glioma (recurrent disease was not required) and were eligible for salvage surgical resection. Patients received 625 mg dordaviprone (ONC201) weekly (Days 1, 8, and 15 of each cycle). Surgical resection was performed approximately 24 hours after at least the second dose of dordaviprone (ONC201).

Drug: Dordaviprone (ONC201)

Arm F

EXPERIMENTAL

Patients had diffuse midline glioma involving the brainstem, thalamus, or spinal cord, without the H3 K27M mutation or with unknown H3 mutation status. Patients received 625 mg dordaviprone (ONC201) weekly (Days 1, 8, and 15 of each cycle).

Drug: Dordaviprone (ONC201)

Interventions

Dordaviprone (ONC201) DRUG

Dordaviprone (ONC201) is a brain-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; Arm C; Arm D; Arm E; Arm F

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• A patient had to meet all of the following criteria to be eligible to participate in the study:
• For Arms A, B, and C: Had histologically confirmed World Health Organization (WHO) Grade IV glioblastoma. For Arm D: Must have had a WHO Grade IV glioma and the tumor must have harbored a 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. The H3 K27M mutation was often reported as H3 K28M in gene sequencing assays. For Arm E: Must have had clinical and/or radiographic evidence of a midline glioma (involving the brainstem, thalamus, spinal cord, hypothalamus, basal ganglia, brainstem \[non-diffuse intrinsic pontine glioma (DIPG)\], cerebellum, cerebellar peduncle, midline cortex, corpus collosum, pineal region, optic tract, or optic chiasm), and was eligible for salvage surgical resection as deemed by the site Investigator. For Arm F: Must have had a diffuse midline glioma that involved the brainstem, thalamus, or spinal cord, without the H3 K27M mutation or with unknown H3 mutation status at the time of enrollment.
• Had previous first line therapy with at least radiotherapy and temozolomide. For patients who had tumors that exhibited unmethylated MGMT promoter, prior treatment with temozolomide was not required. For Arms D, E, and F: Must have had previous first line therapy with at least radiotherapy.
• For Arm A and D: Any number of recurrences were allowable. For Arm B: Must have been first recurrence (only) WHO Grade IV glioma. First recurrence was defined as the progression following initial therapy (i.e., radiation ±chemotherapy). For patients who had prior therapy with radiation or chemotherapy for a low-grade glioma (LGG), the surgical diagnosis of the HGG was considered the first recurrence. For patients who did not receive additional treatment following surgery and diagnosis of the LGG, surgical diagnosis of HGG was not considered the first recurrence. Instead, progression after treatment was considered first recurrence. For Arm C: Patients must have had clinical and/or radiographic evidence of first recurrence of glioblastoma and must have been eligible for salvage surgical resection as deemed by the site Investigator. For Arm E: Recurrent disease was not required. Patients must have had a midline glioma, and must have been eligible for salvage surgical resection as deemed by the site Investigator.
• Had an interval of at least 90 days from the completion of radiotherapy to the first dose of ONC201. If patients were within 90 days of radiotherapy, then the progressive lesion must have been outside of the high-dose radiation target volume or must have had unequivocal evidence of progressive tumor on a biopsy specimen.
• 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), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever was shorter) from other anti-tumor therapies.
• All adverse events Grade \>1 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must have been resolved, except for alopecia.
• Were male or female aged ≥16 years.
• Had a Karnofsky Performance Status (KPS) of ≥60.
• Had adequate organ and marrow function as defined below; all screening labs should have been performed within 14 days of treatment initiation:
• leukocytes: ≥3,000/mcL
• absolute neutrophil count: ≥1,500/mcL
• platelets: ≥100,000/mcL
• hemoglobin: \>8.0 mg/dL
• total bilirubin: \<2.0 × upper limit of normal (ULN)

You may not qualify if:

• A potential patient who met any of the following criteria was ineligible to participate in the study:
• Had a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients.
• Had current or planned participation in a study of an investigational agent or using an investigational device.
• Had uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would have limited compliance with study requirements.
• Had an active infection that required systemic therapy.
• Patients who had prior stereotactic radiotherapy, convection enhanced delivery (CED) or brachytherapy must have had a biopsy to confirm radiographic progression was consistent with progressive tumor and not treatment-related necrosis. If the recurrent lesion was outside of any prior high-dose radiation target volume or distant from the prior CED or brachytherapy site, patients were considered eligible
• Was a pregnant woman because ONC201 is novel agent with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ONC201, breastfeeding should have been discontinued if the mother was treated with ONC201.
• Had known human immunodeficiency virus (HIV)-positive test on combination antiretroviral therapy.
• Had a known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias or bradycardia. Patients who were receiving therapeutic agents known to prolong QT interval were excluded. Patients who had a history of congestive heart failure, myocardial infarction, or stroke within the last 3 months were excluded.
• Had active illicit drug use or diagnosis of alcoholism.
• For Arms A, B, and C: Had prior bevacizumab treatment (this prior treatment was allowable for patients in Arms D, E, and F).
• Had tumors with known isocitrate dehydrogenase 1 (IDH1) or known IDH2 mutations as determined by immunohistochemistry for the IDH1 R132H variant or by direct sequencing.
• Had any known additional malignancies that were progressing or required active treatment within 3 years of start of study drug. Exceptions included basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that had undergone potentially curative therapy.
• Had undergone any surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2 weeks of baseline disease assessments; or were not fully recovered from any side effects of previous procedures.
• Had concomitant use of cytochrome P450 (CYP)3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration.

Sponsors & Collaborators

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

Study Sites (5)

University of California, Los Angeles

Los Angeles, California, 90024, United States

Location

Miami Cancer Institute

Miami, Florida, 33176, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

University of Utah, Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Related Publications (3)

• 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

• Weissenrieder JS, Reed JL, Moldovan GL, Johnson MT, Trebak M, Neighbors JD, Mailman RB, Hohl RJ. Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium-dependent, non-D2 receptor-dependent, manner. Pharmacol Res Perspect. 2021 May;9(3):e00689. doi: 10.1002/prp2.689.

  PMID: 34003586 DERIVED

• Chi AS, Tarapore RS, Hall MD, Shonka N, Gardner S, Umemura Y, Sumrall A, Khatib Z, Mueller S, Kline C, Zaky W, Khatua S, Weathers SP, Odia Y, Niazi TN, Daghistani D, Cherrick I, Korones D, Karajannis MA, Kong XT, Minturn J, Waanders A, Arillaga-Romany I, Batchelor T, Wen PY, Merdinger K, Schalop L, Stogniew M, Allen JE, Oster W, Mehta MP. Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201. J Neurooncol. 2019 Oct;145(1):97-105. doi: 10.1007/s11060-019-03271-3. Epub 2019 Aug 27.

  PMID: 31456142 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

TIC10 compound

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

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 that enrollment would not be competing against the Phase 3 study. The decision to terminate the study was not related to any safety concerns with dordaviprone (ONC201). Note that at the time enrollment was halted, some treatment arms had not completed enrollment.

Results Point of Contact

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

clinicaltrials@chimerix.com

919-806-1074

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: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 14, 2015
• First Posted: August 17, 2015
• Study Start: January 1, 2016
• Primary Completion: April 17, 2023
• Study Completion: April 17, 2023
• Last Updated: December 24, 2024
• Results First Posted: December 24, 2024

Record last verified: 2024-12

Locations

US (5)