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GlioblastomaPhase 2NCT02525692

Oral ONC201 in Adult Recurrent Glioblastoma

A Phase 2 study testing Dordaviprone (ONC201) in people with Glioblastoma and Diffuse Midline Glioma, run by Jazz Pharmaceuticals at 5 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 16 years and older
What is being tested?
Dordaviprone (ONC201)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
84 participants
Where
5 sitesUnited States
Study dates
Jan 2016to 17 Apr 2023
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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 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) high-grade glioma (HGG) criteria, or had documented recurrent glioblastoma or WHO Grade IV glioma on diagnostic biopsy. For Arm E, patients were not required to have evidence of recurrent disease for inclusion.
  • 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.
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  • 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)
  • aspartate aminotransferase/alanine aminotransferase (SGOT)/(SGPT): ≤2.5 × ULN
  • creatinine: ≤ULN OR
  • creatinine clearance: ≥60 mL/min/1.73 m2 for patients who had creatinine levels above normal.
  • Had a CT or MRI within 14 days prior to start of study drug.
  • Corticosteroid dose must have been stable or decreasing for at least 5 days prior to the baseline CT or MRI scan. For Arm B: Corticosteroid dose must have been stable or decreasing for at least 2 weeks prior to study entry.
  • The effects of ONC201 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must have agreed to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman have become pregnant or suspected that she was pregnant while she or her partner were participating in this study, she should have informed her treating physician immediately. Male subjects should have agreed to use adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy.
  • Had archival tissue for evaluation of correlative objectives (if available). Archival tissue was required for Arms B and C.
  • Had the ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • 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
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  • 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.
  • Had concomitant use of potent CYP3A4/5 inducers, which included enzyme inducing antiepileptic drugs (EIAEDs), during the treatment phase of the study and within 2 weeks prior to starting treatment.
  • Had planned concurrent use Optune™. Prior use of the device was allowable.
  • For Arms D and F: Had evidence of leptomeningeal spread of disease.

Trial locations and contacts

5 sites in 1 country.

5 sites in 1 country

United States5 sites

  • Massachusetts General Hospital

    Boston, Massachusetts, 02114

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02115

  • University of California, Los Angeles

    Los Angeles, California, 90024

  • Miami Cancer Institute

    Miami, Florida, 33176

  • University of Utah, Huntsman Cancer Institute

    Salt Lake City, Utah, 84112

Other trials in United States

About this study

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).

Read the detailed description

This study included 6 arms:

  • Patients in Arm A received 625 mg oral dordaviprone (ONC201) every 3 weeks.
  • Patients in Arms B, C, D, E, and F received 625 mg oral dordaviprone (ONC201) every 1 week (Days 1, 8 and 15 of each cycle).
  • Patients in Arms C and E received salvage surgical resection of their brain tumor 1 day after the second (or more) dose of dordaviprone (ONC201).

All patients underwent clinical evaluation after each cycle (defined as every 3 weeks).

Neuroimaging studies (contrast-enhanced brain magnetic resonance imaging or computed tomography for patients unable to undergo MRI) were performed at baseline, 8 weeks from treatment initiation, and then every 8 weeks thereafter.

Assessments of dordaviprone (ONC201) anti-tumor activity were assessed through progression-free survival at 6 months using RANO-HGG criteria. Safety was assessed through the reporting of adverse events, measurement of vital signs, electrocardiograms, and clinical laboratory results.

This study was terminated by an administrative protocol amendment (17 January 2023). The decision to terminate the study was not related to any safety concerns with dordaviprone (ONC201). Before the study was terminated, a total of 84 patients were enrolled and received at least 1 dose of dordaviprone (ONC201).

Being tested
Dordaviprone (ONC201)
Medical subject headings
Glioblastoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Dordaviprone (ONC201)Drug

    Also called Dordaviprone

    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.

Study groups in NCT02525692
Study groupRoleWhat they receive
Arm AExperimentalPatients had histologically confirmed World Health Organization Grade IV glioblastoma with any number of recurrences. Patients received 625 mg dordaviprone (ONC201) once every 3 weeks.
Receives: Drug: Dordaviprone (ONC201)
Arm BExperimentalPatients 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).
Receives: Drug: Dordaviprone (ONC201)
Arm CExperimentalPatients 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.
Receives: Drug: Dordaviprone (ONC201)
Arm DExperimentalPatients 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).
Receives: Drug: Dordaviprone (ONC201)
Arm EExperimentalPatients 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).
Receives: Drug: Dordaviprone (ONC201)
Arm FExperimentalPatients 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).
Receives: Drug: Dordaviprone (ONC201)

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Aug 2015 (estimated)
  2. Study startJan 2016
  3. Primary completion17 Apr 2023
  4. Study completion17 Apr 2023

Why it stopped: The Sponsor terminated the study to prioritize enrollment in a randomized Phase 3 trial of ONC201 in an earlier setting. This decision was unrelated to any safety concerns with dordaviprone (ONC201).

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
84 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02525692
Sponsor's protocol ID
ONC006
Status last verified
Dec 2024
First submitted
14 Aug 2015
Last updated
24 Dec 2024

Publications

  • 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.

    PubMed 38335473

  • 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.

    PubMed 34003586

  • 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.

    PubMed 31456142

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Dordaviprone (ONC201) in people with Glioblastoma and Diffuse Midline Glioma, run by Jazz Pharmaceuticals at 5 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 24 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Dec 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percent of Patients With Probability of Progression-Free Survival at 6 Months (time frame: Progression-free survival assessments were conducted 6 months following treatment initiation.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02525692, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Dec 2024.

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