Diffuse Intrinsic Pontine GliomaPhase 1NCT03416530
ONC201 in Pediatric H3 K27M Gliomas
A Phase 1 study testing Dordaviprone (ONC201) in people with Diffuse Intrinsic Pontine Glioma and Glioma, Malignant, run by Jazz Pharmaceuticals at 8 sites in United States.
Trial summary
This was a Phase 1, open label, multicenter, 8-arm, dose escalation study of dordaviprone (ONC201) in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and recurrent/refractory H3 K27M-mutant gliomas. Read more about this study
- Who is it for?
- Ages 2 to 18 years
- Conditions the study is for
- Diffuse Intrinsic Pontine Glioma, Glioma, Malignant
- What is being tested?
- Dordaviprone (ONC201)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 134 participants
- Where
- 8 sitesUnited States
- Study dates
- 25 Jan 2018to 24 May 2023
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 2 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 2 to less than 19 years of age.
- Patient body weight must be above the minimum necessary for the patient to receive the ONC201 dose indicated for the currently enrolling dose level. The minimum body weight ranges from 10-27.5kg depending on the dose level.
- Arm A and G: Patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy. Evidence of progression is not required so that ONC201 may be administered to patients in the maintenance setting or to patients with recurrent disease. No more than two episodes of recurrence from radiotherapy and/or chemotherapy are allowed. Use of bevacizumab solely for treatment of radiation necrosis, pseudoprogression, or treatment effect will not be considered a recurrence. Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available.
- Arm B: Patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible with or without histologic confirmation. Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available.
- Arm C: Patients with midline gliomas are eligible with or without histologic confirmation and must be eligible for tumor biopsy as deemed by the site Investigator.
- Arm D: Patients with recurrent glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory), have completed at least one line of prior therapy, must be willing to undergo serial lumbar puncture to obtain cerebrospinal fluid (CSF), and must be scheduled to undergo sedated MRIs. Local anesthesia for spinal tap is also allowed. Evidence of progression is not required so that ONC201 may be administered to patients in the maintenance setting or to patients with recurrent disease. No more than two prior episodes of recurrence from radiotherapy and/or chemotherapy are allowed. Use of bevacizumab solely for treatment of radiation necrosis, pseudoprogression, or treatment effect will not be considered a recurrence. Spinal tap should not be performed if treating clinician or lumbar puncture proceduralist has concern of signs of elevated intracranial pressure, including recent worsening in headache or somnolence.
Show all 30Show fewer
- Arm E: Patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) or have diagnosed diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible with or without histologic confirmation. Patients must be 2-12 weeks from completion of first-line radiation. Evidence of progression is not required so that ONC201 may be administered to patients in the maintenance setting or to patients with recurrent disease.
- Arm F:
- Pediatric patients with histologically confirmed diagnosis of high-grade glioma in any tumor sample with a known histone H3 K27M mutation identified by IHC or DNA sequencing test performed in a CLIA setting. Evidence of progressive disease on contrast-enhanced brain MRI as defined by RANO-HGG criteria is required. Patients must have had previous therapy with at least radiotherapy.
- Karnofsky ≥ 50 for patients ≥ 16 years of age, and Lansky ≥ 50 for patients < 16 years of age. For Arm F, Karnofsky ≥ 60 for patients ≥ 16 years of age, and Lansky ≥ 60 for patients < 16 years of age
- 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 is shorter) from other anti-tumor therapies. For patients who have received radiotherapy, patients in any arm must be at least 2 weeks from the completion of local palliative radiotherapy (re-irradiation for progressive disease or upfront radiation at initial diagnosis). For Arm F, patients must be at least 90 days from prior radiation to the first dose of ONC201unless the progressive lesion is outside of the high-dose radiation target volume or there is unequivocal evidence of progressive tumor on a biopsy specimen.
- Adequate organ function defined as:
- Bone Marrow:
- Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 and
- Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
- Renal Function:
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70mL/min/1.73 m2 or normal serum creatinine based on age as shown below or GFR > 70ml/min/1.73m^2: Age < 5 years: 0.8 mg/dL maximum Age 5 to < 10 years: 1.0 mg/dL maximum Age 10 to < 15 years: 1.2 mg/dL maximum Age > 15 years: 1.5 mg/dL maximum
- Liver Function:
- Total Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of institutional normal and
- SGPT (ALT) ≤ 110 U/L and
- Serum albumin ≥ 2 g/dL.
- Neurologic Function:
- Patients with seizure disorder may be enrolled if seizure disorder is well controlled.
- Ability to understand a written informed consent document, and the willingness to sign it. Assent will be obtained when appropriate based on the subjects age.
- All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must be 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.
- For patients post pubertal: Female patients must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. Male patients must be surgically sterile or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. The decision of effective contraception will be based on the judgment of the principal investigator.
- Corticosteroid dose must be stable or decreasing for at least 3 days prior to the baseline CT or MRI scan.
- MRI brain and entire spine MRI within 14 days prior to start of study drug for Arms A, B, C, E, F and G. Subjects undergoing screening for Arm D must have an MRI of brain and entire spine within 3 months prior to start of study drug. Subjects in Arm D will have a baseline MRI of brain and spine with lumbar puncture after study consent is signed and other eligibility criteria are fulfilled.
- For Arms A, B, C, D, F and G: Ability to swallow and retain orally administered capsules.
- Archival tumor specimen: Subjects in all arms must submit at least 5 unstained slides from a tumor specimen that harbors H3 K27M mutation if archival tissue is available. For subjects in Arms A, B, E or G, if no archival tumor tissue is available, or if H3 K27M status of tumor is unknown, then subjects must agree to submit a post-mortem biopsy specimen. Subjects in Arm C do not require prior tumor biopsy or confirmation of the presence of the H3 K27M mutation. Subjects in Arm D must have confirmation of the presence of the H3 K27M mutation in any glioma sample prior to enrollment. Subjects in Arm F must submit at least 5 unstained slides from a tumor specimen that harbors H3 K27M mutation. Note that the H3 K27M mutation is often reported as H3 K28M in gene sequencing assays.
Who cannot join
- For Arms A, B, D, E, F and G: Evidence of diffuse leptomeningeal disease or evidence of CSF dissemination.
- Current or planned participation in a study of another investigational agent or using an investigational device.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
- Any known clinically significant active infection including bacterial, fungal or viral including hepatitis B (HBV), hepatitis C (HCV) or any underlying disease or in the recent past which could compromise enrollment and safety of the patient
- Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias or bradycardia, unless arrhythmia is controlled and after Cardiology has cleared patient to receive ONC201. Receiving therapeutic agents known to prolong QT interval will be excluded, however the use of Zofran is permitted. History of CHF, or MI or stroke in the last 3 months will be excluded.
Show all 13Show fewer
- Active illicit drug use or diagnosis of alcoholism.
- Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug.
- Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration.
- Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs (EIAEDs) (see Appendix B), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent dexamethasone is allowed.
- For Arm F: Exclusively non-contrast-enhancing disease or primary malignant lesion located in the pons or spinal cord.
- For Arm F: Atypical non-astrocytic histologies such as ependymoma, ganglioma and pleomorphic xanthoastrocytoma, pilocytic astrocytoma, or pilocytic astrocytoma and subependymal giant cell astrocytoma (SEGA).
- Prior treatment with ONC201
Trial locations and contacts
8 sites in 1 country.
8 sites in 1 country
United States8 sites
University of Michigan Cancer Center
Ann Arbor, Michigan, 48109
Children's Healthcare of Atlanta, Emory University School of Medicine
Atlanta, Georgia, 30322
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
MD Anderson Cancer Center
Houston, Texas, 77030
Miami Cancer Institute
Miami, Florida, 33176
New York University
New York, New York, 10016
UCSF, Benioff Children's Hospital
San Francisco, California, 94158
Seattle Children's Hospital
Seattle, Washington, 98105
About this study
Official title: ONC201 in Newly Diagnosed Diffuse Intrinsic Pontine Glioma and Recurrent/Refractory Pediatric H3 K27M Gliomas
This was a Phase 1, open label, multicenter, 8-arm, dose escalation study of dordaviprone (ONC201) in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and recurrent/refractory H3 K27M-mutant gliomas.
The primary endpoint of this study was to determine the recommended Phase 2 dose (RP2D) of dordaviprone (ONC201) in pediatric glioma patients as a single agent in combination with radiation.
Read the detailed description
This study was to include 8 arms; the intention for each arm is summarized below:
- Arm A: To define the RP2D for single agent dordaviprone (ONC201) in pediatric patients with glioma who are positive for the H3 K27M mutation and have completed at least 1 line of prior therapy.
- Arm B: To define the RP2D for dordaviprone (ONC201) in combination with radiation in pediatric patients with newly diagnosed DIPG.
- Arm C: To determine intratumoral drug concentrations and biomarker expression in pediatric patients with midline gliomas.
- Arm D: To determine H3 K27M DNA levels and drug concentrations in the cerebral spinal fluid (CSF) of pediatric patients with H3 K27M-mutant glioma.
- Arm E: To define the RP2D for single agent dordaviprone (ONC201) when administered as a liquid formulation in Ora-Sweet to pediatric patients with DIPG and/or H3 K27M-mutant glioma.
- Arm F: A dose expansion cohort to confirm the safety and estimate the efficacy of dordaviprone (ONC201) in recurrent H3 K27M-mutant glioma at the RP2D.
- Arm G: To define the RP2D for single agent dordaviprone (ONC201) when administered on 2 consecutive days of each week in pediatric patients with H3 K27M-mutant glioma who have completed at least 1 line of prior therapy.
- Arm H: To assess intra-tumoral concentrations following twice weekly dosing of dordaviprone (ONC201) in 2 cohorts: pediatric patients with DIPG and pediatric patients with thalamic gliomas. *Note: This arm did not enroll any patients.
Pediatric patients in Arms A through F received dordaviprone (ONC201) once weekly. Patients in Arms C, D, E, and F received dordaviprone (ONC201) at the RP2D determined in either Arm A or Arm B. Pediatric patients in Arm G received dordaviprone (ONC201) twice weekly on 2 consecutive days.
Safety was also assessed, with evaluations including the reporting of adverse events, as well as measurements 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 134 patients were enrolled and had received at least 1 dose of dordaviprone (ONC201). At the time of the administrative protocol amendment, patient enrollment was completed in Arms A, B, C, D, E, and G, and patient enrollment was stopped prior to reaching the targeted enrollment in Arms F and H.
- Being tested
- Dordaviprone (ONC201)
- Medical subject headings
- Diffuse Intrinsic Pontine Glioma, Glioma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dordaviprone (ONC201)Drug
Dordaviprone 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 group | Role | What they receive |
|---|---|---|
| A (recurrent/refractory H3 K27M-mutant glioma) | Experimental | Pediatric patients with relapsed/refractory glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy. Evidence of progression is not required so that ONC201 may be administered to patients in the maintenance setting or to patients with recurrent/refractory disease. Receives: Drug: Dordaviprone (ONC201) |
| B (newly diagnosed DIPG) | Experimental | Pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible with or without histologic confirmation. If H3 K27M status of tumor is unknown or archival tumor tissue is not available, then patients must agree to submit a post-mortem biopsy specimen. Receives: Drug: Dordaviprone (ONC201) |
| C (midline glioma) | Experimental | Pediatric patients with midline gliomas are eligible with or without histologic confirmation and must be eligible for tumor biopsy as deemed by the site Investigator. Receives: Drug: Dordaviprone (ONC201) |
| D (recurrent H3 K27M-mutant glioma; CSF obtained) | Experimental | Pediatric patients with recurrent glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory), have completed at least one line of prior therapy, must be willing to undergo serial lumbar puncture to obtain cerebrospinal fluid (CSF), and must be scheduled to undergo sedated MRIs. Receives: Drug: Dordaviprone (ONC201) |
| E (H3 K27M-mutant glioma or DIPG; liquid formulation) | Experimental | Patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) or have diagnosed diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible with or without histologic confirmation. Patients must be 2-12 weeks from completion of first-line radiation. Patients administered liquid formulation of dordaviprone (ONC201) in Ora-Sweet. Receives: Drug: Dordaviprone (ONC201) |
| F (recurrent/refractory, progressive high-grade H3 K27M-mutant glioma) | Experimental | Pediatric patients with relapsed/refractory, histologically confirmed high-grade glioma with a known H3 K27M mutation, evidence of progressive disease contrast-enhanced brain MRI as defined by RANO-HGG criteria. Prior therapy with at least radiotherapy is required. Receives: Drug: Dordaviprone (ONC201) |
| G (recurrent/refractory H3 K27M-mutant glioma; dosing twice weekly) | Experimental | Pediatric patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy will be enrolled to define the RP2D for single agent dordaviprone (ONC201) given on two consecutive days of each week. Receives: Drug: Dordaviprone (ONC201) |
What is being measured
The primary outcome is the main question the study is designed to answer.
RP2D
Determination of recommended Phase 2 dose (RP2D) as a single agent or in combination with radiation
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Jan 2018
- Study start25 Jan 2018
- Primary completion31 Dec 2022
- Study completion24 May 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
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Diffuse Intrinsic Pontine GliomaStudies of the same condition, open and under way.
- More trials run by Jazz PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 134 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jazz Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Oncoceutics, Inc.
- Responsible party
- Sponsor
- Investigators
- Allen Mellemed, MD, Study director, Chimerix, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03416530
- Sponsor's protocol ID
- ONC014
- Status last verified
- Feb 2025
- First submitted
- 23 Jan 2018
- Last updated
- 14 Feb 2025
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
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 38335473Cantor E, Wierzbicki K, Tarapore RS, Ravi K, Thomas C, Cartaxo R, Nand Yadav V, Ravindran R, Bruzek AK, Wadden J, John V, May Babila C, Cummings JR, Rahman Kawakibi A, Ji S, Ramos J, Paul A, Walling D, Leonard M, Robertson P, Franson A, Mody R, Garton HJL, Venneti S, Odia Y, Kline C, Vitanza NA, Khatua S, Mueller S, Allen JE, Gardner SL, Koschmann C. Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma. Neuro Oncol. 2022 Aug 1;24(8):1366-1374. doi: 10.1093/neuonc/noac030.
PubMed 35137228
Study at a glance
From the registry record, last updated by the sponsor on 14 Feb 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- ONC201 in Newly Diagnosed Diffuse Intrinsic Pontine Glioma and Recurrent/Refractory Pediatric H3 K27M Gliomas
- ClinicalTrials.gov ID
- NCT03416530
- Acronym / sponsor ID
- ONC014
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason 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).
- Enrolment
- 134 participants (actual)
- Lead sponsor
- Jazz PharmaceuticalsIndustry (pharma, biotech, devices)
- Collaborators
- Oncoceutics, Inc.
- Study start
- 25 Jan 2018 (actual)
- Primary completion
- 31 Dec 2022 (actual)
- Study completion
- 24 May 2023 (actual)
- First posted
- 31 Jan 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This was a Phase 1, open label, multicenter, 8-arm, dose escalation study of dordaviprone (ONC201) in pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and recurrent/refractory H3 K27M-mutant gliomas.
The primary endpoint of this study was to determine the recommended Phase 2 dose (RP2D) of dordaviprone (ONC201) in pediatric glioma patients as a single agent in combination with radiation.
Detailed description
This study was to include 8 arms; the intention for each arm is summarized below:
- Arm A: To define the RP2D for single agent dordaviprone (ONC201) in pediatric patients with glioma who are positive for the H3 K27M mutation and have completed at least 1 line of prior therapy.
- Arm B: To define the RP2D for dordaviprone (ONC201) in combination with radiation in pediatric patients with newly diagnosed DIPG.
- Arm C: To determine intratumoral drug concentrations and biomarker expression in pediatric patients with midline gliomas.
- Arm D: To determine H3 K27M DNA levels and drug concentrations in the cerebral spinal fluid (CSF) of pediatric patients with H3 K27M-mutant glioma.
- Arm E: To define the RP2D for single agent dordaviprone (ONC201) when administered as a liquid formulation in Ora-Sweet to pediatric patients with DIPG and/or H3 K27M-mutant glioma.
- Arm F: A dose expansion cohort to confirm the safety and estimate the efficacy of dordaviprone (ONC201) in recurrent H3 K27M-mutant glioma at the RP2D.
- Arm G: To define the RP2D for single agent dordaviprone (ONC201) when administered on 2 consecutive days of each week in pediatric patients with H3 K27M-mutant glioma who have completed at least 1 line of prior therapy.
- Arm H: To assess intra-tumoral concentrations following twice weekly dosing of dordaviprone (ONC201) in 2 cohorts: pediatric patients with DIPG and pediatric patients with thalamic gliomas. *Note: This arm did not enroll any patients.
Pediatric patients in Arms A through F received dordaviprone (ONC201) once weekly. Patients in Arms C, D, E, and F received dordaviprone (ONC201) at the RP2D determined in either Arm A or Arm B. Pediatric patients in Arm G received dordaviprone (ONC201) twice weekly on 2 consecutive days.
Safety was also assessed, with evaluations including the reporting of adverse events, as well as measurements 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 134 patients were enrolled and had received at least 1 dose of dordaviprone (ONC201). At the time of the administrative protocol amendment, patient enrollment was completed in Arms A, B, C, D, E, and G, and patient enrollment was stopped prior to reaching the targeted enrollment in Arms F and H.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| A (recurrent/refractory H3 K27M-mutant glioma) | Experimental | Drug: Dordaviprone (ONC201)Pediatric patients with relapsed/refractory glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy. Evidence of progression is not required so that ONC201 may be administered to patients in the maintenance setting or to patients with recurrent/refractory disease. |
| B (newly diagnosed DIPG) | Experimental | Drug: Dordaviprone (ONC201)Pediatric patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible with or without histologic confirmation. If H3 K27M status of tumor is unknown or archival tumor tissue is not available, then patients must agree to submit a post-mortem biopsy specimen. |
| C (midline glioma) | Experimental | Drug: Dordaviprone (ONC201)Pediatric patients with midline gliomas are eligible with or without histologic confirmation and must be eligible for tumor biopsy as deemed by the site Investigator. |
| D (recurrent H3 K27M-mutant glioma; CSF obtained) | Experimental | Drug: Dordaviprone (ONC201)Pediatric patients with recurrent glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory), have completed at least one line of prior therapy, must be willing to undergo serial lumbar puncture to obtain cerebrospinal fluid (CSF), and must be scheduled to undergo sedated MRIs. |
| E (H3 K27M-mutant glioma or DIPG; liquid formulation) | Experimental | Drug: Dordaviprone (ONC201)Patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) or have diagnosed diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible with or without histologic confirmation. Patients must be 2-12 weeks from completion of first-line radiation. Patients administered liquid formulation of dordaviprone (ONC201) in Ora-Sweet. |
| F (recurrent/refractory, progressive high-grade H3 K27M-mutant glioma) | Experimental | Drug: Dordaviprone (ONC201)Pediatric patients with relapsed/refractory, histologically confirmed high-grade glioma with a known H3 K27M mutation, evidence of progressive disease contrast-enhanced brain MRI as defined by RANO-HGG criteria. Prior therapy with at least radiotherapy is required. |
| G (recurrent/refractory H3 K27M-mutant glioma; dosing twice weekly) | Experimental | Drug: Dordaviprone (ONC201)Pediatric patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy will be enrolled to define the RP2D for single agent dordaviprone (ONC201) given on two consecutive days of each week. |
Who may qualify
- Ages
- 2 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (30 listed)
- 2 to less than 19 years of age.
- Patient body weight must be above the minimum necessary for the patient to receive the ONC201 dose indicated for the currently enrolling dose level. The minimum body weight ranges from 10-27.5kg depending on the dose level.
- Arm A and G: Patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy. Evidence of progression is not required so that ONC201 may be administered to patients in the maintenance setting or to patients with recurrent disease. No more than two episodes of recurrence from radiotherapy and/or chemotherapy are allowed. Use of bevacizumab solely for treatment of radiation necrosis, pseudoprogression, or treatment effect will not be considered a recurrence. Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available.
- Arm B: Patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible with or without histologic confirmation. Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available.
- Arm C: Patients with midline gliomas are eligible with or without histologic confirmation and must be eligible for tumor biopsy as deemed by the site Investigator.
Key exclusion criteria (13 listed)
- For Arms A, B, D, E, F and G: Evidence of diffuse leptomeningeal disease or evidence of CSF dissemination.
- Current or planned participation in a study of another investigational agent or using an investigational device.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
- Any known clinically significant active infection including bacterial, fungal or viral including hepatitis B (HBV), hepatitis C (HCV) or any underlying disease or in the recent past which could compromise enrollment and safety of the patient
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dordaviprone (ONC201)Dordaviprone is a brain-penetrant, small-molecule imipridone that acts as a mitochondrial caseinolytic protease P (ClpP) agonist and a dopamine receptor D2 (DRD2) antagonist. | Drug | A (recurrent/refractory H3 K27M-mutant glioma), B (newly diagnosed DIPG), C (midline glioma), D (recurrent H3 K27M-mutant glioma; CSF obtained), E (H3 K27M-mutant glioma or DIPG; liquid formulation), F (recurrent/refractory, progressive high-grade H3 K27M-mutant glioma), G (recurrent/refractory H3 K27M-mutant glioma; dosing twice weekly) |
Primary outcome
RP2D
Time frame: 28 days
Determination of recommended Phase 2 dose (RP2D) as a single agent or in combination with radiation
Results and safety
The study was stopped early (reason given: 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).). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Feb 2025.
- Derived from this study: PubMed 38335473Arrillaga-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.
- Derived from this study: PubMed 35137228Cantor E, Wierzbicki K, Tarapore RS, Ravi K, Thomas C, Cartaxo R, Nand Yadav V, Ravindran R, Bruzek AK, Wadden J, John V, May Babila C, Cummings JR, Rahman Kawakibi A, Ji S, Ramos J, Paul A, Walling D, Leonard M, Robertson P, Franson A, Mody R, Garton HJL, Venneti S, Odia Y, Kline C, Vitanza NA, Khatua S, Mueller S, Allen JE, Gardner SL, Koschmann C. Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma. Neuro Oncol. 2022 Aug 1;24(8):1366-1374. doi: 10.1093/neuonc/noac030.
- Individual participant dataSharing planned: Undecided
Related trials for Diffuse Intrinsic Pontine Glioma
RecruitingObservational study
International Diffuse Intrinsic Pontine Glioma (DIPG)/Diffuse Midline Glioma (DMG) Registry and Repository
Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, H3 K27M-Mutant
RecruitingPhase 2
ACT001 for the Treatment of Diffuse Intrinsic Pontine Gliomas and H3K27-altered High Grade Gliomas
Diffuse Intrinsic Pontine Gliomas (DIPG), Progressive DIPG
RecruitingPhase 3
Biological Medicine for Diffuse Intrinsic Pontine Glioma (DIPG) Eradication 2.0
Diffuse Intrinsic Pontine Glioma, Diffuse Midline Glioma, H3 K27M-Mutant
RecruitingPhase 2
Illuminate: A Clinical Study Evaluating CAR T Immune Cell Therapy (BCB-276) for Patients With Diffuse Intrinsic Pontine Glioma (DIPG).
Diffuse Intrinsic Pontine Glioma, DIPG
Not yet recruitingPhase 2
Study of Tovorafenib in High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG)
High Grade Glioma (HGG) of the Brain With BRAF Aberration, High Grade Glioma (III or IV)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Allen Mellemed, MD study director
Chimerix, Inc.
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Dordaviprone (ONC201) in people with Diffuse Intrinsic Pontine Glioma and Glioma, Malignant, run by Jazz Pharmaceuticals at 8 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 30 inclusion and 13 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 14 Feb 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: 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).). Results are not available in the source record.
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?
RP2D (time frame: 28 days). 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 NCT03416530, which also lists 2 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 14 Feb 2025.