ONC201 in Pediatric H3 K27M Gliomas

NCT03416530 | Terminated Phase 1 FDA Drug

• 1 other identifier: ONC014
• Study Type: interventional
• Target: 134
• Locations: 1 country
• Sites: 8

Brief 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. 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.

Conditions

Diffuse Intrinsic Pontine Glioma; Glioma, Malignant

Outcome Measures

Primary Outcomes (1)

• RP2D

  Determination of recommended Phase 2 dose (RP2D) as a single agent or in combination with radiation

  28 days

Study Arms (7)

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.

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.

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.

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.

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.

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.

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.

Drug: Dordaviprone (ONC201)

Interventions

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.

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)

Eligibility Criteria

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

You may qualify if:

• 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.
• 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).

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

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

Study Sites (8)

UCSF, Benioff Children's Hospital

San Francisco, California, 94158, United States

Location

Miami Cancer Institute

Miami, Florida, 33176, United States

Location

Children's Healthcare of Atlanta, Emory University School of Medicine

Atlanta, Georgia, 30322, United States

Location

University of Michigan Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

New York University

New York, New York, 10016, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Related Publications (2)

• 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

• Cantor 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.

  PMID: 35137228 DERIVED

MeSH Terms

Conditions

Diffuse Intrinsic Pontine Glioma; 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; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Allen Mellemed, MD

  Chimerix, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 23, 2018
• First Posted: January 31, 2018
• Study Start: January 25, 2018
• Primary Completion: December 31, 2022
• Study Completion: May 24, 2023
• Last Updated: February 14, 2025

Record last verified: 2025-02

Locations

US (8)