Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms

NCT04541082 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: ONC206-001NIH 20C0069
• Study Type: interventional
• Target: 102
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of this Phase 1, open-label, dose-escalation, and exploratory study is to evaluate the safety and tolerability profile (establish the maximum-tolerated dose) and evaluate the occurrence of dose-limiting toxicities (DLTs) following single weekly or multiple-day weekly dose regimens of single-agent, oral ONC206 in patients with recurrent, primary central nervous system (CNS) neoplasms.

Conditions

Central Nervous System Neoplasms; Glioblastoma; Gliosarcoma, Adult; Anaplastic Oligodendroglioma; Anaplastic Astrocytoma; Pilocytic Astrocytoma; Oligodendroglioma; Gliomatosis Cerebri; Pleomorphic Xanthoastrocytoma; Anaplastic Pleomorphic Xanthoastrocytoma; Diffuse Midline Glioma, H3 K27M-Mutant; Ependymoma; Ependymoma, Anaplastic; Medulloblastoma; Teratoid Rhabdoid Tumor; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors; Anaplastic Meningioma; Atypical Meningioma; Choroid Plexus Neoplasms; Pineal Tumor; Diffuse Astrocytoma; Glial Tumor

Keywords

Glioblastoma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Diffuse Astrocytoma; Oligodendroglioma

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD) of single-agent, oral ONC206

  MTD was determined by testing increasing doses up to 200 mg twice daily for 3 successive days a week. MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in \>33% of participants. DLTs will be assessed in the first course of each cohort (28 days), and refer to a study drug-related or possibly related event that meets 1 of the following criteria defined in the subsequent Primary Outcome Measure using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE 5.0).

  28 Days

• Number of Participants who Experienced Dose-Limiting Toxicities (DLTs)

  DLTs will be assessed in the first course of each cohort (28 days), and refer to a study drug-related or possibly related event that meets 1 of the following criteria using NCI CTCAE 5.0: * Grade 3 or higher non-hematologic toxicity. * Grade 4 hematologic toxicity (ANC \<0.5 × 109/L and platelet count \<25 × 109/L). Lymphopenia is not considered a DLT. A confirmed DLT requires 2 consecutive measurements separated by 48 hours. * Grade 3 neutropenia (absolute neutrophil count \[ANC\] \<1.0 × 109/L) with elevated fever (\>101°F). A confirmed DLT requires 2 consecutive measurements. * Grade 3 thrombocytopenia with clinically significant bleeding. * Inability to receive the scheduled Cycle 2, Day 1 dose of study drug within 14 days due to study drug-related toxicity persisting from Cycle 1 or study drug-related toxicity newly encountered on Day 1 of Cycle 2.

  28 Days

Study Arms (1)

ONC206

EXPERIMENTAL

Drug: ONC206

Interventions

ONC206 DRUG

ONC206 is a member of the imipridone class of anti-cancer small molecules that share a unique tri-heterocyclic core chemical structure and target G protein-coupled receptors.

ONC206

Eligibility Criteria

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

You may qualify if:

• Patients must meet all the following criteria to participate in the study:
• Patients aged ≥18 years with a recurrent, primary CNS neoplasm. For all cohorts, patients must have a histologically confirmed primary CNS neoplasm. Primary CNS neoplasms in this study include, but are not limited to, the following: glioblastoma and glioblastoma histologic subtypes, gliosarcoma, primary CNS sarcomas, anaplastic glial neoplasms including anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic mixed neuronal-glial tumors, and pilocytic astrocytoma with anaplastic features, diffuse astrocytoma, oligodendroglioma, gliomatosis cerebri, pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, diffuse midline gliomas and histone mutated gliomas (NOTE: Patients with H3 K27M-mutant diffuse gliomas are excluded unless the primary tumor is located in the pons or spinal cord, or the patient has completed front line radiation or received ONC201 therapy prior to 01 January 2023), ependymoma, anaplastic ependymoma, and all ependymoma subtypes, medulloblastoma and all medulloblastoma subtypes, atypical teratoid/rhabdoid tumor, primary CNS embryonal/primitive neuroectodermal tumors, atypical and anaplastic meningiomas, choroid plexus tumors, and pineal region tumors.
• Patients must have recurrent and measurable disease as defined by RANO criteria, using either the HGG and/or LGG RANO criteria based on tumor type, after having received established standard of care treatment for their disease and have no standard treatment options available as determined by the investigators. There is no limit on the number of total recurrences or prior therapies. However, prior therapies with known clinical benefit (including radiation) for specific tumor types are required. If patients are deemed ineligible for such therapies in the opinion of the Investigator, the Investigator must document the reason the patient is considered ineligible.
• Patients must have a Karnofsky Performance Score (KPS) of greater than or equal to 70. Patients with severe paraparesis/paraplegia who need minimal assistance for self-care due to their motor deficit but are otherwise functionally independent will be considered eligible.
• Patients must not have received prior investigational or approved cytotoxic chemotherapy within 28 days prior to the first dose of study drug (Cycle 1, Day 1); 42 days in the case of nitrosoureas; 42 days in the case of bevacizumab; 28 days or 5 half-lives (whichever is less; but not less than 14 days) in case of investigational or approved molecularly targeted agent; 14 days in the case of radiotherapy.
• Patients with AEs Grade ≥2 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must have all their AEs resolved prior to the first dose of study drug (Cycle 1, Day 1), except for alopecia or neuropathy; Grade 1 or 2 lymphopenia is allowed.
• Patients must not have undergone major surgery 4 weeks prior to the first dose of study drug (Cycle 1, Day 1) and must have completely recovered from any surgery (minor surgical procedures such as skin biopsies and port placement done on an outpatient basis do not require a waiting period).
• Patients must have normal organ and marrow function as defined below:
• Absolute neutrophil count (ANC) ≥1,500/mcL.
• Platelets ≥100,000/mcL.
• Hemoglobin ≥9.0 mg/dL without transfusion in 2 prior weeks.
• Total bilirubin ≤1.5 × upper limit of normal (ULN) (patients with Gilbert's syndrome may be included with total bilirubin \>1.5 × ULN if direct bilirubin is ≤1.5 × ULN).
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤2.5 × ULN.
• Measured or estimated creatinine clearance (CLcr) ≥40 mL/minute for patients with creatinine levels above normal. CLcr will be calculated by the Cockcroft-Gault equation for renal function.
• Patients must provide a tumor specimen (paraffin-embedded block and/or frozen tissue) from a prior resection or biopsy available that is sufficient to perform biomarker assays, ≥15 unstained slides for immunohistochemistry (IHC) analysis must be received by the NOB by the first dose of study drug (Cycle 1, Day 1). For patients with ≥10 to \<15 slides, eligibility will be reviewed on a case-by-case basis.

You may not qualify if:

• Patients who meet any of the following criteria will be excluded from the study:
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC206 (e.g., ONC201) or its excipients.
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who are unable or unwilling to abide by the study protocol or cooperate fully with the Investigator.
• Patients with a known HIV-positive test on combination anti-retroviral therapy are ineligible for this initial first-in-human trial because of the potential for PK interactions with ONC206.
• Patients with active cardiac disease, including any of the following:
• Corrected QT interval (QTc) ≥470 msec on screening electrocardiogram (ECG; using the QTc by Fridericia's \[QTcF\] formula);
• Angina pectoris that requires the use of anti-anginal medication;
• Ventricular arrhythmias except for benign premature ventricular contractions;
• Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;
• Conduction abnormality requiring a pacemaker;
• Valvular disease with documented compromise in cardiac function; and/or
• Symptomatic pericarditis.
• Patients with a history of cardiac dysfunction including any of the following:
• Myocardial infarction within the last 6 months, documented by persistent elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction function;

Sponsors & Collaborators

• Jazz Pharmaceuticals: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

National Institutes of Health

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (1)

• Nguyen TTT, Shang E, Schiffgens S, Torrini C, Shu C, Akman HO, Prabhu VV, Allen JE, Westhoff MA, Karpel-Massler G, Siegelin MD. Induction of Synthetic Lethality by Activation of Mitochondrial ClpP and Inhibition of HDAC1/2 in Glioblastoma. Clin Cancer Res. 2022 May 2;28(9):1881-1895. doi: 10.1158/1078-0432.CCR-21-2857.

  PMID: 35417530 DERIVED

MeSH Terms

Conditions

Central Nervous System Neoplasms; Glioblastoma; Gliosarcoma; Oligodendroglioma; Astrocytoma; Neoplasms, Neuroepithelial; Ependymoma; Medulloblastoma; Typical Teratoid Rhabdoid Tumor; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors; Meningioma; Choroid Plexus Neoplasms; Pinealoma; Glioma

Interventions

ONC206

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Cerebral Ventricle Neoplasms; Brain Neoplasms; Brain Diseases; Central Nervous System Diseases

Central Study Contacts

Clinical Trial Disclosure & Transparency

CONTACT

215-832-3750; ClinicalTrialDisclosure@jazzpharma.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 1, 2020
• First Posted: September 9, 2020
• Study Start: October 26, 2020
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: December 18, 2025

Record last verified: 2025-12

Locations

US (1)