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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04541082
Recruitment Status : Recruiting
First Posted : September 9, 2020
Last Update Posted : October 26, 2023
National Institutes of Health (NIH)
Information provided by (Responsible Party):

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.

Condition or disease Intervention/treatment Phase
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 Drug: ONC206 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A First-in-human Phase I Single-agent Dose-escalation, Food Effect and Dose Expansion Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms
Actual Study Start Date : October 26, 2020
Estimated Primary Completion Date : September 2024
Estimated Study Completion Date : February 2025

Arm Intervention/treatment
Experimental: ONC206 Drug: ONC206
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.

Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of single-agent, oral ONC206 [ Time Frame: 28 Days ]

    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).

  2. Number of Participants who Experienced Dose-Limiting Toxicities (DLTs) [ Time Frame: 28 Days ]

    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Patients must meet all the following criteria to participate in the study:

  1. 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.
  2. 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.
  3. 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.
  4. (Inclusion Criterion #4 was removed in Amendment 3)
  5. 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.
  6. Patients will be required to enroll on the NCI NOB natural history study (Study 16-C-0151).
  7. 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.
  8. 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).
  9. 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 within normal range. For patients with liver metastases, serum bilirubin ≤1.5 × upper limit of normal (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.
  10. (Inclusion Criterion #10 was removed in Amendment 3)
  11. 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.
  12. Dependent upon dose level assignment and drug formulation (i.e., capsules versus powder in bottle [PIB]), patients must be able to either swallow oral capsules or swallow liquids.
  13. Patients must provide study-specific informed consent prior to enrollment. No Durable Power of Attorney or Next of Kin can provide initial consent.
  14. Patients must be able to tolerate a magnetic resonance imaging (MRI) study with intravenous gadolinium contrast.
  15. (Inclusion Criterion #15 was removed in Amendment 6)
  16. Patients must have a negative COVID-19 test within 72 hours of the first dose of study drug (Cycle 1, Day 1). Patients who had documented COVID-19 infection within 90 days of treatment but more than 20 days from infection do not need to be tested.
  17. (Inclusion Criterion #17 was removed in Amendment 6)

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from the study:

  1. (Exclusion Criterion #1 was removed in Amendment 3)
  2. Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC206 (e.g., ONC201) or its excipients.
  3. 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.
  4. Patients who are unable or unwilling to abide by the study protocol or cooperate fully with the Investigator.
  5. 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.
  6. 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.
  7. 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;
    • History of documented congestive heart failure (New York Heart Association functional classification III-IV); and/or
    • Documented cardiomyopathy.
  8. Patients who have had an ischemic or hemorrhagic stroke in the last 3 months. If the patient has had a recent tumor resection, cerebral ischemic or hemorrhagic changes that occur peri operatively are not an exclusion.
  9. Patients with refractory epilepsy are excluded. Patients with primarily or secondarily generalized seizures in the 28 days prior to study enrollment will be excluded. Peri-operative seizures, defined as seizures occurring within the 7 days after a stereotactic biopsy, open biopsy, or surgical resection will not be an exclusion as long as the patient has had no generalized seizures starting 8 days after the surgical procedure. Patients with prior seizures must be on stable doses of 1 or 2 seizure medications for at least 14 days prior to study enrollment.
  10. Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ONC206 (uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
  11. Patients who have been treated with any hematopoietic colony-stimulating growth factors (CSFs) (e.g., granulocyte-CSF, granulocyte-macrophage-CSF) ≤2 weeks prior to starting study drug. Erythropoietin or darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued.
  12. Patients who are currently taking therapeutic doses of warfarin sodium or any other coumadin derivative anticoagulant.
  13. Patients who are taking strong inhibitors or inducers of cytochrome P450 (CYP) 3A4, 2D6, 1A2, 2C9, and 2C19 within at least 14 days prior to the first dose of study drug (Cycle 1, Day 1); these medications are excluded throughout the study.
  14. Women who are pregnant or breast feeding.
  15. Women of child-bearing potential with a positive serum pregnancy test ≤72 hours prior to the first dose of study drug (Cycle 1, Day 1).
  16. Patients who are receiving concomitant standard and/or investigational anti-cancer therapy.
  17. Patients with alcohol or substance abuse which, in the opinion of the Investigator, would interfere with compliance or safety.
  18. Patients with the presence of any other serious and/or unstable pre-existing medical disorder, psychiatric disorder, or other conditions that could interfere with patients' safety, obtaining informed consent or compliance to the study procedures as determined by the Investigators.
  19. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, or men who do not agree to use highly effective contraception during treatment and for 16 additional weeks after the final dose of study drug.

    Highly effective contraception is defined as either:

    • True abstinence: When this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
    • Sterilization: Females must have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks ago. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
    • Male partner sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
    • If patients are not practicing true abstinence and/or if the patient or sexual partner have not had a sterilization procedure as listed above, patients and their sexual partners must follow double barrier contraception in accordance with the guidelines for contraception below:

      • Females of childbearing potential:

        • Must use an intrauterine device or intrauterine system, during dosing of any study agent and for 16 weeks after final dose of study drug; or
        • Must use a double barrier method of contraception: use of an occlusive cap (diaphragm or cervical/vault cap) with spermicide for women combined with use of a condom by their male partners capable of conceiving offspring.
      • Males capable of conceiving offspring must use condoms during dosing of study agent and for an additional 16 weeks after final dose of study drug.

    Note: Oral, implantable, or injectable contraceptives may be affected by CYP interactions, and are therefore not considered effective for this study.

  20. Previous receipt of ONC201, placebo, or blinded study drug from an ONC201 clinical study, or from any other source for H3 K27M-mutant diffuse glioma on or after 01 January 2023.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04541082

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Contact: Chris Tedesco 919-806-1074
Contact: Marion Morrison, MD 919-806-1074

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United States, Maryland
National Institutes of Health Recruiting
Bethesda, Maryland, United States, 20892
Contact: Referrals    240-760-6010   
Contact: Kelly Mentges, RN    240-760-7126   
Sponsors and Collaborators
National Institutes of Health (NIH)
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Principal Investigator: Mark Gilbert, MD National Institutes of Health (NIH)
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Chimerix Identifier: NCT04541082    
Other Study ID Numbers: ONC206-001
NIH 20C0069 ( Other Identifier: National Institutes of Health )
First Posted: September 9, 2020    Key Record Dates
Last Update Posted: October 26, 2023
Last Verified: October 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Chimerix:
Anaplastic Astrocytoma
Anaplastic Oligodendroglioma
Diffuse Astrocytoma
Additional relevant MeSH terms:
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Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Rhabdoid Tumor
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Neuroepithelial
Choroid Plexus Neoplasms
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Vascular Tissue
Meningeal Neoplasms
Neoplasms by Site
Nervous System Diseases
Neoplasms, Complex and Mixed
Brain Neoplasms
Brain Diseases
Central Nervous System Diseases
Cerebral Ventricle Neoplasms