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ONC206 for Treatment of Newly Diagnosed, or Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors (PNOC 023)

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.
 
ClinicalTrials.gov Identifier: NCT04732065
Recruitment Status : Recruiting
First Posted : February 1, 2021
Last Update Posted : May 4, 2022
Sponsor:
Collaborators:
Chimerix
Mithil Prasad Foundation
Storm the Heavens Fund
The ChadTough Defeat DIPG Foundation
Information provided by (Responsible Party):
Sabine Mueller, MD, PhD, University of California, San Francisco

Brief Summary:
This phase I trial studies the effects and best dose of ONC206 alone or in combination with radiation therapy in treating patients with diffuse midline gliomas that is newly diagnosed or has come back (recurrent) or other recurrent primary malignant CNS tumors. ONC206 is a recently discovered compound that may stop cancer cells from growing. This drug has been shown in laboratory experiments to kill brain tumor cells by causing a so called "stress response" in tumor cells. This stress response causes cancer cells to die, but without affecting normal cells. ONC206 alone or in combination with radiation therapy may be effective in treating newly diagnosed or recurrent diffuse midline gliomas and other recurrent primary malignant CNS tumors.

Condition or disease Intervention/treatment Phase
Diffuse Midline Glioma (DMG) Glioblastoma Recurrent Ependymoma Recurrent Malignant Central Nervous System Neoplasm Spinal Cord Glioma WHO Grade III Glioma CNS Tumor Central Nervous System Tumor Drug: ONC206 Radiation: Standard of Care Radiation Therapy Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 256 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PNOC023: Open Label Phase 1 and Target Validation Study of ONC206 in Children and Young Adults With Newly Diagnosed or Recurrent Diffuse Midline Glioma (DMG), and Other Recurrent Primary Malignant Central Nervous System (CNS) Tumors
Actual Study Start Date : August 23, 2021
Estimated Primary Completion Date : January 31, 2024
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A: ONC206 for participants with diffuse midline gliomas + prior therapy
Patients receive ONC206 PO QD on days 1, 8, 15, 22. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
Drug: ONC206
Given orally (PO)
Other Names:
  • antagonist of dopamine receptor D2 (DRD2) /human mitochondrial caseinolytic protease P (ClpP)ClpP Agonist
  • DRD2 antagonist/ClpP agonist

Experimental: Arm B: ONC206 + radiation therapy for newly diagnosed participants
Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO QD on days 1, 8, 15, 22. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
Drug: ONC206
Given orally (PO)
Other Names:
  • antagonist of dopamine receptor D2 (DRD2) /human mitochondrial caseinolytic protease P (ClpP)ClpP Agonist
  • DRD2 antagonist/ClpP agonist

Radiation: Standard of Care Radiation Therapy
Undergo RT
Other Names:
  • Radiation Therapy (RT)
  • Cancer Radiotherapy

Experimental: Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreated
Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO QD on days 1, 8, 15, 22. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
Drug: ONC206
Given orally (PO)
Other Names:
  • antagonist of dopamine receptor D2 (DRD2) /human mitochondrial caseinolytic protease P (ClpP)ClpP Agonist
  • DRD2 antagonist/ClpP agonist

Radiation: Standard of Care Radiation Therapy
Undergo RT
Other Names:
  • Radiation Therapy (RT)
  • Cancer Radiotherapy

Experimental: Arm D: ONC206 Therapy, Primary malignant CNS tumors with progression
Patients receive ONC206 PO QD on days 1, 8, 15, 22. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
Drug: ONC206
Given orally (PO)
Other Names:
  • antagonist of dopamine receptor D2 (DRD2) /human mitochondrial caseinolytic protease P (ClpP)ClpP Agonist
  • DRD2 antagonist/ClpP agonist




Primary Outcome Measures :
  1. Proportion of participants with dose-limiting toxicities (DLT) [ Time Frame: 4 weeks after first dose ]
    A DLT is defined as a treatment-related adverse event (AE) or abnormal laboratory value that occurs in the first cycle of treatment (Cycle 1 for Arm A and D; Cycle 0 for Arm B and C), meets criteria for DLT as outlined below and is assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications, and is judged by the investigator to be related to ONC206 as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0).

  2. Maximum tolerated dose (MTD) of ONC206 [ Time Frame: 4 weeks after first dose ]
    The Bayesian optimal interval (BOIN) design will be used to find the MTD within each arm. MTD is selected based on isotonic regression and this computation is implemented by the shiny app "BOIN" available at http://www.trialdesign.org. Specifically, select as the MTD the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. If there are ties, select the higher dose level when the isotonic estimate is lower than the target toxicity rate and select the lower dose level when the isotonic estimate is greater than or equal to the target toxicity rate.


Secondary Outcome Measures :
  1. Mean maximum concentration (Cmax) of ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
    Concentration-time data will be summarized by N, Mean, Standard Deviation, Median, Min, Max and 95% Confidence Interval

  2. Mean corresponding time (Tmax) of ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
    PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

  3. Area under the curve (AUC) of ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
    PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

  4. Elimination half-life (t1/2) of ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
    PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

  5. Mean Total body clearance (CL) for ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
    PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

  6. Mean Volume of Distribution (Vd) for ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
    PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling



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:   2 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ARM A: Children and young adults with DMG (2-21 years of age) who completed at least one line of prior therapy. Prior treatment must have included focal radiation therapy and patients must be within 4-14 weeks from completion of radiation therapy and have no evidence of disease progression
  • ARM A: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including DMG H3K27M mutant and World Health Organization (WHO) grade III and IV H3 wildtype gliomas. WHO grade II diffuse astrocytomas or other low grade gliomas without H3K27M mutation are not eligible
  • ARM A: Participants must have recovered from all acute side effects of prior therapy. 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), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team)
  • ARM B: Newly diagnosed children and young adults (2-21 years of age) with a diagnosis of DMG are eligible, including spinal cord DMGs
  • ARM B: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including DMG H3K27M mutant and WHO grade III and IV H3 wildtype gliomas. WHO grade II diffuse astrocytomas or other low grade gliomas without H3K27M mutation are not eligible
  • ARM C: Children and young adults with DMGs (2-21 years of age) who have evidence of first progression but have not been treated for this progression and are recommended to get reirradiation
  • ARM C: Patients must have undergone prior focal radiation therapy as part of their initial therapy and should be at least 6 months from prior radiation therapy. If timing is less than 6 months from prior focal radiation, these patients need to be discussed with the study chair(s)
  • ARM C: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including DMG H3K27M mutant and WHO grade III and IV H3 wildtype gliomas. WHO grade II diffuse astrocytomas or other low grade gliomas without H3K27M mutation are not eligible
  • ARM C: Participants must have recovered from all acute side effects of prior therapy
  • ARM C: 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), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team)
  • ARM D: Children and young adults with recurrent primary malignant CNS tumors (2 - 21 years of age) who have evidence of progression but have not been treated for this progression
  • ARM D: Tumor tissue confirmation is mandatory and pathology must be consistent with recurrent primary malignant CNS tumor (diagnosis of recurrent ependymoma is allowed)
  • ARM D: Participants must have recovered from all acute side effects of prior therapy
  • ARM D: 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), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team)
  • ARM D: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 3 days prior to baseline magnetic resonance imaging (MRI) scan
  • TARGET VALIDATION: Newly diagnosed children and adults (2 years of age and above) with imaging consistent with a DMG are eligible
  • TARGET VALIDATION: Children and young adults with recurrent primary malignant CNS tumors, including recurrent DMG, (2 years of age and above) who have evidence of progression but have not been treated for this progression
  • TARGET VALIDATION: Participants must undergo tumor tissue collection as part of their standard of care
  • Participants who are receiving steroids must be on a stable or decreasing dose for at least 3 days prior to baseline MRI scan
  • Peripheral absolute neutrophil count (ANC) >= neutrophil 1.0 g/l
  • Platelet count >= 100 x 10^9/L (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 90 mL/min/1.73 m^2 or a serum creatinine based on age/gender equal upper limit of normal
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase (ALT)) =< 2 x ULN
  • Patients with seizure disorder may be enrolled if seizure disorder is well controlled
  • The effects of ONC206 on the developing human fetus is unknown. For this reason, females of child-bearing potential and males must agree to use adequate contraception. Adequate methods include: hormonal or barrier method of birth control; or abstinence prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation
  • Karnofsky >= 50 for participants > 16 years of age and Lansky >= 50 for participants =< 16 years of age. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Subjects must be willing to provide archival formalin-fixed embedded (FFPE) and frozen tissue specimens for biomarker studies, if available
  • A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate

Exclusion Criteria:

  • Participants who are currently receiving another investigational drug are not eligible
  • Participants who are currently receiving other anti-cancer agents are not eligible
  • Participants with a known disorder that affects their immune system, such as human immunodeficiency virus (HIV) or hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy are not eligible. Note: Participants that are currently using inhaled, intranasal, ocular, topical or other non-oral or non-intravenous (IV) steroids are not necessarily excluded from the study but need to be discussed with the study chair
  • Participants with uncontrolled infection
  • Female participants of childbearing potential must not be pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy
  • Active illicit drug use or diagnosis of alcoholism
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC206
  • Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant or family
  • Any participants with illnesses that may affect absorption of ONC206
  • Any participants on strong inhibitors or inducers of CYP3A4, 2D6, 1A2, 2C9 and 2C19 at least 14 days prior and throughout the study

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 ClinicalTrials.gov identifier (NCT number): NCT04732065


Contacts
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Contact: Kelly Hitchner (415) 502-1600 PNOC023@ucsf.edu

Locations
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United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Kelly Hitchner    415-502-1600    PNOC023@ucsf.edu   
Contact       PNOC023@ucsf.edu   
Principal Investigator: Sabine Mueller, MD, PhD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Carl Koschmann, MD       CCPBTC-CRA@med.umich.edu   
Contact: Andrea Franson, MD         
Switzerland
The University Children's Hospital in Zurich Recruiting
Zürich, Zurich, Switzerland, 8032
Contact: Nicolas Gerber, MD    +41 44 266 3117    nicolas.gerber@kispi.uzh.ch   
Contact: Stephanie Matthes, PhD    +41 44 266 3726    Stephanie.Mathes@kispi.uzh.ch   
Sponsors and Collaborators
Sabine Mueller, MD, PhD
Chimerix
Mithil Prasad Foundation
Storm the Heavens Fund
The ChadTough Defeat DIPG Foundation
Investigators
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Study Chair: Sabine Mueller, MD, PhD University of California, San Francisco
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Sabine Mueller, MD, PhD, Principal Investigator, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04732065    
Other Study ID Numbers: 200814
NCI-2021-00046 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
First Posted: February 1, 2021    Key Record Dates
Last Update Posted: May 4, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data after de-identification.
Supporting Materials: Study Protocol

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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 Sabine Mueller, MD, PhD, University of California, San Francisco:
H3 K27M-Mutant
Additional relevant MeSH terms:
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Neoplasms
Glioblastoma
Glioma
Ependymoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Recurrence
Disease Attributes
Pathologic Processes
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Nervous System Diseases
Neoplasms by Site
Dopamine
Cardiotonic Agents
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protective Agents