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

Primary Purpose

Diffuse Midline Glioma (DMG), Glioblastoma, Recurrent Ependymoma

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
ONC206
Standard of Care Radiation Therapy
Sponsored by
Sabine Mueller, MD, PhD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Midline Glioma (DMG) focused on measuring H3 K27M-Mutant

Eligibility Criteria

2 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California, San FranciscoRecruiting
  • University of MichiganRecruiting
  • The University Children's Hospital in ZurichRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Arm A: ONC206 for participants with diffuse midline gliomas + prior therapy

Arm B: ONC206 + radiation therapy for newly diagnosed participants

Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreated

Arm D: ONC206 Therapy, Primary malignant CNS tumors with progression

Arm Description

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Proportion of participants with dose-limiting toxicities (DLT)
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).
Maximum tolerated dose (MTD) of ONC206
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

Mean maximum concentration (Cmax) of ONC206
Concentration-time data will be summarized by N, Mean, Standard Deviation, Median, Min, Max and 95% Confidence Interval
Mean corresponding time (Tmax) of ONC206
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
Area under the curve (AUC) of ONC206
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
Elimination half-life (t1/2) of ONC206
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
Mean Total body clearance (CL) for ONC206
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
Mean Volume of Distribution (Vd) for ONC206
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

Full Information

First Posted
January 26, 2021
Last Updated
April 4, 2023
Sponsor
Sabine Mueller, MD, PhD
Collaborators
Chimerix, Mithil Prasad Foundation, Storm the Heavens Fund, The ChadTough Defeat DIPG Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT04732065
Brief Title
ONC206 for Treatment of Newly Diagnosed, or Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors (PNOC 023)
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 23, 2021 (Actual)
Primary Completion Date
January 31, 2024 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Sabine Mueller, MD, PhD
Collaborators
Chimerix, Mithil Prasad Foundation, Storm the Heavens Fund, The ChadTough Defeat DIPG Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the safety and tolerability of DRD2 antagonist/ClpP agonist ONC206 (ONC206). II. To determine the maximum tolerated dose (MTD) of ONC206 as single agent in children and young adults with diffuse midline glioma (DMG) who completed at least one line of prior therapy that included focal radiation therapy. (Arm A). III. To determine the MTD of ONC206 in combination with focal radiation therapy in newly diagnosed children and young adults with DMG. (Arm B). IV. To determine the MTD of ONC206 in combination with re-irradiation in children and young adults with first progression of DMG. (Arm C). V. To determine the MTD of ONC206 in children and young adults with recurrent primary malignant CNS tumors including participants with recurrent DMGs if they are not eligible for the other arms. (Arm D). VI. To assess the concentration of ONC206 in tumor tissue from children and young adults with DMG and compare to plasma drug levels pre-surgery. (Target validation). VII. To assess the concentration of ONC206 in tumor tissue in children and young adults with recurrent primary malignant CNS tumors and compare to plasma drug levels pre-surgery. (Target validation). SECONDARY OBJECTIVE: I. To describe the pharmacokinetics associated with ONC206 without radiation therapy. (Arms A and D). EXPLORATORY OBJECTIVES: I. Determine changes in cranial nerve scoring. II. Determine clinical responses within the confines of a phase 1/expansion study. III. Evaluate correlation of amount of serum and cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) with clinical outcome. IV. Evaluate association of clinical outcomes with anatomic location of tumor, H3K27 mutation status and other partner mutations. V. Pharmacodynamic (PD) effects in tumor tissue VI. Assess the overall response rate to ONC206 in patients with prior ONC201 exposure VII. Assess pharmacodynamics (PD) of ONC206 and perform exploratory pharmacokinetic (PK)-PD analyses to investigate and identify the relationship between drug exposure and clinical endpoints for both safety and efficacy. VIII. To assess Health Related Quality of Life (HRQOL) outcomes VIIII. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures. X. To characterize the PK of ONC206 in CSF in patients with DMG and recurrent primary malignant CNS tumors. XI. To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics. OUTLINE: This is a dose-escalation study of ONC206. Patients are assigned to 1 of 4 arms. ARMS A and D: Patients receive ONC206 orally (PO) once daily (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. ARMS B and C: Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 as in Arm A. After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 5 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
H3 K27M-Mutant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
256 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm A: ONC206 for participants with diffuse midline gliomas + prior therapy
Arm Type
Experimental
Arm Description
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.
Arm Title
Arm B: ONC206 + radiation therapy for newly diagnosed participants
Arm Type
Experimental
Arm Description
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.
Arm Title
Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreated
Arm Type
Experimental
Arm Description
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.
Arm Title
Arm D: ONC206 Therapy, Primary malignant CNS tumors with progression
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
ONC206
Other Intervention Name(s)
antagonist of dopamine receptor D2 (DRD2) /human mitochondrial caseinolytic protease P (ClpP)ClpP Agonist, DRD2 antagonist/ClpP agonist
Intervention Description
Given orally (PO)
Intervention Type
Radiation
Intervention Name(s)
Standard of Care Radiation Therapy
Other Intervention Name(s)
Radiation Therapy (RT), Cancer Radiotherapy
Intervention Description
Undergo RT
Primary Outcome Measure Information:
Title
Proportion of participants with dose-limiting toxicities (DLT)
Description
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).
Time Frame
4 weeks after first dose
Title
Maximum tolerated dose (MTD) of ONC206
Description
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.
Time Frame
4 weeks after first dose
Secondary Outcome Measure Information:
Title
Mean maximum concentration (Cmax) of ONC206
Description
Concentration-time data will be summarized by N, Mean, Standard Deviation, Median, Min, Max and 95% Confidence Interval
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)
Title
Mean corresponding time (Tmax) of ONC206
Description
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
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)
Title
Area under the curve (AUC) of ONC206
Description
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
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)
Title
Elimination half-life (t1/2) of ONC206
Description
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
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)
Title
Mean Total body clearance (CL) for ONC206
Description
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
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)
Title
Mean Volume of Distribution (Vd) for ONC206
Description
PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Kelly Hitchner
Phone
(415) 502-1600
Email
PNOC023@ucsf.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sabine Mueller, MD, PhD
Organizational Affiliation
University of California, San Francisco
Official's Role
Study Chair
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kelly Hitchner
Phone
415-502-1600
Email
PNOC023@ucsf.edu
Email
PNOC023@ucsf.edu
First Name & Middle Initial & Last Name & Degree
Sabine Mueller, MD, PhD
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Carl Koschmann, MD
Email
CCPBTC-CRA@med.umich.edu
First Name & Middle Initial & Last Name & Degree
Andrea Franson, MD
Facility Name
The University Children's Hospital in Zurich
City
Zürich
State/Province
Zurich
ZIP/Postal Code
8032
Country
Switzerland
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nicolas Gerber, MD
Phone
+41 44 266 3117
Email
glioma@kispi.uzh.ch
First Name & Middle Initial & Last Name & Degree
Stephanie Matthes, PhD
Phone
+41 44 266 3726
Email
glioma@kispi.uzh.ch

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data after de-identification.
Citations:
PubMed Identifier
35157764
Citation
Przystal JM, Cianciolo Cosentino C, Yadavilli S, Zhang J, Laternser S, Bonner ER, Prasad R, Dawood AA, Lobeto N, Chin Chong W, Biery MC, Myers C, Olson JM, Panditharatna E, Kritzer B, Mourabit S, Vitanza NA, Filbin MG, de Iuliis GN, Dun MD, Koschmann C, Cain JE, Grotzer MA, Waszak SM, Mueller S, Nazarian J. Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas. Neuro Oncol. 2022 Sep 1;24(9):1438-1451. doi: 10.1093/neuonc/noac041.
Results Reference
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ONC206 for Treatment of Newly Diagnosed, or Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors (PNOC 023)

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