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Patients receive ONC206 orally (PO) up to six times per week. 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 up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

Patients receive ONC206 PO once a day (QD) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

ONC206

Standard of Care Radiation Therapy

Optional Proton (1H) MR spectroscopy (MRS)

PNOC Operations

Sabine Mueller, MD, PhD

Carl Koschmann, MD

Andrea Franson, MD

Nicolas Gerber, MD

Stephanie Matthes, PhD

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.

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of DRD2 antagonist/ClpP agonist ONC206 (ONC206).

II. To determine the MTD of ONC206 as single agent in children and young adults with DMG, H3K27 altered, 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, H3K27 altered (Arm B).

IV. To determine the MTD of ONC206 in combination with reirradiation in children and young adults with progression of DMG, H3K27 altered (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 not eligible for other arms. (Arm D).

VI. To assess the concentration of ONC206 in tumor tissue from children and young adults with DMG, H3K27 altered predominantly localized to the thalamus 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 DMG, H3K27 altered predominantly localized to the pons and compare to plasma drug levels pre-surgery. (Target validation).

VIII. To assess the concentration of ONC206 in tumor tissue in children and young adults with DMG, H3K27 altered in non-thalamic and non-pontine locations and compare to plasma drug levels pre-surgery. (Target validation).

IX. 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 characterize the pharmacokinetics (PK) of ONC206 in plasma in patients with DMG, H3K27 altered and recurrent primary malignant CNS tumors.(Arms A and D).

EXPLORATORY OBJECTIVES:

I. To assess the clinical responses within the confines of a phase 1/expansion study.

II. To assess if amount of serum circulating tumor DNA (ctDNA) is correlated with clinical outcome.

III. To assess if amount of cerebrospinal fluid (CSF) ctDNA is correlated with clinical outcome.

IV. To assess if clinical outcomes are associated with anatomic location of tumor, H3K27 mutation status and other partner mutations.

V. To assess biomarkers of response.

VI. To assess the response rate to ONC206 in patients with prior ONC201 exposure.

VII. To assess pharmacodynamics (PD) of ONC206.

VIII. To assess PK-PD and identify the relationship between drug exposure and clinical endpoints for both safety and efficacy.

IX. To characterize the PK of ONC206 in CSF in patients with DMG, H3K27 altered and recurrent primary malignant CNS tumors.

X. To assess PD changes within tumor tissue after ONC206 administration (Target Validation).

XI. To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics.

XII. To assess Health Related Quality of Life (HRQOL) outcomes.

XIII. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures.

XIV. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures in the context of race ethnicity and other health related social risks.

XV. To assess on therapy toxicity and survival in the context of race, ethnicity and other health related social risks.

XVI. To assess if 18F-FET-PET can support response assessment in children treated with ONC206.

XVII. To determine feasibility of measuring ONC206 concentrations in hair samples.

XVIII. To assess feasibility to obtain Proton (1H) MR spectroscopy (MRS) with standard MRI.

OUTLINE: This is a dose-escalation study of ONC206. Patients are assigned to 1 of 4 arms.

ARM A (Children and young adults with DMG H3K27 altered who completed at least one line of prior therapy) and ARM D (Participants with recurrent primary malignant CNS tumors including participants with recurrent DMGs who failed at least one prior therapy including radiation therapy): Patients receive ONC206 orally (PO) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment could possibly proceed up to 24 months.

ARM B (Newly diagnosed children and young adults with DMG H3K27 altered) and ARM C:(Children and young adults with DMG H3K27 altered who have evidence of progression but have not been treated for this progression and are candidates for re-irradiation): Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 as in Arm A.

All participants will be permitted to have an optional MRS scans. After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 5 years.

ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors

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

Individual participant data after de-identification.

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).

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.

Concentration-time data will be summarized by N, Mean, Standard Deviation, Median, Min, Max and 95% Confidence Interval

PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

Spots Global Cancer Trial Database for spinal cord glioma