ONC206 for the Treatment of Newly Diagnosed or Recurrent Diffuse Midline Gliomas or Other Recurrent Primary Malignant Central Nervous System Tumors

Summary

Objectives

PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of DRD2 antagonist/ClpP agonist ONC206 (ONC206) as single agent in children and young adults with diffuse midline glioma (DMG), H3K27 altered, who completed at least one line of prior therapy that included focal radiation therapy. (Arm A)
II. 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)
III. To determine the MTD of ONC206 in combination with re-irradiation in children and young adults with progression of DMG, H3K27 altered. (Arm C)
IV. 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)
V. 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)
VI. 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)
VII. 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)
VIII. 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.

EXPLORATORY OBJECTIVES:
I. To assess the clinical responses within the confines of a phase 1/expansion study. (Dose Escalation/dose expansion)
II. To assess if amount of serum circulating tumor DNA (ctDNA) is correlated with clinical outcome.(Dose Escalation/dose expansion)
III. To assess if amount of cerebrospinal fluid (CSF) ctDNA is correlated with clinical outcome. (Dose Escalation/dose expansion)
IV.To assess if clinical outcomes are associated with anatomic location of tumor, H3K27 mutation status and other partner mutations. (Dose Escalation/dose expansion)
V. To assess biomarkers of response. (Dose Escalation/dose expansion)
VI. To assess the response rate to ONC206 in patients with prior ONC201 exposure. (Dose Escalation/dose expansion)
VII. To assess pharmacodynamics (PD) of ONC206. (Dose Escalation/dose expansion)
VIII. To assess PK-PD and identify the relationship between drug exposure and clinical endpoints for both safety and efficacy. (Dose Escalation/dose expansion)
IX. To characterize the PK of ONC206 in CSF in patients with DMG, H3K27 altered and recurrent primary malignant CNS tumors. (Dose Escalation/dose expansion)
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. (All Phases/Arms)
XII. To assess Health Related Quality of Life (HRQOL) outcomes. (All Phases/Arms)
XIII. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures. (All Phases/Arms)
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. (All Phases/Arms)
XV. To assess on therapy toxicity and survival in the context of race, ethnicity and other health related social risks. (All Phases/Arms)
XVI. To assess if F-18 fluoroethyltyrosine (18F-FET)-positron emission tomography (PET) can support response assessment in children treated with ONC206. (All Phases/Arms)
XVII. To determine feasibility of measuring ONC206 concentrations in hair samples. (All Phases/Arms)
XVIII. To assess feasibility to obtain Proton (1H) magnetic resonance (MR) spectroscopy (MRS) with standard magnetic resonance imaging (MRI). (All Phases/Arms)

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

ARMS A and D: Patients receive ONC206 orally (PO) on days 1, 8, 15, 22 of each cycle, twice daily (BID) on days 1, 2, and 3 of each week during cycles, or once daily (QD) on days 1, 2, and 3 of each week during cycles. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of CSF samples via lumbar puncture during screening and on study, collection of blood samples on study, and MRI scans during screening and on study. Patients may also undergo optional 18F-FET PET scans and MRS imaging on study.

ARMS B and C: Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 as in Arm A. Patients also undergo collection of CSF samples via lumbar puncture during screening and on study, collection of blood samples on study, and MRI scans during screening and on study. Patients may also undergo optional 18F-FET PET scans and MRS imaging on study.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 5 years.