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 central nervous system (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 CNS 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.

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.

Eligibility

1. ARM A: Children and young adults with DMG, H3K27 altered (dose escalation: 2-21 years of age; dose expansion: 2 years of age and above) 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 to registration (patients must start treatment within 1 week from registration), have not started any other therapies post-radiation, and have no evidence of disease progression
2. ARM A: Tumor tissue confirmation of DMG, H3K27 altered is mandatory and pathology must be consistent with a DMG, H3K27 altered
3. ARM A: Participants must have recovered from all acute side effects of prior therapy
4. ARM A: 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)
5. ARM B: Newly diagnosed children and young adults (dose escalation: 2-21 years of age; dose expansion: 2 years of age and above) with a diagnosis of DMG, H3K27 altered are eligible, including spinal cord DMGs
6. ARM B: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG, H3K27 altered
7. ARM C: Children and young adults with DMGs (dose escalation: 2-21 years of age; dose expansion: 2 years of age and above) who have evidence of progression but have not been treated for this progression and are recommended to get re-irradiation
8. 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)
9. ARM C: Tumor tissue confirmation is mandatory and pathology must be consistent with a DMG, H3K27 altered
10. ARM C: Participants must have recovered from all acute side effects of prior therapy
11. 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)
12. ARM D: Children and young adults with recurrent primary malignant CNS tumors (dose escalation: 2-21 years of age; dose expansion: 2 years of age and above ) who have evidence of progression but have not been treated for this progression. Participants who received a surgical resection for that progression are eligible if surgery has no curative intent. These patients need to be discussed with the study team
13. ARM D: Prior tumor tissue confirmation is mandatory and pathology from the primary tumor must be consistent with malignant CNS tumor (diagnosis of ependymoma is allowed). Tissue at the time of progression is not required
14. ARM D: Participants must have recovered from all acute side effects of prior therapy
15. 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). Bevacizumab used for pseudoprogression does not require a wash out period.
16. TARGET VALIDATION: Newly diagnosed children and adults (2 years of age and above) with imaging consistent with a DMG, H3K27 altered are eligible
17. 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
18. TARGET VALIDATION: Participants must undergo tumor tissue collection as part of their standard of care
19. Participants who are receiving steroids must be on a stable or decreasing dose for at least 3 days prior to baseline MRI scan
20. Peripheral absolute neutrophil count (ANC) >= neutrophil 1.0 g/l
21. Platelet count >= 100 x 10^9/L (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
22. A serum creatinine =< 1.5 upper limit of normal (ULN) based on age and gender
23. Total bilirubin =< 1.5 x upper limit of normal (ULN) for age; in presence of Gilbert’s syndrome, total bilirubin =< 3 x ULN or direct bilirubin =< 1.5 x ULN
24. Alanine aminotransferase (ALT) =< 3 x ULN
25. Aspartate aminotransferase (AST) =< 3 x ULN
26. Patients with seizure disorder may be enrolled if seizure disorder is well controlled
27. The effects of ONC206 on the developing human fetus are 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
28. 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
29. Participants must be willing to provide adequate tissue. A minimum of 10-20 paraffin embedded unstained slides OR 1 block with tumor content of 40% or greater is required. Frozen tissue is also acceptable. Participants who previously enrolled on PNOC022 and provided adequate tissue, may not need to submit additional tissue – confirm with Study Chairs. Participants who do not meet this criteria may be discussed on a case-by-case basis with the Study Chairs.
30. A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate
31. Patients must be enrolled on PNOC COMP prior to enrollment on PNOC023 if PNOC COMP is open to accrual at the enrolling institution

Treatment Sites in Georgia