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.
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.
ARM A: Tumor tissue confirmation of DMG, H3K27 altered is mandatory and pathology must be consistent with a DMG, H3K27 altered.
ARM A: Participants must have recovered from all acute side effects of prior therapy.
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)
Arm A & B: For tumors that do not have a pontine or spinal cord epicenter the following specific exclusion criteria apply: Thalamic DMG and cerebellar, H3K27 altered that has undergone standard radiation without concurrent therapy (other than temozolomide).
Arm C & D: Patients who participated in trials investigating ONC201 in the upfront setting will not be eligible. Prior ONC201 exposure as part of PNOC022 or expanded access programs will be allowed.
Participants who are currently receiving another investigational drug are not eligible.
Participants who are currently receiving other anti-cancer agents are not eligible.
Parallel
ONC206
DrugGiven orally (PO)
Standard of Care Radiation Therapy
RadiationUndergo RT
Optional Proton (1H) MR spectroscopy (MRS)
Procedure/SurgeryOptional imaging procedure
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.
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
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Sabine Mueller, MD, PhD
Lead sponsor
University of California, San Francisco
Sponsor institution
Jazz Pharmaceuticals
Collaborator
Mithil Prasad Foundation
Collaborator
Storm the Heavens Fund
Collaborator
The ChadTough Defeat DIPG Foundation
Collaborator
National Cancer Institute (NCI)
Collaborator
Dana-Farber Cancer Institute
Collaborator
