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Anaplastic Pleomorphic Xanthoastrocytoma

ONC206 is a member of the imipridone class of anti-cancer small molecules that share a unique tri-heterocyclic core chemical structure and target G protein-coupled receptors.

ONC206

Chris Tedesco

Marion Morrison, MD

Referrals

Kelly Mentges, RN

Mark Gilbert, MD

The primary objective of this Phase 1, open-label, dose-escalation, and exploratory study is to evaluate the safety and tolerability profile (establish the maximum-tolerated dose) and evaluate the occurrence of dose-limiting toxicities (DLTs) following single weekly or multiple-day weekly dose regimens of single-agent, oral ONC206 in patients with recurrent, primary central nervous system (CNS) neoplasms.

This is a Phase I, open-label, dose-escalation, and exploratory study of ONC206 in patients with recurrent, primary CNS neoplasms. All patients will be informed about the study and potential risks and required to provide written informed consent prior to undergoing study-related procedures.

There will be a total of 11 Dose Levels. Dose-escalation for Dose Levels 1 through 5 proceeded according to standard 3+3 design using a 28-day DLT window. The first cohort of 3 patients enrolled into the study received Dose Level 1 followed by increments as per the modified Fibonacci sequence. It is anticipated that approximately 46 patients will be enrolled in order to determine the MTD of ONC206.

For Dose Levels 1 through 5, a safety evaluation was conducted when 3 evaluable patients have completed 1 cycle (28 days) of therapy. After Protocol Amendment 6, all available PK data will also be considered for dose escalation decisions. Dose levels may be adjusted based on review of PK data but will not exceed maximum dose levels described in Table 6. Additionally, dose frequencies (e.g., once daily or 3 times daily) may be added and/or removed based on emerging PK data and concentration projections.

Prior to advancing/changing dose levels, a cohort summary must be completed and submitted to the sponsor Medical Monitor, for review and approval. Dose escalation for subsequent patients will proceed as follows:

* If no DLT is reported at a dose level, that dose level will be considered safe, and patient(s) will be enrolled at the next dose level. Toxicity information will continue to be evaluated from the time of the first protocol specific intervention, until 30 days from the last dose of study drug.
* If 1 patient in a cohort of 1 experiences a DLT, the dose level will be expanded to obtain an additional 2 evaluable patients.
* If 1 patient in a cohort at a dose level experiences a DLT, the dose level will be expanded to obtain an additional 3 evaluable patients.
* If 2 of 3 patients in a cohort at a dose level experience a DLT, that dose level will not be considered safe, no further dose escalation will take place, and the MTD will have been exceeded\*.
* If 1 patient experiences a DLT among the expanded cohort of evaluable patients, a cohort of 3 patients will be enrolled in the next higher dose level.
* If 2 or more patients experience a DLT among the expanded cohort of evaluable patients, that dose level will not be considered safe, no further dose escalation will take place, and the MTD will have been exceeded\*. The previous dose level at which ≤1 patients experienced a DLT will be declared the MTD.

  * When the MTD has been exceeded:

If less than 6 patients have been treated in the next lower dose level (the possible MTD level), additional patients will be entered into this dose level until there are 6 patients treated. If ≤1 of these 6 patients encountered DLT, then this dose level will be declared to be the MTD. If 2 or more of the 6 patients encounter DLT, then the MTD has been exceeded.

Given the experience with ONC201, it is possible a MTD may not be reached through the planned dose escalation cohorts. If the therapeutic target concentrations have been achieved in the dose escalation cohorts, and no DLT has been identified, then analysis of the safety and PK data will be evaluated by the Investigators and the Sponsor. Further dose levels may then be considered at higher intermittent dosing schedules and will be added by protocol amendment with review by the Institutional Review Board (IRB) before implementation.

Toxicities will be graded using the Common Terminology Criteria for Adverse Events Version 24.0 (CTCAE 24.0). If the CTCAE 24.0 does not apply to an adverse event, it will be graded as mild, moderate, or severe.

DLTs will be assessed during the first course of each cohort (28 days), and refers to a study drug related or possibly related event that meets 1 of the following criteria using the NCI CTCAE version 5.0:

* Grade 3 or higher non-hematologic toxicity.
* Grade 4 hematologic toxicity (ANC \<0.5 × 109/L and platelet count \<25 × 109/L). Lymphopenia is not considered a DLT. A confirmed DLT requires 2 consecutive measurements separated by 48 hours.
* Grade 3 neutropenia (ANC \<1.0 × 109/L) with elevated fever (\>101°F). A confirmed DLT requires 2 consecutive measurements.
* Grade 3 thrombocytopenia with clinically significant bleeding.
* Inability to receive the scheduled Cycle 2, Day 1 dose of study drug within 14 days due to study drug-related toxicity persisting from Cycle 1 or study drug-related toxicity newly encountered on Day 1 of Cycle 2.

Safety and tolerability will be monitored by assessing physical examinations including height (at Screening only) and weight, KPS, vital signs, ECG, laboratory assessments including hematology, chemistry, and coagulation, as well as collecting of the AEs at every visit.

Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms

A First-in-human Phase I Single-agent Dose-escalation, Food Effect and Dose Expansion Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms

MTD was determined by testing increasing doses up to 200 mg twice daily for 3 successive days a week.

MTD reflects the highest dose of drug that did not cause a Dose-Limiting Toxicity (DLT) in \>33% of participants. DLTs will be assessed in the first course of each cohort (28 days), and refer to a study drug-related or possibly related event that meets 1 of the following criteria defined in the subsequent Primary Outcome Measure using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE 5.0).

DLTs will be assessed in the first course of each cohort (28 days), and refer to a study drug-related or possibly related event that meets 1 of the following criteria using NCI CTCAE 5.0:

* Grade 3 or higher non-hematologic toxicity.
* Grade 4 hematologic toxicity (ANC \<0.5 × 109/L and platelet count \<25 × 109/L). Lymphopenia is not considered a DLT. A confirmed DLT requires 2 consecutive measurements separated by 48 hours.
* Grade 3 neutropenia (absolute neutrophil count \[ANC\] \<1.0 × 109/L) with elevated fever (\>101°F). A confirmed DLT requires 2 consecutive measurements.
* Grade 3 thrombocytopenia with clinically significant bleeding.
* Inability to receive the scheduled Cycle 2, Day 1 dose of study drug within 14 days due to study drug-related toxicity persisting from Cycle 1 or study drug-related toxicity newly encountered on Day 1 of Cycle 2.

National Institutes of Health (NIH)

Chimerix

Disease Attributes

Cardiotonic Agents

All Drugs and Chemicals

Dopamine

Sympathomimetics

Dopamine Agents

Neurotransmitter Agents

Protective Agents

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.

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase I Study of Oral ONC206 in Recurrent and Rare Primary Central Nervous System Neoplasms	NCT04541082	Central Nervous... Glioblastoma Gliosarcoma, Ad... Anaplastic Olig... Anaplastic Astr... Pilocytic Astro... Oligodendroglio... Gliomatosis Cer... Pleomorphic Xan... Anaplastic Pleo... Diffuse Midline... Ependymoma Ependymoma, Ana... Medulloblastoma Teratoid Rhabdo... Neuroectodermal... Neuroectodermal... Anaplastic Meni... Atypical Mening... Choroid Plexus ... Pineal Tumor Diffuse Astrocy... Glial Tumor	ONC206	18 Years -	Chimerix
ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors	NCT04732065	Diffuse Midline... Glioblastoma Recurrent Epend... Recurrent Malig... Spinal Cord Gli... World Health Or... CNS Tumor Central Nervous...	ONC206 Standard of Car... Optional Proton...	2 Years - 21 Years	University of California, San Francisco

Spots Global Cancer Trial Database for onc206

Every month we try and update this database with for onc206 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for onc206

Every month we try and update this database with for onc206 cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for onc206 cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.