ONC206 for Treatment of Newly Diagnosed, or Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors (PNOC 023)

• ClinicalTrials.gov Identifier: NCT04732065
• Recruitment Status: Recruiting
• First Posted: February 1, 2021
• Last Update Posted: September 15, 2022
• Sponsor: Sabine Mueller, MD, PhD
• Collaborators: Chimerix; Mithil Prasad Foundation; Storm the Heavens Fund; The ChadTough Defeat DIPG Foundation
• Information provided by (Responsible Party): Sabine Mueller, MD, PhD, University of California, San Francisco

Tracking Information

• First Submitted Date: January 26, 2021
• First Posted Date: February 1, 2021
• Last Update Posted Date: September 15, 2022
• Actual Study Start Date: August 23, 2021
• Estimated Primary Completion Date: January 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 8, 2021)

• Proportion of participants with dose-limiting toxicities (DLT) [ Time Frame: 4 weeks after first dose ]
  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 [ Time Frame: 4 weeks after first dose ]
  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.

Original Primary Outcome Measures (submitted: January 29, 2021)

• Proportion of participants with dose-limiting toxicities (DLT) [ Time Frame: Up to 30 days after discontinuation of treatment, approximately 24 months ]
  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 [ Time Frame: 4 weeks after first dose ]
  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.

Current Secondary Outcome Measures (submitted: January 29, 2021)

• Mean maximum concentration (Cmax) of ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
  Concentration-time data will be summarized by N, Mean, Standard Deviation, Median, Min, Max and 95% Confidence Interval
• Mean corresponding time (Tmax) of ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
  PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
• Area under the curve (AUC) of ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
  PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
• Elimination half-life (t1/2) of ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
  PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
• Mean Total body clearance (CL) for ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
  PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling
• Mean Volume of Distribution (Vd) for ONC206 [ Time Frame: Day 1 (pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose), pre-dose on Day 8, pre-dose on Day 15 of Cycle 1, pre-dose on Day 1 of Cycle 2, 4, 6, etc. (each cycle is 28 days) ]
  PK parameters will be estimated using standard population PK methodologies and non-linear mixed effect modeling

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: January 29, 2021)

• Changes in score on the Cranial Nerve Palsy Examination [ Time Frame: Baseline and 24 months ]
  The Cranial Nerve Palsy Examination is a assessment of the palsy associated with particular nerves. The scores range from 0 (normal), 1 (mild/partial palsy), to 2 (severe/complete palsy). The scores for each of the 9 nerves are added up to create a total score ranging from 0 to 18, with higher scores indicating a greater level of impairment.
• Progression-free survival (PFS6) [ Time Frame: Up to 6 months ]
  PFS will be defined as from the time of treatment initiation until the time of progressive disease or death from any cause in patients with an event and until the time of last follow-up for patients who are progression free at the time of analysis, assessed up to 6 months and summarized by cohort using the Kaplan Meier method. Kaplan-Meier estimates of event rates at 6-months and median time to the event will be presented with the corresponding 95% confidence intervals.
• Progression-free survival (PFS12) [ Time Frame: Up to 12 months ]
  PFS will be defined as from the time of treatment initiation until the time of progressive disease or death from any cause in patients with an event and until the time of last follow-up for patients who are progression free at the time of analysis, assessed up to 12 months and summarized by cohort using the Kaplan Meier method. Kaplan-Meier estimates of event rates at 12-months and median time to the event will be presented with the corresponding 95% confidence intervals.
• Number of participants with defined mutation subtype [ Time Frame: Up to 24 months ]
  H3F3A vs. HIST1H3B vs. Histone wildtype
• Change in tumor tissue [ Time Frame: Baseline and 24 months ]
  Concentration of ONC206 in post-treatment tumor tissue in patients with DMG according to anatomic location (thalamus, pons, or non-thalamic/non-pontine locations) and patients with recurrent primary malignant brain tumors
• Change in Pediatric Quality of Life (PedsQL) 4.0 (Generic Core) [ Time Frame: Baseline and 24 months ]
  The PedsQL 4.0 Generic Core Scales is a multidimensional child self-report and parent proxy report scales to assess health-related quality of life (QOL) in children, adolescents, and young adults ages 2 - 25 years. It consists of a 23-items scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always). Item scores are transformed to a 0 to 100 scale with higher scores indicate lower problems. Subscales include physical functioning, emotional functioning, social functioning, and school functioning.
• Change in Pediatric Quality of Life (PedsQL) 3.0 (cancer module) [ Time Frame: Baseline and 24 months ]
  The PedsQL 3.0 Cancer Module is a multidimensional child self-report and parent proxy report scales to assess health-related quality of life (QOL) in children, adolescents, and young adults ages 2 - 25 years. It consists of a 24-items scored on a 5-point Likert scale from 0 (Never) to 4 (Almost always). Item scores are transformed to a 0 to 100 scale with higher scores indicate lower problems.

Descriptive Information

• Brief Title: ONC206 for Treatment of Newly Diagnosed, or Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors (PNOC 023)
• Official Title: 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
• Brief 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 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.

Detailed Description

PRIMARY OBJECTIVES:

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

II. To determine the maximum tolerated dose (MTD) of ONC206 as single agent in children and young adults with diffuse midline glioma (DMG) 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. (Arm B).

IV. To determine the MTD of ONC206 in combination with re-irradiation in children and young adults with first progression of DMG. (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 they are not eligible for the other arms. (Arm D).

VI. To assess the concentration of ONC206 in tumor tissue from children and young adults with DMG 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 recurrent primary malignant CNS tumors and compare to plasma drug levels pre-surgery. (Target validation).

SECONDARY OBJECTIVE:

I. To describe the pharmacokinetics associated with ONC206 without radiation therapy. (Arms A and D).

EXPLORATORY OBJECTIVES:

I. Determine changes in cranial nerve scoring.

II. Determine clinical responses within the confines of a phase 1/expansion study.

III. Evaluate correlation of amount of serum and cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) with clinical outcome.

IV. Evaluate association of clinical outcomes with anatomic location of tumor, H3K27 mutation status and other partner mutations.

V. Pharmacodynamic (PD) effects in tumor tissue

VI. Assess the overall response rate to ONC206 in patients with prior ONC201 exposure

VII. Assess pharmacodynamics (PD) of ONC206 and perform exploratory pharmacokinetic (PK)-PD analyses to investigate and identify the relationship between drug exposure and clinical endpoints for both safety and efficacy.

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

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

X. To characterize the PK of ONC206 in CSF in patients with DMG and recurrent primary malignant CNS tumors.

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

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

ARMS A and D: Patients receive ONC206 orally (PO) once daily (QD) on days 1, 8, 15, 22. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.

ARMS B and C: Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 as in Arm A.

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

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Diffuse Midline Glioma (DMG)
• Glioblastoma
• Recurrent Ependymoma
• Recurrent Malignant Central Nervous System Neoplasm
• Spinal Cord Glioma
• WHO Grade III Glioma
• CNS Tumor
• Central Nervous System Tumor

Intervention

• Drug: ONC206
  Given orally (PO)
  Other Names:

  • antagonist of dopamine receptor D2 (DRD2) /human mitochondrial caseinolytic protease P (ClpP)ClpP Agonist
  • DRD2 antagonist/ClpP agonist
• Radiation: Standard of Care Radiation Therapy
  Undergo RT
  Other Names:

  • Radiation Therapy (RT)
  • Cancer Radiotherapy

Study Arms

• Experimental: Arm A: ONC206 for participants with diffuse midline gliomas + prior therapy
  Patients receive ONC206 PO QD on days 1, 8, 15, 22. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
  Intervention: Drug: ONC206
• Experimental: Arm B: ONC206 + radiation therapy for newly diagnosed participants
  Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO QD on days 1, 8, 15, 22. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: ONC206
  • Radiation: Standard of Care Radiation Therapy
• Experimental: Arm C: ONC206 + radiation therapy, DMGs with evidence of first progression but previously untreated
  Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 PO QD on days 1, 8, 15, 22. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Drug: ONC206
  • Radiation: Standard of Care Radiation Therapy
• Experimental: Arm D: ONC206 Therapy, Primary malignant CNS tumors with progression
  Patients receive ONC206 PO QD on days 1, 8, 15, 22. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity.
  Intervention: Drug: ONC206

• Publications *: Przystal JM, Cianciolo Cosentino C, Yadavilli S, Zhang J, Laternser S, Bonner ER, Prasad R, Dawood AA, Lobeto N, Chin Chong W, Biery MC, Myers C, Olson JM, Panditharatna E, Kritzer B, Mourabit S, Vitanza NA, Filbin MG, de Iuliis GN, Dun MD, Koschmann C, Cain JE, Grotzer MA, Waszak SM, Mueller S, Nazarian J. Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas. Neuro Oncol. 2022 Sep 1;24(9):1438-1451. doi: 10.1093/neuonc/noac041.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: January 29, 2021): 256
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: January 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• ARM A: Children and young adults with DMG (2-21 years of age) 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 and have no evidence of disease progression
• ARM A: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including DMG H3K27M mutant and World Health Organization (WHO) grade III and IV H3 wildtype gliomas. WHO grade II diffuse astrocytomas or other low grade gliomas without H3K27M mutation are not eligible
• ARM A: Participants must have recovered from all acute side effects of prior therapy. 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 B: Newly diagnosed children and young adults (2-21 years of age) with a diagnosis of DMG are eligible, including spinal cord DMGs
• ARM B: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including DMG H3K27M mutant and WHO grade III and IV H3 wildtype gliomas. WHO grade II diffuse astrocytomas or other low grade gliomas without H3K27M mutation are not eligible
• ARM C: Children and young adults with DMGs (2-21 years of age) who have evidence of first progression but have not been treated for this progression and are recommended to get reirradiation
• 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)
• ARM C: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including DMG H3K27M mutant and WHO grade III and IV H3 wildtype gliomas. WHO grade II diffuse astrocytomas or other low grade gliomas without H3K27M mutation are not eligible
• ARM C: Participants must have recovered from all acute side effects of prior therapy
• 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)
• ARM D: Children and young adults with recurrent primary malignant CNS tumors (2 - 21 years of age) who have evidence of progression but have not been treated for this progression
• ARM D: Tumor tissue confirmation is mandatory and pathology must be consistent with recurrent primary malignant CNS tumor (diagnosis of recurrent ependymoma is allowed)
• ARM D: Participants must have recovered from all acute side effects of prior therapy
• 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)
• ARM D: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 3 days prior to baseline magnetic resonance imaging (MRI) scan
• TARGET VALIDATION: Newly diagnosed children and adults (2 years of age and above) with imaging consistent with a DMG are eligible
• 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
• TARGET VALIDATION: Participants must undergo tumor tissue collection as part of their standard of care
• Participants who are receiving steroids must be on a stable or decreasing dose for at least 3 days prior to baseline MRI scan
• Peripheral absolute neutrophil count (ANC) >= neutrophil 1.0 g/l
• Platelet count >= 100 x 10^9/L (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 90 mL/min/1.73 m^2 or a serum creatinine based on age/gender equal upper limit of normal
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase (ALT)) =< 2 x ULN
• Patients with seizure disorder may be enrolled if seizure disorder is well controlled
• The effects of ONC206 on the developing human fetus is 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
• 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
• Subjects must be willing to provide archival formalin-fixed embedded (FFPE) and frozen tissue specimens for biomarker studies, if available
• A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate

Exclusion Criteria:

• Participants who are currently receiving another investigational drug are not eligible
• Participants who are currently receiving other anti-cancer agents are not eligible
• Participants with a known disorder that affects their immune system, such as human immunodeficiency virus (HIV) or hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy are not eligible. Note: Participants that are currently using inhaled, intranasal, ocular, topical or other non-oral or non-intravenous (IV) steroids are not necessarily excluded from the study but need to be discussed with the study chair
• Participants with uncontrolled infection
• Female participants of childbearing potential must not be pregnant or breast-feeding. Female participants of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy
• Active illicit drug use or diagnosis of alcoholism
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC206
• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant or family
• Any participants with illnesses that may affect absorption of ONC206
• Any participants on strong inhibitors or inducers of CYP3A4, 2D6, 1A2, 2C9 and 2C19 at least 14 days prior and throughout the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Kelly Hitchner; (415) 502-1600; PNOC023@ucsf.edu

• Listed Location Countries: Switzerland, United States

Administrative Information

• NCT Number: NCT04732065
• Other Study ID Numbers: 200814; NCI-2021-00046 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Individual participant data after de-identification.
• Supporting Materials: Study Protocol

• Current Responsible Party: Sabine Mueller, MD, PhD, University of California, San Francisco
• Original Responsible Party: Same as current
• Current Study Sponsor: Sabine Mueller, MD, PhD
• Original Study Sponsor: Same as current

Collaborators

• Chimerix
• Mithil Prasad Foundation
• Storm the Heavens Fund
• The ChadTough Defeat DIPG Foundation

Investigators

• Study Chair: Sabine Mueller, MD, PhD; University of California, San Francisco

• PRS Account: University of California, San Francisco
• Verification Date: September 2022