Combination Therapy for the Treatment of Diffuse Midline Gliomas
This phase II trial determines if the combination of ONC201 with different drugs is effective for treating participants with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for participants with DMGs, and there are few treatment options. This trial will utilize an adaptive platform design in that the different treatment arms for each cohort will be opened and closed based on ongoing preclinical investigation as well as evolving outcome data from the trial.
Novel agents will be continuously added to this study as pre-clinical data emerge to suggest additive or synergistic activity when combined ONC201. Should a novel agent not have an RP2D at the time of incorporation into this study, a phase 1 lead-in will be performed prior to initiation of combination therapy (via study amendment).
Study details:
OUTLINE:. This is a multi-arm/cohort, multi-institutional, open-label trial. The study is divided into cohorts based on stage of disease (newly-diagnosed, post-radiation therapy without disease progression, and at disease progression).
---THIS STUDY IS NOT ENROLLING ON COHORTS 1, 2, 3, and 4 --. COHORT DESCRIPTIONS:. --ENROLLING-- COHORT 5: Includes participants whose tumor demonstrates specific molecular alterations of interest considered targetable by an approved/available agent(s) and recommended by the PNOC022 tumor board.
Participants are also allowed to receive ONC201 monotherapy with radiation or re-irradiation therapy. Cohort 5\^1: Includes newly diagnosed participants who have already undergone tumor tissue collection and have not yet completed radiation therapy. Cohort 5\^2: Includes newly diagnosed participants who have already undergone tumor tissue collection and have completed radiation therapy.
Cohort 5\^3: Includes participants with progressive DMG who are not planned for SOC tumor collection and will undergo re-irradiation. --ENROLLING-- COHORT 6: Includes participants with DMGs who have completed focal radiation therapy and are within 4-14 weeks from completion of radiation therapy without evidence of progression, who will undergo repeated intratumor DNX-2401 infusions. -NOT CURRENTLY ENROLLING- COHORTS 1A \& 2A (Target Validation cohorts); Includes newly diagnosed participants that have not yet undergone tumor tissue collection.
Cohort 1A will include participants with DMG who have not yet completed radiation therapy and Cohort 2A will include participants with DMG who have completed radiation therapy. -NOT CURRENTLY ENROLLING - COHORTS 1B \& 2B: Includes newly-diagnosed participants who have already undergone tumor tissue collection. Cohort 1B will include participants with DMG who have not yet completed radiation therapy and Cohort 2B will include participants with DMG who have completed radiation therapy.
-NOT CURRENTLY ENROLLING- COHORTS 3A \& 3B: Includes participants with progressive DMG. Cohort 3A will include participants planned for standard of care (SOC) tumor tissue collection. Cohort 3B will include participants not planned for SOC tumor tissue collection.
The nomenclature will delineate participants previously enrolled in Cohorts 1 or 2. -NOT CURRENTLY ENROLLING - COMBINATION COHORTS 1, 2 and 3: Participants are randomized to 1 of 3 arms (Arm 2,4,6). ARM 2: During the trial validation phase, participants without prior biopsy receive ONC201 on day -1 prior to standard of care biopsy.
During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 weekly during radiation therapy. During the maintenance phase, participants receive ONC201 weekly and paxalisib daily. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity.
ARM 4: During the trial validation phase, participants without prior biopsy receive ONC201 on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants may receive ONC201 weekly during radiation therapy. During the maintenance phase, participants receive ONC201 weekly and paxalisib.
Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity. ARM 6: During trial validation phase, participants without prior biopsy receive paxalisib on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo radiation therapy five times a week and receive paxalisib during radiation therapy.
During the maintenance phase, participants receive ONC201 and paxalisib during each cycle. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. -NOT CURRENTLY ENROLLING - COHORT 4A and 4B: Includes patients who are currently not eligible for defined combination arms of PNOC022 or other clinical trials investigating ONC201, such as ONC201-108 ACTION trial.
Cohort 4A\^1: Includes newly diagnosed participants that have not yet undergone tumor tissue collection and have not yet completed radiation therapy. Cohort 4A\^2: Includes newly diagnosed participants that have not yet undergone tumor tissue collection and have completed radiation therapy. Cohort 4A\^3: Includes participants with progressive DMG who are planned for SOC tumor collection and will undergo re-irradiation.
Cohort 4B\^1: Includes newly diagnosed participants who have already undergone tumor tissue collection and have not yet completed radiation therapy. Cohort 4B\^2: Includes newly diagnosed participants who have already undergone tumor tissue collection and have completed radiation therapy. Cohort 4B\^3: Includes participants with progressive DMG who are not planned for SOC tumor collection and will undergo re-irradiation.
All Cohorts: After completion of study treatment, participants are followed at 30 days and then every 3 months for up to 5 years, until withdrawal of consent, or until death, whichever occurs first. PRIMARY OBJECTIVES:. I.
To assess efficacy of combination therapy with ONC201 (ONC201) and novel agent in participants with DMG based on median progression-free survival at 6 months (PFS6) (Cohorts 1 and 2). II. To assess efficacy of combination therapy with ONC201 and novel agent in participants with recurrent DMG based on overall survival at 7 months (OS7) (Cohort 3).
III. To assess the safety and toxicity of a revised ONC201 dose and dosing schedule in participants with DMG. (Cohort 4).
IV. To assess the safety and toxicity of a revised ONC201 dosing schedule in combination with radiation or re-irradiation in participants with DMG. (Cohort 4).
V. To evaluate the pharmacokinetic profile of a revised ONC201 dose and dosing schedule in participants with DMG. (Cohort 4).
VI. To assess the safety and toxicity of ONC201 with agent(s) that will be determined by a specialized tumor board recommendation that is based on molecular assessments of tumor tissue or cerebrospinal fluid (CSF). (Cohort 5).
VII. To determine the maximum tolerated number of intratumor infusions of DNX-2401, with a maximum of 6, in participants with thalamic or pontine DMG who completed radiotherapy. (Cohort 6, Phase 1) VIII.
To assess efficacy of repeated intratumor infusions with DNX-2401 in participants with DMG based on overall survival at 15 months. (Cohort 6, expansion cohort). EXPLORATORY OBJECTIVES:.
I. To confirm blood brain barrier (BBB) penetration of ONC201 in DMGs by measuring the concentration of ONC201 in tumor tissue (All cohorts except Cohort 6; target validation phase). II.
To confirm BBB penetration of novel agents in DMGs by measuring the concentration of drug (or metabolite) in tumor tissue All cohorts except Cohort 6; target validation phase). III. To assess changes in immune cell infiltration in DMG tumor tissue after 1 or 2 doses of ONC201 (All cohorts except Cohort 6; target validation phase).
IV. To assess correlation of intratumoral concentration of ONC201 with clinical outcome (All cohorts except Cohort 6; target validation phase). V.
To assess correlation of intratumoral drug concentration of novel agents with clinical outcome. (All cohorts except Cohort 6; target validation phase). VI.
To assess if intratumoral ONC201 concentrations differ in irradiated versus nonirradiated tumor tissue. (All cohorts except Cohort 6; target validation phase). VII.
To assess if intratumoral concentrations of novel agents differ in irradiated versus nonirradiated tumor tissue. (All cohorts except Cohort 6; target validation phase). VIII.
To assess tumor tissue biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts except Cohort 6; target validation phase). IX.
To assess efficacy of combination therapy ONC201 and novel agent based on overall survival at 12 months (OS12). (All cohorts except Cohort 6; maintenance combinations). X.
To assess toxicity of combination therapy ONC201 and novel agents. (All cohorts except Cohort 6; maintenance combinations). XI.
To assess the toxicity of weekly ONC201 in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase). XII.
To assess the toxicity of twice weekly ONC201 in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase). XIII.
To assess the toxicity of novel agents in combination with up-front radiation therapy. (Cohort 1; radiation therapy phase). XIV.
To assess the toxicity of weekly ONC201 in combination with re-irradiation after progression. (Cohort 3). XV.
To assess the toxicity of twice weekly ONC201 in combination with re-irradiation therapy after progression. (Cohort 3). XVI.
To assess the toxicity of novel agents in combination with re-irradiation after progression. (Cohort 3). XVII.
To assess the toxicity of ONC201 in combination with novel agents in participants after re-irradiation after progression. (Cohort 3). XVIII.
To assess efficacy of a revised ONC201 dose and dosing schedule board based on median progression free survival (PFS) and overall survival (OS). (Cohort 4). XIX.
To assess efficacy of ONC201 in combination with targeted agent(s) that will be determined by a specialized tumor board based on median OS. (Cohort 5). XX.
To assess cerebrospinal fluid (CSF) biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts except Cohort 6) XXI. To assess levels of circulating tumor deoxyribonucleic acid (ctDNA) in the context of imaging response criteria and clinical outcome, such as PFS6 and/or OS12.
(All cohorts except Cohort 6) XXII. To assess single cell ribonucleic acid (RNA) sequencing in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts except Cohort 6) XXIII.
To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics. (All cohorts except Cohort 6) XXIV. To assess Health-Related Quality of Life (HRQOL) and cognitive measures.
(All cohorts except Cohort 6) XXV. To assess participants and/or proxy satisfaction with study participation via participant-reported outcome (PRO) measures. (All cohorts except Cohort 6) XXVI.
To assess on therapy toxicity and survival in the context of race, ethnicity and other health related social risks. (All cohorts except Cohort 6) XXVII. To assess volumetric measurements of tumor in correlation with median OS.
(All cohorts except Cohort 6) XXVIII. To assess MR spectroscopy of tumor in correlation with radiographic response, ONC201 exposure and median PFS and OS. (All cohorts except Cohort 6) XXIX.
To assess the therapeutic benefit including overall survival (OS), progression-free survival (PFS), the tumor objective response rate (ORR) and proportion of pseudoprogression (PSP) (Cohort 6) XXX. To assess the persistence of DNX-2401 antigen, DNA and transcripts in the tumor in the context of imaging response criteria and clinical outcome. (Cohort 6) XXXI.
To assess the changes in cellular, molecular, and immunologic variables in the tumor in context of imaging response criteria and clinical outcome. (Cohort 6) XXXII. To assess the microbiome in the context of imaging response and clinical outcome.
(Cohort 6) XXXIII. To assess peripheral blood biomarkers and cfDNA studies in the context of imaging and clinical outcome. (Cohort 6) XXXIV.
To assess CSF biomarkers and cfDNA studies in the context of imaging and clinical outcomes. (Cohort 6) XXXV. To assess changes in functional status and in quality of life applying the PedsQLTM (Generic Score Scale).
(Cohort 6) XXXVI. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures. (Cohort 6) XXXVII.
To assess on therapy toxicity in the context of race, ethnicity and other health related social risks. (Cohort 6) XXXVIII. To assess volumetric measurements of tumor in correlation with median OS.
(Cohort 6) XXXIX. To assess MR spectroscopy of tumor in correlation with radiographic response. (Cohort 6).
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
- New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 1B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma Histone 3 lysine 27 - mutant (H3K27M); World Health Organization (WHO) grade III and IV H3 wildtype gliomas.
- Must be within 6 weeks of diagnosis to begin standard of care radiation therapy on study.
- Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In Cohort 2B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas.
- Participants must be within 4-14 weeks of completion of radiation. Radiation should have started within 6 weeks of diagnosis.
- Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In cohort 3B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas.
- Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 4B^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
- Not currently eligible for any other clinical trials that include administration of ONC201.
- Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.
- Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have completed standard-of-care radiation therapy. In cohort 4B^2, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27-altered.
- Participants must be within 4-14 weeks of completion of radiation and not have received additional therapy beyond completion of radiation therapy. Radiation should have started within 6 weeks of diagnosis.
- Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have completed standard-of-care radiation therapy. In cohort 4B^3, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27-altered.
- Not currently eligible for any other clinical trials that include administration of ONC201.
- Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 5^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
- Not currently eligible for any other clinical trials that include administration of ONC201.
- Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.
- Multifocal and leptomeningeal disease will be eligible for Cohort 5.
- Participant's tumor must demonstrate one of the following molecular alterations considered targetable by an approved agent: BRAFV600E, PDGFRA (DNA point mutation or amplification with >=5 copy numbers), FGFR1 (DNA point mutation, gene fusions, or amplification with >=5 copy numbers), NF1.
- Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 5^2, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
- Not currently eligible for any other clinical trials that include administration of ONC201.
- Participants must be within 4-14 weeks of completion of radiation and not have received additional therapy beyond completion of radiation therapy. Radiation should have started within 6 weeks of diagnosis.
- Multifocal and leptomeningeal disease will be eligible for Cohort 5.
- Participant's tumor must demonstrate one of the following molecular alterations considered targetable by an approved agent: BRAFV600E, PDGFRA (DNA point mutation or amplification with >=5 copy numbers), FGFR1 (DNA point mutation, gene fusions, or amplification with >=5 copy numbers), NF1.
- Diagnosis recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 5^3, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27-altered.
- Not currently eligible for any other clinical trials that include administration of ONC201.
- Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- Multifocal and leptomeningeal disease will be eligible for Cohort 5.
- Participant's tumor must demonstrate one of the following molecular alterations considered targetable by an approved agent: BRAFV600E, PDGFRA (DNA point mutation or amplification with >=5 copy numbers), FGFR1 (DNA point mutation, gene fusions, or amplification with >=5 copy numbers), NF1.
- Age 2 to 39 years
- Participants must have recovered from all acute side effects of prior therapy and be beyond the window for expected ongoing acute toxicities. Any number of prior therapies are allowed.
- Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 kilograms (kg)).
- From the projected start of scheduled study treatment, the following time periods must have elapsed: At least 7 days after last dose of a biologic agent or beyond time during which adverse events are known to occur for a biologic agent, 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies (21 days for bevacizumab when used for tumor-directed therapy, guidance on use for pseudo-progression is below), or, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.
- The use of bevacizumab to control radiation therapy-induced edema is allowed (if used for tumor-directed therapy, please see required time period above).
- Dosing limitations are as follows: Bevacizumab (or equivalent) for up to a maximum of 5 doses, dosing per institutional standard. There is no required washout period.
- Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m2 /dose continuously during radiation therapy for 42 days) or dexamethasone is allowed. Any other agent given throughout radiation therapy must be discussed with the study chairs prior to beginning the agent.
- 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.
- The participant must have adequate organ function defined as: Peripheral absolute neutrophil count (ANC) >= 750/mm^3 (1.0g/l) AND Platelet count >= 75,000/mm^3 (100x10^9/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) >= 70 mL/min/1.73 m^2 OR A serum creatinine within the normal limits for age. Bilirubin (sum of conjugated + unconjugated) <= 1.5 x upper limit of normal (ULN) for age AND Serum glutamate pyruvate transaminase (SGPT)(alanine aminotransferase (ALT)) <= 3 x ULN AND Serum albumin >= 2 g/dL. No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of > 92% while breathing room air.
- Diarrhea < grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
- No history of congestive heart failure or family history of long QT syndrome.
- ECG must be obtained to verify the Corrected QT Interval (QTc). If an abnormal reading is obtained, the ECG should be repeated in triplicate. QTC < 470 msec.
- Participants with history of congestive heart failure, at risk of having or have underlying cardiovascular disease, or with history of exposure to cardiotoxic drugs must have adequate cardiac function as determined by echocardiogram. Shortening fraction of >= 27%.
- Participants with seizure disorder may be enrolled if seizure disorder is well controlled.
- The effects of the study drugs 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.
- 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.
- 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 PNOC023 or on another arm of PNOC022 and provided adequate tissue, may not need to submit additional tissue. Participants who do not meet these criteria must be discussed with Study Chair(s).
- 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
- Prior exposure to radiation therapy.
- Thalamic and Cerebellar H3K27M DMG.
- For tumors that do not have a pontine or spinal cord epicenter the following specific exclusion criteria apply: Thalamic and Cerebellar H3K27M DMG that has undergone standard radiation without concurrent therapy (other than temozolomide).
- Deemed not appropriate for tissue resection/biopsy.
- Prior exposure to re-irradiation for tumor progression.
- Thalamic and cerebellar H3K27M mutant DMG.
- Prior exposure to radiation therapy
- Thalamic and cerebellar H3K27M mutant DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or US patients enrolled while the accelerated approval new drug application for dordaviprone to treat recurrent H3 K27M-mutant diffuse glioma is under review by US FDA.
- Prior exposure to re-irradiation for tumor progression
- Thalamic and cerebellar H3K27M mutant DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or US patients enrolled while the accelerated approval new drug application for dordaviprone to treat recurrent H3 K27M-mutant diffuse glioma is under review by US FDA.
- Prior exposure to radiation therapy
- Thalamic and cerebellar H3K27M DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or US patients enrolled while the accelerated approval new drug application for dordaviprone to treat recurrent H3 K27M-mutant diffuse glioma is under review by US FDA.
- Prior exposure to re-irradiation for tumor progression
- Thalamic and cerebellar H3K27M DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or US patients enrolled while the accelerated approval new drug application for dordaviprone to treat recurrent H3 K27M-mutant diffuse glioma is under review by US FDA.
- Diagnosis of a histone H3 wildtype grade II diffuse astrocytoma.
- Participants who are currently receiving another investigational drug. Investigational imaging agents or agents used to enhance tumor visibility on imaging or during tumor biopsy/resection should be discussed with the study chairs.
- Participants who are currently receiving other anti-cancer agents.
- 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. 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 or other uncontrolled systemic illness.
- 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 (as clinically indicated).
- Active illicit drug use or diagnosis of alcoholism.
- History of allergic reactions attributed to compounds of similar chemical or biologic composition as the agents used in study.
- Evidence of disseminated disease, including diffuse leptomeningeal disease or evidence of CSF dissemination, with the exception of Cohort 5.
- Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug.
- Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration.
- Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs (EIAEDs), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent corticosteroids is allowed.
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE2
Study ID
NCT05009992
Intervention or treatment
DRUG: ONC201
RADIATION: Radiation Therapy
DRUG: Paxalisib
Conditions
- Diffuse Intrinsic Pontine Glioma
- Diffuse Midline Glioma, H3 K27M-Mutant
- Recurrent Diffuse Intrinsic Pontine Glioma
- Recurrent Diffuse Midline Glioma, H3 K27M-Mutant
- Recurrent WHO Grade III Glioma
- WHO Grade III Glioma
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Research sites nearby
Closest Location:
John Hunter Children's Hospital
Select from list below to view details:
John Hunter Children's Hospital
New Lambton Heights, New South Wales, Australia
The Children's Hospital at Westmead
Westmead, New South Wales, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Monash Children's Hospital
Clayton, Victoria, Australia
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Who is running the clinical trial?
University of California, San Francisco
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: NOT CURRENTLY ENROLLING - ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201
| Drug: ONC201, Radiation: Radiation Therapy, Drug: Paxalisib |
EXPERIMENTAL: NOT CURRENTLY ENROLLING - ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201
| Drug: ONC201, Radiation: Radiation Therapy, Drug: Paxalisib |
EXPERIMENTAL: NOT CURRENTLY ENROLLING - ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201
| Drug: ONC201, Radiation: Radiation Therapy, Drug: Paxalisib |
EXPERIMENTAL: NOT CURRENTLY ENROLLING - Cohort 4 - Dose Escalation, Starting Dose 2 (625mg ONC201)
| Drug: ONC201, Radiation: Radiation Therapy |
EXPERIMENTAL: Cohort 5 - ONC201 + Targeted therapies
| Drug: ONC201, Radiation: Radiation Therapy |
EXPERIMENTAL: Cohort 6 - DNX-2401 Repeated Intratumoral Administration
| Drug: DNX-2401 |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only | Percentage of participants alive and free from progression at 6 months after the diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis. | 6 months after diagnosis |
| Progression-free survival at 6 months (PFS6) - Cohorts 2A, 2B Only | Percentage of participants alive and free from progression at 6 months after diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis. | 6 months after diagnosis |
| Overall survival at 7 months (OS7) - Cohort 3A & 3B Only | OS7 is defined as the percentage of participants alive at 7 months after the initiation of the combination of the backbone (i.e., ONC201) with a novel agent given in the maintenance phase of therapy. The primary analysis for OS7 is based on the ITT population, according to treatment arm assignment. OS7 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown survival status at 7 months are considered failures (i.e., dead) for the OS7 analysis. | 7 months after administration of ONC201 in the maintenance phase |
| Proportion of participants reporting dose-limiting toxicities (DLTs) (Cohort 4) | The safety and tolerability of ONC201 at a previously untested dose will be measured by the proportion of participants reporting a DLT within the first cycle of treatment. | Up through the first cycle of maintenance therapy, approximately 8 months |
| Number of participants requiring dose modification through first cycle of maintenance (Cohort 5) | The safety and tolerability of ONC201 in combination with targeted therapies will be measured by the number of participants reporting dose modification during first cycle. | Up through the first cycle of maintenance therapy, approximately 8 months |
Secondary Outcome
References
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