Combination Therapy for the Treatment of Diffuse Midline Gliomas
This phase II trial determines if the combination of ONC201 with paxalisib is effective for treating patients with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for patients with DMGs, and there are few treatment options. ONC201 and paxalisib are both enzyme inhibitors that may stop the growth of tumor cells by clocking some of the enzymes needed for cell growth. This phase II trial assesses different combinations of these drugs for the treatment of DMGs.
Inclusion Criteria
- COHORT 1A AND 1B: 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 H3K27M mutant; World Health Organization (WHO) grade 3 and 4 H3 wildtype gliomas.
- COHORT 1A AND 1B: Must be within 6 weeks of diagnosis to begin standard of care radiation therapy on study.
- COHORT 2A AND 2B: 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 3 and 4 H3 wildtype gliomas.
- COHORT 2A AND 2B: Participants must be within 4-14 weeks of completion of radiation. Radiation should have started within 6 weeks of diagnosis.
- COHORT 3A AND 3B: 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 3 and 4 H3 wildtype gliomas.
- COHORT 3A AND 3B: Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- COHORT 4A^1 AND 4B^1: 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.
- COHORT 4A^1 AND 4B^1: Not currently eligible for any other clinical trials that include administration of ONC201.
- COHORT 4A^1 AND 4B^1: Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.
- COHORT 4A^2 AND 4B^2: 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.
- COHORT 4A^2 AND 4B^2: Not currently eligible for any other clinical trials that include administration of ONC201.
- COHORT 4A^2 AND 4B^2: 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.
- COHORT 4A^3 AND 4B^3: 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.
- COHORT 4A^3 AND 4B^3: Not currently eligible for any other clinical trials that include administration of ONC201.
- COHORT 4A^3 AND 4B^3: Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- COHORT 5^1: 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.
- COHORT 5^1: Not currently eligible for any other clinical trials that include administration of ONC201.
- COHORT 5^1: Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.
- COHORT 5^1: Multifocal and leptomeningeal disease will be eligible for Cohort 5.
- COHORT 5^1: 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.
- COHORT 5^2: 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.
- COHORT 5^2: Not currently eligible for any other clinical trials that include administration of ONC201.
- COHORT 5^2: 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.
- COHORT 5^2: Multifocal and leptomeningeal disease will be eligible for Cohort 5.
- COHORT 5^2: 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.
- COHORT 5^3: 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.
- COHORT 5^3: Not currently eligible for any other clinical trials that include administration of ONC201.
- COHORT 5^3: Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- COHORT 5^3: Multifocal and leptomeningeal disease will be eligible for Cohort 5.
- COHORT 5^3: 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.
- ALL COHORTS (EXCEPT COHORT 6): Age 2 to 39 years.
- ALL COHORTS (EXCEPT COHORT 6): 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.
- ALL COHORTS (EXCEPT COHORT 6): Prior participation in a different PNOC022 cohort or PNOC023 arm is allowed if all other eligibility criteria are met. Prior ONC201 exposure is allowed, except in participants who have participated in Chimerix trials investigating ONC201 in the upfront setting. Participants who participated in trials investigating ONC201 in the upfront setting will not be eligible at any time, with the exception if participants received ONC201 as part of PNOC022 or other expanded access programs such as German sources of ONC201.
- ALL COHORTS (EXCEPT COHORT 6): Prior ONC201 exposure is allowed, except in participants who have participated in Chimerix trials investigating ONC201 in the upfront setting. Participants who participated in trials investigating ONC201 in the upfront setting will not be eligible at any time, with the exception if participants received ONC201 as part of PNOC022 or other expanded access programs such as German sources of ONC201
- ALL COHORTS (EXCEPT COHORT 6): Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 kg).
- ALL COHORTS (EXCEPT COHORT 6): 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 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.
- ALL COHORTS (EXCEPT COHORT 6): Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m^2 /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.
- ALL COHORTS (EXCEPT COHORT 6): Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 3 days prior to baseline MRI scan. This may not be applicable to newly diagnosed participants.
- ALL COHORTS (EXCEPT COHORT 6): Peripheral absolute neutrophil count (ANC) >= 750/mm^3 (1.0g/l).
- ALL COHORTS (EXCEPT COHORT 6): Platelet count >= 75,000/mm^3 (100 x 10^9/l) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
- ALL COHORTS (EXCEPT COHORT 6): Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70mL/min/1.73 m^2 OR a serum creatinine within the normal limits for age.
- ALL COHORTS (EXCEPT COHORT 6): Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age.
- ALL COHORTS (EXCEPT COHORT 6): Serum glutamate pyruvate transaminase (SGPT)(alanine aminotransferase [ALT]) =< 3 x ULN.
- ALL COHORTS (EXCEPT COHORT 6): Serum albumin >= 2 g/dL.
- ALL COHORTS (EXCEPT COHORT 6): No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of > 92% while breathing room air.
- ALL COHORTS (EXCEPT COHORT 6): Diarrhea < grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
- COHORTS 1-3: Non-fasting glucose < 125 mg/dL without the use of antihyperglycemic agents.
- COHORTS 1-3: If non-fasting glucose > 125 mg/dL, a fasting glucose should be done. If fasting glucose =< 160 mg/dL without the use of antihyperglycemic agents, participant will meet adequate metabolic function criteria.
- COHORTS 1-3: Triglycerides of < 300 mg/dl and total cholesterol of < 300 mg/dl – can be on lipid lowering medications as needed to achieve.
- ALL COHORTS (EXCEPT COHORT 6): No history of congestive heart failure or family history of long QT syndrome.
- ALL COHORTS (EXCEPT COHORT 6): Electrocardiogram (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.
- For Cohorts 1, 2 and 3: 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% by echocardiogram.
- ALL COHORTS (EXCEPT COHORT 6): Participants with seizure disorder may be enrolled if seizure disorder is well controlled.
- ALL COHORTS (EXCEPT COHORT 6): 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.
- ALL COHORTS (EXCEPT COHORT 6): 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.
- ALL COHORTS (EXCEPT COHORT 6): 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 this criteria must be discussed with study chair(s).
- ALL COHORTS (EXCEPT COHORT 6): A legal parent/guardian or participant must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.
- COHORT 6: Diagnosis of newly diagnosed thalamic or pontine located DMG with imaging and/or pathology consistent with a DMG, excluding spinal cord tumors, who have completed standard-of-care radiation therapy. If archival tissue is available prior to first biopsy, 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
- COHORT 6: Participants must be within 4-14 weeks of completion of radiation. Radiation should have started within 6 weeks of diagnosis
- COHORT 6: Age 2-39 years
- COHORT 6: 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) is allowed. Any other agent given throughout radiation therapy must be discussed with the study chairs prior to enrollment
- COHORT 6: Participants must have recovered from all acute side effects of prior therapy and be beyond the window for expected ongoing acute toxicities. Washout requirements from prior therapy include: * 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 30 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies (28 days for bevacizumab when used for tumor-directed therapy, guidance on use for pseudo-progression is below), or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies. * At least 4 weeks prior to study enrollment from last immune therapy
- COHORT 6: Corticosteroids: Participants treated with corticosteroids must be on stable or decreasing dose for at least 1 week prior to enrollment, with maximum dexamethasone dose 0.1 mg/kg/day dexamethasone equivalent at time of enrollment
- COHORT 6: Peripheral absolute neutrophil count (ANC) ≥ 750/mm^3 (1.0g/l) and
- COHORT 6: Platelet count ≥ 75,000/mm^3 (100 x10^9/l) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
- COHORT 6: Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m^2 or a serum creatinine within the normal limits for age
- COHORT 6: Total bilirubin ≤ 3 x upper limit of normal (ULN); in presence of Gilbert’s syndrome, total bilirubin ≤ 6 x ULN or direct bilirubin ≤ 3 x ULN
- COHORT 6: ALT ≤ 5 x ULN
- COHORT 6: AST ≤ 5 x ULN
- COHORT 6: Serum albumin ≥ 2 g/dL
- COHORT 6: Diarrhea < grade 2 by CTCAE v 5.0
- COHORT 6: No history of congestive heart failure or family history of long QT syndrome
- COHORT 6: Participants with seizure disorder may be enrolled if seizure disorder is well controlled
- COHORT 6: 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
- COHORT 6: Karnofsky ≥ 70 for Participants > 16 years of age and Lansky ≥ 70 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
Exclusion Criteria
- COHORT 1A AND 1B: Prior exposure to radiation therapy.
- COHORT 1A AND 1B: Thalamic and cerebellar H3K27M DMG.
- COHORT 2A AND 2B: 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).
- COHORT 1A AND 2A: Deemed not appropriate for tissue resection/biopsy.
- COHORT 3A AND 3B: Prior exposure to re-irradiation for tumor progression.
- COHORT 3A AND 3B: Thalamic and cerebellar H3K27M mutant DMG.
- COHORT 4A^1 AND 4B^1: Prior exposure to radiation therapy.
- COHORT 4A^1 AND 4B^1: Thalamic and cerebellar H3K27M mutant DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or United States (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 Food and Drug Administration (FDA).
- COHORT 4A^2 AND 4B^2: 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.
- COHORT 4A^3 and 4B^3: Prior exposure to re-irradiation for tumor progression.
- COHORT 4A^3 and 4B^3: 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.
- COHORT 5^1: Prior exposure to radiation therapy.
- COHORT 5^1: 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.
- COHORT 5^2: 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.
- COHORT 5^3: Prior exposure to re-irradiation for tumor progression.
- COHORT 5^3: 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.
- ALL COHORTS (EXCEPT COHORT 6): Diagnosis of a histone H3 wildtype grade 2 diffuse astrocytoma.
- ALL COHORTS (EXCEPT COHORT 6): 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.
- ALL COHORTS (EXCEPT COHORT 6): Participants who are currently receiving other anti-cancer agents.
- ALL COHORTS (EXCEPT COHORT 6): 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 who 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.
- ALL COHORTS (EXCEPT COHORT 6): Participants with uncontrolled infection or other uncontrolled systemic illness.
- ALL COHORTS (EXCEPT COHORT 6): 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).
- ALL COHORTS (EXCEPT COHORT 6): Active illicit drug use or diagnosis of alcoholism.
- ALL COHORTS (EXCEPT COHORT 6): History of allergic reactions attributed to compounds of similar chemical or biologic composition as the agents used in study.
- ALL COHORTS (EXCEPT COHORT 6): Evidence of disseminated disease, including multi-focal disease, diffuse leptomeningeal disease or evidence of CSF dissemination, with exception of Cohort 5.
- ALL COHORTS (EXCEPT COHORT 6): Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug.
- ALL COHORTS (EXCEPT COHORT 6): Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration.
- ALL COHORTS (EXCEPT COHORT 6): 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 use of corticosteroids is allowed.
- COHORT 6: DMGs located outside the thalamus and pons including bilateral thalamic tumors
- COHORT 6: Unacceptable anesthesia or surgery risk, as determined by the anesthesiologist or the neurosurgeon
- COHORT 6: Evidence of significant mass effect (score > 3)
- COHORT 6: Evidence of herniation on imaging
- COHORT 6: Participants with a known history coagulopathy that increases risk of bleeding or a history of clinically significant hemorrhage within 12 months of registration
- COHORT 6: Participants must not require systemic anti-coagulation that cannot be halted for each intraoperative and perioperative biopsy time-period
- COHORT 6: Participants with active viral infection or who are currently receiving antiviral treatment
- COHORT 6: Participants with active, known, or suspected immunosuppressive disorders, such as acquired or congenital immune deficiency syndromes and autoimmune diseases
- COHORT 6: This virus infects cells with a deficit in the RB gene. Therefore, participants with LiFraumeni Syndrome or a known germ line deficit in the retinoblastoma gene or its related pathway are excluded
- COHORT 6: Participants must not have live or live-attenuated vaccinations within 30 days prior to DNX-2401 administration and while participating in the study. Killed vaccines are permitted
- COHORT 6: Investigational drugs
- COHOHRT 6: 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
- COHORT 6: Participants with a known disorder that affects their immune system, such as HIV or Hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or immunosuppressive therapy. Note: Participants who are currently using inhaled, intranasal, ocular, topical or other non-oral or non-IV steroids are not necessarily excluded from the study but need to be discussed with the study chair(s)
- COHORT 6: Participants with uncontrolled infection or other uncontrolled systemic illness
- COHORT 6: 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)
- COHORT 6: Active illicit drug use or diagnosis of alcoholism
- COHORT 6: History of allergic reactions attributed to compounds of similar chemical or biologic composition as the agents used in the study
- COHORT 6: Evidence of disseminated disease, including multi-focal disease, diffuse leptomeningeal disease or CSF dissemination
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT05009992.
Locations matching your search criteria
United States
Alabama
Birmingham
California
Los Angeles
San Diego
San Francisco
District of Columbia
Washington
Illinois
Chicago
Indiana
Indianapolis
Maryland
Baltimore
Massachusetts
Boston
Michigan
Ann Arbor
Minnesota
Minneapolis
Missouri
Saint Louis
New Jersey
Hackensack
New York
New York
North Carolina
Durham
Ohio
Columbus
Pennsylvania
Philadelphia
Utah
Salt Lake City
Washington
Seattle
PRIMARY OBJECTIVES:
I. To assess efficacy of combination therapy with Akt/ERK inhibitor 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 dose and 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 tasadenoturev (DNX-2401), with a maximum of 6, in participants with thalamic or pontine DMG who completed radiotherapy. (Cohort 6)
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 cohorts)
EXPLORATORY OBJECTIVES:
I. To confirm blood brain barrier (BBB) penetration of ONC201 in DMGs by measuring the concentration of ONC201 in tumor tissue. (Not applicable to 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. (Not applicable to cohort 6; target validation phase)
III. To assess changes in immune cell infiltration in DMG tumor tissue after 1 or 2 doses of ONC201. (Not applicable to cohort 6; target validation phase)
IV. To assess correlation of intratumoral concentration of ONC201 with clinical outcome. (Not applicable to cohort 6; target validation phase)
V. To assess correlation of intratumoral drug concentration of novel agents with clinical outcome. (Not applicable to cohort 6; target validation phase)
VI. To assess if intratumoral ONC201 concentrations differ in irradiated versus non-irradiated tumor tissue. (Not applicable to cohort 6; target validation phase)
VII. To assess if intratumoral concentrations of novel agents differ in irradiated versus non-irradiated tumor tissue. (Not applicable to cohort 6; target validation phase)
VIII. To assess tumor tissue biomarkers in the context of clinical outcome, such as PFS6 and/or overall survival at 12 months (OS12). (Not applicable to cohort 6; target validation phase)
IX. To assess efficacy of combination therapy ONC201 and novel agent based on overall survival at 12 months (OS12). (Not applicable to cohort 6; maintenance combinations)
X. To assess toxicity of combination therapy ONC201 and novel agents. (Not applicable to 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 CSF biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases [except Cohort 6])
XXI. To correlate levels of cell free DNA and other liquid biomarkers (cfDNA) in the context of imaging response criteria and clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases [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/phases [except Cohort 6])
XXIII. To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics. (All cohorts/phases [except Cohort 6])
XXIV. To assess Health-Related Quality of Life (HRQOL) and cognitive measures. (All cohorts/phases [except Cohort 6])
XXV. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures. (All cohorts/phases [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/phases [except Cohort 6])
XXVII. To assess volumetric measurements of tumor in correlation with median OS. (All cohorts/phases [except Cohort 6])
XXVIII. To assess MR spectroscopy of tumor in correlation with radiographic response, ONC201 exposure and median PFS and OS. (All cohorts/phases [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)
OUTLINE: Patients are randomized to 1 of 3 arms.
ARM 2: During the trial validation phase, patients without prior biopsy receive ONC201 orally (PO) or via gastrostomy tube (G tube) or nasogastric tube (NG tube) on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo radiation therapy five times a week and receive ONC201 PO or via G tube or NG tube once a week (QW) during radiation therapy. During the maintenance phase, patients receive ONC201 PO or via G tube or NG tube QW and paxalisib PO daily (QD) during each cycle. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. Patients undergo echocardiography during screening and magnetic resonance imaging (MRI), lumbar puncture and blood, CSF, and/or buccal swab sample collection throughout the study.
ARM 4: During the trial validation phase, patients without prior biopsy receive ONC201 PO or via G tube or NG tube on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo radiation therapy five times a week and receive ONC201 PO or via G tube or NG tube QW during radiation therapy. During the maintenance phase, patients receive ONC201 PO or via G tube or NG tube QW and paxalisib PO QD during each cycle. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity. Patients undergo echocardiography during screening and MRI, lumbar puncture and blood, CSF, and/or buccal swab sample collection throughout the study.
ARM 6: During trial validation phase, patients without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo radiation therapy five times a week and receive paxalisib PO QD during radiation therapy. During the maintenance phase, patients receive ONC201 PO or via G tube or NG tube QW and paxalisib PO QD during each cycle. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. Patients undergo echocardiography during screening and MRI, lumbar puncture and blood, CSF, and/or buccal swab sample collection throughout the study.
Patients who are currently not eligible for defined combination arms above are assigned to Cohort 4, patients whose tumor demonstrates specific molecular alterations considered targetable by an approved/available agent are assigned to Cohort 5, patients who have completed focal radiation therapy and are within 4-14 weeks from completion of radiation therapy without evidence of progression are assigned to Cohort 6.
COHORT 4: During trial validation phase, patients without prior biopsy receive ONC201 PO or via G tube or NG tube on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo radiation therapy five times a week and receive ONC201 PO or via G tube or NG tube during radiation therapy. During the maintenance phase, patients receive ONC201 PO or via G tube or NG tube on day 1 only or on days 1 and 2 QW during each cycle. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. Patients may transition enrollment to Cohort 5 after receiving a tumor pathology report that demonstrates a molecular alteration listed in the eligibility criteria of Cohort 5. Patients undergo echocardiography during screening and MRI, lumbar puncture and blood, CSF, and/or buccal swab sample collection throughout the study.
COHORT 5: During the radiation/re-irradiation phase, patients without prior radiation therapy or have disease progression after radiation therapy undergo radiation therapy five times a week and receive ONC201 PO or via G tube or NG tube during radiation therapy. During the maintenance phase, patients receive ONC201 PO or via G tube or NG tube on day 1 and 2 QW during each cycle. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. Patients also receive targeted therapy per institutional standards. Patients may transition enrollment to Cohort 4 if the patient has difficulties obtaining the recommended targeted agent due to cost/insurance if the patient has not started cycle 1 maintenance phase. Patients undergo echocardiography during screening and MRI, lumbar puncture and blood, CSF, and/or buccal swab sample collection throughout the study.
COHORT 6: Patients receive DNX-2401 via intertumoral infusion, over 67 minutes, on day 1 of each cycle. Cycles repeat every 29 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy on study and MRI blood and CSF sample collection throughout the study.
After completion of study treatment, patients 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.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationUniversity of California San Francisco
Principal InvestigatorSabine Mueller
- Primary ID200821
- Secondary IDsNCI-2021-08386, 21-34189, PNOC022
- ClinicalTrials.gov IDNCT05009992