Combination Therapy for the Treatment of Diffuse Midline Gliomas

A Combination Therapy Trial Using an Adaptive Platform Design for Children and Young Adults With Diffuse Midline Gliomas (DMGs) Including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression

The Chad-Tough Defeat DIPG Foundation, Mithil Prasad Foundation, Storm the Heavens Fund, National Institute of Neurological Disorders and Stroke (NINDS)

This phase II trial determines if the combination of ONC201 with different drugs, panobinostat or 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, panobinostat, and paxalisib are all 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.

OUTLINE: Participants will be randomized at study entry to one of the three study arms and subsequently will be included in one to three phases, and one of 3 cohorts depending on their stage of disease and prior treatment. 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). 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; 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; target validation phase). III. To assess changes in immune cell infiltration in DMG tumor tissue after 1 or 2 doses of ONC201 (All cohorts; target validation phase). IV. To assess correlation of intratumoral concentration of ONC201 with clinical outcome (All cohorts; target validation phase). V. To assess correlation of intratumoral drug concentration of novel agents with clinical outcome. (All cohorts; target validation phase). VI. To assess if intratumoral ONC201 concentrations differ in irradiated versus nonirradiated tumor tissue. (All cohorts; target validation phase). VII. To assess if intratumoral concentrations of novel agents differ in irradiated versus nonirradiated tumor tissue. (All cohorts; target validation phase). VIII. To assess tumor tissue biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts; target validation phase). IX. To assess efficacy of combination therapy ONC201 and novel agent based on overall survival at 12 months (OS12). (All cohorts; maintenance combinations). X. To assess toxicity of combination therapy ONC201 and novel agents. (All cohorts; 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 cerebrospinal fluid (CSF) biomarkers in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases). XIX. 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/phases). XX. To assess single cell ribonucleic acid (RNA) sequencing in the context of clinical outcome, such as PFS6 and/or OS12. (All cohorts/phases). XXI. To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics. XXII. To assess Health-Related Quality of Life (HRQOL) and cognitive measures. (All cohorts/phases). XXIII. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures. (All cohorts/phases). COHORT DESCRIPTIONS: 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. 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. 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. TREATMENT ARM DESCRIPTIONS: ARM 2: During the trial validation phase, patients without prior biopsy receive ONC201 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 weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. ARM 4: During the trial validation phase, patients without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity. 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 weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity. After completion of study treatment, patient are followed every 12 months.

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

Patients may receive a safety lead in of ONC201. During the trial validation phase, patients without prior biopsy receive ONC201 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 weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity

Patients may receive a safety lead in of ONC201. During the trial validation phase, patients without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, patients may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity

Patients may receive a safety lead in of ONC201. 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 weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, patients receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity

TIC10, Antagonist of dopamine receptor D2 (DRD2) and caseinolytic protease proteolytic subunit (ClpP)

Percentage of participants alive and free from progression at 6 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 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.

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.

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 III and IV H3 wildtype gliomas. 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 III and IV H3 wildtype gliomas. COHORT 2A AND 2B: Participants must be within 4-14 weeks of completion of radiation. 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 III and IV 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. Age 2 to 39 years Participants must have recovered from all acute side effects of prior therapy Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 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, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies. For participants who have received radiotherapy, participants in Cohort 2 must be between 4 and 14 weeks from the completion of local up-front radiotherapy and not have received additional therapy beyond completion of radiation therapy. 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. Corticosteroids: 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. Peripheral absolute neutrophil count (ANC) >= 1000/mm^3 (1.0g/l) AND Platelet count >= 100,000/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)) =< 2 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 Non-fasting glucose < 125 mg/dL without the use of antihyperglycemic agents 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, participants will meet adequate metabolic function criteria Triglycerides of < 300 mg/dl and total cholesterol of < 300 mg/dl - can be on lipid lowering medications as needed to achieve. No history of congestive heart failure or family history of long QT syndrome. ECG must be obtained to verify the 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. Participants who do not meet this 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: COHORT 1A AND 1B: Prior exposure to radiation therapy. Thalamic H3K27M DMG. COHORT 2A AND 2B: o For tumors that do not have a pontine or spinal cord epicenter the following specific exclusion criteria apply: o Thalamic H3K27M DMG that has undergone standard radiation without concurrent therapy (other than temozolomide). COHORT 1A AND 2A: o Deemed not appropriate for tissue resection/biopsy. COHORT 3A AND 3B: Prior exposure to re-irradiation for tumor progression. Patients who participated in trials investigating ONC201 in the upfront setting will not be eligible. Prior ONC201 exposure as part of PNOC022 or expanded access programs will be allowed. 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 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.

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.