PNOC022: 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 Progressio

Phase 1

Recruiting

• Conditions: Diffuse Midline Gliomas (DMGs) including Diffuse Intrinsic Pontine Gliomas (DIPGs); MedDRA version: 25.1Level: LLTClassification code: 10087678Term: Diffuse midline glioma H3K27M mutation Class: 100000004848; MedDRA version: 21.1Level: PTClassification code: 10065443Term: Malignant glioma Class: 100000004864; MedDRA version: 21.0Level: LLTClassification code: 10080666Term: Diffuse intrinsic pontine glioma Class: 10029104; MedDRA version: 20.0Level: PTClassification code: 10006143Term: Brain stem glioma Class: 100000004864; Therapeutic area: Diseases [C] - Neoplasms [C04]

• Registration Number: CTIS2023-507598-16-00
• Lead Sponsor: Prinses Maxima Centrum voor Kinderoncologie B.V.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2024-05-02
• Last Update Posted: 22 July 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: All
• Target Recruitment: 324

Inclusion Criteria

Cohort 1A and 1B (participants with newly diagnosed DMG prior to radiation therapy): 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; WHO Grade 3 and 4 H3 wildtype gliomas., All cohorts: 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., All cohorts: Corticosteroids: Participants who are receiving dexamethasone must be on a stable or decreasing dose for at least 3 days prior to baseline MRI scan., All cohorts: The participant must have adequate organ function defined as: Adequate Bone Marrow Function Defined as: • Peripheral absolute neutrophil count (ANC) = 1000/mm3 (1.0g/l) and • Platelet count = 100,000/mm3 (100x109/l) (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). Adequate Renal Function Defined as: • Creatinine clearance or radioisotope GFR = 70mL/min/1.73 m2 or • A serum creatinine within the normal limits for age. Adequate Liver Function Defined as: • Bilirubin (sum of conjugated + unconjugated) = 1.5 x upper limit of normal (ULN) for age and • SGPT (ALT) = 2x ULN and • Serum albumin = 2 g/dL. Adequate Pulmonary Function Defined as: • No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency, and a pulse oximetry of > 92% while breathing room air. Adequate Gastrointestinal Function Defined as: • Diarrhea < grade 2 by CTCAE v5.0. Adequate Metabolic Function Defined as: • 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 = 160mg/dL without the use of antihyperglycemic agents, participant 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. Adequate Cardiac Function Defined as: • 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% by echocardiogram Adequate Neurologic Function Defined as: • Participants with seizure disorder may be enrolled if seizure disorder is well controlled., All cohorts: 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 participat

Exclusion Criteria

Cohort 1A and 1B (participants with newly diagnosed DMG prior to radiation therapy): • Prior exposure to radiation therapy. • Thalamic H3K27M DMG, All cohorts: • 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: • Active illicit drug use or diagnosis of alcoholism., All cohorts: • History of allergic reactions attributed to compounds of similar chemical or biologic composition as the agents used in study., All cohorts: • Evidence of disseminated disease, including multi-focal disease, diffuse leptomeningeal disease or evidence of CSF dissemination., All cohorts: • Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug., All cohorts: • 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: • Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs (EIAEDs; see Appendix I), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent corticosteroids is allowed., Cohort 2A and 2B: 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 (participants with newly diagnosed DMG prior to radiation therapy and who have not previously undergone tumor tissue collection prior to study entry): • Deemed not appropriate for tissue resection/biopsy., Cohort 3A and 3B (participants with DMG at progression): • 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., All cohorts: • Diagnosis of a histone H3 wildtype Grade 2 diffuse astrocytoma, All cohorts: • Investigational Drugs o 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: • Anti-cancer Agents o Participants who are currently receiving other anti-cancer agents., All cohorts: • 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 that 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., All cohorts: • Participants with uncontrolled infection or other uncontrolled systemic illness.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified