H3 K27M-mutant High-Grade Glioma incl. DIPG
Are you or your loved ones suffering from glioma, malignant?
You may be eligible to participate in a glioma, malignant clinical trial.
Are you or your loved ones suffering from glioma, malignant? You may be eligible to participate in a glioma, malignant clinical trial.
Where you'll go
Details for the study
Treatments and/or Procedures
Inclusion Criteria: 1. 2 to less than 19 years of age. 2. Patient body weight must be above the minimum necessary for the patient to receive the ONC201 dose indicated for the currently enrolling dose level. The minimum body weight ranges from 10 to 35kg depending on the dose level. 3. Arm A: Patients with glioma who are positive for the H3 K27M mutation (positive testing in CLIA laboratory) and have completed at least one line of prior therapy. Evidence of progression is not required so that ONC201 may be administered to patients in the maintenance setting or to patients with recurrent disease. No more than two prior episodes of recurrence from radiotherapy and/or chemotherapy are allowed. Use of bevacizumab solely for treatment of radiation necrosis, pseudoprogression, or treatment effect will not be considered a recurrence. Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available. Arm B: Patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible with or without histologic confirmation. Post-mortem biopsy is required if H3 K27M status of tumor is unknown and archival tumor tissue not available. 4. Evaluable disease by RANO. 5. Karnofsky ≥ 50 for patients ≥ 16 years of age, and Lansky ≥ 50 for patients < 16 years of age. 6. From the projected start of scheduled study treatment, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies. 7. Adequate organ function defined as: Bone Marrow: - Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 and - Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). Renal Function: • Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70mL/min/1.73 m2 or normal serum creatinine based on age as shown below or GFR > 70ml/min/1.73m^2: Age < 5 years: 0.8 mg/dL maximum Age 5 to < 10 years: 1.0 mg/dL maximum Age 10 to < 15 years: 1.2 mg/dL maximum Age > 15 years: 1.5 mg/dL maximum Liver Function: - Total Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of institutional normal and - SGPT (ALT) ≤ 110 U/L and - Serum albumin ≥ 2 g/dL. Neurologic Function: • Patients with seizure disorder may be enrolled if seizure disorder is well controlled. 8. Ability to understand a written informed consent document, and the willingness to sign it. Assent will be obtained when appropriate based on the subjects age. 9. All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must be resolved to grade 1 or baseline, except for alopecia and sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment, are acceptable. 10. For patients post pubertal: Female patients must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. Male patients must be surgically sterile or must agree to use effective contraception during the period of the trial and for at least 90 days after completion of treatment. The decision of effective contraception will be based on the judgment of the principal investigator. 11. Corticosteroid dose must be stable or decreasing for at least 3 days prior to the baseline MRI scan. 12. Ability to be able to swallow and retain orally administered medication. 13. Archival tumor specimen: All subjects in Arm A must submit at least 5 unstained slides from a tumor specimen that harbors H3 K27M mutation. For subjects in Arm B, at least 5 unstained slides must be submitted if archival tissue is available from the DIPG. For subjects in any arm, if no archival tumor tissue is available, or if H3 K27M status of tumor is unknown, then subjects must agree to submit a post-mortem biopsy specimen. Exclusion Criteria: 1. Current or planned participation in a study of another investigational agent or using an investigational device. 2. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients. 3. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements. 4. Any known clinically significant active infection including bacterial, fungal or viral including hepatitis B (HBV), hepatitis C (HCV) or any underlying disease or in the recent past which could compromise enrollment and safety of the patient. 5. Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias or bradycardia, unless arrhythmia is controlled and after Cardiology has cleared patient to receive ONC201. Receiving therapeutic agents known to prolong QT interval will be excluded History of CHF, or MI or stroke in the last 3 months will be excluded. 6. Active illicit drug use or diagnosis of alcoholism. 7. Known additional malignancy that is progressing or requires active treatment within 3 years of start of study drug. 8. Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration. 9. Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic drugs (EIAEDs) (see Appendix B), during the treatment phase of the study and within 2 weeks prior to starting treatment. Concurrent dexamethasone is allowed.