Oral ONC201 in Adult Recurrent Glioblastoma

Inclusion Criteria: A patient had to meet all of the following criteria to be eligible to participate in the study: 1. For Arms A, B, and C: Had histologically confirmed World Health Organization (WHO) Grade IV glioblastoma. For Arm D: Must have had a WHO Grade IV glioma and the tumor must have harbored a histone H3 K27M mutation detected in a Clinical Laboratory Improvement Amendment (CLIA) certified laboratory by immunohistochemistry or DNA sequencing test on any glioma tumor sample. The H3 K27M mutation was often reported as H3 K28M in gene sequencing assays. For Arm E: Must have had clinical and/or radiographic evidence of a midline glioma (involving the brainstem, thalamus, spinal cord, hypothalamus, basal ganglia, brainstem \[non-diffuse intrinsic pontine glioma (DIPG)\], cerebellum, cerebellar peduncle, midline cortex, corpus collosum, pineal region, optic tract, or optic chiasm), and was eligible for salvage surgical resection as deemed by the site Investigator. For Arm F: Must have had a diffuse midline glioma that involved the brainstem, thalamus, or spinal cord, without the H3 K27M mutation or with unknown H3 mutation status at the time of enrollment. 2. Had unequivocal evidence of progressive disease on contrast-enhanced brain computed tomography (CT) or magnetic resonance imaging (MRI) as defined by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria, or had documented recurrent glioblastoma or WHO Grade IV glioma on diagnostic biopsy. For Arm E, patients were not required to have evidence of recurrent disease for inclusion. 3. Had previous first line therapy with at least radiotherapy and temozolomide. For patients who had tumors that exhibited unmethylated MGMT promoter, prior treatment with temozolomide was not required. For Arms D, E, and F: Must have had previous first line therapy with at least radiotherapy. 4. For Arm A and D: Any number of recurrences were allowable. For Arm B: Must have been first recurrence (only) WHO Grade IV glioma. First recurrence was defined as the progression following initial therapy (i.e., radiation ±chemotherapy). For patients who had prior therapy with radiation or chemotherapy for a low-grade glioma (LGG), the surgical diagnosis of the HGG was considered the first recurrence. For patients who did not receive additional treatment following surgery and diagnosis of the LGG, surgical diagnosis of HGG was not considered the first recurrence. Instead, progression after treatment was considered first recurrence. For Arm C: Patients must have had clinical and/or radiographic evidence of first recurrence of glioblastoma and must have been eligible for salvage surgical resection as deemed by the site Investigator. For Arm E: Recurrent disease was not required. Patients must have had a midline glioma, and must have been eligible for salvage surgical resection as deemed by the site Investigator. 5. Had an interval of at least 90 days from the completion of radiotherapy to the first dose of ONC201. If patients were within 90 days of radiotherapy, then the progressive lesion must have been outside of the high-dose radiation target volume or must have had unequivocal evidence of progressive tumor on a biopsy specimen. 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 was shorter) from other anti-tumor therapies. 7. All adverse events Grade \>1 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must have been resolved, except for alopecia. 8. Were male or female aged ≥16 years. 9. Had a Karnofsky Performance Status (KPS) of ≥60. 10. Had adequate organ and marrow function as defined below; all screening labs should have been performed within 14 days of treatment initiation: * leukocytes: ≥3,000/mcL * absolute neutrophil count: ≥1,500/mcL * platelets: ≥100,000/mcL * hemoglobin: \>8.0 mg/dL * total bilirubin: \<2.0 × upper limit of normal (ULN) * aspartate aminotransferase/alanine aminotransferase (SGOT)/(SGPT): ≤2.5 × ULN * creatinine: ≤ULN OR * creatinine clearance: ≥60 mL/min/1.73 m2 for patients who had creatinine levels above normal. 11. Had a CT or MRI within 14 days prior to start of study drug. 12. Corticosteroid dose must have been stable or decreasing for at least 5 days prior to the baseline CT or MRI scan. For Arm B: Corticosteroid dose must have been stable or decreasing for at least 2 weeks prior to study entry. 13. The effects of ONC201 on the developing human fetus are unknown. For this reason, women of childbearing potential and men must have agreed to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman have become pregnant or suspected that she was pregnant while she or her partner were participating in this study, she should have informed her treating physician immediately. Male subjects should have agreed to use adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of therapy. 14. Had archival tissue for evaluation of correlative objectives (if available). Archival tissue was required for Arms B and C. 15. Had the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: A potential patient who met any of the following criteria was ineligible to participate in the study: 1. Had a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients. 2. Had current or planned participation in a study of an investigational agent or using an investigational device. 3. Had uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would have limited compliance with study requirements. 4. Had an active infection that required systemic therapy. 5. Patients who had prior stereotactic radiotherapy, convection enhanced delivery (CED) or brachytherapy must have had a biopsy to confirm radiographic progression was consistent with progressive tumor and not treatment-related necrosis. If the recurrent lesion was outside of any prior high-dose radiation target volume or distant from the prior CED or brachytherapy site, patients were considered eligible 6. Was a pregnant woman because ONC201 is novel agent with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ONC201, breastfeeding should have been discontinued if the mother was treated with ONC201. 7. Had known human immunodeficiency virus (HIV)-positive test on combination antiretroviral therapy. 8. Had a known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias or bradycardia. Patients who were receiving therapeutic agents known to prolong QT interval were excluded. Patients who had a history of congestive heart failure, myocardial infarction, or stroke within the last 3 months were excluded. 9. Had active illicit drug use or diagnosis of alcoholism. 10. For Arms A, B, and C: Had prior bevacizumab treatment (this prior treatment was allowable for patients in Arms D, E, and F). 11. Had tumors with known isocitrate dehydrogenase 1 (IDH1) or known IDH2 mutations as determined by immunohistochemistry for the IDH1 R132H variant or by direct sequencing. 12. Had any known additional malignancies that were progressing or required active treatment within 3 years of start of study drug. Exceptions included basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that had undergone potentially curative therapy. 13. Had undergone any surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2 weeks of baseline disease assessments; or were not fully recovered from any side effects of previous procedures. 14. Had concomitant use of cytochrome P450 (CYP)3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration. 15. Had concomitant use of potent CYP3A4/5 inducers, which included enzyme inducing antiepileptic drugs (EIAEDs), during the treatment phase of the study and within 2 weeks prior to starting treatment. 16. Had planned concurrent use Optune™. Prior use of the device was allowable. 17. For Arms D and F: Had evidence of leptomeningeal spread of disease.