Stopped: The Sponsor terminated the study to prioritize enrollment in a randomized Phase 3 trial of ONC201 in an earlier setting. This decision was unrelated to any safety concerns with dordaviprone (ONC201).
United States84 participantsStarted 2016-01
Plain-language summary
This was a Phase 2, open-label, 6-arm, multi-center study of dordaviprone (ONC201) in patients with recurrent glioblastoma (Arms A, B, and C), H3 K27M-mutant diffuse glioma (Arm D), or diffuse midline glioma (Arms E and F).
The primary objective of this study was the assessment of dordaivprone (ONC201) anti-tumor activity through progression-free survival at 6 months using Response Assessment in Neuro-Oncology (RANO) criteria for high-grade glioma (HGG).
Who can participate
Age range16 Years
SexALL
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Inclusion criteria
✓. 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.
✓. 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.
✓. 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.
What they're measuring
1
Percent of Patients With Probability of Progression-Free Survival at 6 Months
Timeframe: Progression-free survival assessments were conducted 6 months following treatment initiation.
. 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.
✓. 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.
✓. 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.
✓. All adverse events Grade \>1 related to prior therapies (chemotherapy, radiotherapy, and/or surgery) must have been resolved, except for alopecia.
✓. Were male or female aged ≥16 years.
Exclusion criteria
✕. Had a history of allergic reactions attributed to compounds of similar chemical or biologic composition to ONC201 or its excipients.
✕. Had current or planned participation in a study of an investigational agent or using an investigational device.
✕. 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.
✕. Had an active infection that required systemic therapy.
✕. 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
✕. 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.
✕. Had known human immunodeficiency virus (HIV)-positive test on combination antiretroviral therapy.
✕. 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.