PRIMARY OBJECTIVES:~I. To determine the safety and tolerability of Akt/ERK Inhibitor ONC201 (ONC201) in combination with radiotherapy before a tumor resection in recurrent glioblastoma (GBM) patients.~II. To determine the ability of ONC201 to decrease glioblastoma-initiating cells as determined by percentage of neurosphere formation of treated brain tumor tissues compared to non-treated brain tumor tissues.~SECONDARY OBJECTIVES:~I. To determine the ability of ONC201 to decrease glioblastoma-initiating cells as determined by expression of glioma stem cells using ribonucleic acid-sequencing (RNA-Seq) of treated brain tumor tissues compared to non-treated brain tumor tissues.~II. To assess the ability of ONC201 to inhibit Akt by evaluating progressive disease (PD) markers by immunohistochemistry such as Sox2, Oct3/4, Nanog, Akt and p-Akt, GSK3 and pGSK3alpha.~EXPLORATORY OBJECTIVES:~I. To estimate progression-free survival (PFS) and overall survival (OS). II. To determine the immunogenicity of the combination of ONC201 + radiation therapy (RT) via immune cell studies.~III. To determine if the combination of ONC201 + RT leads to increase cholesterol synthesis.~IV. To determine molecular markers of response to ONC201 in correlation to survival such as DRD5 expression.~OUTLINE: Patients are randomized to 1 of 2 arms.~ARM I: Patients undergo radiation therapy for 10 fractions over 2 weeks, and receive ONC201 orally (PO) daily on days 1, 2, 8, and 9. Beginning 24 hours after completion of radiation therapy, patients undergo surgical resection. Beginning 7 days from last pre-surgery dose of ONC201, patients receive ONC201 PO daily on two consecutive days weekly (2 days on/5 days off) in the absence of disease progression or unacceptable toxicity.~ARM II: Patients undergo radiation therapy for 10 fractions over 2 weeks. Beginning 24 hours after completion of radiation therapy, patients undergo surgical resection. After recovery from surgery, patients receive ONC201 PO daily on two consecutive days weekly (2 days on/5 days off) in the absence of disease progression or unacceptable toxicity.~After completion of study treatment, patients are followed up at 30 days and then every 3 months.
This phase I trial studies the effects of ONC201 in combination with standard of care radiation therapy in treating patients with glioblastoma that has come back (recurrent). ONC201 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy photons to kill tumors cells and shrink tumors. Giving ONC201 in combination with radiation therapy may help treat patients with recurrent glioblastoma.