Selinexor (KPT-330) in Combination With Temozolomide and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma

Background: Glioblastoma is a type of brain cancer. Treatments include radiation, chemotherapy, and surgery. But survival rates are poor. Researchers think that the drug selinexor, when combined with chemotherapy and radiation, might help. Objective: To learn the highest dose of selinexor that people with brain cancer can tolerate when given with temozolomide and radiation therapy. Eligibility: People ages 18 and older with brain cancer that has not been treated with chemotherapy or radiation. Design: Participants will be screened under another protocol. Before participants start treatment, they will have tests: Neurological and physical evaluations Blood and urine tests Possible computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain if they have not had one in 3 weeks. Participants will lie in a machine that takes pictures of the body. They may have a dye injected into a vein. Surveys about their well-being Participants will have radiation to the brain for up to 6 weeks. This will usually be given once a day, Monday through Friday. Starting the second day of radiation, participants will take selinexor by mouth once a week. They will take it in weeks 1, 2, 4, and 5. The timing may be changed. Starting the first day of radiation, participants will take temozolomide by mouth once a day until they complete radiation. Participants will have blood tests once per week during treatment. Participants will have a follow-up visit 1 month after they complete treatment. Then they will have visits at least every 2 months for the first 2 years, then at least every 3 months for another year. Visits will include MRIs and blood tests.

Background: * Although radiation has been shown to improve outcomes in patients with glioblastoma (GBM), median survival remains poor. Even with the addition of temozolomide (TMZ) to surgical resection and radiotherapy, most GBMs will recur in field or adjacent to the high dose radiation volume. * High rates of local failure indicate that GBM cells in situ are relatively radioresistant and that the effectiveness of GBM radiotherapy would benefit from additional radiosensitization. * Selinexor has recently been shown to enhance the radiosensitivity of glioma cells both in vitro and in vivo. Objectives: -Assess the safety, tolerability, and maximum tolerated dose of selinexor when combined with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma and gliosarcoma. Eligibility: * Men and women greater than 18 years old * Histologically confirmed newly diagnosed glioblastoma or gliosarcoma * Karnofsky Performance Scale (KPS) greater than or equal to 70 * Patients who have not previously been treated with chemotherapy or radiation therapy Design: * This is a Phase I trial to determine the safety and tolerability of selinexor in combination with external beam radiation therapy (RT) and temozolomide in patients with newly diagnosed glioblastoma or gliosarcoma using a "3 plus 3 design" and three dose escalation levels, with 3 patients per dose level (provided no dose limiting toxicity (DLT), a maximum of 21 patients will be enrolled. * Patients will be treated with external beam radiation therapy in a standard manner with temozolomide given daily during radiation. Selinexor will be administered concurrent with the RT/temozolomide. * We anticipate accrual of 21 evaluable patients which will take approximately 2 years. The accrual ceiling has been set to 24 patients.