A PHASE 2 STUDY EVALUATING THE EFFICACY AND SAFETY OF;SELINEXOR (KPT-330) IN PATIENTS WITH RECURRENT GLIOMAS

1. Confirmed diagnoses, as follows:;a. Arms A, B, C, and D: Pathologically confirmed GBM (including all histologic variants) at first diagnosis with radiographic evidence of recurrent disease after treatment with radiotherapy and temozolomide;;b. Arm E: Pathologically confirmed malignant gliomas other than GBM (WHO Grade 2 or Grade 3), with radiographic evidence of recurrent disease after treatment with radiotherapy and at least one line of systemic treatment;;c. Arm F: Pathologically confirmed GBM (including all histologic variants) or AG that is refractory to antiangiogenic treatment (defined as recurrence or progression of disease per RANO criteria during prior therapy with bevacizumab or other direct VEGF/VEGFR inhibitors) with radiographic evidence of recurrent disease after treatment with radiotherapy and temozolomide; ;2. Age >= 18 years; ;3. Karnofsky Performance Status (KPS) >= 60;;4. Patients enrolling in the medical arm (Arms B,C, D, E, and F) must be on a stable or decreasing dose of corticosteroids (or none) for at least 5 days prior to the baseline MRI;;5. Patients must have received prior treatment with radiation therapy and either temozolomide (Arms A, B, C, D, and F) or at least one line of systemic treatment (Arm E).;o Patients enrolling in the medical arm (Arms B, C, D, E, and F) must have an interval of at least 12 weeks from completion of radiation therapy and study unless there is histologic proof of active tumor from intervening resection.;6. Measurable disease (according to RANO guidelines, within 14 days of starting treatment). Measurable disease after surgery on Arm A is not required.;7. Written informed consent obtained prior to any screening procedures. Patients must be willing and able to comply with the protocol and aware of the investigational nature of this study.;8. Patients must have adequate bone marrow function and organ function within 2 weeks of study treatment as defined by the following laboratory criteria;;o Hematopoietic function: total white blood cell (WBC) count >= 3000/mm³, absolute neutrophil count (ANC) >= 1500/mm³, platelet count >= 125,000/mm³; hemoglobin >= 9g/dL.;o Hepatic function: bilirubin <= 2 times the upper limit of normal (ULN), ALT <= 2.5 times ULN, AST <= 2.5 times ULN; unless bilirubin elevation is related to Gilbert*s Syndrome for which bilirubin must be < 4 times ULN.;o Renal function: estimated creatinine clearance of >= 30 mL/min, calculated using the formula of Cockroft and Gault or other standard methods at the treating institution.;9. All female patients of childbearing potential must agree to use reliable methods of birth control during study treatment and for 3 months after the last dose of study drug and have a negative serum pregnancy test at screening. Reliable methods of contraception include intrauterine devices, hormonal contraceptives [contraceptive pills, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release], abstinence or sterilization of the partner.;10. Fertile males must be willing to employ reliable methods of contraception during study treatment and for 3 months after the last dose of study drug.;11. Archived paraffin-embedded tissue: approximately 10 unstained slides (if less, contact Sponsor) or a tumor block must be available for confirmation of tumor diagnosis and correlative studies.;12. Patients in the Surgical Arm (Arm A) must be predicted pre-operatively to have sufficiently sized tumor to be resected and provide tissue samples for exploratory assessments.

1. Patients must not have significant medical illness that in the Investigator*s opinion cannot be adequately controlled with appropriate therapy or would compromise the patient*s ability to tolerate this therapy.;2. < 24 days from prior temozolomide, < 6 weeks from nitrosourea, < 4 weeks from other chemotherapy or investigational agents prior to start of treatment within study. ;3. For Arm F only: < 6 weeks from prior bevacizumab or other direct VEGF/VEGFR inhibitor prior to start of treatment within the study For any question of the definition of a direct VEGF/VEGFR inhibitor, consult Sponsor.;4. Unstable cardiovascular function.;5. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen); hepatitis testing is not required.;6. Known HIV infection; HIV testing is not required.;7. Markedly decreased visual acuity if attributed to other causes than GBM for Arms A, C, and D, malignant gliomas other than GBM (WHO Grade 2 or Grade 3) for Arm E, or GBM or AG that is refractory to antiangiogenic treatment for Arm F.;8. Active infection requiring parenteral systemic antibiotics.;9. Patients with coagulation problems and medically significant bleeding in the month prior to start of treatment (e.g., peptic ulcer, epistaxis, spontaneous bleeding). Prior history of DVT or PE is not exclusionary.;10. Patients who are pregnant or breast-feeding.;11. Other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off all therapy for that disease for a minimum of 3 years.;12. Patients must not have significantly diseased or obstructed gastrointestinal tract, malabsorption, uncontrolled vomiting or diarrhea, or inability to swallow oral medications.;13. Dehydration of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 1.;14. Patients must not have serious psychiatric or medical conditions that could interfere with treatment.;15. History of organ allograft.;16. Concurrent therapy with approved or investigational anticancer therapeutics.;17. Arms A, B, C, and D, only: Prior treatment with bevacizumab or other direct VEGF/ VEGFR inhibitors. For any question of the definition of a direct VEGF/VEGFR inhibitor, consult Sponsor.;18. Arms C and D only: body surface area < 1.2 m2, to avoid a dose exceeding the maximum allowable dose of 70 mg/m2.;.