Mass General - Division of Clinical Research

All participants 1. Age ≥ 18 years old. 2. Confirmed diagnosis of glioblastoma (WHO Grade IV). 3. Agreement to provide archival tumor tissue for exploratory biomarker analysis 4. Ability to undergo serial MRIs. 5. Eastern Cooperative Oncology Group (ECOG) status ≤ 1. 6. Adequate hematologic and end-organ function 7. Females of childbearing potential and non-sterile males must agree to use highly effective methods of birth control throughout the course of study and at least up to 6 months after last dosing. 8. Ability to swallow whole capsules. Participants in Arms A and B (not Arm C) must meet inclusion criteria # 9 - 11: 9. No previous treatment for GBM except surgery. 10. Able to start radiation therapy ≤ 49 days after surgery but ≥ 14 days after a biopsy or ≥28 days after an open biopsy or craniotomy with adequate wound healing. 11. Documented unmethylated MGMT promoter status. Participants in Arm C Escalation (Phase 1b) must meet inclusion criteria # 12 - 15: 12. Documentation of MGMT promoter status 13. No prior systemic chemotherapy other than TMZ for GBM. 14. Histologically confirmed secondary glioblastoma 15. Disease that is evaluable or measurable as defined by Response Assessment in Neuro-Oncology (RANO) criteria Participants in Arm C Expansion (Phase 2), must meet criteria # 16 - 18: 16. Histologically confirmed de novo (primary) glioblastoma with unequivocal first progressive disease (PD) after RT with concurrent/adjuvant TMZ chemotherapy 17. Disease that is measurable as defined by RANO criteria 18. Documentation of MGMT promoter status

All participants 1. Prior chemotherapy, biologic therapy, immunotherapy or investigational agents ≤21 days prior to start of study treatment. 2. Toxicity of ≥ Grade 2 from prior therapy. 3. Major surgery or significant other injury ≤ 4 weeks prior to start of study treatment. 4. History of other active malignancies within 2 years with exception of (i) adequately treated in situ cancer of the cervix, (ii) non-melanoma skin cancer, or (iii) localized adequately treated cancer with curative intent or malignancy diagnosed > 2 years ago with no evidence of disease and no treatment ≤ 2 years prior to study treatment. 5. Active infection requiring systemic treatment. 6. Known human immunodeficiency virus (HIV) or active viral hepatitis. 7. Active, clinically significant cardiac disease or any Class 3 or 4 cardiac disease, ventricular arrhythmia or Cerebrovascular Accident (CVA) ≤ 6 months prior to start of treatment. 8. Active clinically significant gastrointestinal disease. 9. Active bleeding disorder ≤ 6 months prior to start of treatment. 10. Need for therapeutic anti-coagulation with heparin, warfarin or other anticoagulants. 11. Use of any medications or food known to be strong or moderate cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong inducers. 12. Pregnant or nursing females. 13. Significant intercurrent illness that may result in participant's death prior to death from glioblastoma. Arms B and C Only: 14. Known hypersensitivity to any component of TMZ or decarbazine (DTIC). 15. Have hereditary problems of galactose intolerance NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.