Clinical Trial Finder

Inclusion Criteria.

• - Written informed consent in accordance with federal, local, and institutional guidelines.

• - Age ≥18 years at the time of informed consent and ≥22 year for Arm E.

• - Pathologically confirmed glioblastoma (including all histological variants; documentation to be provided) that are newly diagnosed (for Arms A and B) or relapsed disease (for Arm C, D and E) after 1 to 2 line of systemic therapy (RT ± TMZ or RT ± TMZ in combination with other drug) (surgical resection of recurrent disease allowed).

For Arms A and B, MGMT status should be available.

• - Prior therapy: 1.

Arms A and B: participants who have not received RT or any systemic therapy for brain tumor and must be eligible for definitive external beam RT and TMZ. 2. Arm C, D and E: participants must have received prior treatment with RT with or without TMZ and only 1 prior line of therapy (RT ± TMZ in combination with other drug is allowed).

• - Measurable disease according to RANO/modified RANO guidelines is required only for Arm C, D and E; it is not required for Arms A or B.

• - Participants enrolling into Arms C, D, and E must be on a stable or decreasing dose of corticosteroids (or none) for at least 5 days prior to the baseline magnetic resonance imaging (MRI).

• - Karnofsky Performance Score (KPS) ≥70 (for Arms A and B) and 60 (for Arms C, D, and E).

• - Participants must have adequate organ function ≤2 weeks of study treatment as defined by the following laboratory criteria: 1.

Hematological function ≤7 days prior to Cycle 1 Day 1 (C1 D1): Absolute neutrophil count (ANC) ≥1.5*10^9 per Liter (/L); platelet count ≥150*10^9/L; and hemoglobin (Hb) ≥10.0 gram per deciliter (g/dL). Transfusion is not allowed within 7 days prior to C1 D1. 2. Hepatic function: bilirubin ≤2*the upper limit of normal (ULN), alanine transaminase (ALT) ≤2.5*ULN, aspartate transaminase (AST) ≤2.5*ULN; unless bilirubin elevation is related to Gilbert's Syndrome for which bilirubin must be <4*ULN. 3. Renal function: calculated (Cockcroft-Gault) or measured creatinine clearance ≥30 milliliter per minute (mL/min)

• - Female participants of childbearing potential must have a negative serum pregnancy test at Screening and agree to use highly effective methods of contraception throughout the study and for 6 months following the last dose of study treatment.

• - Fertile male participants who are sexually active with a female of childbearing potential must use highly effective methods of contraception throughout the study and for 6 months following the last dose of study treatment.

• - For Arms A and B: participants must have had surgery and/or biopsy not greater than [>] 8 weeks prior to initial screening.

• - Participants must consent to provide tumor tissue and blood samples to be used for future molecular testing for correlative studies.

• - Limited to supratentorial disease for Arm E only.

Exclusion Criteria.

• - Participants who are receiving any other investigational agents and /or have had prior therapy including: For Arms A and B only: 1.

Participants who have previously received RT to the brain. 2. Participants who received chemotherapy for the treatment of their glioma. 3. Participants who are being treated with implanted Gliadel wafers. For Arm C: 4. Prior nitrosoureas. For Arms C, D, and E: 5. <4 weeks from prior TMZ or other chemotherapy, or <4 weeks or 5 half-lives (whichever is shorter) for investigational agents prior to start of study treatment. 6. Prior treatment bevacizumab or other direct Vascular endothelial growth factor/Vascular endothelial growth factor receptor (VEGF/VEGFR) inhibitors. For any questions of the definition of a direct VEGF/VEGFR inhibitor, consult the study Medical Monitor. 7. Any AE which has not recovered to Grade <=1, or returned to baseline, related to the previous GBM therapy, except alopecia, and some other Grade 2 AEs that have been stabilized (upon Medical Monitor approval)

• - Participants who are being treated or plan to be treated during this study with TTField for participants in Arms A to D.

• - Major surgery <2 weeks prior to the start of study treatment for Arms A to C and E, <4 weeks for Arm D.

• - History of allergic reactions attributed to compounds of similar chemical or biological composition to selinexor or other study treatment.

• - Participants must not have significantly diseased or obstructed gastrointestinal tract malabsorption, uncontrolled vomiting or diarrhea, or inability to swallow oral medication.

• - Participants with coagulation problems and medically significant bleeding in the month prior to start of treatment (peptic ulcers, epistaxis, intracranial hemorrhage, spontaneous bleeding).

Prior history of deep vein thrombosis or pulmonary embolism is not exclusionary.

• - Currently pregnant or breastfeeding.

• - For Arms A and B: participants with pre-existing known or suspected radiation sensitivity syndromes will be excluded due to potential confounding effect on outcome.

• - Any life-threatening illness, active medical condition, organ system dysfunction, or serious active psychiatric issue which, in the Investigator's opinion, could compromise the participant's safety or the participant's ability to remain compliant with study procedures.

• - Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to first dose of study treatment; however, prophylactic use of these agents is acceptable even if parenteral.

• - Participants with mutated isocitrate dehydrogenase (IDH) should be excluded for Phase 2.

• - For participants in Arm C, Forced Vital Capacity (FVC) or Carbon Monoxide Diffusing Capacity (DLCO) below 70% of predicted.

• - For Arm E: implanted active electronic medical devices such as programmable intraventricular shunts, spinal cord, vagus nerve or deep brain stimulators, pacemakers or implantable automatic defibrillators, skull defect (i.e. missing bone with no replacement), sensitivity to conductive hydrogels as used in electrocardiograms (ECGs), an underlying serious scalp condition that may interfere with placement of arrays, or bullet fragments, or documented clinically significant arrhythmias.

Arms

Experimental: Phase 1: Arm A: Selinexor+Radiation Therapy

Participants with nGBM uMGMT will receive 60 to 80 milligram (mg) of selinexor oral tablet once weekly (QW) across dose level -1, 1, 2, and 3 in combination with 2 Gray (Gy) radiation therapy (RT) daily for 5 days per week in a 42-day cycle during Cycle 1 radiation period followed by 80 mg of selinexor oral tablet on Day 1 and 15 in a 28-day Cycle 2 and subsequently will continue at 80 mg QW until progressive disease (PD) during adjuvant therapy period.

Active Comparator: Arm A Control: Temozolomide+Radiation Therapy

Participants with nGBM uMGMT will receive 75 milligram per meter square (mg/m^2) of temozolomide oral capsule once daily (QD) in combination with 2 Gy RT daily for 5 days per week in a 42-day cycle during Cycle 1 radiation period followed by 150 mg/m^2 (started from Cycle 3) and increase to 200 mg/m^2 as tolerated per Investigator's judgment, daily for 5 days in a 28-day cycle during Cycles 4 to 8 cycles during adjuvant therapy period.

Experimental: Phase 1: Arm B: Selinexor+Temozolomide+Radiation Therapy

Participants with nGBM mMGMT will receive 40-80 mg of selinexor oral tablet QW across dose level -1, 1, 2, 2a, 2b and 3a and 75 mg/m^2 of temozolomide oral capsule QD in combination with 2 Gy RT daily for 5 days per week in a 42-day cycle during Cycle 1 radiation period followed by 60 mg (dose level 2a) or 80 mg (dose level 2b and 3a) of selinexor oral tablet on Day 1 and 15 in a 28-day Cycle 2, followed by 150 mg/m^2 (started from Cycle 3) and increase to 200 mg/m^2 as tolerated per Investigator's judgment, daily for 5 days in a 28-day cycle during Cycle 4 to 8 during adjuvant therapy period. Participants will continue selinexor weekly per dose level assigned until PD.

Active Comparator: Arm B Control: Temozolomide+Radiation Therapy

Participants with nGBM mMGMT will receive 75 mg/m^2 of temozolomide oral capsule QD in combination with 2 Gy RT daily for 5 days per week in a 42-day cycle during Cycle 1 radiation period followed by 150 mg/m^2 (started from Cycle 3) and increase to 200 mg/m^2 as tolerated per Investigator's judgment, daily for 5 days in a 28-day cycle during Cycles 4 to 8 during adjuvant therapy period.

Experimental: Arm C: Selinexor+Lomustine/Carmustine

Participants with rGBM uMGMT or mMGMT will receive 40-80 mg of selinexor oral tablet QW across dose level -1, 1, 2, 2a, and 3 and 90-110 mg/m^2 of lomustine or 150-200 mg/m^2 of carmustine (substituted if lomustine is not available) capsule on Day 1 of each cycle across dose level -1, 1, 2, 2a, and 3 in a 42-day cycle for all cycles.

Active Comparator: Arm C Control: Lomustine/Carmustine

Participants with rGBM uMGMT or mMGMT will receive 110 mg/m^2 of lomustine or 200 mg/m^2 of Carmustine (substituted if lomustine is not available) capsule on Day 1 of each cycle in a 42-day cycle for all cycles.

Experimental: Arm D: Selinexor+Bevacizumab

Participants with rGBM will receive 60-80 mg of selinexor oral tablet QW across dose level -1, 1 and 10 mg/kg of Bevacizumab intravenous (IV) infusion every 2 weeks (Q2W) in 28-day cycle for all cycles.

Experimental: Arm E: Selinexor+TTField

Participants with rGBM will receive 60-80 mg of selinexor oral tablet QW across dose level -1, 1 and will receive scalp application of 200 kilohertz (kHz) of transducer array ≥18 hours/day daily for each cycle in 28 day cycle for all cycles.

Interventions

Drug: - Selinexor

Dose and Formulation: 20 milligram (mg); Tablet Route of Administration: Oral

Drug: - Temozolomide (TMZ)

Dose strength and Formulation: 5, 20, 100, 140, 180, or 250 mg; Capsule Route of Administration: Oral

Drug: - Lomustine (CCNU)

Dose and Formulation: 10, 40, or 100 mg; Capsule Route of Administration: Oral

Radiation: - Standard Fractionated Radiation therapy (RT)

Radiation Therapy Oncology Group (RTOG) or European Organisation for Research and Treatment of Cancer (EORTC) methodologies of approximately 60 Gy in 30 fractions.

Drug: - Bevacizumab

Dose and Formulation: 10 mg/kg; Route of Administration: Intravenous

Device: - TTField

Dose and Formulation: 200 kHz ≥18h/day; Route of administration: Scalp application of transducer arrays.

Drug: - Carmustine

Dose and Formulation: 150 or 200 mg/m^2; Route of Administration: Intravenous