INdividualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT)

Inclusion Criteria:

• Participants must have histologically confirmed intracranial glioblastoma orgliosarcoma following maximum surgical resection. Tumors primarily localized in theinfratentorial compartment will be excluded.

• Participants may have had prior surgery for glioblastoma or gliosarcoma but nosystemic or radiation therapy.

• Age ≥ 18 years.

• Karnofsky performance status ≥60

• Participants must have normal organ and marrow function as defined below:

• Leukocytes ≥3,000/mL

• Absolute neutrophil count ≥1,500/mL

• Platelets ≥100,000/mL

• Hemoglobin ≥ 9g/dl

• Total bilirubin within normal institutional limits (except for participant'swith Gilbert's disease)

• AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal

• Creatinine ≤ institutional upper limit of normal OR

• Creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatininelevels above institutional normal.

• Potassium within normal institutional range, or correctable with supplements

• Serum amylase ≤ 1.5 x institutional upper limit of normal

• Serum lipase ≤ 1.5 x institutional upper limit of normal

• INR < 2.0

• PTT ≤ institutional upper limit of normal, unless receiving therapeutic lowmolecular weight heparin

• Must be able to swallow pills.

• Participants must plan to begin radiation therapy 14-42 days after surgicalresection.

• Immunohistochemically negative for IDH1 R132H mutation.

• Evidence that the tumor MGMT promoter is unmethylated by standard of care assays.

• Genotyping data available or in process (data must be available at time of initialregistration if randomization probabilities differ across biomarker subgroups asdetermined by the DFCI Coordinating Center) to assign biomarker subgroups throughwhole exome sequencing, whole genome copy number analysis, or a combination asdescribed in Section 9.1.

• MRI with gadolinium should be obtained within 21 days prior to beginning treatment.Patients without measurable disease are eligible. Participants must be able toundergo MRIs (CTs are not allowed for response assessment on study).

• The effects of the experimental agents used in this study on the developing humanfetus are unknown. For this reason and because other therapeutic agents used in thistrial are known to be teratogenic, women of child-bearing potential (women who arenot free from menses for > 2 years, post hysterectomy/oophorectomy, or surgicallysterilized) and men must agree to use adequate contraception (hormonal or barriermethod of birth control; abstinence) prior to study entry and for the duration ofstudy participation unless otherwise specified in sub-study that the participant israndomized to. Should a woman become pregnant or suspect she is pregnant while sheor her partner is participating in this study, she should inform her treatingphysician immediately.

• For women of child bearing potential (women who are not free from menses for > 2years, post hysterectomy/oophorectomy, or surgically sterilized) a negative serumpregnancy test must be documented prior to initial registration.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Participants will not be eligible if the original diagnosis was a lower grade gliomaand a subsequent histologic diagnosis revealed glioblastoma.

• Planned major surgery.

• Participants who are receiving any other investigational agents.

• Participants who have had any prior cranial radiotherapy.

• Planned use of Optune™.

• History of a different malignancy, unless (a) have been disease-free for at least 2years and are deemed by the investigator to be at low risk for recurrence of thatmalignancy, and/or (b) malignancy was cervical cancer in situ, superficial bladdercancer or basal cell or squamous cell carcinoma of the skin, and malignancy has beentreated. Patients who meet the above listed criteria and are only on preventativetreatment will be deemed eligible.

• History of intratumoral or peritumoral hemorrhage if deemed significant by thetreating physician.

• Impaired cardiac function or clinically significant cardiac diseases, including anyof the following:

• Active uncontrolled cardiac disease, including cardiomyopathy, congestive heartfailure (New York Heart Association functional classification of ≥2), unstableangina, myocardial infarction within 12 months of enrollment, or ventriculararrhythmia.

• Known history of congenital QT prolongation or Torsade de pointes (TdP).

• Complete left bundle branch or bifascicular block.

--QTc interval > 450 ms for men or > 470 ms for women.

• Persistent or history of clinically meaningful ventricular arrhythmias or atrialfibrillation.

• Unstable pectoris or myocardial infarction ≤ 3 months prior to starting studytreatment.

• Uncontrolled hypertension (blood pressure ≥ 160/95 mmHg).

• Other clinically significant heart disease such as congestive heart failurerequiring treatment.

• Uncontrolled diabetes mellitus, or subjects with either of the following:

• Fasting blood glucose (FBG defined as fasting for at least 8 hours) ≥ 200 mg/dL (7.0mmol/L), or

• HbA1c ≥ 8%

• Uncontrolled intercurrent illness including, but not limited to ongoing or activeinfection, chronic liver disease (e.g., cirrhosis, hepatitis), chronic renaldisease, pancreatitis, chronic pulmonary disease, or psychiatric illness/socialsituations that would limit compliance with study requirements. Subjects must befree of any clinically relevant disease (other than glioma) that would, in thetreating investigator's opinion, interfere with the conduct of the study or studyevaluations.

• Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNS [qualitative] is detected).

• Known acute or chronic pancreatitis.

• Participants with active diarrhea ≥ CTCAE grade 2 despite medical management.

• Active infection requiring antibiotics.

• Pregnant or breastfeeding.

• Impairment of gastrointestinal (GI) function or GI disease that may significantlyalter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea,vomiting, diarrhea, malabsorption syndrome, or extensive small bowel resection).Participants with unresolved diarrhea ≥ CTCAE grade 2 will be excluded as previouslyindicated.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to any of the experimental agents or other agents used instudy.

• Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital,phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine,rufinamide, and felbamate. Participant must be off any EIAEDs for at least 7 daysprior to planned start of study treatment. A list of EIAED and other inducers ofCYP3A4 is provided. Among non-EIAED, caution is recommended with use of valproicacid due to potential for drug interaction.

• Participants taking a drug known to be strong inhibitors or inducers of isoenzymeCYP3A. Participant must be off CYP3A inhibitors and inducers for at least 7 daysprior to planned start of study treatment. NOTE: participants must avoid consumptionof Seville orange (and juice), grapefruit or grapefruit juice, grapefruit hybrids,pummelos and exotic citrus fruits from 7 days prior to planned start of studytreatment and during the entire study treatment period due to potential CYP3A4interaction.

• Current use of herbal preparations/medications, including but not limited to: St.John's wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA),yohimbe, saw palmetto, ginseng. Participants should stop using these herbalmedications 7 days prior to planned start of study treatment.

• Current use of warfarin sodium or any other coumadin-derivative anticoagulant.Participant must be off Coumadin-derivative anticoagulants for at least 7 days priorto planned start of study treatment. Low molecular weight heparin and factor Xainhibitors are allowed.