Surgical Pembro +/- Olaparib W TMZ for RGBM

Inclusion Criteria:

• Participants must be able to understand and willing to sign a written informedconsent document.

• Participants must be able to adhere to the dosing and visit schedules and agree torecord medication times accurately and consistently in a daily diary.

• Participants must be at least 18 years old on day of signing informed consent.

• Women of childbearing potential are eligible to participate if they are not pregnantor breastfeeding.

• Participants must have a Karnofsky Performance Status (KPS) ≥ 70 and EasternCooperative Oncology Group (ECOG) Performance Status ≤ 1 (see Appendix A).

• Participants must be able to swallow oral medications. Nature of illness andtreatment history

• Participants must have histologically World Health Organization Grade IV IDHwildtype glioblastoma by IDHR132H immunohistochemistry or variants includinggliosarcoma or IDH wildtype diffuse glioma with molecularly features of glioblastoma (EGFR amplification, TERT promoter mutation, or concurrent gain of Chromosome 7 andloss of Chromosome 10) (Brat et al., 2018). IDH mutational status can be establishedvia immunohistochemistry and/or next-generation sequencing.

• Participants must be at first or second relapse of GBM. First relapse is defined asprogression following initial therapy and second relapse is progression followingsecond therapy. The intent therefore is that patients had no more than 2 priortherapies (i.e. radiation +/- chemotherapy if that was used as initial therapy andone additional therapy for first recurrence). If the patient had a surgicalresection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is consideredto constitute 1 relapse.

• Participants must have shown unequivocal evidence for tumor progression by MRI scanper modified RANO criteria (Ellingson et al., 2017).

• MRI should be obtained within 14 days prior to study registration.

• Confirmation of availability of sufficient tissue from a prior surgery demonstratingglioblastoma for correlative studies is required prior to enrollment.

• Cohort 1: 15 unstained FFPE sections (standard 10 micrometer thickness)

• Cohort 2: 1 (FFPE) block (preferred) OR 35 unstained FFPE sections (standard 5micrometer thickness)

• NOTES:

• If the above-mentioned tissue is not available from the most recentsurgery revealing GBM, participants may be enrolled with tissue availablefrom any prior surgery revealing GBM with prospective approval from thePrincipal Investigator.

• If the participant's slides have been reviewed on a previous study andthere has been no interim surgery or biopsy, slides do not need to bere-submitted for histologic confirmation. The site must submit a copy ofthe previous submission forms with the review results to the centraloffice as documentation for the new study.

• Cohort 2 patients only: Surgically resectable disease at progression.

• There must be > 2cm3 enhancing tissue available for resection and submissionfor study correlatives as determined by local treating team.

• For the first 10 patients in Arm A who will have tumor resected for analysis ofolaparib levels, both enhancing and non-enhancing tumor should be available forresection.

• An interval of at least 12 weeks from the completion of radiation therapy to startof study drug unless there is unequivocal histologic confirmation of tumorprogression.

• Participants must have recovered to grade 0 or 1 or pre-treatment baseline fromclinically significant toxic effects of prior therapy (including but not limited toexceptions of alopecia, laboratory values listed per inclusion criteria, andlymphopenia which is common after therapy with temozolomide).

• An interval of at least 4 weeks (to registration) between prior surgical resectionor one week for stereotactic biopsy.

• From registration the following time periods must have elapsed (some previoustherapies are exclusionary; see items 26-29 under Exclusion Criteria):

• 4 weeks or 5 half-lives (whichever is shorter) from any investigational agent;

• 4 weeks from cytotoxic therapy (except 23 days for temozolomide; 6 weeks fromnitrosoureas);

• 4 weeks or 5 half-lives (whichever is shorter) from antibodies;

• 4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies.

• No washout required for tumor treating fields.

Clinical labs - Participants should have adequate organ function, in accordance to the studies outlined below. All screening laboratory tests should be performed within 10 days prior to the first dose of the study intervention.

• Hematology:

• Leukocytes ≥ 3,000/µL

• Absolute neutrophil count (ANC) ≥ 1,500/µL

• Platelet count ≥ 100,000/µL

• Absolute Lymphocyte Count ≥ 500/µL

• Hemoglobin ≥ 9.0 g/dL

• Biochemistry:

• AST (SGOT) and ALT (SGPT) ≤ 2.5 x institution's ULN (or ≤ 5 X institutional ULNfor subjects with Gilberts syndrome)

• Serum bilirubin ≤ 1.5 x institution's ULN or direct bilirubin ≤ institutionalULN for subjects with total bilirubin levels > 1.5 institutional ULN.

• Serum creatinine ≤ 1.5 x institution's ULN or calculated 24-hour creatinineclearance > 50 mL/min

• Serum albumin ≥ 2.5 g/dL

• Coagulation studies:

• INR ≤ 1.5 X institutional ULN

• PTT ≤ institution's ULN, unless receiving therapeutic low molecular weightheparin or oral factor Xa inhibitors.

Other illnesses

• History of known additional malignancy that is progressing or requires activetreatment. Those patients whose natural history or treatment does not have thepotential to interfere with the safety or efficacy assessment of the investigationalregimen will be eligible including, but not limited to, basal cell carcinoma of theskin, squamous cell carcinoma of the skin, localized prostate cancer not requiringtreatment, or in situ cervical cancer that has undergone potentially curativetherapy.

Pregnancy and Reproduction

• Olaparib has been shows to be teratogenic in rats. The effects of pembrolizumab onthe developing human fetus are unknown. For this reason:

• Female Participants:

• A female patient is eligible to participate if she is not pregnant, notbreastfeeding, and at least 1 of the following conditions applies:

• Not a woman of childbearing potential (WOCBP) as defined in AppendixL OR

• A WOCBP who agrees to follow the contraceptive guidance in Appendix Lduring the treatment period and for at least 120 days after the lastdose of study intervention, corresponding to time needed to eliminateany study intervention(s) (ie, olaparib) plus 30 days (a menstruationcycle) for study interventions with risk of genotoxicity.

• Women of child-bearing potential (WOCBP) must have a negative serum orurine β human chorionic gonadotropin (β-hCG) pregnancy test within 7 daysprior to first dose of olaparib and/or pembrolizumab. (NOTE: Pregnancytest will be repeated within 72 hours prior to Day 1 drug if originalscreening pregnancy test is not within 72 hours of Day 1 drug.)

• Male Participants: A male patient must agree to use contraception as detailedin Appendix L of this protocol during the treatment period and for at least 180days, corresponding to time needed to eliminate any study intervention(s) (ie,olaparib) plus a spermatogenesis cycle, after the last dose of studyintervention and refrain from donating sperm during this period.

Exclusion Criteria:

Pathology

• Prior evidence of 1p/19q co-deletion.

• IDH mutation by immunohistochemistry or by sequencing.

• Tumor primarily localized to the brainstem or spinal cord.

• Presence of diffuse leptomeningeal disease or extracranial disease.

Previous therapies

• Participants who have received prior treatment with a PARP inhibitor (e.g. olaparib,niraparib).

• Participants who have received anti-VEGF targeted agents (e.g. bevacizumab,cediranib, aflibercept, vandetanib, cabozantinib, sunitinib etc.).

• Participants who have received prior therapy with an anti-PD-1, anti-PD-L1,anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)antibody (including ipilimumab or any other antibody or drug specifically targetingT-cell co-stimulation or checkpoint pathways).

• Participants who have received prior viral therapy or vaccines for glioblastoma.

• Participant received colony-stimulating factors (e.g., granulocytecolony-stimulating factor [G-CSF0], granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose ofstudy intervention.

Concomitant medications

• Participants requiring treatment with high dose systemic corticosteroids defined asdexamethasone > 2 mg/day or bioequivalent for at least 3 consecutive days within 2weeks of start of study drug.

• Participants who have received systemic immunosuppressive treatments, aside fromsystemic corticosteroids (such as methotrexate, chloroquine, azathioprine, etc.)within six months of start of study drug.

• Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital,phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine,rufinamide, and felbamate. Participants must be off any EIAEDs for at least 14 daysprior to starting study drug. A list of EIAEDs and other inducers of CYP3A4 can befound in Appendix D. Among non-EIAED, caution is recommended with use of valproicacid due to potential for drug interaction.

• Participants taking a drug known to be a strong inhibitor or inducer of isoenzymeCYP3A (Appendix D). Participant must be off CYP3A inhibitors and inducers for atleast 7 days prior to starting study drug. NOTE: participants must avoid consumptionof Seville oranges (and juice), grapefruits or grapefruit juice, grapefruit hybrids,pummelos and exotic citrus fruits from 7 days prior to the first dose of study drugand during the entire study treatment period due to potential CYP3A4 interaction.

• Participants receiving any other investigational agents.

• Current use of herbal preparations/medications, including but not limited to:Cannabinoids, St. John's wort (tablet or tea), Kava, ephedra (ma huang), gingkobiloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, ginseng. Participantsshould stop using these herbal medications 7 days prior to first dose of study drug.

• Current use of warfarin sodium or any other coumadin-derivative anticoagulant.Participants must be off Coumadin-derivative anticoagulants for at least 7 daysprior to starting study drug. Low molecular weight heparin and Factor Xa inhibitorsare allowed.

Other illnesses

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to olaparib, temozolomide and/or pembrolizumab.

• History of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or withfeatures suggestive of MDS/AML.

• History of intratumoral or peritumoral hemorrhage if deemed significant by thetreating investigator. If there are questions, the treating investigator shouldcontact the study Principal Investigator, Patrick Y Wen, MD, at 617-632-2166.

• 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.

• Participant has an active infection requiring systemic therapy and/or known viralinfection (for example, human immunodeficiency virus antibodies, hepatitis B surfaceantigen or hepatitis C antibodies).

• Participant with a known history of active TB (Bacillus Tuberculosis).

• Participant with a diagnosis of immunodeficiency, including a known history of HumanImmunodeficiency Virus (HIV).

• Participant with active autoimmune disease that has required systemic treatment inthe past 2 years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

• Participants who have received a live vaccine within 30 days prior to start of studytreatment. Examples of live vaccines include, but are not limited to, the following:measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoidvaccine.

Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

• Participants with diarrhea ≥ CTCAE grade 2

• Participant has active cardiac disease including any of the following:

• Angina pectoris that requires the use of anti-anginal medications.

• Ventricular arrhythmias except for benign premature ventricular contractions.

• Supraventricular and nodal arrythmias requiring a pacemaker or not controlledwith medication.

• Conduction abnormality requiring a pacemaker.

• Valvular disease with document compromise in cardiac function.

• Symptomatic pericarditis.

• Unstable ischemia

• QTc prolongation >500 ms (calculated via the Fridericia formula)

• Electrolyte disturbances

• Participant has a history of cardiac dysfunction including any of the following:

• Myocardial infarction within the last 6 months prior to start of study drug,documents by persistent elevated cardiac enzymes or persistent regional wallabnormalities on assessment of LVEF function.

• History of documented congestive heart failure (New York Heart Associationfunctional classification III-IV, see Appendix K).

• Documented cardiomyopathy.

• Congenital long QT syndrome.

• Impairment of gastrointestinal (GI) function or GI disease that may significantlyalter the absorption of olaparib and temozolomide (e.g., ulcerative diseases,uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive smallbowel resection). Participants with unresolved diarrhea ≥ CTCAE grade 2 will beexcluded as previously indicated.

• Participants who have undergone major systemic surgery < 4 weeks prior to startingstudy drug or who have not recovered from side effects of such therapy.

• Participants who are pregnant or breastfeeding.

• Participants with history of known coagulopathy that increases risk of bleeding or ahistory of clinically significant hemorrhage within 12 months of start of study drugor gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3within 6 months of start of study drug.

• Has known history of, or any evidence of, active non-infectious pneumonitis.