Pembrolizumab, Olaparib, and Temozolomide for the Treatment of Recurrent Glioma

Inclusion Criteria

• SAFETY LEAD-IN AND COHORT A: Histologically confirmed grade II or III IDH-mutated glioma (absence of known CDKN2A/B deletion) that has recurred after first line therapy (consisting of at least maximum feasible surgical resection). There is no limit on the number of prior therapies or types of therapies patients can have received
• SAFETY LEAD-IN AND COHORT A: Measurable disease by Response Assessment in Neuro-Oncology Criteria (RANO) criteria
• SAFETY LEAD-IN AND COHORT A: Stable dose of corticosteroids for >= 4 weeks prior to baseline magnetic resonance imaging (MRI). Steroid dose not to exceed 2 mg/day dexamethasone (or equivalent)
• COHORT B: Histologically confirmed IDH-wildtype glioma that has recurred following therapy (consisting of at least maximum feasible surgical resection and radiation therapy)
• COHORT B: Standard of care next generation sequencing via a Clinical Laboratory Improvement Act (CLIA) certified platform must be available or planned and at a minimum include IDH status
• COHORT B: Patient with known or suspected deleterious mutations in at least 1 of the specified 15 genes involved in homologous recombination repair (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L)
• COHORT B: Measurable disease by RANO criteria
• COHORT B: Stable dose of corticosteroids for >= 4 weeks prior to baseline MRI. Steroid dose not to exceed 2 mg/day dexamethasone (or equivalent)
• Patients or their legally authorized representative (LAR) must provide written informed consent prior to any screening procedures
• Age 18 or older
• Eastern Cooperative Oncology Group (ECOG) 0 or 1 (Karnofsky performance status [KPS] >= 70)
• Willing and able to comply with scheduled visits, treatment plan, and laboratory tests
• Patient must be able to swallow and retain oral medication
• Patient must have adequate organ function as defined in the following table. Stable dose of corticosteroids for >= 5 days prior to baseline MRI
• Before starting study treatment, patients must have recovered to grade 1 from prior therapy (except for residual alopecia or grade 2 peripheral neuropathy)
• At least 5 half-lives must have elapsed since any prior signaling pathway modulators (e.g., EGFR, FGFR, or other tyrosine kinase inhibitors), at least 3 weeks must have elapsed since temozolomide, 4 weeks must have elapsed since carboplatin or cisplatin, and at least 6 weeks must have elapsed from nitrosoureas (e.g., BCNU, CCNU). At least 5 half-lives much have elapsed since prior IDH-inhibitor use. In general, at least 4 weeks must have elapsed from any other anticancer drug therapy (e.g. bevacizumab)
• Patients must be able to undergo contrast-enhanced MRI scans
• Patients must have shown unequivocal evidence for tumor progression by MRI in comparison to a prior scan
• At least 12 weeks elapsed since prior radiotherapy
• Life expectancy greater than 12 weeks
• A woman of childbearing potential (WOCBP) must not have a positive urine pregnancy test within 72 hours prior to allocation. Women of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 12 months after the last dose of the study therapy
• Male participants must agree to use a contraception during the treatment period and for at least 120 days following the last dose of study treatment and refrain from donation sperm during this period
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a WOCBP OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period for at least 120 days after the last dose of study treatment ** Note: Cases of pregnancy that occur during maternal exposures to treatment should be reported. If a patient is determined to be pregnant following treatment initiation, treatment must be discontinued immediately
• Women must agree not to breast feed while on therapy and for at least 120 days following the last dose of study drug
• Absolute neutrophil count (ANC) >= 1500/uL
• Platelets >= 100 000/uL
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Measured or calculated creatinine clearance >= 36 mL/min/1.73 m^2 for participant with creatinine levels < 1.5 x institutional upper limit of normal (ULN) (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) * Creatinine clearance (CrCl) should be calculated per Cockcroft-Gault equation
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases)
• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

Exclusion Criteria

• No limit on number of prior therapies
• Evidence of significant intracranial hemorrhage
• No other investigational or standard anti-tumor therapy allowed
• Patients must not have a known history of allergic reaction attributed to study drugs or compounds of similar chemical or biologic composition unless allergic reaction was managed by pre-medication
• Patients must not have a serious pre-existing medical condition or uncontrolled intercurrent illness that would preclude participation in this study (for example, uncontrolled ventricular arrhythmia, interstitial lung disease, severe dyspnea at rest of requiring oxygen therapy, history of major surgical resection involving the stomach or bowel, or pre-existing Crohn’s disease or ulcerative colitis or other autoimmune disease,) or psychiatric illness/social situations that would limit compliance with study requirements
• Patients must not have a diagnosis of immunodeficiency or be receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Patients must not have an active systemic fungal and/or known viral infection (for example human immunodeficiency virus antibodies, hepatitis B surface antigen, or hepatitis C antibodies)
• Patients must not have a history of active tuberculosis
• Patients must not have an active infection requiring systemic therapy
• Patients must not have known history of, or any evidence of active, non-infectious pneumonitis
• Concomitant use of known strong CYP3A inhibitors (itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir)
• Concomitant use of known strong CYP3A inducers (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, and St. John’s Wort)
• A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 72 hours prior to allocation
• Patients must not have other active concurrent malignancy. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
• Patients must not have active autoimmune disease that required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Patients must not have received a live vaccine within 30 days of planned start of study (Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccine and are not allowed)
• Concurrent treatment on another clinical trial. Supportive care trials or nontherapeutic trials (i.e., quality of life) are allowed