Pembrolizumab, Olaparib, and Temozolomide for People With Glioma

Inclusion Criteria

• •Safety Lead-In and Cohort A specific inclusion:
• •1. 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.
• •2. Measurable disease by RANO criteria
• •3. Stable dose of corticosteroids for ≥ 4 weeks prior to baseline MRI. Steroid dose not to exceed 2mg/day dexamethasone (or equivalent).
• •Cohort B specific inclusion:
• •1. Histologically confirmed IDH-wildtype glioma that has recurred following therapy (consisting of at least maximum feasible surgical resection and radiation therapy).
• •2. Standard of care next generation sequencing via a CLIA certified platform must be available or planned and at a minimum include IDH status.
• •3. 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)
• •4. Measurable disease by RANO criteria
• •5. Stable dose of corticosteroids for ≥ 4 weeks prior to baseline MRI. Steroid dose not to exceed 2mg/day dexamethasone (or equivalent).
• •All Cohorts:
• •1. Patients or their Legally Authorized Representative (LAR) must provide written informed consent prior to any screening procedures
• •2. Age 18 or older
• •3. ECOG 0 or 1 (KPS ≥ 70) (A lower KPS may be acceptable with prior approval from PI)
• •4. Willing and able to comply with scheduled visits, treatment plan, and laboratory tests
• •5. Patient must be able to swallow and retain oral medication
• •6. Patient must have adequate organ function as defined in the following table. Stable dose of corticosteroids for ≥ 5 days prior to baseline MRI.
• •7. Before starting study treatment, patients must have recovered to grade 1 from prior therapy (except for residual alopecia or grade 2 peripheral neuropathy).
• •8. 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).
• •9. Patients must be able to undergo contrast-enhanced MRI scans.
• •10. Patients must have shown unequivocal evidence for tumor progression by MRI in comparison to a prior scan
• •11. At least 12 weeks elapsed since prior radiotherapy
• •12. Life expectancy greater than 12 weeks
• •13. 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.
• •14. Male participants must agree to use a contraception as detailed in Appendix 3 of this protocol 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.
• •15. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• •i. Not a WOCBP or ii. 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.
• •16. Women must agree not to breast feed while on therapy and for at least 120 days following the last dose of study drug.
• •* Hematological Absolute neutrophil count (ANC) ≥1500/μL Platelets ≥100 000/μL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L
• •* Renal Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels \<1.5 × institutional ULN
• •* Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
• •* Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants