Talazoparib - Carboplatin for Recurrent High-grade Glioma With DDRd

Inclusion Criteria:

1. Histopathologically proven diagnosis of WHO grade 3-4 glioma

2. Tumor with one or more putatively pathogenic mutations or homozygous deletion in thegenes associated with DDR or genomic instability, as listed below, will be eligiblefor the study. Genetic analysis on tumor tissue should be performed withnext-generation-sequencing (NGS) based analysis to screen for the following genomicaberrations, which included,

3. IDH mutation

4. PTEN mutation

5. "BRCAness" signature (ATM, ATR, BAP1, BRCA1, BRCA2, CDK12, CHEK1, CHEK2, FANCA,FANCC, FANCD2, FANCE, FANCF, PALB2, NGS1, WRN, RAD50, RAD51B, RAD51C, RAD51D,MRE11A, BLM, BRIP1) The molecular profiling results will be considered eligiblefor screening only if they are performed in laboratories accredited by theCollege of American Pathologists (CAP) and certified to meet ClinicalLaboratory Improvement Amendments (CLIA).

6. Patients will be eligible if the original histology was lower-grade glioma and asubsequent diagnosis of glioblastoma or gliosarcoma is made.

7. Patients who did not have recent surgery for their glioblastoma must have shownunequivocal radiographic evidence for tumor progression by contrast-enhanced MRIscan (or CT scan for patients with non-compatible devices) within 21 days prior toregistration. Patients who did have surgery with a post-operative contrast-enhancedscan falling outside the 5-week window prior to registration, must have a repeat MRIscan (or CT scan for patients with non-compatible devices) within 21 days prior toregistration.

8. Patients must have passed an interval of 6 months or greater between completion ofprior radiotherapy and registration. If patients have not passed an interval of atleast 6 months, they may still be eligible if they meet one or more of the followingcriteria:

9. New areas of tumor outside the original radiotherapy fields as determined bythe investigator, or

10. Histologic confirmation of tumor through biopsy or resection, or

11. Nuclear medicine imaging, MR spectroscopy, or MR perfusion imaging consistentwith true progressive disease, rather than radiation necrosis obtained within 28 days of registration AND an interval of at least 90 days between completionof radiotherapy and registration.

12. Patients unable to undergo MR imaging because of non-compatible devices can beenrolled provided CT scans are obtained and are of sufficient quality. Patientswithout non-compatible devices may not use CT scans performed to meet thisrequirement.

13. Prior history of standard dose CNS radiation of 50-60Gy in 25-30 fractions, or 40Gyin 15 Fractions.

14. Patients must have recovered from the toxic effects of prior therapy, and there mustbe a minimum time of 28 days prior to registration from the administration of anyinvestigational agent or prior cytotoxic therapy with the following exceptions:

15. 14 days from administration of vincristine

16. 42 days from administration of nitrosoureas

17. 21 days from administration of procarbazine

18. Patients having undergone recent resection of their high-grade glioma (within 5weeks prior to registration) must have recovered from the effects of surgery. ForCNS related core or needle biopsies, a minimum of 7 days must have elapsed prior toregistration.

19. Residual disease following resection of recurrent glioblastoma is not mandated foreligibility into the study. To best assess the extent of residual diseasepost-operatively, a post- operative or intra-operative MRI scan (or CT scan forpatients with non-compatible devices) must be performed prior to registration.

20. At least 18 years of age.

21. World Health Organisation (WHO) performance status 0-2 with no deterioration overthe previous 2 weeks and a minimum life expectancy of 12 weeks

22. Normal bone marrow and organ function as defined below:

23. Marrow: Hemoglobin ≥10.0 gm/dL, absolute granulocyte count (AGC) ≥1,000/mm3platelets ≥100,000/mm3, absolute lymphocyte count ≥1000/mm3.

24. Hepatic: Serum/plasma total bilirubin ≤1.5 x upper limit of normal (ULN) withthe exception of <2.9 mg/dL for patients with Gilbert's disease, ALT (SGPT) andAST (SGOT) ≤2.5 x ULN.

25. Renal: Serum/plasma creatinine (sCr) ≤1.5 x upper limit of normal, orcreatinine clearance (CrCl) ≥50 mL/min.

26. Serum/plasma albumin > 3.0 gm/dL

27. For female patients of childbearing potential, agreement (by patient and/or partner)to use a highly effective form(s) of contraception that results in a low failurerate (< 1% per year) when used consistently and correctly, and to continue its usefor 5 months after the last dose of study treatments. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-onlyhormonal contraception associated with inhibition of ovulation together with anotheradditional barrier method always containing a spermicide, intrauterine device (IUD),intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomizedpartner (on the understanding that this is the only one partner during the wholestudy duration), and sexual abstinence.

28. Ability to understand and willingness to sign an IRB approved written informedconsent document.

Exclusion Criteria:

1. Prior therapy with PARP inhibitor

2. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease freefor a minimum of 1 year (for example, carcinoma in situ of the breast, oral cavity,or cervix are all permissible).

3. Severe, active co-morbidity, defined as follows:

4. Unstable angina and/or congestive heart failure requiring hospitalizationwithin the last 6 months prior to registration

5. Transmural myocardial infarction within the last 6 months prior to registration

6. History of stroke or transient ischemic attack within 6 months prior toregistration.

7. Significant vascular disease (e.g., aortic aneurysm, history of aorticdissection) or clinically

8. Significant peripheral vascular disease.

9. Acute bacterial or fungal infection requiring intravenous antibiotics at thetime of registration

10. Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illnessrequiring

11. Hospitalization or precluding study therapy at the time of registration

12. Hepatic insufficiency resulting in clinical jaundice and/or coagulationdefects; note, however, that laboratory tests for liver function other thanscreening panel and

13. Coagulation parameters are not required for entry into this protocol.

14. Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition;note, however, that HIV testing is not required for entry into this protocol.The need to exclude patients with AIDS from this protocol is necessary becausethe treatments involved in this protocol may be significantlyimmunosuppressive. Protocol-specific requirements may also excludeimmuno-compromised patients.