Trial of Niraparib in Participants with Newly-diagnosed Glioblastoma and Recurrent Glioma

Inclusion Criteria:

1. Arm A participants undergoing resection for a suspected newly diagnosedglioblastoma. For Arm B, participants undergoing resection who have had a priorresection of histologically diagnosed WHO grade II-IV glioma with IDH1 or IDH2mutation and ATRX loss.

2. Arm A participants must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm.

3. Ability to understand and the willingness to sign a written informed consentdocument (personally or by the legally authorized representative, if applicable).

4. Participant has voluntarily agreed to participate by giving written informed consent (personally or via legally authorized representative(s), and assent if applicable).Written informed consent for the protocol must be obtained prior to any screeningprocedures. If consent cannot be expressed in writing, it must be formallydocumented and witnessed, ideally via an independent trusted witness.

5. Willingness and ability to comply with scheduled visits, treatment plans, laboratorytests and other procedures.

6. Age ≥18 at time of consent

7. Have a performance status (PS) of ≤2 on the Eastern Cooperative Oncology (Group (ECOG) scale (Oken et al. 1982)

8. Ability to swallow oral medications.

9. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment orparticipant who is no longer of childbearing potential due to surgical, chemical, ornatural menopause. If the serum pregnancy test is completed > 7 days from Day 1, aurine pregnancy test will be done to confirm a negative result prior to Day 1 doseadministration.

10. For females of reproductive potential: use of highly effective contraception for atleast 1 month prior to treatment and agreement to use such a method during studyparticipation and for an additional 6 months after the end of treatmentadministration.

11. For males of reproductive potential: use of condoms or other methods to ensureeffective contraception with partner and for an additional 3 months after the end oftreatment administration. Avoid sperm donation for duration of the study and for anadditional 6 months after the end of treatment administration.

12. Agreement to adhere to Lifestyle Considerations throughout study duration.

13. Participants who received chemotherapy must have recovered (Common TerminologyCriteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapyexcept for residual alopecia or Grade 2 peripheral neuropathy prior to Day 1. Awashout period of at least 21 days is required between last chemotherapy and Day 1.

14. Females of child-bearing potential must agree not to breastfeed starting atscreening, throughout the study period and for 6 months after final study drugadministration.

15. Participant has normal blood pressure or adequately treated and controlledhypertension (Defined as systolic BP ≤140 mmHg and diastolic BP ≤90 mmHg).

16. Participant has adequate bone marrow and organ function as defined by the followinglaboratory values (as assessed by the local laboratory for eligibility):

• Adequate Bone Marrow Function:

• Absolute Neutrophil Count ≥1,500/mcL

• Platelets (at time of surgery) ≥100,000/mcL

• Hemoglobin ≥9.0 g/dL. Participants may receive erythrocyte transfusions toachieve this hemoglobin level at the discretion of the investigator.Initial treatment must not begin earlier than the day after theerythrocyte transfusion.

• Adequate Hepatic Function:

• Total Bilirubin ≤1.5 X ULN. Participants with Gilbert's syndrome with atotal bilirubin ≤2.0 times ULN and direct bilirubin within normal limitsare permitted.

• AST(SGOT) ≤2.5 X institutional ULN

• ALT(SGPT) ≤2.5 X institutional ULN

• Adequate Renal Function:

• Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 by ChronicDisease Epidemiology Collaboration (CKD-EPI) equation

• INR ≤1.5 x ULN

Exclusion Criteria:

1. Current use of coumarin-derived anticoagulant for treatment, prophylaxis orotherwise, that cannot be discontinued prior to surgery. Therapy with heparin, lowmolecular weight heparin (LMWH) or fondaparinux is allowed.

2. Pregnancy or lactation.

3. Known allergic reactions to components of the niraparib tablet, including FD&CYellow No. 5..

4. Active infection or fever >38.5°C requiring systemic antibiotic, antifungal orantiviral therapy within 4 weeks of Day 1.

5. Known to have active (acute or chronic) or uncontrolled severe infection, liverdisease such as cirrhosis, decompensated liver disease, and active and chronichepatitis as determined by the investigator.

6. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics attime of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known activehepatitis B or C [for example, hepatitis B surface antigen positive]. Screening isnot required for enrollment.

7. Any of the following cardiovascular criteria:

• Current evidence of cardiac ischemia

• Current symptomatic pulmonary embolism

• Acute myocardial infarction ≤ 6 months prior to Day 1

• Heart failure of New York Heart Association Classification III or IV ≤ 6 monthsprior to Day 1 (Appendix 13.2)

• Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to Day 1

• Cerebral vascular accident (CVA) or transient ischemic attack (TIA) ≤ 6 monthsprior to Day 1

8. Participant has myelodysplastic syndrome/acute myeloid leukemia or with featuressuggestive of MDS/AML.

9. Participant has serious and/or uncontrolled preexisting medical condition(s) that,in the judgment of the investigator, would preclude participation in this study (forexample, interstitial lung disease, severe dyspnea at rest or requiring oxygentherapy, severe renal impairment], history of major surgical resection involving thestomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or apreexisting chronic condition resulting in baseline Grade 2 or higher diarrhea).

10. Prior therapy with PARP inhibitors at a therapeutic dose.

11. Treatment with another investigational drug or other intervention within 30 daysprior to enrollment or within 5 half-lives of the investigational product, whicheveris longer.