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

Study Overview
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Brief Summary
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This is an open-label, multi-center Phase 0 study with an expansion phase that will enroll up to 24 participants with newly-diagnosed glioblastoma and up to 18 recurrent glioma participants with IDH mutation and ATRX loss. The trial will be composed of a Phase 0 component (subdivided into Arm A and B) and a therapeutic expansion phase. Patients with tumors demonstrating a positive PK Response (in Arm A) or a positive PD Response (in Arm B) of the Phase 0 component of the study will graduate to a therapeutic expansion phase that combines therapeutic dosing of niraparib plus standard-of-care fractionated radiotherapy (in Arm A) or niraparib monotherapy (in Arm B) until progression of disease.

Official Title
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A Phase 0 'Trigger' Trial of Niraparib in Newly-diagnosed Glioblastoma and Recurrent IDH1/2(+) ATRX Mutant Glioma

Conditions
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Glioblastoma, Glioblastoma Multiforme, Glioma, GBM, Glioma, Malignant, Glioblastoma Multiforme of Brain

Intervention / Treatment
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* Drug: Niraparib
* Radiation: Radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Arm A participants undergoing resection for a suspected newly diagnosed glioblastoma. For Arm B, participants undergoing resection who have had a prior resection of histologically diagnosed WHO grade II-IV glioma with IDH1 or IDH2 mutation and ATRX loss. 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. Ability to understand and the willingness to sign a written informed consent document (personally or by the legally authorized representative, if applicable). 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 screening procedures. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other procedures. Age ≥18 at time of consent Have a performance status (PS) of ≤2 on the Eastern Cooperative Oncology (Group (ECOG) scale (Oken et al. 1982) Ability to swallow oral medications. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or participant who is no longer of childbearing potential due to surgical, chemical, or natural menopause. If the serum pregnancy test is completed > 7 days from Day 1, a urine pregnancy test will be done to confirm a negative result prior to Day 1 dose administration. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to treatment and agreement to use such a method during study participation and for an additional 6 months after the end of treatment administration. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner and for an additional 3 months after the end of treatment administration. Avoid sperm donation for duration of the study and for an additional 6 months after the end of treatment administration. Agreement to adhere to Lifestyle Considerations throughout study duration. Participants who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to Day 1. A washout period of at least 21 days is required between last chemotherapy and Day 1. Females of child-bearing potential must agree not to breastfeed starting at screening, throughout the study period and for 6 months after final study drug administration. Participant has normal blood pressure or adequately treated and controlled hypertension (Defined as systolic BP ≤140 mmHg and diastolic BP ≤90 mmHg). Participant has adequate bone marrow and organ function as defined by the following laboratory 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 to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion. Adequate Hepatic Function: Total Bilirubin ≤1.5 X ULN. Participants with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are 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 Chronic Disease Epidemiology Collaboration (CKD-EPI) equation INR ≤1.5 x ULN Exclusion Criteria: Current use of coumarin-derived anticoagulant for treatment, prophylaxis or otherwise, that cannot be discontinued prior to surgery. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed. Pregnancy or lactation. Known allergic reactions to components of the niraparib tablet, including FD&C Yellow No. 5.. Active infection or fever >38.5°C requiring systemic antibiotic, antifungal or antiviral therapy within 4 weeks of Day 1. Known to have active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis as determined by the investigator. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment), fungal infection, or detectable viral infection (such as known human immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]. Screening is not required for enrollment. 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 months prior 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 months prior to Day 1 Participant has myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of MDS/AML. Participant has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea). Prior therapy with PARP inhibitors at a therapeutic dose. Treatment with another investigational drug or other intervention within 30 days prior to enrollment or within 5 half-lives of the investigational product, whichever is longer.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Presumed Newly-Diagnosed glioblastoma<br>Participants undergoing resection for a presumed newly-diagnosed glioblastoma (WHO grade 4) will be treated with niraparib for 4 days prior to surgical resection. Participants who proceed to the therapeutic expansion phase of this study will receive niraparib in combination with radiation (60 Gy over 6-7 weeks, as per standard of care). Following radiotherapy, eligible study participants may receive niraparib maintenance treatment. | Drug: Niraparib<br>* In Phase 0, 300mg administered orally QD for 4 days prior to resection. In the Expansion cohort/Maintenance phase, niraparib will be administered as described below: For patients weighing <77 kg (<170 lbs) OR with a platelet count <150,000/mcL, the recommended dosage is 200 mg taken orally once daily. For patients weighing ≥77 kg (≥170 lbs) AND a platelet count ≥150,000/ mcL, the recommended dosage is 300 mg taken orally once daily.<br>* Other names: Zejula;Radiation: Radiation therapy<br>* Participants in Arm A who move onto the Expansion cohort will receive 6-7 weeks of radiation therapy per standard of care.<br>|
| Experimental: Arm B: Recurrent Glioma (Grades II-IV)<br>Participants undergoing resection of a recurrent WHO Grade II, III, or IV glioma with IDH1 or IDH2 mutation and ATRX loss will be treated with niraparib for 4 days prior to a planned surgical resection. Participants who proceed to the Expansion cohort will receive niraparib in 28d cycles after surgery. | Drug: Niraparib<br>* In Phase 0, 300mg administered orally QD for 4 days prior to resection. In the Expansion cohort/Maintenance phase, niraparib will be administered as described below: For patients weighing <77 kg (<170 lbs) OR with a platelet count <150,000/mcL, the recommended dosage is 200 mg taken orally once daily. For patients weighing ≥77 kg (≥170 lbs) AND a platelet count ≥150,000/ mcL, the recommended dosage is 300 mg taken orally once daily.<br>* Other names: Zejula;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 0 Arm A: Total and unbound niraparib concentration in enhancing and nonenhancing tissue | Tumor to plasma partition coefficients of niraparib for total (Kp) and unbound (Kp,uu) drug levels | Day 4 Intra-operative sample | 
| Phase 0 Arm B: Presence of Chromosomal fusion | Presence of chromosomal fusion with the cutoff CT value of 35 in niraparib treated glioma tissue with IDH and ATRX loss. | Day 4 Intra-operative sample | 
| Phase 0 Expansion Arm A: Progression-free survival in participants with demonstrated PK effects | 6 month progression-free survival (PFS6) rate measured from the time of surgery to date of recurrence. | 6 months | 
| Phase 0 Expansion Arm B: Progression-free survival in participants with demonstrated PD effects | 6 month progression-free survival (PFS6) rate measured from the time of surgery to date of recurrence. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Drug-related toxicity | Incidence of drug-related toxicity | 24 months | 
| Adverse events | Number of adverse events through study completion, assessed up to 24 months. | 24 months | 
| Deaths | Number and incidence of deaths | 24 months | 
| Incidence of clinical laboratory abnormalities per CTCAE | Clinical laboratory abnormalities per CTCAE | Up to 30 days after the last study dose | 
| Overall survival | Median overall survival | 48 months | 
| Phase 0 Arm A: Pharmacodynamics (PD) of niraparib | Quantification of percentage of PAR positive cells with IHC assay or PAR concentration in tumor homogenates with an HT PARP pharmacodynamic assay II. | Day 4 Intra-operative Tissue | 
| Phase 0 Arm B: Pharmacokinetics (PK) of niraparib | Total and unbound niraparib concentration in Gd-enhancing and non-enhancing tumor tissue | Day 4 Intra-operative Tissue |