Pharmacokinetic and Safety Study of Niraparib With Normal or Moderate Hepatic Impairment Patients

Study Overview
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Brief Summary
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Niraparib (Zejula®)is extensively metabolized and eliminated primarily by hepatic and renal pathways. The purpose of this study is to evaluate pharmacokinetics and safety of niraparib in patients with moderate hepatic impairment, for the purpose of providing recommendations to guide the initial dose and dose titration in this patient population.

Official Title
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An Open-Label, Non-Randomized, Multicenter Study to Determine the Pharmacokinetics and Safety of Niraparib Following a Single Oral Dose in Patients With Advanced Solid Tumors and Either Normal Hepatic Function or Moderate Hepatic Impairment

Conditions
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Ovarian Neoplasms, Neoplasms, Solid Tumor, Hepatic Impairment

Intervention / Treatment
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* Drug: Niraparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis and Criteria for Inclusion: All patients: To be considered eligible to participate in this study, all of the following requirements must be met: Patient, male or female, is at least 18 years of age. Patient has a diagnosis of advanced solid malignancy that has failed standard therapy or for which standard therapy is not likely to provide meaningful benefit, or patient has refused standard therapy. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Patient is able to take oral medications. Female patient, if of childbearing potential, has a negative serum pregnancy test within 72 hours prior to taking study drug and agrees to abstain from activities that could result in pregnancy from enrollment through 120 days after the last dose of study treatment, or be of non-childbearing potential. Non-childbearing potential is defined as (by other than medical reasons): ≥45 years of age and has not had menses for > 1 year. Amenorrheic for < 2 years without a hysterectomy Post hysterectomy, bilateral oophorectomy, or tubal ligation.. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient. Male patient agrees to use an adequate method of contraception starting with the first dose of study treatment through 120 days after the last dose of study treatment.. Patient is able to understand the study procedures and agrees to participate in the study by providing written informed consent. Patients with normal hepatic function (Group 1): Patients screened for the normal hepatic function group must meet the following additional criteria to be eligible for enrollment: Patient has no history of hepatic impairment. Patient has liver function test (LFT) results within normal range: Total bilirubin ≤ ULN Aspartate aminotransferase (AST) ≤ ULN. INR ≤1.5 X ULN unless the patient is receiving anticoagulant therapy and the INR is within therapeutic range of intended use of anticoagulants. Patient has adequate hematologic and renal function as defined below: Absolute neutrophil count ≥1500/µL Platelets ≥100,000/µL Hemoglobin ≥9 g/dL Serum creatinine ≤1.5 × ULN or a calculated creatinine clearance ≥60 mL/min using the Cockcroft-Gault equation. Patients with moderate hepatic impairment (Group 2): Patients screened for the moderate hepatic impairment group must meet the following additional criteria to be eligible for enrollment: Patient has stable, moderate hepatic impairment, defined as: BILI: >1.5 × to 3 × ULN, for at least 2 weeks prior to Day 1 AST: Any value INR less than 1.8 unless the patient is receiving anticoagulant therapy and the INR is within therapeutic range of intended use of anticoagulants. Patient has hematologic and renal function as defined below: Absolute neutrophil count ≥1000/µL Platelets ≥75,000/µL Hemoglobin ≥8 g/dL Serum creatinine ≤1.5 × ULN or a calculated creatinine clearance ≥60 mL/min using the Cockcroft-Gault equation. Patient's hepatic disease is deemed stable by the Investigator Criteria for Exclusion: Patients will not be eligible for study entry if any of the following criteria are met: All patients: Patient has undergone palliative radiotherapy within 1 week of study drug administration, encompassing >20% of the bone marrow. Patient is starting chemotherapy within 3 weeks of study drug administration. Patient has a known hypersensitivity to the components of niraparib or excipients Patients who received colony-stimulating factors within 2 weeks prior to the first dose of study treatment are not eligible. Patient has persistent chemotherapy associated Grade 2 or greater toxicity except for neuropathy, alopecia or fatigue. Patient has symptomatic uncontrolled brain or leptomeningeal metastases. Patient has undergone major surgery within 3 weeks of starting the study or patient has not recovered from any effects of any major surgery. Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder (other than hepatic impairment) or active, uncontrolled infection. Patient has received a transfusion (platelets or red blood cells) within 3 weeks of receiving niraparib. Patient is pregnant, breastfeeding, or expecting to conceive children while receiving study treatment or for 3 months after the last dose of study treatment. Patient has a known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). NOTE: Exclusion Criteria 12-16 apply patients participating in the PK phase of the study. Patient is currently receiving, or unable to refrain from taking from 4 days prior to dosing until the time of the last PK blood draw, any of the following cytochrome (CYP) 1A2 substrates: alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine, and theophylline. Patient is unable to refrain from any intake of grapefruit or grapefruit juice within 4 days of the first administration of niraparib until the final PK sample collection. Patient is currently receiving, or unable to refrain from taking from 4 days prior to dosing until the last PK blood draw, any of the following P-glycoprotein (P-gp) inhibitors: amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan, cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole, ketoconazole, lopinavir and ritonavir, quercetin, quinidine, ranolazine, ticagrelor and verapamil. Patient is taking proton pump inhibitors, antacids, or histamine 2 (H2) blockers within 48 hours prior to niraparib administration, and/or within 6 hours after niraparib administration. Patient has esophagogastrointestinal disease or resection that is likely to interfere with the absorption of niraparib. Patients with moderate hepatic impairment (Group 2): Patients screened for the moderate hepatic impairment group who meet any of the following additional criteria will be excluded from the study: Patient has hepatic encephalopathy, severe portal hypertension and/or porto-systemic shunt. Patient has fluctuating or rapidly deteriorating hepatic function as determined by the investigator within the screening period. Patient has acute liver disease caused by drug toxicity or by an infection. Patient has biliary obstruction or other causes of hepatic impairment not related to parenchymal disorder and/or disease of the liver. Patient has esophageal variceal bleeding within the past 2 months. Patient is receiving anticoagulant therapy with warfarin or related coumarins. Patient has a history of hepatic transplant, systemic lupus erythematosus, or hepatic coma.

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Normal hepatic function (Group 1):<br>To evaluate the pharmocokinetics and safety of niraparib | Drug: Niraparib<br>* Niraparib is a potent, orally active PARP1 and PARP2 inhibitor being developed as a treatment for patients with tumors that harbor defects in the homologous recombination DNA repair pathway or that are driven by PARP-mediated transcription factors.<br>* Other names: Zejula®;|
| Experimental: Moderate hepatic impairment (Group 2):<br>To evaluate the pharmocokinetics and safety of niraparib | Drug: Niraparib<br>* Niraparib is a potent, orally active PARP1 and PARP2 inhibitor being developed as a treatment for patients with tumors that harbor defects in the homologous recombination DNA repair pathway or that are driven by PARP-mediated transcription factors.<br>* Other names: Zejula®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of Niraparib and Its Major Metabolite (M1) During PK Phase | Blood samples were collected at indicated time points to evaluate AUC (last) of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis. | Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1 | 
| Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC 0-infinity) of Niraparib and M1 During PK Phase | Blood samples were collected at indicated time points to evaluate AUC (0-infinity) of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis. | Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1 | 
| Observed Maximum Plasma Concentration (Cmax) of Niraparib and M1 During PK Phase | Blood samples were collected at indicated time points to evaluate Cmax of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis. | Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1 | 
| Time to Maximum Concentration (Tmax) of Niraparib and M1 During PK Phase | Blood samples were collected at indicated time points to evaluate tmax of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis. | Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1 | 
| Terminal Half-life (t½) of Niraparib and M1 During PK Phase | Blood samples were collected at indicated time points to evaluate t1/2 of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis. | Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1 | 
| Apparent Total Body Clearance (CL/F) of Niraparib and M1 During PK Phase | CL/F is calculated as Dose/(AUC 0-inf). Blood samples were collected at indicated time points to evaluate CL/F of niraparib and M1. PK parameters were calculated by standard non-compartmental analysis. Not applicable (NA) indicates that CL/F could not be measured for M1 since the dose of metabolite is unknown and only known dose is that of parent niraparib. | Pre-dose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 120, 168 hours post dose Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAE) Including Non-serious Adverse Events (Non-SAEs), Serious Adverse Events (SAEs) and Discontinuations Due to AEs During PK Phase | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event(s) requiring medical or scientific judgment. Treatment-emergent are any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. | Up to Day 8 | 
| Change From Baseline in Hemoglobin (Hb) During PK Phase | Blood samples were collected from participants for evaluation of Hb. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline and at Day 8 | 
| Change From Baseline in Platelets, Neutrophils, Monocytes, Lymphocytes and Leukocyte During PK Phase | Blood samples were collected to analyze hematology parameters:Leukocyte, Lymphocytes, Monocytes, Neutrophils and Platelets. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline and Day 8 | 
| Change From Baseline in Clinical Chemistry Parameter of Protein and Albumin During PK Phase | Blood samples were collected to analyze clinical chemistry parameters: protein and albumin. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline and Day 8 | 
| Change From Baseline in Clinical Chemistry Parameter of Alkaline Phosphatase, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Lactate Dehydrogenase (LDH) During PK Phase | Blood samples were collected at indicated time-points for analysis of clinical chemistry parameters: alkaline phosphatase, ALT, AST and LDH. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline and Day 8 | 
| Change From Baseline in Clinical Chemistry Parameter of Amylase During PK Phase | Blood samples were collected at indicated time-points for analysis of clinical chemistry parameter: Amylase. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline and Day 8 | 
| Change From Baseline in Clinical Chemistry Parameter of Bilirubin and Creatinine During PK Phase | Blood samples were collected at indicated time-points for analysis of clinical chemistry parameters: Bilirubin and Creatinine. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline and Day 8 | 
| Change From Baseline in Chemistry Parameters: Glucose, Calcium, Chloride, Phosphate, Potassium, Sodium, Magnesium and Blood Urea Nitrogen (BUN) During PK Phase | Blood samples were collected at indicated time-points for analysis of clinical chemistry parameter:Glucose, Calcium, Chloride, Phosphate, Potassium, Sodium, Magnesium and BUN. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline and Day 8 | 
| Change From Baseline in Weight During PK Phase | Weight was measured at indicated time-points. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline, Day 2 and Day 8 | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) During PK Phase | Vital signs including SBP and DBP were measured at indicated time-points. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline, Day 2 and Day 8 | 
| Change From Baseline in Pulse Rate During PK Phase | Vital sign including pulse rate was measured at indicated time-points. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline, Day 2 and Day 8 | 
| Change From Baseline in Body Temperature During PK Phase | Vital sign including body temperature was measured at indicated time-points. Baseline is defined as the most recent measurement prior to the first administration of study drug in PK phase. Change from Baseline was calculated as post dose value minus Baseline value. | Baseline, Day 2 and Day 8 | 
| Number of Participants With TEAE Including Non-SAEs, SAEs and Discontinuations Due to AEs During Extension Phase | An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product, and which does not necessarily have to have a causal relationship with this treatment. SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event(s) requiring medical or scientific judgment. Treatment-emergent are any event that was not present prior to the initiation of study treatment or any event already present that worsens in either intensity or frequency following exposure to study treatment. | Up to 28 months | 
| Change From Baseline in Hb During Extension Phase | Blood samples were collected from participants for evaluation of Hb. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 1 (Days 8, 15, 21), Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 6 Day 1 (each cycle was of 28 days) | 
| Change From Baseline in Platelets, Neutrophils, Monocytes, Lymphocytes and Leukocytes During Extension Phase | Blood samples were collected to analyze hematology parameters: Lymphocytes, Leukocytes, Monocytes, Neutrophils and Platelets. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 1 (Days 8, 15, 21), Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1, and Cycle 6 Day 1 (each cycle was of 28 days) | 
| Change From Baseline in Clinical Chemistry Parameter of Protein and Albumin During Extension Phase | Blood samples were collected to analyze clinical chemistry parameters: protein and albumin. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1 (each cycle was of 28 days) | 
| Change From Baseline in Clinical Chemistry Parameter of Alkaline Phosphatase, ALT, AST and LDH During Extension Phase | Blood samples were collected at indicated time-points for analysis of clinical chemistry parameters: alkaline phosphatase, ALT, AST and LDH. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1 (each cycle was of 28 days) | 
| Change From Baseline in Clinical Chemistry Parameter of Amylase During Extension Phase | Blood samples were collected at indicated time-points for analysis of clinical chemistry parameter: Amylase. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1 (each cycle was of 28 days) | 
| Change From Baseline in Clinical Chemistry Parameter of Bilirubin and Creatinine During Extension Phase | Blood samples were collected at indicated time-points for analysis of clinical chemistry parameter: Bilirubin and Creatinine. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1 (each cycle was of 28 days) | 
| Change From Baseline in Chemistry Parameters: Glucose, Calcium, Chloride, Phosphate, Potassium, Sodium, Magnesium and BUN During Extension Phase | Blood samples were collected at indicated time-points for analysis of clinical chemistry parameter:Glucose, Calcium, Chloride, Phosphate, Potassium, Sodium, Magnesium and BUN. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1 (each cycle was of 28 days) | 
| Change From Baseline in Weight During Extension Phase | Weight was measured at indicated time-points. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1 (each cycle was of 28 days) | 
| Change From Baseline in SBP and DBP During Extension Phase | Vital signs including SBP and DBP were measured at indicated time-points. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1 (each cycle was of 28 days) | 
| Change From Baseline in Pulse Rate During Extension Phase | Vital sign including pulse rate was measured at indicated time-points. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1 (each cycle was of 28 days) | 
| Change From Baseline in Temperature During Extension Phase | Vital sign including temperature was measured at indicated time-points. Baseline is defined as the most recent measurement prior to the first administration of study drug in extension phase. Change from Baseline was calculated as post dose value minus Baseline value. NA indicates standard deviation could not be calculated as a single participant was analyzed. | Baseline and Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1 (each cycle was of 28 days) |