Clinical trial NCT03359850
Conditions: Ovarian Neoplasms Neoplasms Solid Tumor Hepatic Impairment
Sponsor: Tesaro, Inc.
Start date: 2018-02-20; Completion date: 2020-06-24
Enrollment: 17 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:

Arms: arm 1: To evaluate the pharmocokinetics and safety of niraparib arm 2: To evaluate the pharmocokinetics and safety of niraparib
Interventions: intervention 1: Niraparib
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_000.pdf: 
1. 
TITLE PAGE 
 
NIRAPARIB (ZEJULA®) 
3000-01-003 
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  
Sponsor: 
TESARO  
1000 Winter Street 
Suite 3300 
Waltham, MA 02451 
 
Sponsor’s Responsible Representative: 
 
, MD 
Medical Director 
 
Principal Investigator: 
, MD 
USC Norris Comprehensive Cancer Center 
1441 Eastlake Ave, Suite 3440 
Los Angeles, CA 90033 
Phone: 
 
Sponsor Protocol No.: 
3000-01-003 
IND No.: 
100,996 
EudraCT No: 
2013-000685-11 
Study Drug Names: 
niraparib capsules 
Development Phase: 
1 
Date of Original Protocol: 
16 June 2017 
Date of Amendment 1: 
04 October 2017 
Date of Amendment 2: 
Version of Protocol: 
15 January 2018 
3 
The study will be conducted according to the protocol and in compliance with Good Clinical Practice 
(GCP), with the Declaration of Helsinki, and with other applicable regulatory requirements.  
Confidentiality Statement 
All information contained in this document is privileged and confidential to TESARO.  Any 
distribution, copying, or disclosure is strictly prohibited without prior written approval by 
TESARO.  
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INVESTIGATOR’S AGREEMENT 
I have read this study protocol, including all appendices. By signing this protocol, I agree to 
conduct the clinical study, following approval by an Independent Ethics Committee/Institutional 
Review Board, in accordance with the study protocol, the current International Council for 
Harmonisation Guidelines for Good Clinical Practice, and applicable regulatory requirements. I 
will ensure that all personnel involved in the study under my direction will be informed about the 
contents of this study protocol and will receive all necessary instructions for performing the 
study according to the study protocol.  
 
 
 
 
Printed Name of Investigator 
Investigator’s Institution 
 
 
 
 
 
 
Signature of Investigator 
 
Date 
 
 


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2. 
SYNOPSIS 
Name of Sponsor/Company: TESARO 
Name of Investigational Product: niraparib (ZEJULA®) 
Name of Active Ingredient: niraparib 
Title of Study: 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 
Study Center(s): Multi-Center 
Principal Investigator:  
, MD 
Studied Period (years):  
Estimated date first patient enrolled: January 2018 
Estimated date last patient completed: November 2018 
Phase of Development: 1 
 
Objectives:  
Primary: 
• 
To characterize the pharmacokinetics (PK) of niraparib and its major metabolite (M1) when 
administered as a single dose in cancer patients with normal hepatic function compared to patients 
with moderate hepatic impairment. 
Secondary: 
• 
To evaluate the safety of niraparib when administered as a single dose in patients with moderate 
hepatic impairment. 
• 
To obtain additional safety data through the extension phase, in which patients have the option to 
continue receiving niraparib. 
Rationale for Study: 
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. 
Methodology:  
This is a Phase 1, open-label, parallel-group, single-dose study in patients with advanced solid tumors and with 
either normal hepatic function or moderate hepatic impairment. 
Patients with solid tumors will be recruited and enrolled within the following groups: 
• 
Group 1: normal hepatic function (total bilirubin [BILI] and aspartate aminotransferase [AST] ≤ 
upper limit of normal [ULN]) 
• 
Group 2: moderate hepatic impairment (BILI >1.5 × to 3 × ULN) and any degree of AST elevation  
PK Phase 
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All patients will receive a single dose of 300 mg niraparib administered as 3 × 100 mg capsules on Day 1. 
Patients will undergo PK sampling up to 168 hours (7 days) following niraparib administration. 
Pharmacokinetic parameters to be calculated include area under the concentration × time curve calculated to last 
measured concentration (AUC0-t), area under the concentration × time curve calculated to infinity (AUC0-∞), 
maximum concentration (Cmax), time to maximum concentration (tmax), terminal half-life (t½), and apparent total 
clearance (CL/F). Protein binding parameters to be calculated include fraction of unbound drug (Fu) and 
clearance of free drug (CLfu/F). The study will be considered complete when the final PK evaluable patient 
completes all assessments in the PK phase of the study.  
Safety will be assessed through adverse event assessment, physical examination, vital sign measurements, 
clinical laboratory tests, and monitoring of concomitant medications. 
AEs are required to be captured through 30 days after cessation of study treatment; SAEs are required to be 
captured through 90 days after cessation of study treatment (or to a minimum of 30 days post-treatment if the 
patient starts alternative anticancer therapy); and any pregnancies that occur within 180 days post-treatment are 
to be captured. Study drug-related SAEs and adverse events of special interest (AESIs) will be collected via 
telephone every 90 ± 14 days after the last dose of study drug until study closeout, or as otherwise indicated in 
AESI, Section 12.2.7. AESIs must be reported as soon as the investigator becomes aware of them. All AEs and 
SAEs experienced by a patient, regardless of the suspected causality, will be monitored until the AE or SAE has 
resolved, until any abnormal laboratory values have returned to baseline or normalized, until there is a 
satisfactory explanation for the change(s) observed, until the patient is lost to follow-up or withdraws consent, 
or until the patient has died. 
Extension Phase 
On the same day that patients complete the final study assessments for the PK phase, patients may be eligible to 
continue receiving niraparib in the extension phase of the study, if the investigator believes it is in the best 
clinical interest of the patient. Patients will receive their first therapeutic dose of niraparib on Cycle 1/Day 1 of 
the extension phase. Patients will return to the study center during Cycle 1 on Days 8, 15, and 21 to undergo 
safety assessments (including complete blood counts [CBCs]). Thereafter, patients will return on the first day of 
every treatment cycle (28 ±3 days) to receive study drug and for safety assessments (including CBCs). Dose 
modification (dose interruption and/or reduction) may be implemented for any grade toxicity considered 
intolerable by the patient, and must be implemented for any Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 3 or 4 non-hematologic adverse event considered by the Investigator related to study treatment 
or for hematologic toxicity as outlined in the protocol. Patients may continue in the extension phase until 
disease progression (assessed by Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 and clinical 
signs and symptoms), unacceptable toxicity, death or discontinuation from the study treatment for any other 
reason. Patients in the extension phase will be monitored for AEs, SAEs, and AESIs according to the same 
schedule as the PK phase. At end of study (EOS), safety assessments will be completed. No new capsules will 
be dispensed at EOS. 
Number of Patients (planned): 16 patients (PK-evaluable) 
Normal hepatic function (Group 1): 8 patients (PK-evaluable) 
Moderate hepatic impairment (Group 2): 8 patients (PK-evaluable) 
Patients may be replaced until there are 8 PK evaluable patients in each group of the study. 
Diagnosis and Criteria for Inclusion:  
All patients:  


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To be considered eligible to participate in this study, all of the following requirements must be met:  
1. Patient, male or female, is at least 18 years of age. 
2. 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.  
3. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to1. 
4. Patient is able to take oral medications. 
5. 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 180 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 and oophorectomy and a follicle-
stimulating hormone (FSH) value in the postmenopausal range upon pre-study (screening) 
evaluation. 
− 
Post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented hysterectomy or 
oophorectomy must be confirmed with medical records of the actual procedure or confirmed 
by an ultrasound. Tubal ligation must be confirmed with medical records of the actual 
procedure, otherwise the patient must be willing to use  highly effective contraception (see 
Appendix 1) throughout the study, starting with the screening visit through 180 days after the 
last dose of study therapy. Information must be captured appropriately within the site’s source 
documents. 
Note: Abstinence is acceptable if this is the established and preferred contraception for the patient. 
6. Male patient agrees to use an adequate method of contraception and not donate sperm, starting with the 
first dose of study treatment through 90 days after the last dose of study treatment. Note: Abstinence is 
acceptable if this is the established and preferred contraception for the patient. 
7. 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: 
1. Patient has no history of hepatic impairment, including but not limited to chronic Hepatitis C or 
chronic hepatitis B. 
2. 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. 


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3. Patient has adequate hematologic and renal function as defined below (Note: CBC test should be 
obtained without transfusion or receipt of colony stimulating factors within 4 weeks before obtaining 
sample): 
− 
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: 
1. 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. 
2. Patient has hematologic and renal function as defined below (Note: CBC test should be obtained 
without transfusion or receipt of colony stimulating factors within 4 weeks before obtaining sample): 
− 
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. 
3. Patient's hepatic disease is deemed stable by the Investigator (i.e. no clinically significant change in 
hepatic disease status within 30 days prior to Screening). 
Criteria for Exclusion:  
Patients will not be eligible for study entry if any of the following criteria are met:  
All patients: 
1. Patient has undergone palliative radiotherapy within 1 week of study drug administration, 
encompassing >20% of the bone marrow. 
2. Patient is starting chemotherapy within 3 weeks of study drug administration. 
3. Patient has a known hypersensitivity to the components of niraparib or excipients 
4. Patients who received colony-stimulating factors (e.g. granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage colony stimulating factor [GM-CSF], or recombinant erythropoietin) within 2 
weeks prior to the first dose of study treatment are not eligible. 


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5. Patient has persistent chemotherapy associated Grade 2 or greater toxicity except for neuropathy, 
alopecia or fatigue. 
6. Patient has symptomatic uncontrolled brain or leptomeningeal metastases. To be considered 
“controlled,” the patient must have undergone treatment (e.g. radiation or chemotherapy) at least 1 
month prior to study entry. The patient must not have any new or progressive signs or symptoms 
related to the central nervous system [CNS] disease and must be taking ≤ 10 mg of prednisone or 
equivalent per day or no steroids. Patients who have untreated brain metastases and who are not 
symptomatic may enroll if the Investigator feels that treatment of these metastases is not indicated. A 
scan to confirm the absence of brain metastases is not required. Patients with spinal cord compression 
may be considered if they have received definitive treatment for this and evidence of clinically stable 
disease for 28 days. 
7. Patient has undergone major surgery within 3 weeks of starting the study or patient has not recovered 
from any effects of any major surgery. 
8. Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder (other than 
hepatic impairment) or active, uncontrolled infection. Examples include, but are not limited to, 
uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major 
seizure disorder, unstable spinal cord compression, superior vena cava syndrome, uncontrolled 
hypertension, active uncontrolled coagulopathy or any psychiatric disorder that prohibits obtaining 
informed consent. 
9. Patient has received a transfusion (platelets or red blood cells) within 3 weeks of receiving niraparib. 
10. Female patient is pregnant or is expecting to conceive children while receiving study drug or for up to 
180 days after the last dose of study drug. Male patient is expecting to donate sperm or father children 
while receiving study drug or for up to 90 days after the last dose of study drug. 
11. Female patient is breastfeeding or is expecting to breastfeed within 30 days of receiving final dose of 
study drug (women should not breastfeed or store breastmilk for use, during treatment and for 30 days 
after receiving the final dose of study treatment). 
12. Patient has a known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). 
NOTE: Exclusion Criteria 13-17 apply only to the PK phase of the study. 
13. 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. 
14. 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. 
15. 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. 
16. 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. 


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17.  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: 
1. Patient has hepatic encephalopathy, severe portal hypertension and/or porto-systemic shunt. 
2. Patient has fluctuating or rapidly deteriorating hepatic function as determined by the investigator 
within the screening period. 
3. Patient has acute liver disease caused by drug toxicity or by an infection. 
4. Patient has biliary obstruction or other causes of hepatic impairment not related to parenchymal 
disorder and/or disease of the liver. 
5. Patient has esophageal variceal bleeding within the past 2 months. 
6. Patient is receiving anticoagulant therapy with warfarin or related coumarins. 
7. Patient has a history of hepatic transplant, systemic lupus erythematosus, or hepatic coma. 
Investigational Product, Dosage and Mode of Administration:  
PK Phase (all patients) (niraparib 300 mg (3 × 100-mg capsules) orally 
Extension Phase (patients with normal hepatic function) The starting dose of niraparib will be based on the 
patient’s screening actual body weight or current platelet count. Patients with a screening actual body weight of 
≥77 kg and current platelet count of ≥150,000/µL at C1D1 (or at screening if done 72 hours prior to C1D1) will 
take three capsules of 100 mg strength (300 mg/day) at each dose administration. Patients with a screening 
actual body weight of <77 kg and/or current platelet count of <150,000/µL C1D1 (or at screening if done 72 
hours prior to C1D1) will take two capsules of 100 mg strength (200 mg) at each dose administration. 
Additional dose modifications will not be based upon changes in the patient’s actual body weight during study 
participation.   
Extension Phase (patients with moderately impaired hepatic function: niraparib 200 mg (2 × 100-mg capsules) 
orally 
Duration of Treatment:  
PK phase: single dose, one day 
Extension phase: once daily (QD) dosing until treatment discontinuation 
Reference Therapy, Dosage and Mode of Administration:  
None 
Criteria for Evaluation: 
Pharmacokinetics: 
Pharmacokinetic parameters to be assessed include: 
• 
AUC0-t: Area under the plasma concentration-time curve from time 0 to the time of the last 
quantifiable concentration 
• 
AUC0-∞: Area under the plasma concentration-time curve from time 0 extrapolated to infinity 
• 
Cmax: Observed maximum plasma concentration 
• 
tmax: Time to Cmax 


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• 
t½: Terminal half-life 
• 
CL/F: Apparent total body clearance 
Additional plasma samples will be drawn for the assessment of unbound concentrations of niraparib and M1 (if 
appropriate). The following will be calculated for protein binding:  
• 
Fu: Fraction of unbound niraparib 
• 
CLfu/F: Clearance of free niraparib 
Blood Sample Collection: 
Blood (approximately 5 mL per sample) will be collected during the study for PK assessments at the following 
time points relative to niraparib dosing: predose (within 30 minutes prior to dosing) and at 1, 2, 3, 4, 6, 8, 12, 
24, 48, 72, 120, and 168 hours post dose. The following excursions are permitted relative to the protocol-
specified PK sampling times. Deviations outside of these time windows must be documented: 
• 
Predose: ≤ 30 minutes 
• 
1, 2, 3, and 4 hours: ±5 minutes 
• 
6, 8, and 12 hours: ±15 minutes 
• 
24 hours: ±30 minutes 
• 
48 and 72 hours: ±60 minutes 
• 
120 and 168 hours: ± 120 minutes 
The volume of blood collected for PK assessments for each patient during the study will be approximately 65 
mL. Blood sample collection, processing, and shipping details will be outlined in a separate laboratory manual. 
In brief, blood will be collected into potassium ethylene diamine tetraacetic acid (K3EDTA) tubes, processed 
and plasma analyzed by a validated method of liquid chromatography coupled to tandem mass spectrometry 
detection (LC/MS/MS) for determination of the concentrations of niraparib and M1. The pharmacokinetic 
parameters will be calculated from the plasma concentration-time profiles. The non-compartmental analysis will 
be performed using WinNonlin, version 5.1 or higher. 
Blood (approximately 5 mL per sample) will be collected during the study for plasma protein binding 
evaluations at predose (within 30 minutes prior to dosing) and at 3 hours and 168 hours.  
Safety: 
Safety will be assessed based on adverse events (AEs), physical examinations, vital signs, clinical laboratory 
results, and monitoring of concomitant medications. 
Statistical Methods: 
A statistical analysis plan (SAP) will be issued as a separate document, providing detailed methods for the 
safety analyses outlined in this section. Any deviations from the planned analyses will be described and justified 
in the final integrated clinical study report (CSR). 
Study completion status will be summarized for all patients. Categories summarized will include those patients 
who were screened, enrolled, completed the study, or discontinued early (including reason for discontinuation). 
Demographic characteristics of all patients enrolled will be summarized descriptively by group and will include 
age, sex, race, height, and weight. 
Protocol deviations will be listed by patient. 
Pharmacokinetic Analyses: 


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The pharmacokinetic population for the evaluation of the PK of niraparib and M1 in patients with normal 
hepatic function and in patients with hepatic impairment will consist of all patients who receive niraparib and 
have sufficient evaluable samples for the determination of Cmax, AUC0-t, and AUC0-∞.  
Plasma concentrations over time and PK parameters of niraparib will be evaluated after single dose 
administration. Individual and mean plasma concentrations over time will be plotted by hepatic function group. 
Individual patient PK parameter values will be derived by non-compartmental methods using WinNonlin, 
version 5.1 or higher. Nominal or actual time will be used in the data analysis. Plasma concentrations and PK 
parameters will be summarized in terms of the number of patients, arithmetic mean, standard deviation (StDev), 
coefficient of variation, median, minimum and maximum by group. 
To assess the effects of hepatic impairment on niraparib PK, linear models will be applied to the log-
transformed Cmax, and AUC0-t, AUC0- ∞. The independent variable in the analyses will be liver function (normal 
hepatic function [control] or moderate hepatic impairment). Point estimates and 90% CIs for differences 
between means on the log scale will be exponentiated to express the results as ratios of geometric means on the 
original scale. Patients with normal hepatic function (Group 2) will be used as reference group to which Group 
1 will be compared. No adjustments will be made for multiplicity. 
Box plots of PK parameters (Cmax, AUC0-t, AUC0- ∞, CL/F, and CLfu/F) by hepatic function group will be 
provided.  
Similar analyses will be performed on M1 if appropriate. 
The effect of hepatic dysfunction on unbound concentrations of niraparib and M1 may be assessed applying a 
general linear model with a factor for hepatic impairment status. 
Safety Analyses: 
The safety population will consist of all patients who receive drug. 
All data will be summarized by group. Continuous variables will be summarized using descriptive statistics 
(number of patients, mean, StDev, minimum, median, and maximum). Categorical variables will be summarized 
using counts of patients and percentages. 
All AEs will be listed. The number and percent of patients who experienced an AE will be summarized by 
timing/treatment for each system organ class (SOC) and preferred term. AEs will also be tabulated accordingly 
by intensity and causality. Descriptive comparisons of event rates for each group will be presented.  
Serious AEs (SAEs) will be listed separately. 
All AEs will be coded using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). 
The adverse events of special interest (AESIs) for this study are myelodysplastic syndrome (MDS), acute 
myeloid leukemia (AML), pneumonitis, embryo-fetal toxicity, and secondary cancer (new malignancies other 
than MDS/AML). AESIs must be reported to the Sponsor as soon as the Investigator becomes aware of them. 
Individual data listings of laboratory test results will be presented. Flags will be attached to values outside of the 
laboratory's reference limits along with the Investigator's assessment. Clinically significant laboratory test 
abnormalities that were considered AEs by the Investigator will be presented in the AE listing. 
Clinical laboratory tests (observed values and changes from baseline) will be summarized descriptively in 
tabular format. Shift tables will be presented for select laboratory parameters (chemistry and hematology). 


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Individual data listings of vital signs (observed and change from Baseline) will be presented for each patient. 
Individual clinically significant vital sign findings that were considered AEs by the Investigator will be 
presented in the AE listing. 
All physical examination findings, including abnormal findings, will be listed. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
5. 
INTRODUCTION ......................................................................................................21 
5.1. 
Background of Niraparib ............................................................................................21 
5.2. 
Niraparib Metabolism .................................................................................................24 
5.3. 
Rationale for Current Study ........................................................................................25 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................26 
6.1. 
Primary Objective .......................................................................................................26 
6.2. 
Secondary Objectives .................................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.1.1. 
PK Phase .....................................................................................................................27 
7.1.1.1. 
Fasting and Study Drug Administration for the PK Phase .........................................27 
7.1.2. 
Extension Phase ..........................................................................................................27 
7.2. 
Number of Patients .....................................................................................................28 
7.3. 
Treatment Assignment ................................................................................................28 
7.4. 
Schedule of Assessments ............................................................................................29 
7.5. 
Assessments by Visit ..................................................................................................34 
7.5.1. 
Screening Visit (Days -28 to -1) .................................................................................34 
7.5.2. 
PK Phase .....................................................................................................................34 
7.5.2.1. 
Day 1 ...........................................................................................................................35 
7.5.2.2. 
Day 2 ...........................................................................................................................35 
7.5.2.3. 
Day 3 ...........................................................................................................................35 
7.5.2.4. 
Day 4 ...........................................................................................................................35 
7.5.2.5. 
Day 5 ...........................................................................................................................35 


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7.5.2.6. 
Day 6 ...........................................................................................................................35 
7.5.2.7. 
Day 7 ...........................................................................................................................35 
7.5.2.8. 
Day 8 / End of PK Phase ............................................................................................35 
7.5.3. 
Extension Phase ..........................................................................................................36 
7.5.4. 
Cycle 1/ Day 1 ............................................................................................................36 
7.5.4.1. 
Cycle 1/ Day 8 ............................................................................................................36 
7.5.4.2. 
Cycle 1/ Day 15 ..........................................................................................................36 
7.5.4.3. 
Cycle 1/ Day 21 ..........................................................................................................37 
7.5.4.4. 
Cycle n/ Day 1 ............................................................................................................37 
7.5.4.5. 
End of Study ...............................................................................................................37 
7.5.5. 
Safety Follow-up (30 days [+ 7 days] Post-treatment) ...............................................37 
8. 
SELECTION AND DISCONTINUATION OF PATIENTS .....................................39 
8.1. 
Patient Inclusion Criteria ............................................................................................39 
8.2. 
Patient Exclusion Criteria ...........................................................................................41 
8.3. 
Patient Discontinuation Criteria .................................................................................43 
8.3.1. 
Discontinuation from treatment ..................................................................................43 
8.3.2. 
Discontinuation from the Study ..................................................................................43 
8.3.3. 
Replacement of Patients .............................................................................................44 
9. 
TREATMENT OF PATIENTS ..................................................................................45 
9.1. 
Randomization and Blinding ......................................................................................45 
9.2. 
Description of Study Drug ..........................................................................................45 
9.3. 
Administration ............................................................................................................45 
9.4. 
Dose Adjustment Criteria ...........................................................................................46 
9.4.1. 
Niraparib Dose Modifications for Adverse Events ....................................................46 
9.4.2. 
Niraparib Dose Modifications for Nonhematologic Toxicity ....................................47 
9.4.3. 
Niraparib Dose Modifications for Hematologic Toxicity ..........................................48 
9.5. 
Concomitant Medications and Study Restrictions ......................................................51 
9.5.1. 
Prohibited Medications ...............................................................................................51 
9.5.1.1. 
PK Phase .....................................................................................................................51 
9.5.1.2. 
PK and Extension Phases ............................................................................................51 
9.5.2. 
Study Restrictions .......................................................................................................52 
9.5.2.1. 
Restrictions Specific to Patients with Moderate Hepatic Impairment ........................52 


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9.5.2.2. 
Dietary and Fluid Restrictions ....................................................................................52 
9.5.2.3. 
Other Restrictions .......................................................................................................52 
9.6. 
Duration of Therapy ...................................................................................................52 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................53 
10.1. 
Study Drug Packaging, Labeling, and Storage ...........................................................53 
10.2. 
Study Drug Accountability .........................................................................................53 
10.3. 
Study Drug Handling and Disposal ............................................................................53 
11. 
PHARMACOKINETIC ASSESSMENTS .................................................................54 
11.1. 
Pharmacokinetic Parameters .......................................................................................54 
11.2. 
Blood Sample Collection ............................................................................................54 
11.2.1. 
Pharmacokinetic Assessment ......................................................................................54 
11.2.2. 
Plasma Protein Binding ..............................................................................................54 
12. 
ASSESSMENT OF SAFETY .....................................................................................55 
12.1. 
Safety Parameters .......................................................................................................55 
12.1.1. 
Clinical Laboratory Assessments ...............................................................................55 
12.1.2. 
Physical Examination and Vital Signs ........................................................................55 
12.1.3. 
Eastern Cooperative Oncology Group Performance Status ........................................56 
12.2. 
Adverse Events ...........................................................................................................56 
12.2.1. 
Definitions ..................................................................................................................56 
12.2.2. 
Assessment of Adverse Events ...................................................................................58 
12.2.2.1. 
Severity Assessment ...................................................................................................58 
12.2.2.2. 
Expectedness ...............................................................................................................58 
12.2.2.3. 
Causality .....................................................................................................................58 
12.2.3. 
Collecting and Recording Adverse Events .................................................................59 
12.2.4. 
Follow-Up of Adverse Events ....................................................................................59 
12.2.5. 
Reporting of Serious Adverse Events .........................................................................60 
12.2.6. 
Submission and Distribution of Serious Adverse Events ...........................................61 
12.2.7. 
Adverse Events of Special Interest .............................................................................61 
12.2.8. 
Special Situations ........................................................................................................61 
12.2.9. 
Pregnancy Reporting and Follow-up ..........................................................................62 
13. 
STATISTICS ..............................................................................................................63 
13.1. 
Determination of Sample Size ....................................................................................63 


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13.2. 
Study Population .........................................................................................................63 
13.2.1. 
Patient Disposition ......................................................................................................63 
13.2.2. 
Demographic Information and Baseline Characteristics ............................................63 
13.2.3. 
Protocol Deviations ....................................................................................................63 
13.2.4. 
Analysis Populations ..................................................................................................63 
13.3. 
General Considerations ...............................................................................................63 
13.4. 
Pharmacokinetic Analyses ..........................................................................................64 
13.5. 
Safety Analyses ..........................................................................................................64 
13.5.1. 
Adverse Events ...........................................................................................................64 
13.5.2. 
Clinical Laboratory Tests ...........................................................................................65 
13.5.3. 
Vital Signs ..................................................................................................................65 
13.5.4. 
Physical Examination .................................................................................................65 
14.
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ....................................66
14.1. 
Data Quality Assurance ..............................................................................................66 
14.2. 
Access to Source Data/Documents .............................................................................66 
14.3. 
Archiving Study Documents .......................................................................................67 
14.4. 
Good Clinical Practice ................................................................................................67 
14.5. 
Informed Consent .......................................................................................................67 
14.6. 
Protocol Approval and Amendment ...........................................................................67 
14.7. 
Study Monitoring ........................................................................................................68 
14.8. 
Audits and Inspections ................................................................................................68 
14.9. 
Ethical Considerations ................................................................................................68 
14.10. 
Publication Policy .......................................................................................................68 
15.
LIST OF REFERENCES ............................................................................................69
APPENDIX 1. CONTRACEPTION GUIDELINES ..................................................................70 
APPENDIX 2. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .......................................................................................71 


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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 2:  
Progression-Free Survival in Ovarian Cancer Patients in NOVA ..............................22 
Table 3: 
PK Phase Schedule of Assessments ...........................................................................29 
Table 4: 
Extension Phase Schedule of Assessments .................................................................31 
Table 5: 
Pharmacokinetic Sampling .........................................................................................33 
Table 6: 
Study Treatment ..........................................................................................................45 
Table 7: 
Recommended Dose Modifications for Adverse Reactions .......................................47 
Table 8: 
Niraparib Dose Reductions for Nonhematologic Toxicity in Patients with 
Normal or Impaired Hepatic Function. .......................................................................47 
Table 9: 
Management of Hematologic Toxicities in Patients with Normal Hepatic 
Function ......................................................................................................................49 
Table 10:  Management of Hematologic Toxicities in Patients with Impaired Hepatic 
Function ......................................................................................................................50 
 


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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
ADL 
activity of daily living 
ADP 
adenosine diphosphate 
AESI 
adverse event of special interest 
aPTT 
activated partial thromboplastin time 
AME 
absorption, metabolism, and distribution 
AML 
acute myeloid leukemia 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the concentration × time curve 
AUC0-t 
area under the concentration × time curve calculated to 
last measured concentration  
AUC0-∞ 
area under the concentration × time curve calculated to 
infinity 
BILI 
bilirubin 
BRCA 
breast cancer (gene) 
CI 
confidence interval 
Cmax 
maximum concentration 
CBC 
complete blood count 
CLcr
creatinine clearance 
CL/F 
apparent total clearance 
CLFu/F 
clearance of free niraparib 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP1A2 
cytochrome 1A2 
DNA 
deoxyribonucleic acid 
ECG 
Electrocardiogram 


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Abbreviation or Specialist Term 
Explanation 
ECOG 
Easter Cooperative Oncology Group 
eCRF 
electronic case report form 
EDTA 
ethylene diamine tetraacetic acid 
EOS 
end of study 
FDA 
US Food and Drug Administration 
Fu 
fraction of unbound niraparib 
G-CSF 
granulocyte colony-stimulating factor 
gBRCAmut 
germline breast cancer gene mutation 
gBRCAwt 
germline breast cancer wild type gene 
GCP 
Good Clinical Practice 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
H2 
histamine 2 
HRD 
homologous recombination deficiency 
HRDneg 
homologous recombination deficiency (negative) 
HRDpos 
homologous recombination deficiency (positive) 
IB 
Investigator’s Brochure 
IC 
inhibitory concentration 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LC/MS/MS 
liquid chromatography-tandem mass spectrometry 
LFT 
liver function test 
M1 
major metabolite 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDS 
myelodysplastic syndrome 
MRI 
magnetic resonance imaging 
PARP 
poly (ADP-ribose) polymerase 
P-gp 
P-glycoprotein 
PFS 
progression-free survival 
PK 
pharmacokinetics 


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Abbreviation or Specialist Term 
Explanation 
PI 
Principal Investigator 
PO 
oral(ly) 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SOP 
standard operating procedure 
StDev 
standard deviation 
t½  
terminal half-life 
tmax  
time to maximum concentration  
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
Vd/F 
apparent volume of distribution 
WHO 
World Health Organization 
 


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5. 
INTRODUCTION 
5.1. 
Background of Niraparib 
Niraparib (ZEJULA®) is a poly (adenosine diphosphate [ADP]-ribose polymerase) (PARP) 
inhibitor indicated for the maintenance treatment of adult patients with recurrent epithelial 
ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to 
platinum-based chemotherapy. Niraparib received FDA approval in March 2017. For more 
details, refer to ZEJULA® label.1 
In vitro studies have shown that niraparib-induced cytotoxicity may involve inhibition of PARP 
enzymatic activity and increased formation of PARP-deoxyribonucleic acid (DNA) complexes 
resulting in DNA damage, apoptosis and cell death. Increased niraparib-induced cytotoxicity was 
observed in tumor cell lines with or without deficiencies in BRCA1/2. Niraparib decreased tumor 
growth in mouse xenograft models of human cancer cell lines with deficiencies in BRCA1/2 and 
in human patient-derived xenograft tumor models with homologous recombination deficiency 
that had either mutated or wild type BRCA1/2. 
Niraparib co-crystallized with the human PARP-1 catalytic domain and was shown to inhibit 
PARP-1 and PARP-2 activity in vitro with an inhibitory concentration (IC50) of 3.8 and 2.1 nM, 
respectively. In cultured cells, niraparib inhibited PARP-dependent PARylation stimulated by 
DNA damage with an IC50 of 4 nM and an IC90 of 40 nM. 
The crystalline tosylate monohydrate salt of niraparib is being developed as a monotherapy agent 
for tumors with defects in the homologous recombination DNA repair pathway, as a sensitizing 
agent in combination with cytotoxic agents and radiotherapy, and in combination with immune-
oncology biologics.  
Nonclinical data, including cell-derived and patient-derived xenograph studies demonstrating 
response to niraparib in both BRCA mutated (gBRCAmut) and BRCA wild-type (gBRCAwt) 
tumors, are discussed in detail in the Investigator’s Brochure (IB). 
There are 3 ongoing Phase 3 niraparib studies, Study PR-30-5010-C (BRAVO), 
Study PR-30-5017-C (PRIMA), and Study PR-30-5011-C (NOVA). There isA also 1 ongoing 
Phase 1/2 study, Study 3000-PN162-01-001 (TOPACIO) and 1 ongoing Phase 2 study, Study 
PR-30-5020-C (QUADRA).  
The ENGOT-OV16/NOVA study4 is a double-blind, 2:1 (niraparib:placebo) randomized, 
placebo-controlled study of maintenance treatment with niraparib compared with placebo in 
patients with platinum- sensitive ovarian cancer who have received at least 2 platinum-based 
regimens, had a response to their last regimen, and have no measurable disease >2 cm and 
normal cancer antigen 125 (CA-125) (or >90% decrease) following their last treatment. There 
were 2 independent patient cohorts comprising patients who have deleterious gBRCAmut versus 
those who have a tumor with high-grade serous histology but without gBRCAmut (non-
gBRCAmut). Patients in the non- gBRCAmut cohort are further characterized by tumor HRD 
status (positive or negative). 
A total of 553 patients were randomized into this Phase 3 study at 107 centers worldwide. The 
study population comprises 203 patients randomized into the gBRCAmut cohort and 350 patients 
randomized into the non-gBRCAmut cohort. Among the 350 patients in the non-gBRCAmut 


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cohort, 162 had tumors that were defined as HRDpos and 134 had tumors that were HRD 
negative (HRDneg). HRD status was not determined (HRDnd) for 54 patients.  
Demographic and baseline characteristics were well-balanced. 
Table 3 shows the results for the PFS primary endpoint for each of the 3 primary efficacy 
populations (ie, gBRCAmut cohort, HRDpos cohort, and overall non-gBRCAmut cohort). In 
addition, median PFS in patients with HRD negative (HRDneg) tumors was 6.9 months (95% CI: 
5.6, 9.6) in the niraparib arm compared to 3.8 months (95% CI: 3.7, 5.6) in the placebo arm with 
an HR of 0.58 (95% CI: 0.361, 0.922) (p=0.0226).    
Table 2:  
Progression-Free Survival in Ovarian Cancer Patients in NOVA 
  
gBRCAmut Cohort 
non-gBRCAmut Cohort 
(regardless of HRD status) 
HRDpos  
(within non-gBRCAmut cohort) 
Nirapari
b 
(N=138) 
Placebo 
(N=65) 
Niraparib 
(N=234) 
Placebo 
(N=116) 
Niraparib 
(N=106) 
Placebo (N=56) 
PFS Median 
(95% CI)a 
21.0 
(12.9, 
NR) 
5.5 
(3.8, 7.2) 
9.3 
(7.2, 11.2) 
3.9 
(3.7, 5.5) 
12.9 
(8.1, 15.9) 
3.8 
(3.5, 5.7) 
p-value 
<0.0001 
<0.0001 
<0.0001 
Hazard 
Ratio 
(Nir:Plac) 
(95% CI) 
0.27 
(0.173, 0.410) 
0.45 
(0.338, 0.607) 
0.38 
(0.243, 0.586) 
Progression-free survival is defined as the time in months from the date of randomization to progression or 
death. 
The primary data to support the safety of treatment with niraparib in this proposed indication are 
derived from the ENGOT-OV16/NOVA main study in which a total of 546 patients received 
study treatment. Safety presentations for the NOVA study are derived from the analyses included 
in the clinical study report and include comparisons of the safety profile of niraparib 
maintenance treatment versus placebo in women with platinum-sensitive recurrent ovarian 
cancer. 
All patients who received niraparib and 171 (96%) of 179 patients who received placebo 
experienced at least 1 treatment-emergent adverse event (TEAE). The high rate of TEAEs in the 
placebo group indicates the burden of prior chemotherapy and the patient’s underlying ovarian 
cancer. Review of the data across study cohorts for TEAE incidence showed that, in general, the 
results were similar in the gBRCAmut and non-gBRCAmut cohorts. In the overall safety 
population, for the niraparib versus placebo treatment arms, the incidences of Grade 3/4 TEAEs 
(74% vs 23%), serious adverse events (SAEs) (30% vs 15%), TEAEs leading to treatment 
interruption (69% vs 5%), TEAEs leading to dose reduction (67% vs 15%), and TEAEs leading 
to treatment discontinuation (15% vs 2%) were higher for niraparib. There were no on-treatment 
deaths reported. The incidence of myelodysplastic syndrome (MDS)/acute myeloid leukemia 
(AML) in patients who received niraparib (5 of 367; 1.4%) was similar to the incidence in 
patients who received placebo (2 of 179; 1.1%). MDS/AML and secondary cancers (new 
malignancies other than MDS or AML) are potential risks of PARP inhibitors.  


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The selection of the 300 mg starting dose of niraparib for the phase 3 randomized double-blind 
trial of maintenance with niraparib versus placebo in the ENGOT-OV16/NOVA study was based 
on data from the Phase 1 MAD study PN001 conducted by Merck & Co. There were no formal 
Phase 2 dose-ranging studies conducted. The Phase 1 study included both a dose escalation 
phase to determine the maximal tolerated dose and an expansion arm to further evaluate the 
selected dose. A total of 104 patients with advanced solid tumors were evaluated in this study, 
including 60 during dose escalation from 30 mg to 400 mg and 54 during expansion at the 300 
mg dose level. The dose escalation stage determined that 400 mg exceeded the maximal tolerated 
dose (by traditional dose-limiting toxicity evaluations and by using the pooled adjacent violators 
algorithm). No dose-limiting toxicities were observed at 290 or 300 mg dose levels. In the Phase 
3 study, daily niraparib improved progression-free survival (PFS) in a cohort of patients with 
gBRCA mutation as well as in a cohort of patients without gBRCA mutation. Within the 
gBRCAmut cohort, the median PFS was 21.0 months in patients on niraparib versus 5.5 months 
on placebo (hazard ratio [HR], 0.27; p < 0.0001). In recurrent ovarian cancer patients, efficacy 
was assessed in patients with HRD-positive tumors as identified by the Myriad’s myChoice 
HRD test as well in the overall non-gBRCA mutation cohort regardless of HRD status. As 
observed in the gBRCAmut cohort, PFS was significantly longer with niraparib in the 
homologous recombination deficient-positive group of the non-gBRCAmut (without germline 
BRCA mutation) cohort (median, 12.9 months vs 3.8 months; HR, 0.38; p < 0.0001). Lastly, PFS 
was significantly improved in the overall non-gBRCAmut cohort (median, 9.3 months vs 
3.9 months; HR, 0.45; p < 0.0001). Secondary endpoints, including chemotherapy-free interval, 
time to first subsequent therapy (TFST), and progression-free survival 2 (PFS2), confirmed the 
PFS benefit of niraparib treatment in both cohorts. This provides compelling evidence that 
niraparib does not diminish responsiveness to subsequent therapy and that the niraparib treatment 
effect persists. Subsequently in 2017, a recommendation to consider niraparib maintenance 
therapy in this setting in cases of CR and PR was added to the National Comprehensive Cancer 
Network (NCCN) guidelines.5  
The most commonly observed non-hematologic treatment-emergent adverse events (TEAEs) of 
any National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-
CTCAE) grade were nausea, fatigue, constipation, and vomiting; the majority of the non-
hematologic TEAEs were mild to moderate in severity. The most commonly observed 
hematologic TEAEs (any grade) were anemia (48.5%), thrombocytopenia 66.2%), and 
neutropenia (31.4%).  
TEAEs leading to treatment interruption, reduction or discontinuation were 68.9%, 66.5% and 
14.7% respectively. Approximately 50% of patients required dose interruption during the first 
month of niraparib therapy, and 47% required dose reduction during the second month of 
therapy. Most patients achieved their individual maximal tolerated dose by the third month. The 
average dose of niraparib during the study was 206 mg. After Month 3 or 4, new incidents of 
thrombocytopenia were reported in < 1% of patients. Although Grade 3 or 4 hematologic 
laboratory events were common at the initiation of treatment, no severe clinical sequelae were 
observed, and relatively few patients discontinued due to these AEs (discontinuation rate was 
3.3% for thrombocytopenia, 1.4% for anemia and 1.9% for neutropenia). Dose adjustment based 
on individual tolerability during the first 3 cycles substantially reduced the incidence of these 
events beyond Cycle 3. Furthermore, PFS in patients who were dose reduced to either 200 mg or 


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100 mg was consistent with PFS for the patients who remained at 300 mg indicating that patients 
who required dose reduction do not appear to have decreased efficacy relative to those who 
remain at the 300 mg starting dose.  
These data support that each patient has an optimal benefit/risk at their individualized dose. As 
lower doses are associated with substantial improvements in the incidence of TEAEs while not 
appearing to compromise efficacy, approaches to quickly transition patients to their 
individualized optimal dose, particularly patients at the highest risk of grade 3 or 4 
thrombocytopenia in cycle 1were further evaluated. In addition, an exploratory analysis was 
conducted to determine if risk factors could be identified for a subgroup of patients which were 
associated with higher rates of hematologic toxicity.  In the updated analysis, two factors were 
identified as being associated with thrombocytopenia, baseline platelet count and baseline body 
weight. 
For a complete discussion on the activity and safety of niraparib, refer to the Investigator’s 
Brochure. 
5.2. 
Niraparib Metabolism 
In a dose escalation study in cancer patients (PN001), niraparib exhibited linear PK, and dose- 
proportional exposure (AUC and Cmax). Moreover, the consistent tmax and t½ across the range of 
doses evaluated (30-400 mg) suggest overall dose-independent absorption and clearance. 
Following repeat administrations of the daily recommended dose of 300 mg, niraparib 
accumulation on Day 21 was consistent for both AUC and Cmax (~2-3 folds). Niraparib was 
shown to be highly orally bioavailable (F ~73%) (PR-30-3015-C). A high-fat meal exhibited a 
negligible effect on the extent and rate of absorption niraparib (PR-30-5011-C2-FE); therefore, 
niraparib can be administered with or without food.  
Niraparib was moderately protein bound to human plasma (83.0%) (PK002). The apparent 
volume of distribution (Vd/F) was 1220 L (PR-30-5015-C), indicating an extensive tissue 
distribution of niraparib. In the population pharmacokinetic analysis of niraparib, the Vd/F was 
1074 L in cancer patients. In nonclinical species (PK001), niraparib exhibited a high volume of 
distribution, i.e. Vd/F ~ 6.9 and 12.3 L/kg in rats and dogs, respectively. It is readily distributed 
to the brain and cerebrospinal fluid (CSF) of rats and monkeys, respectively (KB-0039-DA-RI 
and PK004). 
A multiple enzyme-mediated metabolism was established in vitro (PK002) and in vivo 
(absorption, metabolism, and excretion [AME] study PR-30- 5015-C). The carboxylesterases-
catalyzed amide hydrolysis was delineated to be the major primary pathway, followed by the 
UDP-glucuronosyltransferases (UGTs)-mediated glucuronidation and the other minor secondary 
pathway (i.e. methylation). The major circulating metabolites in humans are the carboxylic acid 
(M1) and the glucuronides of M1. The metabolic profile seen in humans is consistent with what 
was detected in the experimental species (rats and dogs) (PK003).  
In the AME study in cancer patients using 14C-radioactive niraparib (N = 6, PR-30-5015-C), a 
mean measured total of 86.2% (ranged from 71.1% to 91.0%) of the radioactive dose was 
recovered in urine and fecal samples collected daily from 0 to 504 hours (21 days) postdose after 
single oral administration of 14C-niraparib. Total radioactivity recovered in the urine accounted 
for 47.5% (ranged from 33.4% to 60.2%) and in the feces for 38.8% (ranged from 28.3% to 


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47.0%) of the dose. Therefore, the overall recovery in the excreta following the continuous 
collection up to 21 days was virtually complete, suggestive of minimal long-term retention of 
niraparib or its metabolites. Moreover, hepatobiliary clearance and renal excretion are the major 
routes of elimination in humans. 
5.3. 
Rationale for Current Study 
Niraparib 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. 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
• To characterize the pharmacokinetics (PK) of niraparib and its major metabolite (M1) 
when administered as a single dose in cancer patients with normal hepatic function 
compared to patients with moderate hepatic impairment. 
6.2. 
Secondary Objectives 
• To evaluate the safety of niraparib when administered as a single dose in patients with 
moderate hepatic impairment. 
• To obtain additional safety data through the extension phase, in which patients have 
the option to continue receiving niraparib. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 1, open-label, parallel-group, single-dose study in patients with advanced solid 
tumors and with either normal hepatic function or moderate hepatic impairment.  
Patients with solid tumors will be recruited and enrolled within the following groups: 
• Group 1: normal hepatic function (total bilirubin [BILI] and aspartate 
aminotransferase [AST] ≤ upper limit of normal [ULN]) 
• Group 2: moderate hepatic impairment (BILI >1.5 × to 3 × ULN) and any degree of 
AST elevation 
7.1.1. 
PK Phase 
All patients will receive a single dose of 300 mg niraparib administered as 3 × 100 mg capsules 
on Day 1. Patients will undergo PK sampling up to 168 hours (7 days) following niraparib 
administration. Pharmacokinetic parameters to be calculated include area under the concentration 
× time curve calculated to last measured concentration (AUC0-t), area under the concentration × 
time curve calculated to infinity (AUC0-∞), maximum concentration (Cmax), time to maximum 
concentration (tmax), terminal half-life (t½), and apparent total clearance (CL/F). Protein binding 
parameters to be calculated include fraction of unbound drug (Fu) and clearance of free drug 
(CLfu/F). The study will be considered complete when the final PK evaluable patient completes 
all assessments in the PK phase of the study.  
Safety will be assessed through adverse event assessment, physical examination, vital sign 
measurements, clinical laboratory tests, and monitoring of concomitant medications (Section 12). 
7.1.1.1. 
Fasting and Study Drug Administration for the PK Phase 
During the PK Phase of the study, patients should come to the clinic on the morning of Day 1 of 
the PK period following a 12-hour overnight fast. During the overnight fast, patients are 
permitted to consume water (but no other beverages) until up to 2 hours prior to dosing of the 
study drug. Patients may take their routine medications with sips of water. 
Patients will receive a single dose (300 mg) of the formulation with approximately 250 ml of 
water on Day 1 of the PK period. Patients may resume their regular diet 4 hours after taking the 
study drug. 
7.1.2. 
Extension Phase 
On the same day that patients complete the final study assessments for the PK phase, patients 
may be eligible to continue receiving niraparib in the extension phase of the study, if the 
investigator believes it is in the best clinical interest of the patient. Patients will receive their first 
therapeutic dose of niraparib on Cycle 1/Day 1 of the extension phase.  For patients with normal 
hepatic function, the starting dose of niraparib will be based on the patient’s screening actual 
body weight or current platelet count. Patients with a screening actual body weight of ≥ 77 
kg and current platelet count of ≥150,000/µL at C1D1 (or at screening if done 72 hours prior to 
C1D1) will take three capsules of 100 mg strength (300 mg/day) at each dose 


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administration.  Patients with a screening actual body weight of < 77 kg and current platelet 
count of <150,000/µL at C1D1 (or at screening if done 72 hours prior to C1D1 will take two 
capsules of 100 mg strength (200 mg) at each dose administration. Additional dose modifications 
will not be based upon changes in the patient’s actual body weight during study participation. 
Patients with moderately impaired hepatic function will receive an oral daily dose of niraparib 
200 mg (2 × 100-mg capsules).  
Patients will return to the study center during Cycle 1 on Days 8, 15, and 21 to undergo safety 
assessments (including complete blood counts [CBCs]). Thereafter, patients will return on the 
first day of every treatment cycle (28 ±3 days) to receive study drug and for safety assessments 
(including CBCs). Dose modification (dose interruption and/or reduction) may be implemented 
for any grade toxicity considered intolerable by the patient, and must be implemented for any 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 non-hematologic 
adverse event considered by the Investigator related to study treatment or for hematologic 
toxicity as outlined in the protocol. Patients may continue in the extension phase until disease 
progression (assessed by Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 and 
clinical signs and symptoms), unacceptable toxicity, death or discontinuation from the study 
treatment for any other reason. At end of study (EOS), safety assessments will be completed. No 
new capsules will be dispensed at EOS. 
Table 4 and Table 5 presents the schedule of assessments. Section 7.5 details the procedures to 
be performed on each study day/visit. 
7.2. 
Number of Patients 
Approximately 16 patients will be enrolled. 
7.3. 
Treatment Assignment 
This study is open-label, and all patients will receive niraparib.  


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7.4. 
Schedule of Assessments 
Table 3: 
PK Phase Schedule of Assessments  
Assessment 
Screening 
PK Phase 
Day of Procedure 
-28 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/ exclusion criteria review 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical, surgical, cancer, and medication 
history 
X 
 
 
 
 
 
 
 
 
Investigator-assessed tumor assessmenta 
X 
 
 
 
 
 
 
 
 
Vital signs  
X 
Xb 
X 
 
 
 
 
 
X 
Height and weight 
X 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
Clinical laboratory assessments 
 
 
 
 
 
 
 
 
 
CBCc 
X 
 
 
 
 
 
 
 
X 
Serum chemistry 
X 
 
 
 
 
 
 
 
X 
Coagulation 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
Xd 
 
 
 
 
 
 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
X 
CLcr calculation or Creatinine clearance 
X 
 
 
 
 
 
 
 
 
Blood sample for PK analysis 
 
X 
X 
X 
X 
 
X 
 
X 
Blood sample for plasma protein binding 
analysis 
 
X 
 
 
 
 
 
 
X 


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Assessment 
Screening 
PK Phase 
Day of Procedure 
-28 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
Concomitant medications/ procedures 
 
Recorded from first dose of study drug through 
Safety follow-up 
 
AE monitoringe 
X 
X 
X 
X 
X 
Xe 
X 
Xe 
X 
Niraparib treatment dispensed 
 
X 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CBC = complete blood count; CLcr = creatinine clearance; CT = computed 
tomography; ECOG= Eastern Cooperative Oncology Group; EOS = end of study; ICF = informed consent form; MRI = magnetic resonance imaging; 
PK = pharmacokinetic; SAE = serious adverse event. 
a RECIST (v1.1) tumor assessment via a CT or MRI scan of clinically indicated areas and evaluation of clinical signs and symptoms should be performed at 
minimum at screening in the PK Phase and as described in Table 5 for the Extension Phase. 
b To be collected prior to niraparib dosing 
c During the extension phase, test complete blood counts weekly for the first month, monthly for the next 11 months of treatment and periodically after this time. 
Medical and supportive therapy should be optimized for management of toxicities. 
d Serum or urine pregnancy test within 72 hours prior to first dose of niraparib 
e Collection of AEs begins when ICF is signed. AE monitoring on PK Phase Days 5 and 7 may be performed by telephone.   
 
 


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Table 4: 
Extension Phase Schedule of Assessments  
Assessment 
Extension Phase 
Cycle 1 
Cycle n/Day 1 
EOS 
Safety Follow-up 
Day of Procedure (window) 
1a 
8 
15 
21 
1 
(+ 7 Days post-treatment)  
30 (+ 7 Days) 
Investigator assessed tumor assessmentb 
 
 
 
 
X 
X 
 
Vital signs  
X 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
ECOG 
X 
 
 
 
 
X 
X 
Weight 
 
 
 
 
 
 
X 
CBCc 
X 
X 
X 
X  
X  
X 
X 
Serum chemistry 
 
 
 
 
X 
X 
X 
Pregnancy test 
 
 
 
 
X 
X 
X 
Urinalysis 
 
 
 
 
 
 
X 
Physical exam 
X 
 
 
 
X 
X 
X 
Concomitant medications/ procedures 
 
Recorded from first dose of study drug through 
Safety follow-up 
AE monitoringd 
X 
X 
X 
X 
X 
X 
X 
Niraparib treatment dispensed 
Xe 
 
 
 
X 
 
 
a May be the same as PK Day 8/End of PK Phase 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CBC = complete blood count; CLcr = creatinine clearance; CT = computed 
tomography; ECOG= Eastern Cooperative Oncology Group; EOS = end of study; ICF = informed consent form; MRI = magnetic resonance imaging; 
PK = pharmacokinetic; SAE = serious adverse event.  
b Tumor assessment via a CT or MRI scan of clinically indicated areas and evaluation of clinical signs and symptoms should be performed at a minimum at 
screening and, during the extension phase, every three cycles or per the Institution’s standard practice. The Investigator will evaluate the patient scans and 
clinical symptoms to evaluate disease status and progression, discontinue niraparib and initiate subsequent anticancer treatment as necessary.  
c During the extension phase, test complete blood counts weekly for the first month, monthly for the next 11 months of treatment and periodically after this time. 
Medical and supportive therapy should be optimized for management of toxicities. 


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d AEs are required to be captured through 30 days after cessation of study treatment; SAEs are required to be captured through 90 days after cessation of study 
treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy). Study drug-related SAEs and adverse events of special 
interest (AESIs) will be collected via telephone every 90 ± 14 days after the last dose of study drug until study closeout, or as otherwise indicated in AESI, 
Section 12.2.7. AESIs must be reported as soon as the investigator becomes aware of them.  
e If Cycle 1/Day 1 is the same day as Day 8 of the PK phase, then niraparib treatment must be dispensed after all other assessments (including PK) have been 
completed. 
 
 


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Table 5: 
Pharmacokinetic Sampling 
Pharmacokinetic Assessments 
Timepoint 
Collection window 
Predose 
within 30 minutes prior to dosing 
1 hr postdose 
± 5 min 
2 hrs postdose 
± 5 min 
3 hrs postdose 
± 5 min 
4 hrs postdose 
± 5 min 
6 hrs postdose 
± 15 min 
8 hrs postdose 
± 15 min 
12 hrs postdose 
± 15 min 
24 hrs postdose 
± 30 min 
48 hrs postdose 
± 60 min 
72 hrs postdose 
± 60 min 
120 hrs postdose 
± 120 min 
168 hrs postdose 
± 120 min 
Plasma protein binding 
Predose 
within 30 minutes prior to dosing 
3 hrs postdose 
± 5 min 
168 hrs postdose 
± 120 min 
 
 
 


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7.5. 
Assessments by Visit 
Assessment details to be performed during the study are described in Section 11 (PK 
Assessments) and Section 12 (Assessments of Safety). Where PK and vital sign assessments 
coincide, vital signs should be performed first, then PK (drawn on timepoint). 
Concomitant medications/ procedures are to be recorded from first dose of study drug throughout 
safety follow-up. 
7.5.1. 
Screening Visit (Days -28 to -1) 
Screening will take place from Day -28 to Day -1. The following procedures will be performed 
at the Screening visit: 
• Informed consent 
• Inclusion/ exclusion criteria review 
• Demographics 
• Medical, surgical, cancer, and medication history 
• Investigator-assessed tumor assessment:  Tumor assessment via a computed 
tomography (CT) or magnetic resonance imaging (MRI) scan of clinically indicated 
areas should be performed at screening  
• Vital signs 
• Height and weight 
• Eastern Cooperative Oncology Group (ECOG) performance status 
• Clinical laboratory assessments (Section 12.1.1) 
− CBC 
− Serum chemistry 
− Coagulation 
− Pregnancy test (serum, to be conducted within 72 hours prior to niraparib dose) 
− Urinalysis 
• Physical exam 
• Calculation of creatinine clearance (Clcr) per Cockcroft-Gault as follows: 
Clcr (mL/min) = (140 – age) x weight (in kg) x 0.85 if female 
 
72 x serum creatinine (mg/dL) 
• AE monitoring 
7.5.2. 
PK Phase 
The following procedures and assessments will be completed during the PK phase: 


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7.5.2.1. 
Day 1 
• Vital signs 
• Blood samples for PK determination and for plasma protein binding analysis as 
described in Table 4 and Section 11 
• AE monitoring  
• Niraparib dosing 
7.5.2.2. 
Day 2 
• Vital signs 
• Blood samples for PK determination analysis as described in Table 4 and Section 11 
• AE monitoring  
7.5.2.3. 
Day 3 
• Blood samples for PK determination analysis as described in Table 4 and Section 11 
• AE monitoring  
7.5.2.4. 
Day 4 
• Blood samples for PK determination analysis as described in Table 4 and Section 11 
• AE monitoring  
7.5.2.5. 
Day 5 
• AE monitoring (may be via telephone) 
7.5.2.6. 
Day 6 
• Blood samples for PK determination analysis as described in Table 4 and Section 11 
7.5.2.7. 
Day 7 
• AE monitoring (may be via telephone) 
7.5.2.8. 
Day 8 / End of PK Phase 
• Note that if a patient is continuing onto the extension phase, the Day 8/ end of PK phase 
may be the same day as Cycle 1/ Day 1/ Extension phase. 
• Vital signs (only if not continuing onto extension phase) 
• Clinical laboratory assessments (Section 12.1.1): 
− CBC 
− Serum chemistry 
− Pregnancy test (serum or urine) 


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• Physical exam 
• Blood samples for PK determination and for plasma protein binding analysis as 
described in Table 4 and Section 11 
• AE monitoring 
If a patient is not continuing to Cycle 1/Day 1 in the Extension Phase, then the procedures in the 
End of Study and Safety Follow Up must be completed. 
7.5.3. 
Extension Phase 
Note: During the extension phase, tumor assessment via a CT or MRI scan of clinically indicated 
areas and evaluation of clinical signs and symptoms should be performed at minimum every 
three cycles or per the Institution’s standard practice. The Investigator will evaluate the patient 
scans and clinical symptoms to evaluate disease status and progression and initiate subsequent 
anticancer treatment as necessary. 
7.5.4. 
Cycle 1/ Day 1 
In addition to assessments performed for all patients during PK Day 8 (end of PK phase), the 
following assessments must be performed on Cycle 1/Day 1 for patients continuing onto the 
extension phase: 
• Vital signs 
• Physical exam 
• CBC (if this does not coincide with Day8/end of PK phase) 
• AE monitoring 
• Niraparib treatment dispensed (if Cycle 1/Day 1 is the same day as Day 8 of the PK 
phase, then niraparib treatment must be dispensed after all other assessments 
[including PK] have been completed). 
7.5.4.1. 
 Cycle 1/ Day 8 
• CBC (during the extension phase, test complete blood counts weekly for the first 
month, monthly for the next 11 months of treatment and periodically after this time. 
Medical and supportive therapy should be optimized for management of toxicities). 
• AE monitoring 
7.5.4.2. 
Cycle 1/ Day 15 
• CBC (during the extension phase, test complete blood counts weekly for the first 
month, monthly for the next 11 months of treatment and periodically after this time. 
Medical and supportive therapy should be optimized for management of toxicities). 
• AE monitoring 


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7.5.4.3. 
Cycle 1/ Day 21 
• CBC (during the extension phase, test complete blood counts weekly for the first 
month, monthly for the next 11 months of treatment and periodically after this time. 
Medical and supportive therapy should be optimized for management of toxicities). 
• AE monitoring 
7.5.4.4. 
Cycle n/ Day 1 
• Vital signs 
• Clinical laboratory assessments (Section 12.1.1):  
− CBC (during the extension phase, test complete blood counts weekly for the first 
month, monthly for the next 11 months of treatment and periodically after this 
time. Medical and supportive therapy should be optimized for management of 
toxicities). 
− Serum chemistry 
− Pregnancy text (serum or urine) 
• Physical exam 
• Tumor assessment via a CT or MRI scan of clinically indicated areas and evaluation 
of clinical signs and symptoms should be performed at minimum every three cycles 
or per the Institution’s standard practice.  
• AE monitoring 
• Niraparib treatment dispensed 
7.5.4.5. 
End of Study 
• Investigator-assessed RECIST (v. 1.1) tumor assessment (see note above, 
Section 7.5.3) 
• Vital signs 
• ECOG 
• Clinical laboratory assessments (Section 12.1.1): 
− CBC 
− Serum chemistry 
− Pregnancy test (serum or urine) 
• Physical exam 
• AE monitoring 
7.5.5. 
Safety Follow-up (30 days [+ 7 days] Post-treatment) 
• Physical exam 


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• Clinical laboratory assessments: may be done at the study center’s local laboratory or 
at a laboratory local to the patient if the laboratory is included on FDA Form 1572: 
− CBC 
− Serum chemistry 
− Pregnancy test (urine) 
− Urinalysis 
• Vital signs 
• ECOG 
• Weight 
• AE monitoring: AEs are required to be captured through 30 days after cessation of 
study treatment; SAEs are required to be captured through 90 days after cessation of 
study treatment (or to a minimum of 30 days post-treatment if the patient starts 
alternative anticancer therapy); and any pregnancies that occur within 180 days post-
treatment are to be captured. Study drug-related SAEs and adverse events of special 
interest (AESIs) will be collected via telephone every 90 ± 14 days after the last dose 
of study drug until study closeout, or as otherwise indicated in AESI, Section 12.2.7. 
AESIs must be reported as soon as the investigator becomes aware of them. All AEs 
and SAEs experienced by a patient, regardless of the suspected causality, will be 
monitored until the AE or SAE has resolved, until any abnormal laboratory values 
have returned to baseline or normalized, until there is a satisfactory explanation for 
the change(s) observed, until the patient is lost to follow-up or withdraws consent, or 
until the patient has died.  
 


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8. 
SELECTION AND DISCONTINUATION OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
All patients 
To be considered eligible to participate in this study, all of the following requirements must be 
met:  
1. Patient, male or female, is at least 18 years of age. 
2. 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.  
3. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 
to1. 
4. Patient is able to take oral medications. 
5. 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 180 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 and oophorectomy and a 
follicle-stimulating hormone value in the postmenopausal range upon prestudy 
(screening) evaluation. 
− Post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented 
hysterectomy or oophorectomy must be confirmed with medical records of the 
actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed 
with medical records of the actual procedure; otherwise the patient must be 
willing to use highly effective contraception (see Appendix 1) throughout the 
study, starting with the screening visit through 180 days after the last dose of 
study therapy. Information must be captured appropriately within the site’s source 
documents. 
Note: Abstinence is acceptable if this is the established and preferred contraception for 
the patient. 
6. Male patient agrees to use an adequate method of contraception and not donate sperm, 
starting with the first dose of study treatment through 90 days after the last dose of study 
treatment.  
Note: Abstinence is acceptable if this is the established and preferred contraception for 
the patient. 
7. Patient is able to understand the study procedures and agrees to participate in the study by 
providing written informed consent. 


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Patients with normal hepatic function (Group 1)  
Patients screened for the control group must meet the following additional criteria to be eligible 
for enrollment: 
1. Patient has no history of hepatic impairment, including but not limited to chronic 
hepatitis C or chronic hepatitis B. 
2. Patient has liver function test (LFT) results within normal range:  
− Total bilirubin ≤ ULN 
− Aspartate aminotransferase (AST) ≤ ULN 
− INR ≤1.5 ULN unless patient is receiving anticoagulant therapy and the INR is 
within therapeutic range of intended use of anticoagulants. 
3. Patient has adequate hematologic and renal function as defined below (Note: CBC test 
should be obtained without transfusion or receipt of colony stimulating factors within 4 
weeks before obtaining sample): 
− Absolute neutrophil count ≥1,500/µL 
− Platelets ≥100,000/µL  
− Hemoglobin ≥9 g/dL  
− Serum creatinine ≤1.5 × ULN or a calculated creatinine clearance (CLcr) 
≥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: 
1. 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 
− International normalized ratio (INR) ≤1.8 unless the patient is receiving 
anticoagulant therapy and the INR is within the therapeutic range of intended use 
of anticoagulants 
2. Patient has hematologic and renal function as defined below (Note: CBC test should be 
obtained without transfusion or receipt of colony stimulating factors within 4 weeks 
before obtaining sample): 
− 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. 


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3. Patient's hepatic disease is deemed stable by the Investigator (i.e. no clinically significant 
change in hepatic disease status within 30 days prior to Screening). 
8.2. 
Patient Exclusion Criteria 
Patients will not be eligible for study entry if any of the following criteria are met: 
All patients: 
1. Patient has undergone palliative radiotherapy within 1 week of study drug administration, 
encompassing >20% of the bone marrow. 
2. Patient is starting chemotherapy within 3 weeks of study drug administration. 
3. Patient has a known hypersensitivity to the components of niraparib or excipients 
4. Patients who received colony-stimulating factors (e.g. granulocyte colony-stimulating 
factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], or 
recombinant erythropoietin) within 2 weeks prior to the first dose of study treatment are 
not eligible. 
5. Patient has persistent chemotherapy associated Grade 2 or greater toxicity except for 
neuropathy, alopecia or fatigue.  
6. Patient has symptomatic uncontrolled brain or leptomeningeal metastases. To be 
considered “controlled,” the patient must have undergone treatment (e.g. radiation or 
chemotherapy) at least 1 month prior to study entry. The patient must not have any new 
or progressive signs or symptoms related to the central nervous system [CNS] disease 
and must be taking ≤ 10 mg of prednisone or equivalent per day or no steroids. Patients 
who have untreated brain metastases and who are not symptomatic may enroll if the 
Investigator feels that treatment of these metastases is not indicated. A scan to confirm 
the absence of brain metastases is not required. Patients with spinal cord compression 
may be considered if they have received definitive treatment for this and evidence of 
clinically stable disease for 28 days. 
7. Patient has undergone major surgery within 3 weeks of starting the study or patient has 
not recovered from any effects of any major surgery. 
8. Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder 
(other than hepatic impairment); nonmalignant systemic disease; or active, uncontrolled 
infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, 
recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, 
unstable spinal cord compression, superior vena cava syndrome, uncontrolled 
hypertension, active uncontrolled coagulopathy or any psychiatric disorder that prohibits 
obtaining informed consent. 
9. Patient has received a transfusion (platelets or red blood cells) within 3 weeks of 
receiving niraparib. 
10. Female patient is pregnant or is expecting to conceive children while receiving study 
drug or for up to 180 days after the last dose of study drug. Male patient is expecting to 
donate sperm or father children while receiving study drug or for up to 90 days after the 
last dose of study drug. 


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11. Female patient is breastfeeding or is expecting to breastfeed within 30 days of receiving 
final dose of study drug (women should not breastfeed or store breastmilk for use, during 
treatment and for 30 days after receiving the final dose of study treatment). 
12. Patient has a known history of myelodysplastic syndrome (MDS) or acute myeloid 
leukemia (AML). 
NOTE: Exclusion Criteria 13-17 apply only to the PK phase of the study. 
13. 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. 
14. Patient is unable to refrain from any intake of grapefruit or grapefruit juice within starting 
4 days prior to of the first administration of niraparib until the final PK sample collection. 
15. 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. 
16. 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. 
17. 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: 
1. Patient has hepatic encephalopathy, severe portal hypertension and/or porto-systemic 
shunt. 
2. Patient has fluctuating or rapidly deteriorating hepatic function as determined by the 
investigator during the screening period.  
3. Patient has acute liver disease caused by drug toxicity or by an infection. 
4. Patient has biliary obstruction or other causes of hepatic impairment not related to 
parenchymal disorder and/or disease of the liver. 
5. Patient has esophageal variceal bleeding within 2 months. 
6. Patient is receiving anticoagulant therapy with warfarin or related coumarins. 
7. Patient has a history of hepatic transplant, systemic lupus erythematosus, or hepatic 
coma. 


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8.3. 
Patient Discontinuation Criteria 
8.3.1. 
Discontinuation from treatment 
Patients may be discontinued from study treatment at any time. Specific reasons for 
discontinuing all study treatments include the following: 
• AE 
• Disease progression as determined by the Investigator 
• Clinical disease progression based on clinical criteria by Investigator 
• Risk to patient as judged by the Investigator and/or the Sponsor 
• Severe noncompliance with the protocol as judged by the Investigator and/or the 
Sponsor 
• Patient request 
• Patient becomes pregnant 
• Sponsor decision to terminate study 
• Death 
Details of required niraparib dose modifications, including interruptions, dose reductions, and 
permanent discontinuations, related to toxicity, are provided in Section 9.4  
Discontinuation of treatment may be considered for patients who have attained a confirmed 
complete response (CR) and have had at least 2 cycles of treatment beyond the date when the 
initial CR was declared. 
Patients who discontinue from study treatments will continue to receive follow-up assessments 
(Table 4) as part of the study unless they are discontinued from the study (Section 8.3.2). 
8.3.2. 
Discontinuation from the Study 
Patients may be discontinued from the study for any of the following reasons: 
• Withdrawal of consent by the patient, who is at any time free to discontinue their 
participation in the study, without prejudice to further treatment 
• Death from any cause 
• Loss to follow-up 
• Sponsor decision to terminate study 
• Investigator’s decision 
Patients who withdraw from study drug will be asked to continue study visits and assessments as 
outlined in the schedule of procedures (Table 4). If a patient is lost to follow-up, attempts should 
be made to contact the patient to determine the reason for discontinuation. For patients who are 
lost to follow-up, at least 3 documented attempts, including 1 via certified mail, should be made 
to contact the patient before considering the patient lost to follow-up.  


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8.3.3. 
Replacement of Patients 
Patients may be replaced so that there are 8 PK-evaluable patients per group. 


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9. 
TREATMENT OF PATIENTS 
9.1. 
Randomization and Blinding 
This is an open-label study, and patients will not be randomized. 
9.2. 
Description of Study Drug 
Table 6: 
Study Treatment 
 
Study Treatment 
Product Name: 
niraparib 
Dosage Form: 
100 mg capsules 
Unit Dose 
PK phase: 3 capsules of 100 mg (300 mg) 
Administered on Day 1 only 
Extension phase: capsules of 100 mg strength 
administered once daily (QD), 28 day cycles 
Patients with normal hepatic function:  
≥ 77 kg and platelet count of ≥150,000/µL: 300 
(3 x 100) mg/day 
<77 kg and/or platelet count of <150,000 u/L: 
200 mg/day (2 x 100) mg/day  
Patients with moderately impaired function: 2 
capsules of 100 mg (200 mg) Administered 
once daily (QD), 28 day cycles 
Route of Administration 
Oral 
Physical Description 
Capsule 
Manufacturer 
QS Pharma LLC 
Abbreviations: PK = pharmacokinetic; QD; once daily 
9.3. 
Administration 
Niraparib will be supplied as 100-mg capsules.  
PK Phase: A single dose (3 capsules of 100-mg strength (300 mg/day) will be administered on 
Day 1.  
Extension phase: For patients with normal hepatic function, the starting dose of niraparib will 
be based on the patient’s screening actual body weight or current platelet count. Patients with a 
screening actual body weight of ≥77 kg and current platelet count of ≥150,000/µL at C1D1 (or 
at screening if done 72 hours prior to C1D1) will take three capsules of 100 mg strength (300 
mg/day) at each dose administration. Patients with a screening actual body weight of <77 kg 
and/or current platelet count of <150,000/µL C1D1 (or at screening if done 72 hours prior to 
C1D1) will take two capsules of 100 mg strength (200 mg) at each dose administration. 


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Additional dose modifications will not be based upon changes in the patient’s actual body weight 
during study participation.  
Extension phase: Patients with moderately impaired hepatic function will receive an oral daily 
dose of niraparib 200 mg (2 × 100-mg capsules).  
Patients will be instructed to take their niraparib dose at the same time each day. Bedtime 
administration may be a potential method for managing nausea. Patients must swallow and not 
chew all capsules. The consumption of water and food is permissible. 
Niraparib will be dispensed to patients on Day 1 of every cycle (every 28 days) thereafter until 
the patient discontinues study treatment. The Pharmacy Manual contains descriptions of the 
packaging of niraparib and instructions for the preparation and administration of niraparib. 
9.4. 
Dose Adjustment Criteria  
During the extension phase, study treatment dosing interruptions are permitted in the case of 
adverse events, medical/surgical events or logistical reasons not related to study therapy (e.g. 
surgery, unrelated medical events, patient vacation, or holidays). Patients should resume study 
therapy within 28 days of the scheduled interruption, unless otherwise discussed with the 
Sponsor. 
All treatment interruptions and dose reductions (including any missed doses) and the reasons for 
the reductions/interruptions are to be recorded in the electronic case report form (eCRF). 
Dose interruption of niraparib may be implemented at any time per the Investigator’s judgment. 
See the following sections for permitted duration of interruption prior to required discontinuation 
from treatment. 
Niraparib dose reduction will be allowed based on treatment side effects. Dose reductions to 
1 capsule daily (100 mg) will be allowed (Table 8). No further dose reductions will be allowed. 
The timing of efficacy or safety evaluations should not be affected by dose interruptions or 
reductions. 
9.4.1. 
Niraparib Dose Modifications for Adverse Events 
During the extension phase, dose modification may be implemented by the treating physician at 
any time for any grade of toxicity, when deemed in the best interest of the patient. In the case of 
severe adverse reactions, treatment should be withheld and then resumed per Table 8 and 
Table 9. 
The recommended dose modifications for hematologic adverse reactions are listed in Table 10. 
 
 


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Table 7: 
Recommended Dose Modifications for Adverse Reactions 
Dose level 
Dose for PK 
Phase 
Patients with 
Normal Hepatic 
Function in the 
Extension Phase 
 
Patients with 
Normal Hepatic 
Function in the 
Extension Phase 
 
Dose for Patients 
with Moderately 
Impaired Hepatic 
Function in the 
Extension Phase 
 
All Patients 
Patients ≥77 kg 
and with platelet 
count of 
≥150,000/µL 
patients <77 kg 
and/or with 
platelet count of 
<150,000 u/L will 
receive 200 
mg/day 
 
Starting dose 
300 mg/day 
300 mg/day 
200 mg/day 
200 mg/day 
First dose 
reduction 
200 mg/day 
200 mg/day 
100 mg/day 
100 mg/day 
Second dose 
reduction 
100 mg/day* 
100 mg/day* 
N/A 
N/A 
*If further dose reduction below 100 mg/day is required, discontinue niraparib.  
9.4.2. 
Niraparib Dose Modifications for Nonhematologic Toxicity 
During the extension phase, treatment with niraparib must be interrupted for any treatment-
related nonhematologic Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 
4 event. If toxicity is appropriately resolved to Grade 1 or less within 28 days of interruption, the 
patient may restart treatment with niraparib with a dose level reduction according to Table 9 
unless prophylaxis is considered feasible. If the event recurs at a similar or worse grade, 
treatment should be interrupted. 
If the toxicity requiring dose interruption has not resolved to CTCAE Grade 1 or less during a 
maximum 4-week (28-day) dose interruption period, or the patient has already undergone a dose 
reduction (to a minimum dose of 100 mg QD), or both, the patient must permanently discontinue 
treatment with niraparib. Once the dose of niraparib has been reduced, any re-escalation must be 
discussed with the Sponsor.  
Table 8: 
Niraparib Dose Reductions for Nonhematologic Toxicity in Patients with 
Normal or Impaired Hepatic Function. 
Nonhematologic CTCAE ≥ Grade 3 treatment-related 
adverse reaction where prophylaxis is not considered 
feasible or adverse reaction event persists despite treatment 
Withhold niraparib for a maximum of 
28 days or until resolution of adverse 
reaction. 
Resume niraparib at a reduced dose per 
Table 8. Up to 2 dose reductions are 
permitted. 
CTCAE ≥ Grade 3 treatment-related adverse reaction event 
lasting more than 28 days while patient is administered 
niraparib 100 mg/day 
Discontinue medication. 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events 


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9.4.3. 
Niraparib Dose Modifications for Hematologic Toxicity 
The dose interruption/modification criteria for niraparib for any hematologic toxicities noted 
during the extension phase will be based on blood counts and are outlined in Table 10 (Normal 
Hepatic Function) and Table 11  (Impaired Hepatic Function). 
If clinically indicated, use of G-CSF is allowed according to current American Society of 
Clinical Oncology (ASCO) guidelines.5 If clinically indicated, red blood cell transfusions are 
allowed according to institutional guidelines. 
If the hematologic toxicity does not recover to the specified level within 4 weeks (28 days) of 
dose interruption and/or the patient has already undergone 1 dose reduction (to a minimum dose 
of 100 mg QD), then niraparib should be discontinued.  
Patients with normal hepatic function requiring transfusion of platelets or red blood cells (1 or 
more units) or hematopoietic growth factor support may undergo a niraparib dose reduction upon 
recovery if study treatment is resumed. 
Once the dose of study treatment has been reduced, any re-escalation must be discussed with the 
Sponsor’s Medical Monitor. 
It is strongly recommended that the patient be referred to a hematologist for further evaluation 
(1) if transfusions are required on more than 1 occasion or (2) if the treatment-related 
hematologic toxicities have not recovered to CTCAE ≤ Grade 1 within 4 weeks. If a diagnosis of 
MDS/AML is confirmed by a hematologist, the patient must permanently discontinue niraparib.  
The reason for interruption, reduction, or discontinuation of niraparib should be recorded in the 
eCRF.


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Table 9: 
Management of Hematologic Toxicities in Patients with Normal Hepatic 
Function 
Medical and supportive therapy should be optimized for management of toxicities. 
Platelet count <100,000/µL 
 
First occurrence:  
Withhold niraparib for a maximum of 28 days and monitor blood 
counts weekly until platelet counts return to ≥100,000/µL. 
Resume niraparib at the same or reduced dose per Table 8.   
If platelet count is <75,000/µL, resume at a reduced dose. 
Second occurrence: 
Withhold niraparib for a maximum of 28 days and monitor blood 
counts weekly until platelet counts return to ≥100,000/µL. 
Resume niraparib at a reduced dose. 
Discontinue niraparib if the platelet count has not returned to 
acceptable levels within 28 days of the dose interruption period, or if 
the patient has already undergone dose reduction to 100 mg QD. 
Neutrophil <1,000/µL 
Withhold niraparib for a maximum of 28 days and monitor blood 
counts weekly until neutrophil counts return to ≥1,500/µL. 
Resume niraparib at a reduced dose. 
Discontinue niraparib if neutrophil level has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the patient 
has already undergone dose reduction to 100 mg QD. 
Hemoglobin <8 g/dL 
Withhold niraparib for a maximum of 28 days and monitor blood 
counts weekly until hemoglobin returns to ≥9 g/dL. 
Resume niraparib at a reduced dose. 
Discontinue niraparib if hemoglobin has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the patient 
has already undergone dose reduction to 100 mg QD. 
Hematologic adverse reaction requiring 
transfusion or hematopoietic growth 
factor support 
For patients with platelet count ≤10,000/μL, platelet transfusion 
should be considered. If there are other risk factors such as co-
administration of anticoagulation or antiplatelet drugs, consider 
interrupting these drugs and/or transfusion at a higher platelet count. 
Resume niraparib at a reduced dose. 
Confirmed diagnosis of MDS or AML 
Permanently discontinue niraparib. 
Abbreviations: MDS = myelodysplastic syndrome, AML = acute myeloid leukemia, CBC = complete blood 
count, MDS = myelodysplastic syndrome, QD = once daily. 
 
 


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Table 10: 
Management of Hematologic Toxicities in Patients with Impaired Hepatic 
Function 
Medical and supportive therapy should be optimized for management of toxicities. 
Platelet count <50,000/µL 
 
First occurrence:  
Withhold niraparib for a maximum of 28 days and monitor blood 
counts weekly until platelet counts return to ≥75,000/µL. 
Resume niraparib at the same or reduced dose per Table 8.   
If platelet count is <25,000/µL, resume at a reduced dose. 
Second occurrence: 
Withhold niraparib for a maximum of 28 days and monitor blood 
counts weekly until platelet counts return to ≥75,000/µL. 
Resume niraparib at a reduced dose. 
Discontinue niraparib if the platelet count has not returned to 
acceptable levels within 28 days of the dose interruption period, or if 
the patient has already undergone dose reduction to 100 mg QD. 
Neutrophil <750/µL 
Withhold niraparib for a maximum of 28 days and monitor blood 
counts weekly until neutrophil counts return to ≥1000/µL. 
Resume niraparib at a reduced dose. 
Discontinue niraparib if neutrophil level has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the patient 
has already undergone dose reduction to 100 mg QD. 
Hemoglobin <7 g/dL 
Withhold niraparib for a maximum of 28 days and monitor blood 
counts weekly until hemoglobin returns to ≥8 g/dL. 
Resume niraparib at a reduced dose. 
Discontinue niraparib if hemoglobin has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the patient 
has already undergone dose reduction to 100 mg QD. 
Hematologic adverse reaction requiring 
transfusion or hematopoietic growth 
factor support 
For patients with platelet count ≤10,000/μL, platelet transfusion 
should be considered. If there are other risk factors such as co-
administration of anticoagulation or antiplatelet drugs, consider 
interrupting these drugs and/or transfusion at a higher platelet count. 
Resume niraparib at a reduced dose. 
Confirmed diagnosis of MDS or AML 
Permanently discontinue niraparib. 
Abbreviations: MDS = myelodysplastic syndrome, AML = acute myeloid leukemia, CBC = complete blood 
count, MDS = myelodysplastic syndrome, QD = once daily. 
If clinically indicated, use of G-CSF is allowed according to current ASCO guidelines.5 If 
clinically indicated, red blood cell transfusions are allowed according to institutional guidelines. 
If the hematologic toxicity does not recover to the specified level within 4 weeks (28 days) of 
dose interruption and/or the patient has already undergone 1 dose reduction (to a minimum dose 
of 100 mg QD), then niraparib should be discontinued. 
Once the dose of study treatment has been reduced, any re-escalation must be discussed with the 
Sponsor’s Medical Monitor. 


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It is strongly recommended that the patient be referred to a hematologist for further evaluation 
(1) if transfusions are required on more than 1 occasion or (2) if the treatment-related 
hematologic toxicities have not recovered to CTCAE ≤ Grade 1 within 4 weeks. If a diagnosis of 
MDS/AML is confirmed by a hematologist, the patient must permanently discontinue niraparib. 
The reason for interruption, reduction, or discontinuation of niraparib should be recorded in the 
eCRF. 
9.5. 
Concomitant Medications and Study Restrictions 
Any medication the patient takes during the study other than the study treatments, including 
herbal and other nontraditional remedies, is considered a concomitant medication. All 
concomitant medications must be recorded in the eCRF. The following information must be 
recorded in the eCRF for each concomitant medication: generic name, route of administration, 
start date, stop date, dosage, and indication. Any changes in the dosage or regimen of a 
concomitant medication must be recorded in the eCRF. 
The identity, dose and regimen of all concomitant drugs must be recorded in the eCRF. All such 
concomitant medications should remain unchanged for 14 days before dosing with study drug 
and for the duration of the study. Concomitant medication will not be administered 4 hours 
before or after dose of niraparib.  
At screening, patients will be asked what medications they have taken during the last 30 days. At 
each subsequent study visit, patients will be asked what concomitant medications they are 
currently taking or have taken since the previous visit. 
9.5.1. 
Prohibited Medications 
9.5.1.1. 
PK Phase 
During the PK Phase of the study, patients should not be receiving, and must refrain from taking 
from 4 days prior to dosing and until the time of the last PK blood draw, the following CYP1A2 
substrates: alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine, and theophylline. 
Patients must not be receiving, and must refrain from taking from 4 days prior to dosing until the 
time of the last PK blood draw, any of the following 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.  
Patients must not be taking proton pump inhibitors, antacids, or H2 blockers within 48 hours 
prior to niraparib administration, and/or within 6 hours after niraparib administration.  
9.5.1.2. 
PK and Extension Phases 
Patients are prohibited from receiving the following therapies during the screening, PK, and 
extension phase of this study: 
• Antineoplastic systemic chemotherapy, biological therapy, or hormonal therapy 
• Chemotherapy or immunotherapy not specified in this protocol 
• Investigational agents other than niraparib 


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• Prophylactic cytokines (e.g., G-CSF). During the extension phase, prophylactic 
cytokines should not be administered in the first cycle but may be administered in 
subsequent cycles according to current ASCO guidelines.5 
If there is a clinical indication for any medication specifically prohibited during the study, 
discontinuation from study therapy may be required. The Investigator should discuss any 
questions regarding this with the Sponsor. The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the patient’s primary physician. The decision to 
continue the patient on study therapy, however, requires the mutual agreement of the 
Investigator, the Sponsor, and the patient. 
The niraparib safety profile includes thrombocytopenia; therefore, use caution with 
anticoagulation and antiplatelet drugs. 
9.5.2. 
Study Restrictions 
9.5.2.1. 
 Restrictions Specific to Patients with Moderate Hepatic Impairment  
Patients enrolled in the moderate hepatic impairment group should be cautioned about the 
concomitant use of acetaminophen (Tylenol®, Percocet®, or other analgesic combination tablets 
containing acetaminophen). 
Patients with hepatic impairment may receive standard therapy for diseases related to cirrhosis. 
9.5.2.2. 
Dietary and Fluid Restrictions 
Patient must refrain from any intake of grapefruit or grapefruit juice within 4 days of the first 
administration of niraparib until the final PK sample collection. 
9.5.2.3. 
Other Restrictions 
Niraparib is known to have properties that require the patient to use contraception. For details, 
refer to the IB.  
Patients who are blood donors should not donate blood during the study and for 90 days after the 
last dose of study treatment. 
Patients should maintain a normal diet unless modifications are required to manage an AE, such 
as diarrhea, nausea, or vomiting. 
9.6. 
Duration of Therapy 
A single dose of niraparib is administered on Day 1 of the PK phase of the study, and PK 
assessments are conducted for 7 days. Following completion of the PK phase, patients may be 
eligible to continue QD niraparib treatment in an extension phase until the patient meets any of 
the study withdrawal criteria (Section 8.3).  


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug Packaging, Labeling, and Storage 
Niraparib 100-mg capsules may be packed in high-density polyethylene bottles with 
child-resistant closures or in blister cards. The sponsor is exploring a change in packaging 
configuration to blister cards, which may be implemented at some point during the study.  
The label text of the study treatments will comply with Good Manufacturing Practice and 
national legislation to meet the requirements of the participating countries. The study treatment 
will be open-label and non-patient specific. 
All study treatment supplies must be stored in accordance with the Pharmacy Manual 
instructions and package labeling. Until dispensed or administered to the patients, the study 
treatment will be stored in a securely locked area, accessible to authorized personnel only. 
10.2. 
Study Drug Accountability 
The Investigator or designee is responsible for maintaining accurate dispensing records of the 
study treatments throughout the clinical study. Study drug accountability should be maintained 
by each site based on capsules dispensed vs. returned to the clinic at each visit and the number 
days since last visit. 
Details of maintaining drug accountability, including information on the accountability log, will 
be provided in the Pharmacy Manual. 
All dispensation and accountability records will be available for Sponsor review. The Study 
Monitor will assume the responsibility to reconcile the study treatment accountability log. The 
pharmacist will dispense study treatment for each patient according to the protocol and 
Pharmacy Manual, if applicable. 
10.3. 
Study Drug Handling and Disposal 
At the end of study (EOS), when all patients have stopped protocol treatment, complete drug 
reconciliation per batch should be available at the site for verification in order to allow drug 
destruction or return procedure. After receiving the Sponsor’s approval in writing, the 
investigational site is responsible for destruction of study drug according to local regulations. If a 
site does not have the capability for on-site destruction, the Sponsor will provide a return for 
destruction service to a third party. Both the unused and expired study medication must be 
destroyed, upon authorization of the Sponsor, according to local regulations and procedures, and 
a copy of the destruction form must be filed in the study binder. 
The drug provided for this study is to be used only as indicated in this protocol and only for the 
patients entered in this study. 


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11. 
PHARMACOKINETIC ASSESSMENTS 
11.1. 
Pharmacokinetic Parameters 
Pharmacokinetic parameters to be assessed include the following: 
• AUC0-t: Area under the plasma concentration-time curve from time 0 to the time of 
the last quantifiable concentration 
• AUC0-∞: Area under the plasma concentration-time curve from time 0 extrapolated to 
infinity 
• Cmax: Observed maximum plasma concentration 
• tmax: Time to Cmax 
• t½: Terminal half-life 
• CL/F: Apparent total body clearance 
Additional plasma samples will be drawn for the assessment of unbound concentrations of 
niraparib and M1. The following will be calculated for protein binding:  
• Fu: Fraction of unbound niraparib 
• CLfu/F: Clearance of free niraparib 
11.2. 
Blood Sample Collection 
Blood will be collected during the study for PK assessments and protein binding at the 
timepoints relative to niraparib dosing as described in Table 6. In total, approximately 80 mL of 
blood will be collected from each patient. 
11.2.1. 
Pharmacokinetic Assessment 
The volume of blood collected for PK assessments from each patient (approximately 5 mL per 
sample) during the study will be approximately 65 mL. Blood sample collection, processing, and 
shipping details will be outlined in a separate laboratory manual. In brief, blood will be collected 
into potassium ethylene diamine tetraacetic acid (K3EDTA) tubes, processed and plasma 
analyzed by a validated method of liquid chromatography coupled to tandem mass spectrometry 
detection (LC/MS/MS) for determination of the concentrations of niraparib and M1. The 
pharmacokinetic parameters (Section 11.1) will be calculated from the plasma concentration-
time profiles. The non-compartmental analysis will be performed using WinNonlin, version 5.1 
or higher. 
11.2.2. 
Plasma Protein Binding 
The total volume of blood collected during the study for plasma protein binding from each 
patient (approximately 5 mL per sample) will be approximately 15 mL. Blood sample collection, 
processing, and shipping details will be outlined in a separate laboratory manual. In brief, plasma 
protein binding will be performed by equilibrium dialysis (MWCO 10kD). At the end of dialysis, 
aliquots from both compartments will be analyzed to determine the concentration of the 
unchanged drug using a modified LC/MS/MS method. 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety parameters evaluated during the conduct of the study include TEAEs, discontinuations 
due to AEs, clinical laboratory assessments (including CBC, serum chemistry, and urinalysis), 
vital signs, physical examination findings, and monitoring of concomitant medications. 
12.1.1. 
Clinical Laboratory Assessments 
The following laboratory variables will be determined in accordance with the schedule of events 
(Table 4 and Table 5 ). These tests will be performed by the local laboratory at the clinical site. 
• Complete blood count: 
− Hemoglobin 
− Platelets 
− White blood cell count 
− Differential white cell count 
• Serum chemistry: 
− Sodium 
− Total bilirubin 
− Potassium 
− Alkaline phosphatase 
− Chloride 
− Aspartate aminotransferase 
− Creatinine 
− Alanine aminotransferase 
− Urea or blood urea nitrogen 
− Glucose  
− Total protein  
− Albumin 
− Calcium  
− Amylase 
− Phosphate 
− Magnesium 
− Lactate dehydrogenase  
• Urinalysis: 
− Specific gravity 
− Glucose 
− Blood 
− Bilirubin 
− Protein 
 
• Serum or urine pregnancy testing  
12.1.2. 
Physical Examination and Vital Signs 
Physical examinations, including height (screening only), weight, and vital signs (blood pressure, 
pulse, and temperature), will be performed in accordance with the schedule of assessments 
(Table 4 and Table 5). 


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Any physical examination or vital signs assessed as clinically significant should be recorded as 
an AE or SAE. If SAE criteria are met or the abnormality is an AESI (see Section 12.2.7), the 
event should be recorded and reported according to the SAE reporting process (see 
Section 12.2.5). 
12.1.3. 
Eastern Cooperative Oncology Group Performance Status 
Performance status will be assessed using the ECOG scale (Appendix 2) in accordance with the 
schedule of assessments (Table 4 and Table 5). The same observer should assess performance 
status each time. 
12.2. 
Adverse Events 
12.2.1. 
Definitions 
Adverse event (AE): An AE is any untoward medical occurrence that occurs in a patient or 
clinical investigation subject administered a pharmaceutical product, and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including clinically significant abnormal laboratory findings), 
symptom, or disease temporally associated with the use of an investigational product, whether or 
not considered related to the product. 
AEs may include the onset of new illness and the exacerbation of pre-existing medical 
conditions. An AE can include an undesirable medical condition occurring at any time, including 
baseline or washout periods, even if no study treatment has been administered. A TEAE will be 
defined as any new AE that begins, or any preexisting condition that worsens in severity during 
the Treatment Period.  
Serious adverse event (SAE): A SAE is defined as any untoward medical occurrence that, at 
any dose as follows: 
• Results in death 
• Is life-threatening 
− Note: This means that the patient is at immediate risk of death at the time of the 
event; it does not mean that the event hypothetically might have caused death if it 
were more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Any AE that prolongs hospitalization will be considered an SAE. 
− Exception: Preplanned hospitalization (e.g. for observation, protocol compliance, 
elective procedures, social reasons) will not be considered an SAE; however, the 
reason for the planned hospitalization should be captured in medical history 
section of the eCRF. Complications experienced during these hospitalizations 
must be reported as AEs (or SAEs, if hospitalization is prolonged due to the AE). 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 


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• Is an important medical event(s) 
− Medical and scientific judgement should be exercised in determining whether 
situations or events should be considered serious adverse events; An important 
medical event may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or require intervention to prevent 
one of the above outcomes. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. (See section 12.2.5 for information about SAE 
reporting) 
Treatment-Emergent Adverse Events (TEAEs): 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. 
Adverse Events of Special Interest (AESI): Any AE (serious or non-serious) that is of 
scientific and medical concern specific to the study treatment, for which ongoing monitoring and 
rapid communication by the investigator to the Sponsor is appropriate. 
Special Situations: Abuse, Misuse, Medication Errors, Overdose, and Accidental or 
Occupational Exposure: 
• Abuse: the persistent or sporadic, intentional excessive use of the study treatment 
which is accompanied by harmful physical or psychological effects.  
• Misuse: medicinal product is intentionally and inappropriately used not in accordance 
with the authorized/approved product information. 
• Medication error: any preventable incident that may cause or lead to inappropriate 
study treatment use or patient harm while the study treatment is in the control of the 
health care professionals or patients. Such incident may be due to health care 
professional practice, product labeling, packaging and preparation, procedures for 
administration, and systems, including the following: prescribing, order 
communication, nomenclature, compounding, dispensing, distribution, 
administration, education, monitoring, and use. 
• Overdose: a deliberate or accidental administration of study treatment to a study 
patient, at a dose greater than that which was assigned to that patient per the study 
protocol and under the direction of the Investigator.  If an overdose occurs, the 
Investigator and the Sponsor should be notified immediately, and the patient should 
be observed closely for AEs. Associated AEs should be treated and monitored by the 
Investigator. The dosage of study drug administered, any associated AEs, and/or 
treatment provided to the patient because of the overdose, should be documented on 
the applicable sections within the eCRF. An overdose (including an AE or SAE 
resulting from the overdose, if any) will be reported as described in Section  
• Accidental /Occupational exposure: the unintentional exposure to a study treatment 
as a result of one's professional or non-professional occupation, or accidental 
exposure to a non-professional to whom exposure was not intended (i.e. study product 
given to wrong patient).  


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Reporting Special Situations:  All occurrences of abuse, misuse, medication error, overdose, and 
accidental or occupational exposure with any study treatment must be reported on an SAE 
Report Form [or designated Special Form] to the Sponsor regardless of whether or not an AE or 
SAE has occurred. If the abuse, misuse, medication error, overdose, or accidental / occupational 
exposure is associated with an SAE, an SAE report form must be submitted to the Sponsor 
within 24 hours of awareness. If there is no AE or SAE, the occurrence must be submitted on the 
designated Special Form (indicate ‘no AE has occurred’) as soon as possible. 
12.2.2. 
Assessment of Adverse Events 
12.2.2.1. Severity Assessment 
All AEs will be assessed by the Investigator for severity according to Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03: 14 June 2010; National Institutes of Health (NIH), 
National Cancer Institute (NCI). The CTCAE severity grades 1 through 5 provide unique clinical 
descriptions of severity of each adverse event. The CTCAE v4.03 is available on the NCI/NIH 
website. 
Please note that there is a distinction between serious and severe AEs: Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 12.2.1. For example, a mild 
degree of gastrointestinal bleeding requiring an overnight hospitalization for monitoring 
purposes may be considered an SAE but is not necessarily severe. 
12.2.2.2. Expectedness 
The Sponsor will be responsible for determining whether an adverse event is ‘expected’ or 
‘unexpected’. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information provided in the Reference Safety Information of 
the effective niraparib Investigator Brochure (IB).   
12.2.2.3. Causality 
The Investigator will assess the causality/relationship between the study drug and the AE. One of 
the following categories should be selected based on medical judgment, considering the 
definitions and all contributing factors: 
• Definitely related: A clinical event, including laboratory test abnormality, occurs in a 
plausible time relationship to treatment administration, and which concurrent disease 
or other drugs or chemicals cannot explain. The response to withdrawal of the 
treatment should be clinically plausible. 
• Possibly related: A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the treatment, unlikely to be attributed 
to concurrent disease or other drugs or chemicals. 
• Unlikely related: A clinical event, including laboratory test abnormality, with a 
temporal relationship to treatment administration which makes a causal relationship 
improbable, or in which other drugs, chemicals or underlying disease provide likely 
explanations. 


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•
Unrelated: A clinical event, including laboratory test abnormality, with little or no
temporal relationship with treatment administration. Typically explained by
extraneous factors (e.g. concomitant disease, environmental factors, or other drugs or
chemicals).
12.2.3. 
Collecting and Recording Adverse Events 
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, non-leading question such as: “How have 
you been feeling since you were last asked?” The Investigator will document the nature of AE, 
date of onset of the AE (and time, if known), date of outcome of the AE (and time, if known), 
severity of the AE, action taken with study drug as a result of the AE, assessment of the 
seriousness of the AE, and assessment of the causal relationship of the AE to study drug and/or 
study procedure. 
AEs, including laboratory abnormalities that are assessed as clinically significant or require 
intervention, should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be recorded as a separate AE. 
All SAEs will be monitored through 90 days after cessation of study treatment (or to a minimum 
of 30 days post-treatment if the patient starts alternative anticancer therapy) and recorded in the 
eCRF. SAEs will also be reported on an SAE form as described in section 12.2.5 of this protocol. 
SAEs considered by the Investigator to be related to study medication are reported until the 
patient is lost to follow-up or until the patient has died. 
All AEs, regardless of the source of identification (e.g. physical examination, laboratory 
assessment, reported by patient), must be documented in the eCRF for each patient from the 
signing of the ICF for this study up to 30 days after the last dose of study treatment. 
Concomitant illnesses that existed before entry into the study will not be considered an AE 
unless the illness worsens during the treatment period. Pre-existing conditions will be recorded in 
the eCRF as well as on the SAE Report Form medical history section. 
Disease progression is an efficacy criterion and is therefore not considered an AE or SAE (even 
if fatal). Disease progression should be reported within the eCRF. If AEs/SAEs occur in relation 
to disease progression that are not consistent with the natural progression of the patient’s disease, 
these AEs/SAEs must be reported per AE/SAE reporting requirements described in 
Section 12.2.5 
12.2.4. 
Follow-Up of Adverse Events 
All AEs experienced by a patient, regardless of the suspected causality, will be monitored until 
the AE or SAE has resolved, until any abnormal laboratory values have returned to baseline or 
normal levels, until stabilized with a satisfactory explanation for the changes observed, until the 
patient is lost to follow-up, or until the patient has died. 
If an Investigator becomes aware of an SAE after the specified follow up period and considers 
the SAE related to the study drug, the Investigator should report the SAE to the Sponsor 
according to timelines for reporting SAEs described in Section 12.2.5. 


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12.2.5. 
Reporting of Serious Adverse Events 
The Investigator must report all SAEs within 24 hours of becoming aware of the initial SAE or 
any follow-up information regarding the SAE using the SAE reporting contact information as 
printed on the SAE forms and in the SAE Completion guidelines. SAEs can be reported after 
study completion, if the SAE is assessed study-drug related. 
For all SAEs, an SAE report form must be completed by the Investigator for all initial and 
follow-up SAEs. A follow-up SAE report must be completed each time the Investigator becomes 
aware of any additional information regarding the SAE. For the follow-up SAE Report Form, the 
following fields must be completed on each form: follow-up number, site number, patient 
number, protocol number, and the SAE term(s) and date of awareness. Additionally, only the 
appropriate field(s) on the SAE Report Form where the Investigator received additional or 
updated information should be completed. Previously provided information does not have to be 
entered on the follow-up SAE Report Form. 
Initial and follow-up SAE reports and any additional supporting documentation, as requested 
(e.g. hospital reports, consultant reports, death certificates, autopsy reports) included with the 
SAE report should be sent to the Sponsor (or designee) within 24 hours of the Investigator/site 
awareness or receipt. If supporting documentation is provided, the Investigator should highlight 
all relevant and pertinent information. It is the responsibility of the Investigator to review source 
documentation and describe pertinent information on the SAE form. Also, any additional SAE 
documentation must be a clear photocopy with the patient’s personal identifiers removed. The 
Investigator must sign and date all SAE forms. 
After receipt of the initial report, the Sponsor (or designee) will review the information and, if 
necessary, contact the Investigator to obtain further information. The Investigator must promptly 
respond to queries from the Sponsor. 
The minimum information required for an initial SAE report are the following: 
•
Name of person sending the report (i.e. name, address of the Investigator)
•
Investigator signature
•
Patient identification (screening/randomization number, initials [if permitted by local
data privacy regulations], NOT patient name)
− Protocol number
•
Description of SAE with diagnosis if possible
− Causality assessment
− Seriousness assessment
The Sponsor (or designee) will confirm receipt of all email reports (as long as the email is not 
coming from “no reply” domain) within 1 business day.  
After receipt of the initial report, the Sponsor (or designee) will review the information and, if 
necessary, contact the Investigator to obtain further information. The Investigator should 
promptly respond to queries from the Sponsor. 


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SAE REPORTING CONTACT INFORMATION 
Email: 
 
Fax: 
 
Telephone: 
 
12.2.6. 
Submission and Distribution of Serious Adverse Events 
Per regulatory requirements, if an event is assessed by the Sponsor as a Serious Unexpected 
Adverse Reaction (SUSAR), it is the responsibility of the Sponsor to submit the SUSAR 
Regulatory Authorities according to applicable regulations. 
In addition, the SUSAR will be distributed to the Investigators/sites, utilizing a Council for 
International Organizations of Medical Sciences (CIOMS) report form, or the MedWatch 3500A 
form). The Investigator/site will submit a copy of the report to their respective Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC) per the governing institutional 
requirements and in compliance with local laws and guidelines. 
12.2.7. 
Adverse Events of Special Interest 
Adverse Events of Special Interest (AESI) for niraparib are the following:  
• Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) 
• Secondary cancers (new malignancies [other than MDS or AML]) 
• Pneumonitis 
• Embryo-fetal toxicity 
Reporting AESIs:  All occurrences AESIs must be reported to the Sponsor within 24 hours of 
awareness. If the AESI is serious, it should be reported on an SAE Report Form [and designated 
Special Form]. If the AESI is not serious, it should be reported on the relevant designated Special 
Form. 
AESIs should also be collected and reported as follows: 
• MDS and AML along with other secondary cancers should be reported to the Sponsor until 
death or loss to follow-up. 
 
• Pneumonitis should be reported to the Sponsor through 90 days after the last dose of study 
drug (or until the start of alternate anticancer therapy, whichever occurs first). 
 
• Embryo-fetal toxicity should be reported as outlined in Section 12.2.9. 
12.2.8. 
Special Situations 
 All occurrences of abuse, misuse, medication error, overdose, and accidental occupational 
exposure with any study treatment must be reported on a Special Situation Form to the Sponsor 
regardless of whether an AE or SAE has occurred. The form should be submitted as soon as 
possible, and if there is no AE or SAE, it should be indicated that ‘no AE has occurred’. If the 
abuse, misuse, medication error, overdose, or accidental / occupational exposure is associated 
PPD
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PPD


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with an SAE, an SAE report form must be submitted to the Sponsor within 24 hours of 
awareness. 
12.2.9. 
Pregnancy Reporting and Follow-up 
The Investigator should complete the Initial Pregnancy Notification report form and forward it to 
the Sponsor (or designee) within 24 hours of knowledge of the pregnancy. If there is an 
associated serious outcome, then both the Initial Pregnancy Notification report form and SAE 
report form should be completed. 
The site will follow-up with the patient at least monthly and document the patient’s status until 
the pregnancy has been completed or terminated. The Investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the fetus or 
newborn to the Sponsor. The Pregnancy Outcome report form should be completed and 
submitted to the Sponsor within 24 hours after the Investigator becomes aware of the pregnancy 
outcome. If an SAE occurred, then the SAE form must be completed and submitted as well. 
In the event the pregnancy outcome occurs following the end of the study and database lock, the 
Investigator will report the pregnancy outcome to the Sponsor (or designee) within 24 hours after 
the outcome of the pregnancy is known to the Investigator in accordance with the procedure for 
reporting SAEs (Section 12.2.5). 
Pregnancy alone is not regarded as an AE unless there is a possibility that the study drug may 
have interfered with the effectiveness of a contraceptive medication. Elective abortions without 
complications should not be considered AEs unless they were therapeutic abortions, but should 
be reported to the Sponsor. Hospitalization for normal delivery of a healthy newborn should not 
be considered an SAE. Pregnancy is not considered an SAE unless there is an associated serious 
outcome. Spontaneous abortions should always be reported as SAEs. 
Any SAE that occurs during pregnancy must be recorded on the Pregnancy Outcome Report 
Form (e.g. maternal serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, 
neonatal death, congenital anomaly, birth defect) and reported within 24 hours in accordance 
with the procedure for reporting SAEs. 


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13. 
STATISTICS 
A statistical analysis plan (SAP) will be issued as a separate document, providing detailed 
methods for the safety analyses outlined in this section. Any deviations from the planned 
analyses will be described and justified in the final integrated clinical study report (CSR). 
13.1. 
Determination of Sample Size 
16 PK-evaluable patients will be enrolled in the study (8 with normal hepatic function and 8 with 
moderate hepatic impairment). This is a descriptive study and no formal sample size calculations 
were performed. The proposed sample size is consistent with the recommendations in the FDA 
document (at least 6 subjects), Guidance for Industry for Hepatic Function studies (Guidance for 
Industry 2003). 
13.2. 
Study Population 
13.2.1. 
Patient Disposition 
Study completion status will be summarized for all patients. Categories summarized will include 
those patients who were screened, enrolled, completed the study, or discontinued early 
(including reason for discontinuation). 
13.2.2. 
Demographic Information and Baseline Characteristics 
Demographic characteristics of all patients enrolled will be summarized descriptively by group 
and will include age, sex, race, height, and weight. 
13.2.3. 
Protocol Deviations 
Protocol deviations will be listed by patient. 
13.2.4. 
Analysis Populations 
The pharmacokinetic population for the evaluation of the PK of niraparib and M1 in patients 
with normal hepatic function and in patients with hepatic impairment will consist of all patients 
who receive niraparib and have sufficient evaluable samples for the determination of Cmax, 
AUC0-t, and AUC0-∞.  
The safety population will consist of all patients who receive drug. 
13.3. 
General Considerations 
All data will be summarized by group. Continuous variables will be summarized using 
descriptive statistics (number of patients, mean, standard deviation [StDev], minimum, median, 
and maximum). Categorical variables will be summarized using counts of patients and 
percentages. 


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13.4. 
Pharmacokinetic Analyses 
Plasma concentrations over time and PK parameters of niraparib will be evaluated after single 
dose administration. Individual and mean plasma concentrations over time will be plotted by 
hepatic function group. 
Individual patient PK parameter values will be derived by non-compartmental methods using 
WinNonlin, version 5.1 or higher. Nominal or actual time will be used in the data analysis. 
Plasma concentrations and PK parameters will be summarized in terms of the number of 
patients, arithmetic mean, standard deviation, coefficient of variation, median, minimum and 
maximum by group. 
To assess the effects of hepatic impairment on niraparib PK, linear models will be applied to the 
log-transformed Cmax, and AUC0-t, AUC0- ∞. The independent variable in the analyses will be 
liver function (normal hepatic function [control] or moderate hepatic impairment). Point 
estimates and 90% CIs for differences between means on the log scale will be exponentiated to 
express the results as ratios of geometric means on the original scale. Patients with normal 
hepatic function (Group 2) will be used as reference group to which Group 1 will be compared. 
No adjustments will be made for multiplicity. 
Box plots of PK parameters (Cmax, AUC0-t, AUC0-∞, CL/F, and CLfu/F) by hepatic function 
group will be provided.  
Similar analyses will be performed on M1 if appropriate. 
The effect of hepatic dysfunction on unbound concentrations of niraparib and M1 may be 
assessed applying a general linear model with a factor for hepatic impairment status. 
13.5. 
Safety Analyses 
13.5.1. 
Adverse Events 
All AEs will be listed. The number and percent of patients who experienced an AE will be 
summarized by timing/treatment for each system organ class and preferred term. AEs will also 
be tabulated accordingly by intensity and causality. Descriptive comparisons of event rates for 
each group will be presented.  
Serious AEs will be listed separately. 
All AEs will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA). 
Individual data listings of laboratory test results will be presented. Flags will be attached to 
values outside of the laboratory's reference limits along with the Investigator's assessment. 
Clinically significant laboratory test abnormalities that were considered AEs by the Investigator 
will be presented in the AE listing. 
Clinical laboratory tests (observed values and changes from baseline) will be summarized 
descriptively in tabular format. Shift tables will be presented for select laboratory parameters 
(chemistry and hematology). 


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Individual data listings of vital signs (observed and change from Baseline) will be presented for 
each patient. Individual clinically significant vital sign findings that were considered AEs by the 
Investigator will be presented in the AE listing. 
All physical examination findings, including abnormal findings, will be listed. 
13.5.2. 
Clinical Laboratory Tests 
Individual data listings of laboratory test results will be presented. Flags will be attached to 
values outside of the laboratory's reference limits along with the Investigator's assessment. 
Clinically significant laboratory test abnormalities that were considered AEs by the Investigator 
will be presented in the AE listing. 
Clinical laboratory tests (observed values and changes from baseline) will be summarized 
descriptively in tabular format. Shift tables will be presented for select laboratory parameters 
(chemistry and hematology). 
13.5.3. 
Vital Signs 
Individual data listings of vital signs (observed and change from Baseline) will be presented for 
each patient. Individual clinically significant vital sign findings that were considered AEs by the 
Investigator will be presented in the AE listing. 
13.5.4. 
Physical Examination 
All physical examination findings, including abnormal findings, will be listed. 


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14. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
14.1. 
Data Quality Assurance 
The Sponsor or its designee will conduct a study initiation visit to verify the qualifications of the 
Investigator, inspect the facilities, and inform the Investigator of responsibilities and procedures 
for ensuring adequate and correct documentation. 
The Investigator must prepare and maintain adequate and accurate records of all observations and 
other data pertinent to the clinical study for each study participant. Frequent communication 
between the clinical site and the Sponsor is essential to ensure that the safety of the study is 
monitored adequately. The Investigator will make all appropriate safety assessments on an ongoing 
basis. The Sponsor’s Medical Monitor may review safety information as it becomes available 
throughout the study. 
All aspects of the study will be carefully monitored with respect to Good Clinical Practices (GCP) 
and standard operating procedures (SOPs) for compliance with applicable government regulations. 
The Study Monitor will be an authorized individual designated by the Sponsor. The Study Monitor 
will have access to all records necessary to ensure integrity of the data and will periodically review 
the progress of the study with the Investigator or designee. 
14.2. 
Access to Source Data/Documents 
An electronic data capture system to manage data collection will be utilized during this trial. The 
electronic data capture system is a software tool designed to ensure quality assurance and facilitate 
data capture during clinical trials. The system is fully Code of Federal Regulations (CFR) 21 part 
11 compliant. 
The Investigator will ensure the accuracy, completeness, and timeliness of the data reported to the 
Sponsor. Data collection processes and procedures will be reviewed and validated to ensure 
completeness, accuracy, reliability, and consistency. A complete audit trail will be maintained of 
all data changes. The Investigator or designee will cooperate with the Sponsor’s representative(s) 
for the periodic review of study documents to ensure the accuracy and completeness of the data 
capture system at each scheduled monitoring visit. 
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the respective study sites by means 
of electronic or manual queries. 
The Investigator or designee will prepare and maintain adequate and accurate study documents 
(e.g. medical records, AE reporting, and concomitant medication reporting, raw data collection 
forms) designed to record all observations and other pertinent data for each patient receiving study 
treatment. 
The Investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the Institutional Review Board (IRB) to have direct access to all 
documents pertaining to the study. 


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14.3. 
Archiving Study Documents  
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected. Master files should be established at the beginning of the study, 
maintained for the duration of the study, and retained according to the appropriate regulations. 
According to International Council on Harmonization (ICH) guidelines, essential documents 
should be retained for a minimum of 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development of 
the study treatment. 
14.4. 
Good Clinical Practice 
This study will be conducted in accordance with ICH GCP and the Declaration of Helsinki 
(Version 2008). The clinical study will also be carried out in keeping with national and local 
regulatory requirement(s). 
14.5. 
Informed Consent 
Before each patient is enrolled in the clinical study, written informed consent will be obtained from 
the patient according to the regulatory and legal requirements of the participating country. As part 
of this procedure, the Investigator must explain orally and in writing the nature, duration, and 
purpose of the study, and the action of the study treatment in such a manner that the patient is 
aware of the potential risks, inconveniences, or AEs that may occur. The patient should be 
informed that he/she is free to withdraw from the study at any time. The patient will receive all 
information that is required by regulatory authorities and ICH guidelines. The Investigator or 
designee will provide the Sponsor with a copy of the IRB/IEC-approved ICF prior to the start of 
the study. 
The ICF must be signed and dated; 1 copy will be given to the patient and the Investigator will 
retain 1 copy as part of the clinical study records. The Investigator will not undertake any 
investigation specifically required for the clinical study until written consent has been obtained. 
The terms of the consent and when it was obtained must also be documented. 
If a protocol amendment is required, then the ICF may need to be revised to reflect the changes to 
the protocol. If the ICF is revised, it must be reviewed and approved by the responsible IRB/IEC, 
and signed by all patients subsequently enrolled in the clinical study as well as those currently 
enrolled in the clinical study. 
14.6. 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the responsible IRB/IEC/Competent Authorities, in accordance with local legal requirements. 
The Sponsor must ensure that all ethical and legal requirements have been met before the first 
patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, receive 
approval from the appropriate personnel, and receive IRB/IEC/Competent Authority approval 
prior to implementation (if appropriate). In the US: Following approval, the protocol 
amendment(s) will be submitted to the IND under which the study is being conducted. 


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Administrative changes (not affecting the patient benefit/risk ratio) may be made without the need 
for a formal amendment. All amendments will be distributed to all protocol recipients with 
appropriate instructions. 
14.7. 
Study Monitoring 
Monitoring and auditing procedures approved by the Sponsor will be followed, in order to comply 
with GCP guidelines. On-site checking of the CRFs for completeness and clarity, cross-checking 
with source documents, and clarification of administrative matters will be performed. 
The study will be monitored by the Sponsor or its designee. Monitoring will be done by personal 
visits from a representative of the Sponsor (site monitor) who will review the CRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and by communications (letter, 
telephone, and fax). 
All unused study treatment and other study materials will be returned to the Sponsor after the 
clinical phase of the study has been completed. 
14.8. 
Audits and Inspections 
Responsible IRB/IEC/Competent Authorities and/or the Sponsor's clinical quality assurance 
group, or its designee, may request access to all source documents, CRFs, and other study 
documentation for on-site audit or inspection. Direct access to these documents must be guaranteed 
by the Investigator, who must provide support at all times for these activities. 
14.9. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki (Version 2008). The IRB/IEC will review all appropriate study documentation in order 
to safeguard the rights, safety and well-being of the patients. The study will only be conducted at 
sites where IRB/IEC approval has been obtained. The protocol, IB, ICF, advertisements (if 
applicable), written information given to the patients, safety updates, annual progress reports, and 
any revisions to these documents will be provided to the IRB/IEC by the Investigator. 
14.10. 
Publication Policy 
Information regarding publication of study results is contained in the Steering Committee Charter. 


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15. 
LIST OF REFERENCES 
1. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. American journal of clinical oncology. 1982;5(6):649-655. 
2. 
Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-
Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016. 
3. 
Niraparib (ZEJULA) Prescribing Information. TESARO. Available at: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf. 
4. 
Ricks TK, Chiu HJ, Ison G, et al. Successes and Challenges of PARP Inhibitors in 
Cancer Therapy. Front Oncol. 2015;5:222. 
5. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the 
use of white blood cell growth factors: an evidence-based clinical practice guideline. J 
Clin Oncol. 2006;24(19):3187-3205. 
 
 


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APPENDIX 1. CONTRACEPTION GUIDELINES 
Patients of childbearing potential who are sexually active and their partners must agree to the use 
of a highly effective form of contraception throughout their participation during the study 
treatment and for 180 days after last dose of study treatment(s): 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− oral route 
− intravaginal route 
− transdermal route 
• Progestogen-only hormonal contraception associated with inhibition of ovulation  
− oral 
− injectable 
− implantable  
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence, if the preferred and usual lifestyle of the subject  


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APPENDIX 2. EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS 
Description 
Grade 
Source: 1 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.

SAP_001.pdf: 
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Statistical Analysis Plan
Protocol No: 3000-01-003
 
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     Page 1 | 26 
 
STATISTICAL ANALYSIS PLAN 
 
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 
 
Protocol Number: 
3000-01-003 
Protocol Version and Date: 
V3.0 January 15, 2018 (Amendment 2) 
v2.0 October 04, 2017 (Amendment 1) 
v1.0 June 16, 2017 (Original) 
Study Drug Name: 
Niraparib Capsules 
Phase: 
Phase 1 
Sponsor: 
TESARO, a GSK Company 
Analysis Plan Date: 
March 31, 2020 
Analysis Plan Version: 
Version 1.1 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
All information contained in this document is privileged and confidential to TESARO. 
Any distribution, copying, or disclosure is strictly prohibited without prior written 
approval by TESARO. 


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Protocol No: 3000-01-003
 
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Protocol Title: 
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 
 
Protocol Number: 
3000-01-003 
 
Sponsor:  
TESARO, a GSK Company 
1000 Winter Street 
Waltham MA 02451 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidance and guidelines. 
 
Author:  
 
, PhD 
Senior Director, Biostatistics 
 
Reviewer: 
Signature:  
Date: 
,  MD 
Senior Medical Director 
 
Signature:  
Date: 
 
 
 
PPD
PPD
PPD
PPD


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SPONSOR SIGNATURE PAGE ................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
TABLES INCLUDED IN THE TEXT ........................................................................................... 5 
ABBREVIATIONS ........................................................................................................................ 6 
1 
INTRODUCTION ................................................................................................................... 7 
2 
STUDY DESIGN OVERVIEW .............................................................................................. 8 
2.1.1 
Pharmacokinetic Phase ............................................................................................. 8 
2.1.2 
Extension Phase ........................................................................................................ 8 
3 
STUDY OBJECTIVES ......................................................................................................... 13 
4 
STUDY ENDPOINTS AND EVALUATIONS .................................................................... 14 
5 
PLANNED ANALYSIS ........................................................................................................ 15 
6 
ANALYSIS POPULATIONS AND APPLICATIONS ........................................................ 16 
7 
STATISTICAL CONSIDERATIONS .................................................................................. 17 
7.2.1 
Patients Enrollment ................................................................................................. 17 
7.2.2 
Patients Disposition ................................................................................................ 17 


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7.8.1 
Adverse Events ....................................................................................................... 20 
7.8.2 
Adverse Events of Special Interests (AESI) ........................................................... 21 
7.8.3 
Extent of Exposure .................................................................................................. 22 
7.8.4 
Clinical Laboratory Tests ........................................................................................ 23 
7.8.5 
Vital Signs ............................................................................................................... 24 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .................................... 25 
 
 
 
 
 


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Table 1: Pharmacokinetic Phase Schedule of Assessments .......................................................... 10 
Table 2: Extension Phase Schedule of Assessments..................................................................... 11 
Table 3: Application of Safety Population for Tables .................................................................. 16 
 
 
 
 
 
 
 
 
 


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ABBREVIATION 
DEFINITION 
AE 
adverse event 
AESI 
adverse event of special interest 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
 Anatomical Therapeutic Chemical 
BILI 
bilirubin 
BMI 
body mass index 
CBC 
complete blood count 
CI 
confidence interval 
CLcr 
creatinine clearance 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECOG 
Easter Cooperative Oncology Group 
eCRF 
electronic Case Report Form 
EOS 
end of study 
FDA 
US Food and Drug Administration 
ICF 
informed consent form 
INR 
international normalized ratio  
M1 
major metabolite 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
PD 
protocol deviation 
PK 
pharmacokinetics 
PT 
preferred term 
Q1 
first quartile 
Q3 
third quartile 
RECIST 
Response Evaluation Criteria in Solid Tumors 
Rel Days 
relative study days 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
WHO 
World Health Organization 
 


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1 INTRODUCTION  
This statistical analysis plan (SAP) is designed to outline the statistical methods for safety analyses 
and data presentation of investigational drug niraparib for study protocol 3000-01-003.  
Pharmacokinetics (PK) analysis will be described in a separate pharmacokinetic analysis plan.  
This document has been prepared based on Study Protocol Amendment 3 dated 15 January 2018. 
Patient populations to be used for analyses, data handling rules, statistical methods, and formats 
for data presentation and summary are identified and provided. 
 


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2 STUDY DESIGN OVERVIEW 
2.1 
Overall Study Design 
This is a Phase 1, open-label, parallel-group, single-dose study in patients with advanced solid 
tumors and with either normal hepatic function or moderate hepatic impairment.  
 
Patients with solid tumors will be recruited and enrolled within the following groups: 
 Group 1: normal hepatic function (total bilirubin [BILI] and aspartate aminotransferase 
 
 Group 2: moderate hepatic impairment (BILI >1.5 × to 3 × ULN) and any degree of AST 
elevation 
 
All patients will receive niraparib. Approximately 16 patients will be enrolled. Patients may be 
replaced so that there are 8 PK-evaluable patients per group. 
 
2.1.1 Pharmacokinetic Phase   
All patients will receive a single dose of 300 mg niraparib administered as 3 × 100 mg capsules 
on Day 1. Patients will undergo PK sampling up to 168 hours (7 days) following niraparib 
administration. Pharmacokinetic parameters to be calculated include area under the concentration 
× time curve calculated to last measured concentration, area under the concentration × time curve 
calculated to infinity, maximum concentration, time to maximum concentration, terminal half-life, 
and apparent total clearance. Protein binding parameters to be calculated include fraction of 
unbound drug and clearance of free drug. The study will be considered complete when the final 
PK evaluable patient completes all assessments in the PK phase of the study. 
Safety will be assessed through adverse event assessment, physical examination, vital sign 
measurements, clinical laboratory tests, and monitoring of concomitant medications. 
2.1.2 Extension Phase  
On the same day that patients complete the final study assessments for the PK phase, patients 
may be eligible to continue receiving niraparib in the extension phase of the study, if the 
investigator believes it is in the best clinical interest of the patient. Patients will receive their first 
therapeutic dose of niraparib on Cycle 1/Day 1 of the extension phase. Patients with normal 
hepatic function will receive an oral daily dose of 300 mg (3 x 100 mg capsules), and patients 
with moderately impaired hepatic function will receive an oral daily dose of niraparib 200 mg 
(2× 100 mg capsules). Patients will return to the study center during Cycle 1 on Days 8, 15, and 
21 to undergo safety assessments (including complete blood counts [CBCs]). Thereafter, patients 
will return on the first day of every treatment cycle (28 ±3 days) to receive study drug and for 
safety assessments (including CBCs). Dose modification (dose interruption and/or reduction) 
may be implemented for any grade toxicity considered intolerable by the patient, and must be 
implemented for any Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 


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non-hematologic adverse event considered by the Investigator related to study treatment or for 
hematologic toxicity as outlined in the protocol. Patients may continue in the extension phase 
until disease progression (assessed by Response Evaluation Criteria in Solid Tumors [RECIST] 
v1.1 and clinical signs and symptoms), unacceptable toxicity, death or discontinuation from the 
study treatment for any other reason. At end of study (EOS), safety assessments will be 
completed. No new capsules will be dispensed at EOS. 
 
The schedule of assessments for each phase is presented in Table 1  and Table 2 respectively
 
 


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Table 1: Pharmacokinetic Phase Schedule of Assessments 
Assessment 
Screening 
PK Phase 
Day of Procedure 
-28 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/ exclusion criteria 
review 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical, surgical, cancer, and 
medication history 
X 
 
 
 
 
 
 
 
 
Investigator-assessed tumor 
assessmenta 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
Xb
X 
 
 
 
 
 
X 
Height and weight 
X 
 
 
 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
Clinical laboratory assessments 
 
 
 
 
 
 
 
 
 
            CBCc 
X 
 
 
 
 
 
 
 
X 
            Serum chemistry 
X 
 
 
 
 
 
 
 
X 
            Coagulation 
X 
 
 
 
 
 
 
 
 
            Pregnancy test 
Xd
 
 
 
 
 
 
 
X 
            Urinalysis 
X 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
 
 
 
 
 
 
X 
CLcr calculation or Creatinine 
clearance 
X 
 
 
 
 
 
 
 
 
Blood sample for PK analysis 
 
X 
X 
X 
X 
 
X 
 
X 
Blood sample for plasma protein 
binding analysis 
  
X 
 
 
 
 
 
 
X 
Concomitant medications/ 
procedures 
 
Recorded from first dose of study drug through 
Safety follow-up 
 
AE monitoringe 
X 
X 
X 
X 
X 
Xe
X 
Xe
X 
Niraparib treatment dispensed 
 
X 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CBC = complete blood count; CLcr 
= creatinine clearance; CT = computed tomography; ECOG= Eastern Cooperative Oncology Group; EOS = end of 
study; ICF = informed consent form; MRI = magnetic resonance imaging; PK = pharmacokinetic; SAE = serious 
adverse event. 
a RECIST (v1.1) tumor assessment via a CT or MRI scan of clinically indicated areas and evaluation of clinical 
signs and symptoms should be performed at minimum at screening in the PK Phase and as described in Table 2 for
the Extension Phase. 
b To be collected prior to niraparib dosing 
c During the extension phase, test complete blood counts weekly for the first month, monthly for the next 11 months 
of treatment and periodically after this time. 
Medical and supportive therapy should be optimized for management of toxicities. 
d Serum or urine pregnancy test within 72 hours prior to first dose of niraparib 
e Collection of AEs begins when ICF is signed. AE monitoring on PK Phase Days 5 and 7 may be performed by 
telephone.


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Table 2: Extension Phase Schedule of Assessments 
Assessment 
Extension Phase 
Cycle 1 
Cycle n 
/Day 1 
EOS 
Safety 
Follow-up 
Day of Procedure 
(window) 
1a 
8 
15 
21 
1 
(+ 7 Days 
post-treatment) 
30 (+ 7 Days) 
Investigator assessed tumor 
assessmentb 
 
 
 
 
X 
X 
 
Vital signs 
X 
 
 
 
X 
X 
X 
ECOG 
X 
 
 
 
 
X 
X 
Weight 
 
 
 
 
 
 
X 
         CBCc
X 
X 
X 
X 
X 
X 
X 
         Serum chemistry 
 
 
 
 
X 
X 
X 
         Pregnancy test 
 
 
 
 
X 
X 
X 
         Urinalysis 
 
 
 
 
 
 
X 
Physical exam 
X 
 
 
 
X 
X 
X 
Concomitant medications/ 
procedures 
 
Recorded from first dose of study drug through Safety follow-up 
AE monitoringd
X 
X 
X 
X 
X 
X 
X 
Niraparib treatment 
dispensed 
Xe 
 
 
 
X 
 
 
a May be the same as PK Day 8/End of PK Phase 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; CBC = complete blood count; CLcr 
= creatinine clearance; CT = computed tomography; ECOG= Eastern Cooperative Oncology Group; EOS = end of 
study; ICF = informed consent form; MRI = magnetic resonance imaging; PK = pharmacokinetic; SAE = serious 
adverse event. 
b Tumor assessment via a CT or MRI scan of clinically indicated areas and evaluation of clinical signs and   
symptoms should be performed at a minimum at screening and, during the extension phase, every three cycles or  
evaluate disease status and progression, discontinue niraparib and initiate subsequent anticancer treatment as   
necessary. 
c During the extension phase, test complete blood counts weekly for the first month, monthly for the next 11 months   
of treatment and periodically after this time. 
Medical and supportive therapy should be optimized for management of toxicities. 
d AEs are required to be captured through 30 days after cessation of study treatment; SAEs are required to be 
captured through 90 days after cessation of study   treatment (or to a minimum of 30 days post-treatment if the 
patient starts alternative anticancer therapy); and any pregnancies that occur within 180 days post-treatment are to 
be captured. Study drug-related SAEs and adverse events of special interest (AESIs) will continue to be monitored 
via   telephone every 90 ± 14 days after the last dose of study drug. 
e If Cycle 1/Day 1 is the same day as Day 8 of the PK phase, then niraparib treatment must be dispensed after all 
other assessments (including PK) have been completed. 
 
 
 
 


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2.2 
Sample Size  
16 PK-evaluable patients will be enrolled in the study, in which 8 patients are with normal hepatic 
function and 8 patients are with moderate hepatic impairment.  
 
This is a descriptive study and no formal sample size calculations were performed. The proposed 
sample size is consistent with the recommendations in the FDA document (at least 8 subjects), 
Guidance for Industry for Hepatic Function studies (Guidance for Industry 2003). 
 
2.3 
Randomization and Blinding 
This is an open-label study, and patients will not be randomized. 
 
 


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3 STUDY OBJECTIVES 
3.1 
Primary Objective 
 To characterize the pharmacokinetics (PK) of niraparib and its major metabolite (M1) 
when administered as a single dose in cancer patients with normal hepatic function 
compared to patients with moderate hepatic impairment. 
 
3.2 
Secondary Objective 
 To evaluate the safety of niraparib when administered as a single dose in patients with 
moderate hepatic impairment. 
 To obtain additional safety data through the extension phase, in which patients have the 
option to continue receiving niraparib. 
 


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4 STUDY ENDPOINTS AND EVALUATIONS  
4.1 
Safety Evaluations 
The safety evaluations include:  
 Treatment emergent adverse events (TEAEs) 
 Clinical laboratory assessments (including CBC, serum chemistry, and urinalysis) 
 Serum or urine pregnancy testing 
 Vital signs (including weight) 
 Physical examination findings 
 ECOG performance status  
 
4.2 
Other Evaluations 
Other evaluations include: 
 Demographics and baseline characteristics 
 Medical history 
 General medical history 
 Surgical history 
 Primary cancer history  
 Prior anticancer treatment 
 Prior anticancer treatment for primary cancer 
 Previous radiotherapy 
 Previous cancer related surgery 
 Medication history (prior medications) and concomitant medications/Procedures 
 Growth factors 
 Transfusion 
 Tumor lesion assessment 
 
 


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5 PLANNED ANALYSIS 
5.1 
Changes from Planned Analyses in the Protocol 
There are no changes from planned analyses in the Protocol. 
5.2 
Final Analyses and Reporting 
All final planned analyses per protocol and this SAP will be performed after database lock. 
 


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6 ANALYSIS POPULATIONS AND APPLICATIONS  
6.1 
All Patients Population 
This population includes all patients who sign an informed consent form (ICF). 
6.2 
Safety Population 
Safety Population for PK phase includes patients who receive at least one dose of the 
investigational drug niraparib during the PK Phase.  
Safety Population for extension phase includes patients who receive at least one dose of the 
investigational drug niraparib during the extension Phase.  
6.3 
Application of Analysis Populations 
Safety Population that will be used for creating the summary table(s) of each type is provided in 
Table 3.  All data will be presented in listings either for All Patients Population or for Safety 
Population. 
Table 3: Application of Safety Population for Tables  
Type 
PK Phase 
Extension Phase 
Disposition 
X 
X 
Demographics and baseline characteristics 
X 
 
Protocol deviations 
X 
 
Prior and concomitant medications 
X 
X 
Safety evaluations 
X 
X 
Extent of Exposure 
 
X 
 


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7 STATISTICAL CONSIDERATIONS 
All analyses described in this plan are considered a priori analyses in that they have been defined 
prior to locking the database.  All other analyses, if any, designed subsequently to locking the 
database, will be considered post hoc analyses and will be described as exploratory analyses in the 
Clinical Study Report.  
All summaries and statistical analysis will be performed by SAS v9.3 or later.  
7.1 
General Statistical Procedures 
Frequency distributions for categorical variables will be provided as counts of patients and 
percentages.  Percentages will be based on the number of patients with a non-missing parameter 
unless missing category is presented or based on number of population as indicated below. 
Percentages will be reported to one decimal place.  
The descriptive statistics for continuous variables will be number of patients, mean, standard 
deviation (SD), median, quartiles (Q1, Q3), minimum and maximum.   Mean, median, Q1, and Q3 
will be reported to 1 more decimal place than the raw data, while the SD will be reported to 2 more 
decimal places than the raw data. 
All data listings that contain an evaluation date will also contain relative study day (Rel days) 
which is defined as number of days relative to the first dose date of study drug (see Section 8.2 for 
details). 
7.2 
Enrollment and Disposition  
7.2.1 Patients Enrollment 
Patients enrollment will be summarized for each analysis population. The number of patients in 
each analysis population will be presented by hepatic function group and overall. 
Enrollment information will be provided in a data listing for All Patients Population. 
7.2.2 Patients Disposition 
Study completion status will be summarized for each hepatic function group. Number and 
percentage of patients who complete the study, number and percentage of patients discontinued 
the study early by primary reasons will be presented. The denominators for calculating the 
percentages will be based on number of patients in Safety Population for each hepatic function 
group.  
Discontinued patients will be provided in a data listing for Safety Population. 
7.3 
Protocol Deviations 
Important or significant protocol deviations (PDs) will be assessed by sponsor personnel following 
Protocol Deviation Guideline outlined in Clinical Management Plan.  


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A PD is classified as important if there is the potential to impact the completeness, accuracy, and/or 
l-being. An important PD is 
classified as significant if it is confirmed to adversely impact the completeness, accuracy, and/or 
-being.  
All PDs will be identified and finalized prior to database lock and documented in a separate 
Medical Data Review Plan (MDRP).   
Number and percentage of patients with a significant or important PD will be tabulated by type of 
deviation. The denominators for calculating the percentages will be based on number of patients 
in Safety Population for each hepatic function group.  
All protocol deviations will be listed for Safety Population.  
7.4 
Demographics and Baseline Characteristics 
Demographic and baseline (see Section 8.1 for definition) characteristics will be tabulated using 
descriptive statistics for all patients and by hepatic function group. The following variables will be 
included in the tables:  
 The demographic data are: 
 Age  
 Sex 
 Race 
 Ethnicity 
 Baseline characteristics include: 
 Baseline weight (kg) 
 Baseline height (cm) 
 BMI (Body mass index, kg/m2, calculated as weight (kg) / height (m)2) 
 ECOG performance status at baseline 
 
   Conversions for height and weight are as follows: 
height (cm) = height (inches) x 2.54 
weight (kg) = weight (lb) x 0.4536 
 
Demographics and baseline characteristics will be listed for Safety Population. 
 
7.5 
Prior Anticancer Treatment 
Prior anticancer treatment will be tabulated using descriptive statistics for all patients and by 
hepatic function group. The following variables will be included in the tables:  
 Primary tumor site at first and most recent diagnosis 
 Cancer stage at first and most recent diagnosis 
 Best response during last treatment 


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 Number of prior treatments, any surgeries/procedures related to cancer 
A data listing of prior anticancer treatment including surgical/procedures, primary cancer history 
and previous radiotherapy will be provided for Safety Population. 
7.6 
Medical History 
The medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary, v22.0. The frequency count and percentage of patients experiencing any 
medical conditions will be tabulated by system organ classifications (SOC) and preferred term 
(PT) of MedDRA for all patients and by hepatic function group for each phase.  The denominators 
for calculating the percentages will be based on number of patients in Safety Population for each 
phase for each hepatic function group.  
A data listing of medical history including general medical, surgical and primary cancer history 
will be provided for Safety Population. 
7.7 
Prior and Concomitant Medication /Therapy 
All medications as documented by the investigator will be coded using the World Health 
Organization (WHO) Drug Dictionary (WHO-DD Sept 2018). The count and percentage of 
patients who took prior and concomitant medications will be provided by hepatic function group, 
ATC level 3 and WHO Drug preferred term (PT) for each phase.  The denominators for calculating 
percentages will be based on the number of patients in Safety Population for each hepatic group. 
For the summary tables, if a patient has taken a prior or concomitant medication more than once, 
the patient will be counted only once for the medication. 
Prior non-anticancer medications are defined as any medications, other than study treatment, 
medications for cancer treatment and pre-medications for study treatment, which ended prior to 
the first dose date of study treatment. 
 
Concomitant medications are medications other than study treatments, being taken on or after the 
initial study treatment dosing date through 30 days after the last dose or until the start of 
subsequent antitumor therapy, specifically  
 
 PK Phase: 
o If patient discontinued study during PK phase, concomitant medications are 
medications being taken on or after first dose date in PK Phase through 30 days 
after the first dose date in PK Phase 
o If patient did not discontinued study during PK phase, concomitant medications 
are medications being taken on or after first dose date in PK phase but prior to the 
first dose date in Extension phase. 
 
 Extension Phase: 
o Concomitant medications are medications being taken on or after first dose date in 
Extension Phase through 30 days after the last dose date in Extension Phase + 30 


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days (including those medications that started from PK Phase, but not stopped 
prior to Extension Phase) 
 
The use of prior medications (including non-anticancer and anticancer) and concomitant 
medications will be provided in a by-patient data listing for Safety Population. 
 
7.8 
Analysis of Safety Data  
7.8.1 Adverse Events 
AEs will be coded using MedDRA and will be classified by SOC and PT of MedDRA v 22.0. 
Severity of AEs will be assessed by investigators according to CTCAE (v4.03).  
 
A treatment-emergent AE (TEAE) will be defined as any new AE that begins, or any preexisting 
condition that worsens in severity during the treatment period.  For the determination of the TEAEs 
during the treatment period, AEs with the greatest severity before the baseline will be used as the 
benchmark for the comparison of the AEs occurring within 30 days after last dose date or until the 
start of subsequent antitumor treatment, or 90 days after last dose date for serious AEs. Specifically: 
 
 PK Phase: 
o If patient discontinued study during PK phase, TEAE period is from first dose 
date in PK Phase to first dose date in PK Phase + 30 days 
o If patient did not discontinued study during PK phase, TEAE period is first dose 
date in PK phase to first dose date in Extension phase. 
 
 Extension Phase: 
o TEAE period is from first dose date in Extension Phase to last dose date in 
Extension Phase + 30 days 
 
AEs that have a possible or definite relationship to study drug niraparib will be defined to be related 
Any AEs for which the 
relationship to study drug niraparib is missing will be considered as related to study drug. AEs 
with the closest relationship to drug niraparib will be used for summary.    
 
The number and percentage of patients who experienced an AE will be summarized by hepatic 
function group for each phase. The denominator for calculating the percentages will be based on 
the number of patients for each hepatic function group in the Safety Population of each phase.  
   
The following types of summaries will be provided for each phase of the study: 
 Overview of TEAEs 
 TEAEs by SOC and PT 
 TEAEs by SOC, PT, and Maximum CTCAE toxicity grade 
 TEAEs by SOC, PT, and Maximum CTCAE toxicity grade  3 


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 TEAEs by PT in decreasing frequency 
 Drug-related TEAEs by SOC and PT 
 Drug-related TEAEs by PT in decreasing frequency 
 Serious TEAEs by SOC and PT 
 TEAEs leading to treatment discontinuation by SOC and PT 
 TEAEs leading to dose interruption by SOC and PT  
 TEAEs leading to dose reduction by SOC and PT 
 TEAEs of special interest by special interest category, SOC, and PT. 
 
If a preferred term or system organ class was reported more than once for a patient, the patient 
would only be counted once in the incidence for that preferred term or system organ class.  
 
In tabulation by severity (i.e., CTCAE v 4.03 toxicity grade),  
 For a given preferred term, only the most severe preferred term for each patient will be 
included.   
 For a given system organ class, only the most severe system organ class for each patient 
will be included.   
 
Similarly, in tabulation by relationship, 
 For a given preferred term, the most closely related preferred term to the study drug for 
each patient will be included.  
 For a given system organ class, the most closely related system organ class to the study 
drug for each patient will be included.  
 
Adverse events, serious adverse events, and adverse events leading to discontinuation from the 
study will be provided in separate data listings.  
7.8.2 Adverse Events of Special Interests (AESI) 
Analyses of AESIs are based on pre-defined MedDRA PTs below in Table 4.  
Table 4: Adverse Events of Special Interest 
AESI  
Preferred Term 
Myelodysplastic Syndromes (MDS) 
and Acute Myeloid Leukemia (AML)  
 
5q minus syndrome 
 
Bone marrow infiltration 
 
Chronic myelomonocytic leukaemia 
 
Chronic myelomonocytic leukaemia (in 
remission) 
 
Granulocytes maturation arrest 
 
Myelodysplastic syndrome 
 
Myelodysplastic syndrome transformation 
 
Myelodysplastic syndrome unclassifiable 


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AESI  
Preferred Term 
 
Myeloid maturation arrest 
 
Myeloid metaplasia 
 
Platelet maturation arrest 
 
Platelet production decreased 
 
Proerythroblast count increased 
 
Refractory anaemia with an excess of blasts 
 
Refractory anaemia with ringed sideroblasts 
 
Refractory cytopenia with multilineage dysplasia 
 
Refractory cytopenia with unilineage dysplasia 
 
Acute myeloid leukaemia 
 
Acute myeloid leukaemia (in remission) 
 
Acute myeloid leukaemia recurrent 
 
Acute myeloid leukaemia refractory 
 
Transformation to acute myeloid leukaemia 
 
Secondary cancers (new malignancies 
[other than MDS or AML])  
Malignant tumors (Narrow) SMQ, see Hepatic SAP 
AESI_MedDRA22.pdf for details 
Pneumonitis  
 
 
Interstitial lung disease 
 
Pulmonary fibrosis 
 
Acute interstitial pneumonitis 
 
Alveolitis 
 
Alveolitis necrotizing 
 
Hypersensitivity pneumonitis 
 
Pulmonary toxicity 
 
Non-infectious pneumonitis  
Embryo-fetal toxicity 
Pregnancy and neonatal topics (SMQ) , see Hepatic SAP 
AESI_MedDRA22.pdf for details 
Lists will be finalized based on most recent MedDRA version prior to the data cutoff. 
7.8.3 Extent of Exposure  
The number and percentages of patients exposed to study drug in each phase will be provided for 
each hepatic function group. The denominators for percentages will be based on the number of 
patients exposed to study drug in each hepatic function group.  
Additionally, study drug exposure and dose intensity will be summarized by hepatic function 
group using descriptive statistics for extension phase including: 
 Number of exposure cycles (start from first cycle in extension phase) as a continuous 
variable 
 Number and percentage of patients treated by maximum cycles 
from first cycle in extension phase).  
 Duration of exposure (days), defined as  
 last dose date  firs dose date in extension phase + 1 
 Number of patients with dose interruptions or dose reduction 
 Actual cumulative dose (mg), defined as 
 Sum of all doses actually administered in extension phase 


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 Actual dose intensity (mg/day), defined as 
 Actual cumulative dose (mg) divided by the duration of exposure (days)  
 Relative dose intensity (%), defined as  
 Actual dose intensity (mg/cycle) divided by the intended dose intensity (mg/day), 
expressed in percentage 
 
Details of study drug exposure and dose intensity for extension phase will be listed for Safety 
Population. 
7.8.4 Clinical Laboratory Tests 
converting values in original units to values in SI units and classified as normal, low, or high based 
on normal ranges supplied by the local laboratories and upon employing standardization. Both 
l
SI units will be listed for Safety Population.  
changes from baseline) will be summarized by visit and hepatic function group using descriptive 
statistics.  
 
Laboratory test results will be categorized by CTCAE v 4.03 toxicity grades based on the values 
and normal ranges reported by the local laboratories.  Within each hepatic function group, 
comparisons of CTCAE grades at baseline to grades at each post-baseline visit for each laboratory 
parameter will be summarized in 5-by-5 shift tables (grade 1 to grade 5). Denominators for 
calculating the percentages will be based on be number of patients with evaluable shifts at each 
post-baseline visit for Safety Population for each hepatic function group. Laboratory results with 
toxicity grades missing at either baseline or at post-baseline will not be used for summary in shift 
tables. 
 
Coagulation parameters international normalized ratio (INR) and activated partial thromboplastin 
time (aPTT) will be tabulated by each hepatic function group.  
 
In general, all by visit summaries of clinical laboratory parameters will only be summarized up 
to and including month 6 and at the treatment discontinuation visit. The maximum and minimum 
calculations will use all post-baseline data, including any unscheduled assessments.  
Unscheduled measurements will not be used in computing the descriptive statistics for change 
from baseline at each post-baseline time point. However, they will be used in assessing the 
minimum and maximum of all visits and in the analysis of notable post-baseline results (for 
example shift tables). 


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7.8.5 Vital Signs 
Observed vital signs and changes from baseline will be summarized by visit for each hepatic 
function group for each parameter.  
 
A patient-detailed listing of vital signs will be provided for Safety Population.  
 
7.9 
Additional Data Presentation as Listing   
 Inclusion/exclusion criteria not met 
 Serum or urine pregnancy testing  
 Physical examination findings including abnormal findings  
 CLcr calculation or Creatinine clearance  
 Growth factors 
 Transfusion 
 Tumor lesion assessment 
 Tumor response per RECIST 1.1 
 Malignancy reported in long term safety follow-up 


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8 DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Definition of Baseline 
PK Phase: 
For all evaluations unless otherwise noted, baseline for PK Phase is defined as the most recent 
measurement prior to the first administration of study drug in PK phase. Baseline can be the same 
date as first dose, given the measurement is expected prior to first dose when only date information 
is available. 
Extension Phase: 
For all evaluations unless otherwise noted, baseline is defined as the most recent measurement 
prior to the first administration of study drug in Extension phase. Baseline can be the same date as 
first dose, given the measurement is expected prior to first dose when only date information is 
available. 
8.2 
Definition of Relative Study Days 
Unless otherwise noted, relative study days (Rel Days) of an evaluation are defined as number of 
days relative to the first dose date of study drug which is designated as Day 1, and the preceding 
day is Day -1, the day before that is Day -2, etc. Relative study days are calculated as an evaluation 
date minus first dose date of study drug, and plus 1 day if evaluation date is on or after first dose 
date.   
Relative study days take negative values if evaluation date occurs prior to first dose date, and take 
positive values if evaluation date occurs on or after first dose date of study drug. 
8.3 
Analysis Visit Window 
For safety parameters excluding clinical laboratory data, measurements collected from 
unscheduled visits will not be included in the by-visit summary tables but will be included in the 
listings. Early termination visits for safety measurements will not be mapped to any scheduled 
post-baseline visit, but will be used as the last assessment during treatment period.  
8.4 
Safety Data Handling 
For all safety data, only observed data will be used for analyses, and missing data will not be 
imputed. 
8.5 
Handling of Partial Dates for AEs   
When determining the treatment emergent AE, partial dates will be handled as follows.  
 If the day of the month is missing, the onset day will be set to the first day of the month 
unless it is the same month and year as study treatment. In this case, the onset date will be 
assumed to be the date of treatment. 
 If the onset day and month are both missing, the day and month will be assumed to be 
January 1, unless the event occurred in the same year as the study treatment. In this case, 


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the event onset will be coded to the day of treatment to conservatively report the event as 
treatment-emergent.  
 A missing onset date will be coded as the day of treatment. If the resulting onset date is 
after a reported date of resolution, the onset date will be set equal to the date of resolution.  
 Imputation of partial dates is used only to determine whether an event is treatment-
emergent; data listings will present the partial date as recorded in the eCRF. 
8.6 
Handling of Partial Dates for Medications  
When determining prior or concomitant medications, partial start dates of prior and concomitant 
medications will be assumed to be the earliest possible date consistent with the partial date. 
Partial stop dates of prior and concomitant medications will be assumed to be the latest possible 
date consistent with the partial date. In the case of completely missing stop date, medication will 
be assumed to be ongoing. In the case of complete missing start date, medication will be 
assumed to be prior medication. 


Tesaro, Inc. 
Study 3000-01-003 
20 September 2018 
 
 
 
CONFIDENTIAL 
Page 1 of 18 
 
 
 
 
PHARMACOKINETIC DATA ANALYSIS PLAN 
 
 
 
 
PROTOCOL NUMBER: 
 
3000-01-003 
PROTOCOL TITLE: 
 
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 
 
SPONSOR: 
 
TESARO, Inc. 
1000 Winter Street 
Suite 3300 
Waltham, MA 02451 
VERSION/DATE 
 
Version 1.0, 20 September 2018 
PREPARED BY: 
 
SAJE Consulting LLC 
 
 
 


Tesaro, Inc. 
Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 2 of 18 
SIGNATURE PAGE 
SAJE CONSULTING LLC AUTHORS: 
, Ph.D. 
SAJE Consulting LLC 
Date 
SPONSOR APPROVAL: 
, Ph.D. 
Tesaro, Inc. 
Date 
PPD
PPD
PPD
Sept. 20, 2018


Tesaro, Inc. 
 
Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 3 of 18 
 
1 
INTRODUCTION 
This study is 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. 
Niraparib 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. 
This data analysis plan is consistent with Section 11, Pharmacokinetic Assessments of the study 
protocol (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 
Version3, Amendment 2, dated 15 January 2018) and includes additional details of the estimates 
of pharmacokinetic (PK) parameters, statistical analysis of the PK parameters, and summaries to 
be included in the pharmacokinetic analysis report. 
2 
STUDY DESIGN AND OBJECTIVES 
2.1 
Study Design 
This is a Phase 1, open-label, parallel-group, single-dose study in patients with advanced solid 
tumors and with either normal hepatic function or moderate hepatic impairment. 
Patients with solid tumors were recruited and enrolled within the following groups: 
• Group 1: normal hepatic function (total bilirubin [BILI] and 
aspartate aminotransferase [AST] ≤ upper limit of normal [ULN]) 
• Group 2: moderate hepatic impairment (BILI >1.5 × to 3 × ULN) and any degree 
of AST elevation 
All patients will receive a single dose of 300 mg niraparib administered as 3 × 100 mg capsules 
on Day 1. Patients will undergo PK sampling up to 168 hours (7 days) following niraparib 
administration. Pharmacokinetic parameters to be calculated include area under the 
concentration × time curve calculated to last measured concentration (AUC0-t), area under the 
concentration × time curve calculated to infinity (AUC0-∞), maximum concentration (Cmax), 
time to maximum concentration (tmax), terminal half-life (t½), and apparent total clearance 
(CL/F). Protein binding parameters to be calculated include fraction of unbound drug (Fu) and 
clearance of free drug (CLfu/F). The study will be considered complete when the final PK 
evaluable patient completes all assessments in the PK phase of the study. 
During the PK Phase of the study, patients should come to the clinic on the morning of Day 1 
of the PK period following a 12-hour overnight fast. During the overnight fast, patients are 


Tesaro, Inc. 
 
Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 4 of 18 
 
permitted to consume water (but no other beverages) until up to 2 hours prior to dosing of the 
study drug. Patients may take their routine medications with sips of water. 
Patients will receive a single dose (300 mg) of the formulation with approximately 250 ml of 
water on Day 1 of the PK period. Patients may resume their regular diet 4 hours after taking the 
study drug. 
2.2 
Study Objectives 
The PK objectives of this study are: 
 
The primary objectives of this study are as follows: 
• To characterize the pharmacokinetics (PK) of niraparib and its major metabolite (M1) if 
appropriate when administered as a single dose in cancer patients with normal hepatic 
function compared to patients with moderate hepatic impairment. 
The secondary objectives of this study are as follows: 
• To evaluate the safety of niraparib when administered as a single dose in patients with 
moderate hepatic impairment. 
• To obtain additional safety data through the extension phase, in which patients have the 
option to continue receiving niraparib. 
This PK analysis plan and the resulting PK report will address the PK objectives of the study.  
The PK report will be included as an appendix to the clinical CSR.  
3 
PHARMACOKINETIC ASSESSMENTS 
3.1 
Pharmacokinetic Analysis 
Blood will be collected during the study for PK assessments and protein binding at the 
timepoints relative to niraparib dosing as described below. In total, approximately 80 mL of 
blood will be collected from each patient. 
Pharmacokinetic Assessments 
Timepoint 
Collection window 
Predose 
within 30 minutes prior to dosing 
1 hr postdose 
± 5 min 
2 hrs postdose 
± 5 min 
3 hrs postdose 
± 5 min 
4 hrs postdose 
± 5 min 
6 hrs postdose 
± 15 min 


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20 September 2018 
CONFIDENTIAL 
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8 hrs postdose 
± 15 min 
12 hrs postdose 
± 15 min 
24 hrs postdose 
± 30 min 
48 hrs postdose 
± 60 min 
72 hrs postdose 
± 60 min 
120 hrs postdose 
± 120 min 
168 hrs postdose 
± 120 min 
Plasma protein binding 
Predose 
  within 30 minutes prior to dosing 
3 hrs postdose 
± 5 min 
168 hrs postdose 
± 120 min 
 
The volume of blood collected for PK assessments from each patient (approximately 5 mL per 
sample) during the study will be approximately 65 mL. Blood sample collection, processing, and 
shipping details will be outlined in a separate laboratory manual. In brief, blood will be collected 
into potassium ethylene diamine tetraacetic acid (K3EDTA) tubes, processed and plasma 
analyzed by a validated method of liquid chromatography coupled to tandem mass spectrometry 
detection (LC/MS/MS) for determination of the concentrations of niraparib and M1 if 
appropriate. The pharmacokinetic parameters (Section 11.1) will be calculated from the plasma 
concentration-time profiles.  
The total volume of blood collected during the study for plasma protein binding from each 
patient (approximately 5 mL per sample) will be approximately 15 mL. Blood sample collection, 
processing, and shipping details will be outlined in a separate laboratory manual. In brief, plasma 
protein binding will be performed by equilibrium dialysis (MWCO 10kD). At the end of dialysis, 
aliquots from both compartments will be analyzed to determine the concentration of the 
unchanged drug using a modified LC/MS/MS method. 
The following PK parameters will be calculated, within Phoenix WinNonlin Version 8.0, if 
appropriate:  
• Cmax: Observed maximum plasma concentration 
• 
tmax: Time to Cmax 
• Kel:, the terminal elimination rate constant, will be estimated at terminal phase by linear 
regression after log-transformation of the concentrations 
o Only those data points that are judged to describe the terminal log-linear decline 
will be used in the regression.  


Tesaro, Inc. 
 
Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 6 of 18 
 
o A minimum number of three descending data points in the terminal phase will be 
used in calculating Kel with the line of regression starting at any post-Cmax data 
point (Cmax should not be part of the regression slope). 
o The adjusted correlation coefficient (R2 adj) in general should be greater than 
0.80.  
o An appropriate number of decimal places should be used for Kel to enable the 
reported value of t1/2 to be calculated. 
• AUC0-t: Area under the concentration-time curve up to the last observable concentration 
calculated using linear trapezoidal summation from time 0 to time t, where t is the time of 
the last measurable concentration (Ct); 
• AUC0-inf: Area under the concentration-time curve up to infinity calculated using linear 
trapezoidal summation from time 0 to time infinity using the linear up log down method, 
AUC(0-inf) = AUC(0-t) + Ct/Kel, where Kel is the terminal elimination rate constant (the 
slope of elimination phase of the log-concentration versus time plot) and Ct is the last 
measurable plasma concentration.  AUC0-inf  will not be reported if the % extrapolated 
exceeds 20% ; 
• CL/F: Apparent total clearance of drug after oral administration, calculated as CL/F = 
Dose/AUC.  Units will be volume / time (e.g. L/hr); 
• t1/2: Terminal half-life time estimated by 0.693/Kel (Kel is determined by the slope of 
terminal phase of log concentration versus time plot). 
Additional plasma samples will be drawn for the assessment of unbound concentrations of 
niraparib. The following will be calculated for protein binding: 
• Fu: Fraction of unbound niraparib 
• CLfu/F: Clearance of free niraparib 
The mean plasma concentration over time by hepatic function group and the individual subject 
plasma concentration versus time data will be plotted. Nominal times will be used for plotting 
the mean plasma concentrations over time by hepatic function group and actual sampling times 
will be used for the individual figures and for the non-compartmental analysis.  
The PK parameters will be summarized descriptively including the number of observations, 
arithmetic mean, SD, CV, minimum, median, maximum, geometric mean and geometric CV%.  
All PK parameters will be rounded to 3 significant figures except for Tmax which will be 
rounded to two decimal places. 


Tesaro, Inc. 
 
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20 September 2018 
CONFIDENTIAL 
Page 7 of 18 
 
Mean SD, Median, Min, Max, and geometric mean will be presented to 3 significant figures for 
all PK parameters except Tmax, Tmax will be presented to 2 decimal places; CV% and 
geometric CV% will be presented to 1 decimal place.  
3.2 
Non-Quantifiable Concentrations 
All plasma concentration values reported as No Results/Not Reportable (NR) values will be 
treated as missing and will appear in the data set as “.”.  Values below the quantifiable limit 
(BQL) that occur prior to the first measurable concentration will be treated as zero. All other 
BQL values will be treated as missing and set to “.”. 
3.3 
Statistical Analysis of PK parameters of Niraparib   
To assess the effects of hepatic impairment on niraparib PK, linear models will be applied to the 
log-transformed Cmax, and AUC0-t, AUC0- inf. The independent variable in the analyses will be 
liver function (normal hepatic function [control] or moderate hepatic impairment). Point 
estimates and 90% CIs for differences between means on the log scale will be exponentiated to 
express the results as ratios of geometric means on the original scale. Patients with normal 
hepatic function (Group 2) will be used as reference group to which Group 1 will be compared. 
No adjustments will be made for multiplicity. 
Box plots of PK parameters (Cmax, AUC0-t, AUC0-inf, CL/F, and CLfu/F) by hepatic function 
group will be provided. 
The effect of hepatic dysfunction on unbound concentrations of niraparib may be assessed 
applying a general linear model with a factor for hepatic impairment status. 
Descriptive statistics (number, arithmetic mean, arithmetic standard deviation [SD], median, 
minimum, maximum, geometric mean, and geometric coefficient of variation [CV%]) will be 
calculated for plasma concentrations and PK parameters of niraparib and M1 if appropriate. 
 
 


Tesaro, Inc. 
 
Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 8 of 18 
 
4 
TABLES, FIGURES AND LISTINGS (MOCKS) 
 
List of Figures 
Figure 4.1-1  
Mean niraparib concentrations (units) by hepatic function group (linear 
scale) .....................................................................................................................9 
Figure 4.1-2  
Mean niraparib concentrations (units) by hepatic function group (log-
linear scale) ........................................................................................................10 
Figure 4.1-3  
Mean (+SD) concentration time profiles for niraparib following 
administration to patients with moderate hepatic impairment or normal 
hepatic function .................................................................................................10 
Figure 4.1-4  
Boxplot of Niraparib PK parameters by hepatic function ............................11 
Figure 4.4-1 
Individual Niraparib Concentrations Following Administration of 
Niraparib to Patients with Moderate Hepatic Impairment or Normal 
Hepatic Function ...............................................................................................18 
Figure 4.4-2   
Combined Individual Niraparib Concentrations Following 
Administration of Niraparib to Patients with Moderate Hepatic 
Impairment or Normal Hepatic Function ......................................................18 
 
List of Tables 
Table 4.2-1   
Summary of Plasma Concentrations (units) of Niraparib by Hepatic 
Function .............................................................................................................12 
Table 4.2-2 
Summary of Pharmacokinetic Parameters of Niraparib by Hepatic 
Function .............................................................................................................13 
 
List of Listings 
 
Listing 4.3-1 
Niraparib Plasma Concentrations (unit) Following Dose Administration 
of 300 mg Niraparib to Patients with Normal Hepatic Function .................14 
Listing 4.3-2 
Niraparib Plasma Concentrations (unit) Following Dose Administration 
of 300 mg Niraparib to Patients with Moderate Hepatic Impairment ........15 
Listing 4.3-3 
Niraparib Plasma Pharmacokinetic Parameters Following 
Administration of 300 mg Niraparib to Patients with Normal Hepatic 
Function .............................................................................................................16 
Listing 4.3-4 
Niraparib Plasma Pharmacokinetic Parameters Following 
Administration of 300 mg Niraparib to Patients with Moderate Hepatic 
Impairment ........................................................................................................17 
 
 


Tesaro, Inc. 
 
Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 9 of 18 
 
4.1 
Figures 
Figure 4.1-1  Mean niraparib concentrations (units) by hepatic function group (linear 
scale) 
 
 
 
Normal hepatic function
Moderate hepatic impairment 


Tesaro, Inc. 
 
Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 10 of 18 
 
Figure 4.1-2  Mean niraparib concentrations (units) by hepatic function group (log-linear 
scale) 
 
Figure 4.1-3  Mean (+SD) concentration time profiles for niraparib following 
administration to patients with moderate hepatic impairment or normal hepatic function 
 
 
 
Normal hepatic function
Moderate hepatic impairment 


Tesaro, Inc. 
 
Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 11 of 18 
 
Figure 4.1-4  Boxplot of Niraparib PK parameters by hepatic function 
PK Parameter
0
100
200
300
400
500
Normal 
Mild impairment
 
 
 
 
 


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Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 12 of 18 
 
4.2 
Tables 
Table 4.2-1   Summary of Plasma Concentrations (units) of Niraparib by Hepatic 
Function  
  
  
Time (hours) 
0 
xxx 
xxx 
xxx 
xxx 
xxx 
Group 
  
XXX concentration (units) 
Normal 
N 
X 
X 
X 
X 
X 
X 
  
Mean 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
  
SD 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
 
Min 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Median 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Max 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
CV% 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
Moderate Hepatic 
Impairment 
N 
X 
X 
X 
X 
X 
X 
  
Mean 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
  
SD 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
 
Min 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Median 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Max 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
CV% 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
 
 


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Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 13 of 18 
 
Table 4.2-2 
Summary of Pharmacokinetic Parameters of Niraparib by Hepatic Function 
Group 
  
Tmax 
(units) 
Cmax 
(units) 
AUC0-t 
(units) 
AUC0-inf  
(units) 
Vz/F 
(units) 
 
CL/F 
(units) 
 
Kel 
(units) 
t1/2  
(units) 
Normal 
N 
X 
X 
X 
X 
X 
X 
X 
X 
  
Mean 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
  
SD 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
Min 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Median 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Max 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
CV% 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
Moderate 
Hepatic 
Impairment 
N 
X 
X 
X 
X 
X 
X 
X 
X 
  
Mean 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
SD 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
  
Min 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Median 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Max 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
CV% 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
 
 
 


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20 September 2018 
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Page 14 of 18 
 
 
4.3 
Subject Data Listings 
Listing 4.3-1 Niraparib Plasma Concentrations (unit) Following Dose Administration of 
300 mg Niraparib to Patients with Normal Hepatic Function 
  
Time (hours) 
0 
XXX 
XXX 
XXX 
XXX 
XXX 
Group 
Subject 
XXX Concentration (unit) 
Normal 
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
… 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
N 
X 
X 
X 
X 
X 
X 
  
Mean 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
  
SD 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
  
Min 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Median 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Max 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
CV% 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
 
 


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20 September 2018 
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Listing 4.3-2 Niraparib Plasma Concentrations (unit) Following Dose Administration of 
300 mg Niraparib to Patients with Moderate Hepatic Impairment  
  
Time (hours) 
0 
XXX 
XXX 
XXX 
XXX 
XXX 
Group 
Subject 
XXX Concentration (unit) 
Moderate 
Hepatic 
Impairment 
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
XXX 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
… 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
N 
X 
X 
X 
X 
X 
X 
  
Mean 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
  
SD 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
  
Min 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Median 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Max 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
CV% 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
 
 


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20 September 2018 
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Listing 4.3-3 Niraparib Plasma Pharmacokinetic Parameters Following Administration of 
300 mg Niraparib to Patients with Normal Hepatic Function 
Group 
Subject  
Tmax 
(units) 
Cmax 
(units) 
AUC0-t 
(units) 
AUC0-inf  
(units) 
Vz/F 
(units) 
 
CL/F 
(units) 
 
Kel 
(units) 
t1/2  
(units) 
Normal 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
N 
X 
X 
X 
X 
X 
X 
X 
X 
  
Mean 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
  
SD 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
Min 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Median 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Max 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
CV% 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
 
 
 


Tesaro, Inc. 
 
Study 3000-01-003 
20 September 2018 
CONFIDENTIAL 
Page 17 of 18 
 
Listing 4.3-4 Niraparib Plasma Pharmacokinetic Parameters Following Administration of 
300 mg Niraparib to Patients with Moderate Hepatic Impairment 
Group 
Subject  
Tmax 
(units) 
Cmax 
(units) 
AUC0-t 
(units) 
AUC0-inf  
(units) 
Vz/F 
(units) 
 
CL/F 
(units) 
 
Kel 
(units) 
t1/2  
(units) 
Moderate 
Hepatic 
Impairment 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
XXX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
 
… 
… 
… 
… 
… 
… 
… 
… 
… 
N 
X 
X 
X 
X 
X 
X 
X 
X 
  
Mean 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
X.XX 
  
SD 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
X.XXX 
Min 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Median 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
  
Max 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
CV% 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
X.X 
 
 
 


Tesaro, Inc. 
 
Study 3000-01-004 
20 September 2018 
 
 
 
CONFIDENTIAL 
Page 18 of 18 
4.4 
Individual Subject Plots 
Figure 4.4-1 Individual Niraparib Concentrations Following Administration of Niraparib 
to Patients with Moderate Hepatic Impairment or Normal Hepatic Function 
1 Subject per plot 
Figure 4.4-2   Combined Individual Niraparib Concentrations Following Administration of 
Niraparib to Patients with Moderate Hepatic Impairment or Normal Hepatic Function 
By group 
 
 
Additional Tables or Figures may be generated if deemed appropriate.