Clinical trial NCT03497429
Conditions: Advanced Solid Tumors
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2018-04-05; Completion date: 2020-02-10
Enrollment: 9 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of Niraparib in Japanese participants with advanced solid tumors.

Detailed description:
The drug being tested in this study is called Niraparib. Niraparib is being tested to treat Japanese participants with advanced solid tumors. This study will look at the safety, tolerability and pharmacokinetics of Niraparib administered once daily orally.

The study will enroll approximately 12 participants as a maximum. Participants will be assigned to Cohort 1 (21-day treatment cycle). After that, participants will be assigned to Cohort 2 when safety and tolerability of the 200 mg dose will be demonstrated.

This single-center trial will be conducted in Japan. The overall time to participate in this study is approximately 16 months. Participants will make multiple visits to the clinic with final visit approximately 28 days after last dose of study drug for a follow-up assessment.

Arms: arm 1: Niraparib 200 milligrams (mg), capsule, once orally on Days 1 - 21 of each 21-day treatment cycle. arm 2: Niraparib 300 mg, capsule, once orally on Days 1 - 21 of each 21-day treatment cycle.
Interventions: intervention 1: Niraparib
Intervention descriptions: intervention 1: Niraparib capsule

Protocol documents:
Prot_000.pdf: 
 
 
Title: A Phase 1, Open-label Study of Niraparib as Single Agent in Patients 
With Advanced Solid Tumors 
 
NCT Number: NCT03497429 
Protocol Approve Date: 18-JAN-2018 
 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


 
PROTOCOL 
A Phase 1, Open-label Study of Niraparib as Single Agent in Patients 
With Advanced Solid Tumors 
Sponsor: 
Takeda Pharmaceutical Company Limited. 
4-1-1 Doshomachi, Chuo-ku, Osaka 540-8645
Study Number: 
Niraparib-1001
IND Number: 
Not Applicable 
EudraCT Number:
Not Applicable 
Compound: 
Niraparib (MK-4827)
Date: 
18 January 2018 
(English translation: 
16 March 2018) 
Version/Amendment 
Number: 
Initial version 
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1.0 
ADMINISTRATIVE 
1.1 
Contacts 
A separate contact information list will be provided to each site. 
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site. 
Contact Type/Role 
Contact 
Serious adverse event and pregnancy reporting 
See Section 10.0. 
Medical Monitor 
(medical advice on protocol and compound) 
See Protocol Annex 
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1.2 
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following: 
•
The ethical principles that have their origin in the Declaration of Helsinki.
•
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated
Guideline.
•
All applicable laws and regulations, including, without limitation, data privacy laws, clinical
trial disclosure laws, and regulations.
SIGNATURES 
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page. 
Electronic Signatures may be found on the last page of this document. 
Program Clinical Lead (or designee) 
Study Clinical Science Lead (or designee) 
Date 
Statistician 
Biostatistics Lead 
Date 
Clinical Pharmacology Lead 
Date 
PPD
PPD
PPD
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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE ...........................................................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
2.0 
STUDY SUMMARY...........................................................................................................9 
3.0 
STUDY REFERENCE INFORMATION .........................................................................14 
3.1 
Study-Related Responsibilities ....................................................................................14 
3.2 
Clinical Study Report Signatory Investigator’s Responsibilities .................................14 
3.3 
List of Abbreviations ...................................................................................................15 
4.0 
INTRODUCTION .............................................................................................................17 
4.1 
Background ..................................................................................................................17 
4.1.1 
Nonclincal Studies .................................................................................................17 
4.1.2 
Clinical Studies ......................................................................................................18 
4.2 
Rationale for the Proposed Study ................................................................................21 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................23 
5.1 
Objectives ....................................................................................................................23 
5.1.1 
Primary Objectives .................................................................................................23 
5.1.2 
Secondary Objectives .............................................................................................23 
5.1.3 
Additional Objectives ............................................................................................23 
5.2 
Endpoints .....................................................................................................................23 
5.2.1 
Primary Endpoints .................................................................................................23 
5.2.2 
Secondary Endpoints .............................................................................................23 
5.2.3 
Additional Endpoints .............................................................................................23 
6.0 
STUDY DESIGN...............................................................................................................24 
6.1 
Overview of Study Design ...........................................................................................24 
6.2 
Number of Patients ......................................................................................................25 
6.3 
Duration of Study .........................................................................................................25 
6.3.1 
Duration of an Individual Patient’s Study Participation ........................................25 
6.3.2 
End of Study/Study Completion Definition and Planned Reporting .....................25 
6.3.3 
Timeframes for Primary and Secondary Endpoints to Support Disclosures .........25 
6.3.4 
Total Study Duration..............................................................................................26 
7.0 
STUDY POPULATION ....................................................................................................27 
7.1 
Inclusion Criteria .........................................................................................................27 
7.2 
Exclusion Criteria ........................................................................................................28 
8.0 
STUDY DRUG ..................................................................................................................30 
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8.1 
Study Drug Administration ..........................................................................................30 
8.2 
Definitions of DLT ......................................................................................................30 
8.3 
Dose Escalation Rules..................................................................................................31 
8.4 
Dose Modification Guidelines .....................................................................................32 
8.4.1 
Criteria for Dose Reduction, Interruption, and Discontinuation ............................32 
8.4.2 
Re-Escalation After Dose Reduction .....................................................................35 
8.4.3 
Criteria for Beginning or Delaying a Subsequent Treatment Cycle ......................35 
8.5 
Excluded Concomitant Medications and Procedures ..................................................35 
8.6 
Permitted Concomitant Medications and Procedures ..................................................36 
8.7 
Precautions and Restrictions ........................................................................................36 
8.7.1 
Pregnancy and Contraception ................................................................................36 
8.7.2 
Other Precautions and Restrictions ........................................................................37 
8.8 
Management of Clinical Events ...................................................................................37 
8.8.1 
Hematologic Toxicities ..........................................................................................37 
8.8.2 
Myelodysplastic Syndrome/Acute Myeloid Leukemia .........................................38 
8.8.3 
Hypertension, Including Hypertensive Crisis ........................................................38 
8.8.4 
Diarrhea ..................................................................................................................38 
8.8.5 
Nausea and/or Vomiting ........................................................................................38 
8.9 
Blinding and Unblinding..............................................................................................38 
8.10 
Description of Investigational Agents .........................................................................39 
8.11 
Preparation, Reconstitution, and Dispensation ............................................................39 
8.12 
Packaging and Labeling ...............................................................................................39 
8.13 
Storage, Handling, and Accountability ........................................................................39 
8.14 
Other Protocol-Specified Materials .............................................................................39 
9.0 
STUDY CONDUCT ..........................................................................................................40 
9.1 
Study Personnel and Organizations .............................................................................40 
9.2 
Arrangements for Recruitment of Patients ..................................................................40 
9.3 
Treatment Group Assignments ....................................................................................40 
9.4 
Study Procedures .........................................................................................................40 
9.4.1 
Informed Consent...................................................................................................40 
9.4.2 
Patient Demographics ............................................................................................40 
9.4.3 
Medical History .....................................................................................................40 
9.4.4 
Physical Examination.............................................................................................41 
9.4.5 
Patient Height and Weight .....................................................................................41 
9.4.6 
Vital Signs ..............................................................................................................41 
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9.4.7 
ECOG .....................................................................................................................41 
9.4.8 
Pregnancy Test .......................................................................................................42 
9.4.9 
Concomitant Medications and Procedures .............................................................42 
9.4.10 Adverse Events ......................................................................................................42 
9.4.11 Enrollment..............................................................................................................42 
9.4.12 Electrocardiogram ..................................................................................................42 
9.4.13 Clinical Laboratory Evaluations ............................................................................42 
9.4.14 Disease Assessment ...............................................................................................44 
9.4.15 Pharmacokinetic Measurements ............................................................................45 
9.4.16 Hospitalization .......................................................................................................45 
9.4.17 Dosing Compliance (Patient Diary) .......................................................................45 
9.5 
Documentation of Screen Failure ................................................................................45 
9.6 
Completion of Investigational Product Administration / Study Treatment (for 
Individual Patients) ......................................................................................................46 
9.7 
Completion of Study (for Individual Patients).............................................................46 
9.8 
Discontinuation of Treatment With Study Drug ..........................................................46 
9.9 
Withdrawal of Subjects From Study ............................................................................46 
9.10 
Study Compliance ........................................................................................................47 
10.0 
ADVERSE EVENTS .........................................................................................................48 
10.1 
Definitions....................................................................................................................48 
10.1.1 Adverse Event Definition ......................................................................................48 
10.1.2 Serious Adverse Event Definition .........................................................................48 
10.2 
Procedures for Recording and Reporting Adverse Events and Serious Adverse 
Events ...........................................................................................................................49 
10.3 
Monitoring of Adverse Events and Period of Observation ..........................................50 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ..........50 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) .....................................................................................................................50 
10.6 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities .........................51 
11.0 
STUDY-SPECIFIC COMMITTEES .................................................................................52 
12.0 
DATA HANDLING AND RECORDKEEPING ..............................................................53 
12.1 
eCRFs ...........................................................................................................................53 
12.2 
Record Retention .........................................................................................................53 
13.0 
STATISTICAL METHODS ..............................................................................................55 
13.1 
Statistical and Analytical Plans ....................................................................................55 
13.1.1 Analysis Sets ..........................................................................................................55 
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13.1.2 Analysis of Demographics and Other Baseline Characteristics ............................55 
13.1.3 Efficacy Analysis ...................................................................................................55 
13.1.4 Pharmacokinetic Analysis ......................................................................................55 
13.1.5 Safety Analysis ......................................................................................................56 
13.2 
Interim Analysis and Criteria for Early Termination ...................................................56 
13.3 
Determination of Sample Size .....................................................................................56 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................57 
14.1 
Study-Site Monitoring Visits .......................................................................................57 
14.2 
Protocol Deviations ......................................................................................................57 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................57 
15.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................58 
15.1 
IRB Approval ...............................................................................................................58 
15.2 
Subject Information, Informed Consent, and Subject Authorization ..........................58 
15.3 
Subject Confidentiality ................................................................................................59 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................60 
15.4.1 Publication .............................................................................................................60 
15.4.2 Clinical Trial Registration ......................................................................................60 
15.4.3 Clinical Trial Results Disclosure ...........................................................................60 
15.5 
Insurance and Compensation for Injury .......................................................................60 
16.0 
REFERENCES ..................................................................................................................62 
 
LIST OF IN-TEXT TABLES 
Table 4.a 
Progression-Free Survival in the Primary Efficacy Cohorts (ITT Population, 
N=553) ...................................................................................................................20 
Table 6.a 
Primary and Secondary Endpoints for Disclosures ...............................................26 
Table 8.a 
Dose Escalation Rules............................................................................................32 
Table 8.b 
Dose Reductions for Non-Hematologic Toxicities (Cycle 2 and Onwards) ..........33 
Table 8.c 
Dose Interruption/Modification for Hematologic Toxicities (Cycle 2 and 
Onwards) ................................................................................................................34 
Table 9.a 
Clinical Chemistry and Hematology Tests ............................................................43 
Table 9.b 
Clinical Urinalysis Tests ........................................................................................43 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Overview of Study Design .....................................................................................24 
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CCI
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2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Pharmaceutical Company, Ltd. 
Compound: 
Niraparib (MK-4827) 
Title of Protocol: A Phase 1, Open-label Study of 
Niraparib as Single Agent in Patients With Advanced 
Solid Tumors 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Number: Niraparib-1001 
Phase: 1 
Study Design: 
This study is a phase 1, open-label, non-randomized, cohort-based, dose-escalation study to establish the safety 
and tolerability of niraparib in Japanese patients with advanced solid tumors. A total of 6 to 12 patients are 
treated with 200 mg once daily (QD) (Cohort 1) or 300 mg QD (Cohort 2). 
Niraparib will be administered QD, continuously for 21 days in Cycle 1. There will be no drug holiday. 
Niraparib will be administered QD, continuously in 21-day cycles from Cycle 2 onward. Episodes of dose-
limiting toxicity (DLT) within the first 21 days of Cycle 1 are used to decide whether to escalate the dose. 
Subjects will receive niraparib under inpatient hospitalization (hospitalization from Cycle 1 Day 1 to Cycle 1 
Day 8 will be mandatory) and monitored for DLTs. Escalation to the next dose level does not occur until the 
results of safety measurements from Cycle 1 have been obtained and reviewed. 
Dose-escalation will proceed according to a 3+3 design. The initial niraparib dose will be 200 mg QD (Cohort 1) 
and will be escalated to 300 mg QD (Cohort 2), provided that the safety and tolerability of the 200 mg dose have 
been demonstrated. 
Primary Objective: 
To evaluate the safety and tolerability of niraparib administered orally QD to Japanese patients with advanced 
solid tumors. 
Secondary Objective: 
To evaluate the pharmacokinetics of niraparib administered orally QD to Japanese patients with advanced solid 
tumors. 
Subject Population: 
Japanese patients with locally advanced and/or metastatic solid tumors who have failed standard therapy or for 
whom no standard therapy exists. 
Number of Subjects: 
6 to 12 patients (3 to 6 patients per Cohort) 
Number of Sites: 
1 site in Japan 
Dose Level(s): 
Niraparib will be administered QD, given 
continuously in 21-day cycles. 
The initial niraparib dose will be 200 mg 
QD (Cohort 1) and will escalate to 300 mg 
QD (Cohort 2), provided that the safety and 
tolerability of the 200 mg dose has been 
demonstrated. 
Route of Administration: 
Oral 
Duration of Treatment: 
Treatment will continue until disease 
progression (PD), unacceptable toxicities, or 
withdrawal due to other reasons. 
Period of Evaluation: 
It is anticipated that this study will last for approximately 16 
months [from first patient in (FPI) to last patient last visit 
(LPLV)]. 
Subjects will be followed for 28 days after the last dose of 
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niraparib. 
Main Criteria for Inclusion: 
1. Japanese male or female patients aged 20 years or older on the day of signing informed consent. 
2. Patients must have a cytologically- or histologically-confirmed metastatic or locally advanced solid tumor 
and have failed or progressed after standard therapy, or for which standard therapy does not exist in the 
opinion of the investigator. 
3. Patients must have Performance Status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Status Scale. 
4. Patients must have adequate organ function as indicated by the following laboratory values: 
a. 
Hematology 
‒ 
Absolute neutrophil count: ≥1500/μL 
‒ 
Platelet count: ≥100,000/μL 
‒ 
Hemoglobin: ≥9 g/dL 
b. Kidney 
‒ 
Serum creatinine: ≤1.5 × institutional upper limit of normal (ULN), OR creatinine clearance of 
≥50 mL/min (as calculated using the Cockcroft Gault equation or measured using 24-hour urine 
creatinine clearance) for patients with creatinine levels ≥1.5 × institutional ULN. 
c. 
Liver 
‒ 
Total bilirubin in serum: ≤1.5 × ULN (except in patients with Gilbert's syndrome). Patients with 
Gilbert's syndrome may be enrolled if the patient's direct bilirubin is ≤1.5 ×ULN of the direct 
bilirubin. 
‒ 
AST and ALT: ≤2.5 × ULN OR ≤5 × ULN if patients have liver metastases. 
d. Coagulation (does not pertain to patients receiving anticoagulants) 
‒ 
Prothrombin time (PT): ≤1.2 × ULN 
‒ 
Activated partial thromboplastin time (aPTT): ≤1.2 × ULN 
5. Female patients who: 
 
Are postmenopausal for at least 1 year before the screening visit, OR 
 
Are surgically sterile, OR 
 
If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 
additional effective (barrier) method at the same time, from the time of signing the informed consent 
through 180 days after the last dose of study drug, OR 
 
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the 
patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], condoms 
only, withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.) 
Male patients, even if surgically sterilized (ie, vasectomy), who: 
 
Agree to practice effective barrier contraception during the entire study treatment period and through 
120 days after the last dose of study drug. If the female partner of a male subject is of child bearing 
potential, it should also be advised to use a highly effective method of contraception, OR 
 
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the 
patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the 
female partner], condoms only, withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used together.) 
6. Voluntary written consent must be given before performance of any study related procedure not part of 
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standard medical care, with the understanding that consent may be withdrawn by the patient at any time 
without prejudice to future medical care. 
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Main Criteria for Exclusion: 
1. Patient who have received chemotherapy, radiotherapy, hormonal or biological therapy within 14 days 
(within 28 days for anticancer monoclonal antibody, within 42 days for nitrosoureas or mitomycin C) prior 
to Cycle 1 Day 1. If the patient has residual toxicity from prior chemotherapy treatment, such toxicity must 
be ≤Grade 1 (NOTE: patients with Grade 2 alopecia may qualify for this study). If bevacizumab had been 
used in the past, all bevacizumab-related toxicities must have resolved. Patients with prostate cancer may 
have been treated with luteinizing hormone-releasing hormone (LH-RH) analogs. 
2. Patients who received a known or putative poly (ADP-ribose) polymerase (PARP) inhibitor or other drugs 
that may inhibit the PARP, either as part of a clinical trial or as standard of care. 
3. Patients who initiated bisphosphonate therapy or are adjusting bisphosphonate dose/regimen within 30 days 
prior to Cycle 1 Day 1. Patients on a stable bisphosphonate regimen are eligible and may continue the 
treatment. 
4. Treatment with any investigational products within 28 days or 5 half-lives (whichever was longer) before 
Cycle 1 Day 1. 
5. Patients who have symptomatic ascites or a symptomatic pleural effusion. A patient who is treated and 
clinically stable for these conditions is eligible. 
6. Patients with a known primary central nervous system (CNS) tumor. 
7. Patients with known CNS metastases and/or carcinomatous meningitis are excluded. However, patients with 
CNS metastases who have completed a course of therapy would be eligible for the study provided they are 
clinically stable for 30 days prior to Cycle 1 Day 1 defined as: (1) no evidence of new or enlarging CNS 
metastases, (2) off steroids, or (3) on a stable dose and administration of steroids. 
8. Patients who have a hypersensitivity to the components of the study drugs or their analogs. 
9. Patients who are considered to be at high medical risk due to a serious, uncontrolled disease, non-malignant 
systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled 
ventricular arrhythmia, recent (within 90 days prior to Cycle 1 Day 1) myocardial infarction, uncontrolled 
major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, uncontrolled 
hypertension, or any psychiatric disorder that prohibits obtaining informed consent. 
10. Patients who have a history or current evidence of any condition, therapy, or lab abnormality that might 
confound the results of the study, interfere with the patient's participation throughout the study period, or 
study participation is not in the best interest of the patient. 
11. Known gastrointestinal (GI) disease or GI surgery that could interfere with the GI absorption of study drug, 
such as difficulty swallowing capsules and total gastrectomy. 
12. Patients who have a psychiatric disorder that may interfere with the conduct of the trial. 
13. Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit 
drugs or had a recent history (within the past year) of drug or alcohol abuse. 
14. Patients who are pregnant or breast-feeding, or expecting to conceive or be a father of children within the 
planned duration of the study.  
NOTE: If a breast-feeding woman discontinue breast-feeding, she may be enrolled in the study. 
15. Known HIV positive. 
16. Known hepatitis B surface antigen (HBsAg) positive, or known or suspected active hepatitis C virus (HCV) 
infection. 
NOTE: Patients who are positive for hepatitis B core antibody (HBcAb) or hepatitis B surface antibody 
(HBsAb) can be enrolled but must have an undetectable hepatitis B virus (HBV) viral load. Patients who 
have positive hepatitis C virus antibody (HCVAb) must have an undetectable HCV viral load. 
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Main Criteria for Evaluation and Analyses: 
Primary Endpoints: 
 
The number and percentage of subjects with DLTs during Cycle 1. 
 
The number and percentage of subjects with treatment-emergent adverse events (TEAEs). 
 
The number and percentage of subjects with Grade 3 or higher TEAEs. 
 
The number and percentage of subjects with serious TEAEs. 
 
The number and percentage of subjects who discontinued the study drug because of TEAEs. 
Secondary Endpoints: 
 
Pharmacokinetic (PK) parameters of niraparib on Cycle 1 Day 1 and Day 21: maximum observed 
concentration (Cmax), time of first occurrence of Cmax (Tmax) and area under the plasma concentration-time 
curve from time 0 to 24 hours (AUC24) 
Additional Endpoints: 
 
Overall response rate (ORR) (complete response [CR] + partial response [PR]) as measured by the Response 
Evaluation Criteria in Solid Tumors (RECIST) guidelines. 
 
Laboratory safety assessments, ECOG performance status, electrocardiograms and vital signs. 
 
PK parameters of a metabolite, M1, on Cycle 1 Day 1 and Day 21: Cmax, Tmax and AUC24 
Statistical Considerations: 
The number of cases and incidence of DLTs during Cycle 1 will be tabulated using DLT-evaluable set. 
Adverse events (AEs) will be tabulated by dose level using the safety analysis set for TEAEs, drug-related 
TEAEs, Grade 3 or higher TEAEs, Grade 3 or higher drug-related TEAEs, serious TEAEs and TEAEs leading to 
drug discontinuation. 
Summary statistics will be provided by dose levels using the PK analysis set for pharmacokinetic parameters 
including AUC, Cmax, and Tmax on niraparib and metabolite M1. 
Sample Size Justification: 
This study will use a 3+3 design. In the study, 2 ascending dose cohorts (3 to 6 patients per Cohort) are planned 
and approximately 6 to 12 DLT evaluable patients will be enrolled. 
 
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3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
protocol annex. The identified vendors in the protocol annex for specific study-related activities 
will perform these activities in full or in partnership with the sponsor. 
3.2 
Clinical Study Report Signatory Investigator’s Responsibilities 
Takeda will select a signatory for the clinical study report (CSR) from the investigators who 
participate in the study. Selection criteria for this investigator will include significant knowledge 
of the study protocol, the study medication, their expertise in the therapeutic area and the 
conduct of clinical research as well as study participation. The signatory investigator will be 
required to review and sign the CSR and by doing so agrees that it accurately describes the 
results of the study. 
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3.3 
List of Abbreviations 
AE 
adverse event 
AML 
acute myeloblastic leukemia 
aPTT 
activated partial thromboplastin time 
AUC24 
area under the plasma concentration-time curve from time 0 to 24 hours 
BRCA 
breast cancer gene 
Cmax 
maximum observed concentration 
CBC 
complete blood cell count 
CNS 
central nervous system 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FDA 
(United States) Food and Drug Administration 
FPI 
first patient in 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCVAb 
hepatitis C virus antibody 
HRD 
homologous recombination deficiency 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IRB 
institutional review board 
ITT 
intent-to-treat 
LPLV 
last patient last visit 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
overall response rate 
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PARP 
poly (adenosine diphosphate [ADP]-ribose) polymerase 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease (disease progression) 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency of Japan 
PR 
partial response 
PT 
prothrombin time 
QD 
once daily 
RP2D 
recommended Phase 2 dose 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
time of first occurrence of Cmax 
TEAE 
treatment-emergent adverse event 
t1/2 
terminal disposition phase half-life 
ULN 
upper limit of normal 
 
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4.0 
INTRODUCTION 
4.1 
Background 
Niraparib is an orally available, potent, and highly selective poly (adenosine diphosphate [ADP]-
ribose) polymerase (PARP) -1 and -2 inhibitor. 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. 
PARP-1 and -2 are zinc-finger DNA-binding enzymes that detect damaged DNA and promote 
DNA repair. PARP detects DNA damage and converts it into intracellular signals that activate 
the base excision repair (BER) pathway. This pathway is particularly important in cells that are 
deficient in a second cellular mechanism for high-fidelity DNA repair, homologous 
recombination. Homologous recombination deficiency (HRD) is generally induced by 
inactivation of genes such as breast cancer gene 1 (BRCA1), BRCA2, ataxia telangiectasia 
mutated (ATM) and others. Therefore, tumors with a deficiency in the homologous 
recombination DNA repair pathway are particularly sensitive to PARP inhibitors [1], a situation 
known as synthetic lethality. 
Clinical studies have shown that PARP inhibitors have antitumor activity in patients with certain 
types of cancer, including but not limited to those with defined BRCA mutations[2]-[5]. BRCA1 
and BRCA2 mutations are found in the majority of patients with inherited breast or ovarian 
cancer[6][7], and inactivation of BRCA1 and BRCA2 and other genes in the homologous 
recombination repair pathway by somatic mutations or gene silencing due to promoter 
hypermethylation occurs in a significant portion of sporadic tumors[8][9]. In particular, germline 
BRCA1 or BRCA2 mutations are found in 10% to 15% of all newly diagnosed epithelial ovarian 
carcinomas, and strongly reduced expression of BRCA1 has been observed in a significant 
portion of sporadic ovarian cancers[8][10]. Collectively, over half of newly diagnosed ovarian 
cancers have defects in the homologous recombination pathway and may be sensitive to PARP 
inhibitors[11]-[13]. 
Niraparib has been approved in the US in March 2017 and in the EU in November 2017 for the 
maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or 
primary peritoneal cancer who are in complete or partial response to platinum-based 
chemotherapy. Currently, niraparib is being evaluated for the treatment of several types of solid 
tumors including breast cancer and prostate cancer. 
Nonclinical and clinical study result summaries are shown below. 
4.1.1 Nonclincal Studies 
In preclinical animal models, maximal in vivo efficacy was achieved in mutant breast cancer-1 
(BRCA1mut) ovarian tumor models with once daily oral administration of niraparib at a dose 
sufficient to suppress 90% of the PARP enzymatic activity in the tumor at 8 hours postdose. 
Administration of the same dose translated to a >50% inhibition of PARP activity in peripheral 
blood mononuclear cells (PBMCs) at 8 hours postdose. Clinical development data from the 
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niraparib Phase 1 study demonstrated 50% inhibition of PARP activity in PBMCs at dose levels 
of ≥80 mg. 
Nonclinical tests found that tumors containing BRCA mutations or otherwise positive by the 
myChoice® homologous recombination deficiency (HRD) test regressed in response to niraparib 
treatment. Moreover, tumor growth inhibition was observed in a subset of HRD negative models, 
suggesting there is a gradient of response to niraparib that is observed on a population basis by 
use of different biomarkers. 
4.1.2 Clinical Studies 
In overseas, TESARO-sponsored clinical studies are ongoing in patients with advanced solid 
tumors. 
4.1.2.1 Study PN001 (Overseas Phase 1 Monotherapy) 
The primary objective of the open-label study PN001 was to establish the safety, tolerability, 
pharmacokinetic (PK), pharmacodynamics, and recommended phase 2 dose (RP2D) of niraparib 
in patients with advanced solid tumors. 
The first part of the study (Part A) was a dose escalation and confirmation scheme to determine 
the maximum tolerated dose (MTD) and RP2D of niraparib in patients with advanced solid 
tumors. The second part of the study (Part B) was a cohort expansion in patients with platinum-
resistant, recurrent, high-grade serous ovarian cancer or prostate cancer at the MTD established 
in Part A. Part D included patients with colorectal cancer, endometrial cancer, partially platinum-
sensitive high-grade serous ovarian cancer, or breast cancer. Due to non-clinical reasons, Part C 
of the study did not enroll patients (T-cell prolymphocytic leukemia or chronic lymphocytic 
leukemia). 
MTD and RP2D 
A total of 60 patients were treated in Part A once daily (QD) at 10 dose levels of niraparib 
ranging from 30 to 400 mg. A total of 40 patients were treated in Part B at the MTD of niraparib 
300 mg QD as determined in Part A. 
Based upon information obtained in Part A, an MTD of 300 mg QD was determined for 
niraparib. During dose escalation, 1 dose-limiting toxicity (DLT) of Grade 3 fatigue was reported 
out of 6 patients treated at 30 mg. One DLT of Grade 3 pneumonitis was reported out of 7 
patients treated at 60 mg. The DLT of Grade 4 thrombocytopenia was observed in 2 of 6 patients 
treated at 400 mg, establishing that level as having exceeded MTD, per study design. During 
dose escalation and dose confirmation, none of the patients treated at either 290 or 300 mg had a 
DLT, confirming 300 mg as the MTD. 
The RP2D determined on the basis of cumulative data from Part A and Part B was 300 mg QD. 
PK 
PK exposures had moderate to high variability, with coefficient of variance values generally less 
than 75%. An exploratory analysis of dose proportionality indicated no dose-dependent trends in 
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dose-normalized area under the plasma concentration-time curve from time 0 to 24 hours 
(AUC24) and maximum observed concentration (Cmax) values, suggesting dose-proportional 
increases in exposure across the range of doses studied. Following multiple days of dosing, 
accumulation levels were consistent across all doses. Time of first occurrence of Cmax (Tmax) and 
terminal disposition phase half-life (t1/2) did not display dose-dependent trends, suggesting the 
lack of any nonlinearities in absorption or elimination pathways. 
Following multiple oral doses of 30 to 400 mg niraparib per day for 21 days (Parts A and B), 
niraparib was rapidly absorbed, with a median Tmax ranging from 3.0 to 3.6 hours on Day 1 and 
1.5 to 4.0 hours on Day 21 (last day of administration). By inspection, the average plasma 
concentration profiles following multiple doses fall from peak levels in an approximately 
biphasic manner. Trough concentrations generally approach steady-state by Day 12 across all 
dose levels. For the 30 to 400 mg dose range studied, the AUC24 and Cmax geometric mean 
accumulation ratios (Day 21/Day 1) after 21 days of dosing ranged from 1.99 to 4.22 and 1.55 to 
3.62, respectively. Mean terminal t1/2 ranged from 32.8 to 46.0 hours over the 60 to 400 mg dose 
range. 
The maximum steady-state exposures observed on Day 21 following multiple 400 mg doses of 
niraparib were 79,055 nmol/L∙hr and 4,448 nmol/L for AUC24 and Cmax, respectively. 
4.1.2.2 Study PR-30-5011-C (NOVA main) (Overseas Phase 3) 
The main study of PR-30-5011-C is a double-blind, 2:1 randomized, placebo-controlled study in 
platinum-sensitive ovarian cancer patients who have either gBRCAmut or a tumor with high-
grade serous histology, but without a gBRCA mutation (non-gBRCAmut) who were in response 
to their last platinum-based therapy. Enrollment into the cohorts was determined prospectively 
by the results of Myriad’s Integrated BRACAnalysis® testing. 
A total of 203 patients were enrolled in the gBRCAmut cohort and 350 patients were enrolled in 
the non-gBRCAmut cohort. Overall, 553 patients were randomized, 372 patients to niraparib and 
181 patients to placebo. Preliminary efficacy data (as of the data cut date of 30 May 2016) are 
available for the 553 patients who comprised the intent-to-treat (ITT) population and the 546 
patients who comprised the safety population. 266 patients remain on-treatment. 
Efficacy 
The primary endpoint, progression-free survival (PFS), was determined by central independent 
assessment per Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 [14] or clinical 
signs and symptoms and increased cancer antigen 125 (CA-125). PFS was measured from the 
time of randomization to disease progression (PD) or death. 
In this study, niraparib met the primary endpoint of prolonging PFS versus placebo in all 3 
prospectively defined primary patient populations (gBRCAmut cohort, HRDpos group of the 
non-gBRCAmut cohort, and the overall non gBRCAmut cohort) as displayed in Table 4.a. 
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Table 4.a 
Progression-Free Survival in the Primary Efficacy Cohorts (ITT Population, 
N=553) 
Treatment 
Median PFS (a) 
(95% CI) 
(Months) 
Hazard Ratio (b) 
(95% CI) 
p-value (c) 
% of Patients without Progression or 
Death at (d): 
6 Months 
12 Months 
18 Months 
gBRCAmut Cohort 
Niraparib (n = 138) 
21.0 (12.9, NE) 
0.27 (0.173, 0.410) 
p<0.0001 
80% 
62% 
50% 
Placebo (n = 65) 
5.5 (3.8, 7.2) 
43% 
16% 
16% 
HRDpos Group 
Niraparib (n = 106) 
12.9 (8.1, 15.9) 
0.38 (0.243, 0.586) 
p<0.0001 
69% 
51% 
37% 
Placebo (n = 56) 
3.8 (3.5, 5.7) 
35% 
13% 
9% 
Non-gBRCAmut Cohort 
Niraparib (n = 234) 
9.3 (7.2, 11.2) 
0.45 (0.338, 0.607) 
p<0.0001 
61% 
41% 
30% 
Placebo (n = 116) 
3.9 (3.7, 5.5) 
36% 
14% 
12% 
Source: PR-30-5011-C (NOVA main) CSR 
Abbreviations: gBRCA, breast cancer susceptibility gene; CI, confidence interval; gBRCAmut, germline BRCA 
mutation; HRDpos, homologous recombination deficiency positive; ITT, intent-to-treat; NE, not estimated; non-
gBRCAmut, without a germline BRCA mutation; PFS, progression-free survival. 
(a) Progression-free survival is defined as the time in months from the date of randomization to progression or 
death. 
(b) Niraparib:Placebo, based on the stratified Cox Proportional Hazards Model using randomization stratification 
factors. 
(c) Based on stratified log-rank test using randomization stratification factors. 
(d) Estimates from product-limit method. Confidence intervals constructed using log-log transformation. 
Safety 
The most commonly observed non-hematologic treatment-emergent adverse events (TEAEs) (all 
grades) of niraparib were nausea, fatigue, constipation, and vomiting. The majority of the non-
hematological TEAEs were mild to moderate in severity. The most commonly observed 
hematologic TEAEs (all grades) of niraparib were anemia (48.5%), thrombocytopenia (66.2%), 
and neutropenia (31.4%). 
TEAEs that led to dose interruption, dose reduction or discontinuation of treatment 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 first 2 
months of therapy. Most patients achieved their individual MTD by the third month. The average 
dose of niraparib during the study was 206 mg. After 3 to 4 months of treatment, new incidents 
of thrombocytopenia were reported in <1% of patients. Although Grade 3 or 4 hematologic 
laboratory events were common at the beginning of treatment, no severe clinical sequelae were 
observed, and relatively few patients discontinued due to these adverse events (AEs) 
(discontinuation rate was 3.3% for thrombocytopenia 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 for patients whose dose were 
reduced to either 200 mg or 100 mg was consistent with that for patients whose dose remained at 
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300 mg, indicating that patients who required dose reduction do not appear to have decreased 
efficacy relative to those whose dose remain at the starting dose of 300 mg. 
4.1.2.3 Study MK-4827/005 (Japanese Phase 1 study) 
Study PN005, sponsored by Banyu Pharmaceutical Company Limited (current Merck Sharp and 
Dohme [MSD] K.K), was designed to evaluate the recommended clinical dose, the safety, 
tolerability, PK, and efficacy of niraparib in Japanese patients with solid tumors. The study was 
terminated after 3 patients received the study drug in the first cohort (150 mg QD). 
4.1.2.4 Population Pharmacokinetic and Pharmacodynamic Analysis 
A population PK/pharmacodynamics analysis was performed using the data collected in overseas 
Phase 1 study (PN001) and Phase 3 (Study PR-30-5011-C) datasets. The concentration-time data 
for niraparib were modeled using a compartmental approach and the effects of study variables 
were examined to determine if they influenced drug exposure. In addition, the relationship 
between measures of exposure at steady-state of niraparib and measures of efficacy and safety 
were explored. 
A two-compartment model was selected for the population PK analysis. None of the covariates 
investigated (age, race, baseline body weight, serum chemistry, etc.) had a statistically 
significant impact on the PK of niraparib. Population PK/pharmacodynamics analysis suggested 
that there is a relationship between the exposure to niraparib and the PFS in gBRCAmut, non-
gBRCAmut, and HRDpos populations. For TEAEs of interest (thrombocytopenia, vomiting, 
neutropenia, and fatigue) explored for potential relationship with niraparib exposure, no 
statistically significant relationship was observed. Possible relationships between body weight, 
platelet count, absolute neutrophil count, etc. and incidence of thrombocytopenia were further 
explored, and correlation were seen between the baseline platelet count and thrombocytopenia. 
For further details, refer to the current Investigator’s Brochure and package inserts in 
regions/countries where niraparib is approved. 
4.2 
Rationale for the Proposed Study 
In overseas Phase 1 study (PN001), investigating the safety, tolerability and AE profile of 
niraparib in patients with locally advanced or metastatic solid tumors who have failed standard 
therapy or for whom no standard therapy exists, niraparib at doses of 30 to 400 mg QD has been 
administered to 104 patients. The MTD determined in Part A was 300 mg QD in continuous 21-
day treatment cycles. During dose escalation (Part A), 1 DLT of Grade 3 fatigue was reported 
out of 6 patients treated at 30 mg. One DLT of Grade 3 pneumonitis was reported out of 7 
patients treated at 60 mg. The DLT of Grade 4 thrombocytopenia was observed in 2 of 6 patients 
treated at 400 mg, establishing that level as having exceeded MTD, per study design. During 
dose escalation and dose confirmation, 0 of 5 patients treated at 290 mg and 0 of 10 patients 
treated at 300 mg had a DLT, confirming 300 mg as the MTD. The safety data indicated that a 
niraparib dose of 300 mg QD is generally well tolerated, with an AE profile that is acceptable 
and predictable. 
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Based on preclinical and clinical safety and/or efficacy data, it is anticipated that the 
administration of niraparib can be reasonably well tolerated and effective as monotherapy in 
Japanese patients with advanced and/or metastatic solid tumors. Current population PK analyses 
of niraparib indicated that race had no significant impact on the PK of niraparib. The starting 
dose in this study is 200 mg QD, which is two thirds of the recommended dose of niraparib as 
monotherapy (300 mg) determined based on results of previous clinical studies. 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 Primary Objectives 
To evaluate the safety and tolerability of niraparib administered orally QD to Japanese patients 
with advanced solid tumors. 
5.1.2 Secondary Objectives 
To evaluate the pharmacokinetics of niraparib administered orally QD to Japanese patients with 
advanced solid tumors. 
5.1.3 Additional Objectives 
To evaluate the anti-tumor activity of niraparib administered orally QD to Japanese patients with 
advanced solid tumors. 
5.2 
Endpoints 
5.2.1 Primary Endpoints 
• The number and percentage of subjects with DLTs during Cycle 1. 
• The number and percentage of subjects with TEAEs. 
• The number and percentage of subjects with Grade 3 or higher TEAEs. 
• The number and percentage of subjects with serious TEAEs. 
• The number and percentage of subjects who discontinued the study drug because of TEAEs. 
5.2.2 Secondary Endpoints 
• PK parameters of niraparib on Cycle 1 Day 1 and Day 21: Cmax, Tmax and AUC24 
5.2.3 Additional Endpoints 
• Overall response rate (ORR) (complete response [CR] + partial response [PR]) as measured 
by the RECIST guidelines. 
• Laboratory safety assessments, Eastern Cooperative Oncology Group (ECOG) performance 
status, electrocardiograms (ECGs) and vital signs. 
• PK parameters of a metabolite, M1, on Cycle 1 Day 1 and Day 21: Cmax, Tmax and AUC24 
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minimum of 100 mg) will be permitted only in case of DLTs during Cycle 1 and any toxicity 
from Cycle 2 onward. Individual subjects who experienced DLTs may also resume the treatment 
with niraparib and continue treatment from Cycle 2 onward if they meet the criteria for restarting 
the study drug after onset of DLTs. The dose modification guidelines are shown in Section 8.4. 
6.2 
Number of Patients 
Approximately 6 to 12 patients will be enrolled in this study from 1 study center in Japan. 
Enrollment is defined as the time when the sponsor sends an enrollment sheet back to the 
investigational site. 
Patients who did not receive ≥80% of the study medication in Cycle 1 for reasons other than 
related toxicities must be replaced. 
6.3 
Duration of Study 
6.3.1 Duration of an Individual Patient’s Study Participation 
Patients may receive study drug until they experience PD, unacceptable toxicity, withdrawal of 
consent, or for any of the other reasons outlined in Section 9.9. 
Patients will be followed for 28 days after the last dose of niraparib or the start of subsequent 
alternative anticancer therapy to permit the detection of any delayed treatment-related AEs. 
6.3.2 End of Study/Study Completion Definition and Planned Reporting 
The final analyses for the primary endpoint and authoring of a CSR will be conducted after all 
patients enrolled in the study have completed the study treatment with niraparib and the 28-day 
safety follow-up. It is anticipated that this study will last for approximately 16 months (from first 
patient in [FPI] to last patient last visit [LPLV]). 
6.3.3 Timeframes for Primary and Secondary Endpoints to Support Disclosures 
Please refer to Table 6.a for disclosures information for all primary and secondary endpoints. 
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Table 6.a 
Primary and Secondary Endpoints for Disclosures 
Endpoint 
Definition 
Maximum Time Frame (a) 
Primary: 
 
 
 The number and percentage of 
subjects with DLTs during Cycle 
1. 
The number and percentage of patients 
with DLTs during Cycle 1 in the DLT-
evaluable set. 
Prior to administration on Cycle 2 
Day 1 
 The number and percentage of 
subjects with TEAEs. (b) 
The number and percentage of patients 
with TEAEs in the safety analysis set. 
Approximately 13 months. 
 The number and percentage of 
subjects with Grade 3 or higher 
TEAEs. (b) 
The number and percentage of patients 
with Grade 3 or higher TEAEs in the 
safety analysis set. 
Approximately 13 months. 
 The number and percentage of 
subjects with serious TEAEs. (b) 
The number and percentage of patients 
with serious TEAEs in the safety 
analysis set. 
Approximately 13 months. 
 The number and percentage of 
subjects who discontinued the 
study drug because of TEAEs. (b) 
The number and percentage of patients 
with TEAEs leading to study drug 
discontinuation in the safety analysis 
set. 
Approximately 13 months. 
Secondary: 
 
 
 PK parameters of niraparib on 
Cycle 1 Day 1 and Day 21: Cmax, 
Tmax and AUC24 
Descriptive statistics for PK 
parameters of niraparib on Cycle 1 
Day 1 and Day 21 in the PK-evaluable 
set. 
Up to Cycle 1 Day 2 and Cycle 2 
Day 1 
Abbreviations: AUC24, area under the plasma concentration-time curve from time 0 to 24 hours; Cmax, maximum 
observed concentration; DLT, dose-limiting toxicity; Tmax, time of first occurrence of Cmax; TEAE, treatment-
emergent adverse event. 
(a) Time to last assessment for that endpoint for an individual patient. 
(b) TEAEs are defined as AEs that occur after the first dose of study drug until 30 days after the last dose of study 
drug. 
6.3.4 Total Study Duration 
It is anticipated that patient enrollment into both cohorts will be completed approximately 4 
months from the enrollment of the first patient into Cohort 1. This estimation is based on the 
condition that no DLTs occur and only 3 patients per cohort are enrolled. 
It is anticipated that this study will last for approximately 16 months (from FPI to LPLV). 
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7.0 
STUDY POPULATION 
The study will be conducted in Japanese patients with locally advanced and/or metastatic solid 
tumors for which standard therapy does not exist or is not available. 
7.1 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Japanese male or female patients aged 20 years or older on the day of signing informed 
consent. 
2. Patients must have a cytologically- or histologically-confirmed metastatic or locally 
advanced solid tumor and have failed or progressed after standard therapy, or for which 
standard therapy does not exist in the opinion of the investigator. 
3. Patients must have Performance Status of ≤1 on the ECOG Performance Status Scale. 
4. Patients must have adequate organ function as indicated by the following laboratory values: 
a. Hematology 
– Absolute neutrophil count: ≥1500/μL 
– Platelet count: ≥100,000/μL 
– Hemoglobin: ≥9 g/dL 
b. Kidney 
– Serum creatinine: ≤1.5 × institutional upper limit of normal (ULN), OR creatinine 
clearance of ≥50 mL/min (as calculated using the Cockcroft Gault equation or measured 
using 24-hour urine creatinine clearance) for patients with creatinine levels ≥1.5 × 
institutional ULN. 
c. Liver 
– Total bilirubin in serum: ≤1.5 × ULN (except in patients with Gilbert's syndrome). 
Patients with Gilbert's syndrome may be enrolled if the patient's direct bilirubin is ≤1.5 
×ULN of the direct bilirubin. 
– AST and ALT: ≤2.5 × ULN OR ≤5 × ULN if patients have liver metastases. 
d. Coagulation (does not pertain to patients receiving anticoagulants) 
– Prothrombin time (PT): ≤1.2 × ULN 
– Activated partial thromboplastin time (aPTT): ≤1.2 × ULN 
5. Female patients who: 
• Are postmenopausal for at least 1 year before the screening visit, OR 
• Are surgically sterile, OR 
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• If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing the informed consent through 180 days after the last dose of study drug, OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], condoms only, withdrawal, spermicides only, and lactational amenorrhea are not 
acceptable methods of contraception. Female and male condoms should not be used 
together.) 
Male patients, even if surgically sterilized (ie, vasectomy), who: 
• Agree to practice effective barrier contraception during the entire study treatment period 
and through 120 days after the last dose of study drug. If the female partner of a male 
subject is of child bearing potential, it should also be advised to use a highly effective 
method of contraception, OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner], condoms only, withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and male 
condoms should not be used together.) 
6. Voluntary written consent must be given before performance of any study related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care. 
7.2 
Exclusion Criteria 
Patients who meet any of the following criteria will not be enrolled in the study: 
1. Patient who have received chemotherapy, radiotherapy, hormonal or biological therapy 
within 14 days (within 28 days for anticancer monoclonal antibody, within 42 days for 
nitrosoureas or mitomycin C) prior to Cycle 1 Day 1. If the patient has residual toxicity from 
prior chemotherapy treatment, such toxicity must be ≤Grade 1 (NOTE: patients with Grade 2 
alopecia may qualify for this study). If bevacizumab had been used in the past, all 
bevacizumab-related toxicities must have resolved. Patients with prostate cancer may have 
been treated with luteinizing hormone-releasing hormone (LH-RH) analogs. 
2. Patients who received a known or putative PARP inhibitor or other drugs that may inhibit the 
PARP, either as part of a clinical trial or as standard of care. 
3. Patients who initiated bisphosphonate therapy or are adjusting bisphosphonate dose/regimen 
within 30 days prior to Cycle 1 Day 1. Patients on a stable bisphosphonate regimen are 
eligible and may continue the treatment. 
4. Treatment with any investigational products within 28 days or 5 half-lives (whichever was 
longer) before Cycle 1 Day 1. 
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5. Patients who have symptomatic ascites or a symptomatic pleural effusion. A patient who is 
treated and clinically stable for these conditions is eligible. 
6. Patients with a known primary central nervous system (CNS) tumor. 
7. Patients with known CNS metastases and/or carcinomatous meningitis are excluded. 
However, patients with CNS metastases who have completed a course of therapy would be 
eligible for the study provided they are clinically stable for 30 days prior to Cycle 1 Day 1 
defined as: (1) no evidence of new or enlarging CNS metastases, (2) off steroids, or (3) on a 
stable dose and administration of steroids. 
8. Patients who have a hypersensitivity to the components of the study drugs or their analogs. 
9. Patients who are considered to be at high medical risk due to a serious, uncontrolled disease, 
non-malignant systemic disease or active, uncontrolled infection. Examples include, but are 
not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days prior to Cycle 1 
Day 1) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, uncontrolled hypertension, or any psychiatric 
disorder that prohibits obtaining informed consent. 
10. Patients who have a history or current evidence of any condition, therapy, or lab abnormality 
that might confound the results of the study, interfere with the patient's participation 
throughout the study period, or study participation is not in the best interest of the patient. 
11. Known gastrointestinal (GI) disease or GI surgery that could interfere with the GI absorption 
of study drug, such as difficulty swallowing capsules and total gastrectomy. 
12. Patients who have a psychiatric disorder that may interfere with the conduct of the trial. 
13. Patient is, at the time of signing informed consent, a regular user (including “recreational 
use”) of any illicit drugs or had a recent history (within the past year) of drug or alcohol 
abuse. 
14. Patients who are pregnant or breast-feeding, or expecting to conceive or be a father of 
children within the planned duration of the study. 
NOTE: If a breast-feeding woman discontinue breast-feeding, she may be enrolled in the 
study. 
15. Known HIV positive. 
16. Known hepatitis B surface antigen (HBsAg) positive, or known or suspected active hepatitis 
C virus (HCV) infection. 
NOTE: Patients who are positive for hepatitis B core antibody (HBcAb) or hepatitis B 
surface antibody (HBsAb) can be enrolled but must have an undetectable hepatitis B virus 
(HBV) viral load. Patients who have positive hepatitis C virus antibody (HCVAb) must have 
an undetectable HCV viral load. 
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8.0 
STUDY DRUG 
8.1 
Study Drug Administration 
Niraparib will be administered QD orally, given continuously in 21-day cycles. 
Dose escalation will follow a 3+3 escalation scheme. Starting dose is 200 mg QD (Cohort 1), 
which is a two thirds (2/3) of the recommended dose of niraparib as monotherapy in previous 
clinical studies. If 200 mg QD is safe and tolerable, then the dose will proceed to 300 mg QD 
(Cohort 2). This is the recommended dose of niraparib as monotherapy in previous clinical 
studies. 
Subjects may receive study drug until they experience objective PD, experience unacceptable 
toxicity or until study discontinuation due to any other reasons. 
The study drug should be administered at approximately the same time every day. In the event of 
missed doses or vomited doses, the dose will not be re-administered. The study drug should not 
be chewed before swallowing. The study drug may be taken with water. 
Subjects are required to fast for 2 hours before and after administration of niraparib when PK 
samples are to be drawn. 
8.2 
Definitions of DLT 
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective 14 June 2010 [15]. 
DLT will be defined as any of the following events that are considered by the investigator or 
subinvestigator to be related to treatment with niraparib (note that AEs for which the relationship 
to study drug cannot be ruled out should be considered related to study drug). 
Hematologic DLTs: 
• Any Grade 5 hematologic toxicity. 
• Any Grade 4 hematologic toxicity, except Grade 4 neutropenia <7 days in duration. 
• Grade 3 or Grade 4 neutropenia with fever >38.5°C and/or infection requiring antibiotic or 
anti-fungal treatment. 
Non-hematologic DLTs: 
Any Grade 3, 4, or 5 non-hematologic toxicity with the exception of: 
• Grade 3 nausea, vomiting, diarrhea, or dehydration occurring in the setting of inadequate 
compliance with supportive care and lasting less than 48 hours. 
• Inadequately treated hypersensitivity reactions. 
• Grade 3 acidosis or alkalosis that responds to intervention by improving to ≤Grade 2 within 
48 hours. 
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• Isolated, asymptomatic Grade 3 amylase elevation. 
• Grade 3 hypercholesterolemia. 
• Grade 3 hypertriglyceridemia. 
Additional DLTs: 
• Any treatment-related AE, regardless of NCI CTCAE grade, leading to an interruption of 
niraparib for greater than 14 days. 
For determination of MTD, only DLTs occurring between Cycle 1 Day 1 and Cycle 2 Day 1 
(predose) will be considered. In Cycle 1, treatment may be interrupted at any time for any grade 
of toxicity if the investigator or subinvestigator deems that the toxicity will interfere with safe 
continuation of the study treatment. If dose interruption was required in Cycle 1, the patient 
should be continuously monitored during Cycle 2 Day 1 onwards to determine whether or not the 
toxicity is a DLT, and confirm the required duration of dose interruption. If any DLT is 
observed, the dose may be reduced at any time, but dose reduction for reasons other than DLT 
will not be allowed. 
Patients who did not receive ≥80% of the study medication in Cycle 1 for reasons other than 
related toxicities will not be taken into account for dose escalation purposes and must be 
replaced for DLT counting purposes and for full assessment of the safety of that dose level. 
8.3 
Dose Escalation Rules 
Dose-escalation will proceed according to a 3+3 design. The initial niraparib dose will be 
200 mg QD in Cohort 1 and will be escalated to 300 mg QD (Cohort 2), provided that the safety 
and tolerability of the 200 mg dose have been demonstrated. 
If 0 of 3 subjects experience a DLT in Cohort 1, the cohort is proceeded to the next dose level 
(Cohort 2). If 2 of 3 or all subjects experience a DLT in Cohort 1, this dose is considered 
exceeded MTD, and the dose-escalation of the trial will be terminated. If 1 of 3 subjects 
experience a DLT, 3 more subjects will be enrolled at this dose level. If 1 of 6 patients in the 
combined dose-group experience a DLT, the cohort is proceeded to the next dose level (Cohort 
2). If ≥2 of 6 subjects experience a DLT, this dose is considered exceeded MTD, and the dose-
escalation of the trial will be terminated. 
If 0 of 3 subjects experience a DLT in Cohort 2, MTD is considered 300 mg or higher, and the 
dose-escalation of the trial will be completed. If 2 of 3 or all subjects experience a DLT in 
Cohort 2, this dose is considered exceeded MTD. If 1 of 3 subjects experience a DLT in Cohort 
2, 3 more subjects will be enrolled at this dose level. If 1 of 6 subjects experience a DLT, MTD 
is considered 300 mg or higher, and the dose-escalation of the trial will be completed. If ≥2 of 6 
subjects experience a DLT, this dose is considered exceeded MTD. Further dose-escalation 
beyond Cohort 2 (300 mg QD) is not anticipated in this study. 
These rules are shown in Table 8.a. 
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Table 8.a 
Dose Escalation Rules 
DLT occurred in 
Decision 
0/3 subjects (a) 
Go to next cohort 
1/3 subjects 
Reevaluation with 3 more subjects 
 
1/6 subjects (a) 
Go to next cohort 
 
≥2/6 subjects (b) 
Exceeded MTD 
≥2/3 subjects (b) 
Exceeded MTD 
 
(a) If 0 of 3 or 1 of 6 subject experiences a DLT, proceed to the next dose level (Cohort 2) in Cohort 1 or and dose-
escalation is completed in Cohort 2 (no further dose-escalation). 
(b) If ≥2/3 or ≥2/6 subjects experience a DLT in Cohort 1 (200 mg QD), this dose is considered exceeded MTD, and 
not escalate to the next dose level (Cohort 2). Subjects who are considered safe at this dose of niraparib by the 
investigator or subinvestigator may continue to receive the study drug at the same dose. 
8.4 
Dose Modification Guidelines 
8.4.1 Criteria for Dose Reduction, Interruption, and Discontinuation 
In Cycle 1, treatment may be interrupted at any time for any grade of toxicity if the investigator 
or subinvestigator deems that the toxicity will interfere with safe continuation of the study 
treatment. If dose interruption was required in Cycle 1, the patient should be continuously 
monitored during Cycle 2 Day 1 onwards to determine whether or not the toxicity is a DLT, and 
confirm the required duration of dose interruption. If any DLT is observed, the dose may be 
reduced at any time, but dose reduction for reasons other than DLT will not be allowed. 
In Cycle 2 onwards, treatment may be interrupted and/or dose reduced at any time for any grade 
of toxicity if the investigator or subinvestigator deems that the toxicity will interfere with safe 
continuation of the study treatment. 
Treatment must be interrupted for any NCI CTCAE (v.4.03) Grade 3 or 4 non-hematologic 
toxicity which the investigator or subinvestigator considers to be related to administration of 
niraparib. If toxicity is appropriately resolved to baseline or Grade 1 or less within 28 days, the 
patient may restart treatment with niraparib at the same dose level. However, if prophylaxis with 
medication or blood transfusion is not considered feasible, treatment with niraparib should be 
restarted with a dose level reduction according to Table 8.b. If the event recurs at the same or 
worse grade, treatment should be interrupted again and, upon resolution, a further dose reduction 
must be made. No more than 2 dose reductions will be permitted. 
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Table 8.b 
Dose Reductions for Non-Hematologic Toxicities (Cycle 2 and Onwards) 
Event 
Dose(a) 
 
Cohort 1 
Cohort 2 
Initial dose 
200 mg QD 
300 mg QD 
1st dose reduction for NCI CTCAE Grade 3 or 4 
treatment-related SAE/AE where prophylaxis with 
medication or blood transfusion is not considered feasible 
100 mg QD 
200 mg QD 
2nd dose reduction for NCI CTCAE Grade 3 or 4 
treatment-related SAE/AE where prophylaxis with 
medication or blood transfusion is not considered feasible 
Discontinue study 
medication 
100 mg QD 
Continued NCI CTCAE Grade 3 or 4 treatment-related 
SAE/AE ≥28 days 
Discontinue study 
medication 
Discontinue study 
medication 
Abbreviations: AE, adverse events; NCI CTCAE, National Cancer Institute Common Terminology Criteria for 
Adverse Events; QD, once daily; SAE, serious adverse events. 
(a) Dose not to be decreased below 100 mg QD. 
If the toxicity requiring dose interruption has not resolved completely or to NCI CTCAE Grade 1 
during the maximum 4 week (28 day) dose interruption period, and/or the patient has already 
undergone a maximum of 2 dose reductions (to a minimum dose of 100 mg QD), the patient 
must permanently discontinue treatment with niraparib. 
The dose interruption/modification criteria for hematologic parameters will be based on blood 
counts and are outlined in Table 8.c. 
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Table 8.c 
Dose Interruption/Modification for Hematologic Toxicities (Cycle 2 and 
Onwards) 
Finding 
Modification 
Platelet count: 75,000-99,999/μL Study medications must be interrupted until platelet counts are ≥100,000/μL, 
with weekly blood counts for CBC monitored until recovery. Study medication 
may then be resumed at same dose or reduced dose based on clinical judgment. 
2nd occurrence of platelet count: 
75,000-99,999/μL 
Study medications must be interrupted until platelet counts are ≥100,000/μL, 
with weekly blood counts for CBC monitored until recovery. Study medication 
may then be resumed at a reduced dose. 
Platelet count: <75,000/μL* 
Study medications must be interrupted until platelet counts are ≥100,000/μL, 
with weekly blood counts for CBC monitored until recovery. Study medication 
may then be resumed at a reduced dose. 
Neutrophil: <1,000/μL 
Study medications must be interrupted until neutrophil counts are ≥1,500/μL, 
with weekly blood counts for CBC monitored until recovery. Study medication 
may then be resumed at a reduced dose. 
Hemoglobin: <8 g/dL 
Study medications must be interrupted until hemoglobin is ≥9 g/dL, with 
weekly blood counts for CBC monitored until recovery. Study medication may 
then be resumed at a reduced dose. 
Abbreviation: CBC, complete blood cell count. 
*For patients with platelet count ≤10,000/μL prophylactic platelet transfusion per guidelines may be 
considered[16][17]. 
For patients taking anticoagulation or antiplatelet drugs consider the risk/benefit of interrupting these drugs and/or 
prophylactic transfusion at an alternate threshold, such as ≤20,000/μL. 
If dose interruption or modification is required at any point on study because of hematologic 
toxicity, to ensure safety of the new dose, weekly blood draws for complete blood cell count 
(CBC) will be required for an additional 4 weeks after the AE has been resolved to the specified 
levels. If the hematologic toxicity has not recovered to the specified levels within 4 weeks (28 
days) of the dose interruption period, and/or the patient has already undergone a maximum of 2 
dose reductions (to a minimum dose of 100 mg QD), the patient must permanently discontinue 
treatment with niraparib. 
Any patient requiring transfusion of platelets or red blood cells (1 or more units) or 
hematopoietic growth factor support must undergo a dose reduction upon recovery if study 
treatment is resumed. 
The patient must be referred to a hematologist for further evaluation (1) if transfusions are 
required on 1 or more occasions or (2) if the treatment-related hematologic toxicities have not 
recovered to NCI CTCAE Grade 1 or less after 4 weeks. If a diagnosis of myelodysplastic 
syndrome (MDS)/acute myeloblastic leukemia (AML) is confirmed by a hematologist, the 
patient must permanently discontinue study treatment. 
For major surgery while on treatment, up to 28 days of drug interruption is allowed. 
All dose interruptions and reductions (including any missed doses), and the reasons for the 
reductions/interruptions, are to be recorded in the electronic case report from (eCRF). 
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8.4.2 Re-Escalation After Dose Reduction 
Once the dose of study treatment has been reduced, any re-escalation must be discussed with the 
medical monitor. 
8.4.3 Criteria for Beginning or Delaying a Subsequent Treatment Cycle 
Niraparib will be administered in continuous cycles; therefore, study drug should be 
administered continuously unless TEAEs occur that meet the dose modification criteria outlined 
in Section 8.4.1 (Criteria for Dose Reduction, Interruption and Discontinuation). 
If dose interruption was required due to TEAE at the beginning of a Cycle, the Cycle should not 
be postponed. Once the patient recovers from the TEAE, the study treatment will be resumed in 
the middle of the cycle, without waiting for the first day of the next Cycle. 
However, the timing of efficacy and safety evaluations will not be affected by the dose 
interruption or dose reduction. 
8.5 
Excluded Concomitant Medications and Procedures 
The following medications, procedures and foods are prohibited during the study: 
• Other anticancer therapies other than study treatment, with the exception as follows: 
– Patients with prostate cancer may have been treated with LH-RH analogs (Section 7.2, 
exclusion criterion 1). 
– Patients who initiated bisphosphonate therapy ≥30 days prior to Cycle 1 Day 1 may 
continue the treatment (Section 7.2, exclusion criterion 3). 
– Patients with a stable dose and administration of steroids ≥30 days prior to Cycle 1 Day 1 
may continue the administration (Section 7.2, exclusion criterion 7). 
– Palliative radiotherapy is allowed for pre-existing small areas of painful metastases that 
cannot be managed with local or systemic analgesics as long as no evidence of PD is 
present. 
• Medications that prolong QTc. 
• Conventional chemotherapy drugs, live virus and bacterial vaccines (an increased risk of 
infection have been observed with concomitant administration of these medications). 
• Prophylactic cytokine (granulocyte colony-stimulating factor [GCSF]) administration should 
not be given in Cycle 1; however, if the patient experiences a DLT, prophylactic cytokine 
can be given thereafter. Prophylactic cytokine may be administered in Cycle 2 onwards 
according to local guidelines, etc. 
The following medications, procedures, and foods should be used with caution during the study. 
• Drugs that are substrates for cytochrome P450 (CYP) 1A2 (Appendix G) (niraparib is a 
CYP1A2 inducer). 
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• Drugs that are inhibitors or substrates for P-glycoprotein (P-gp) (niraparib is a substrate for 
P-gp). 
• Anticoagulation and antiplatelet drugs (niraparib potential risk includes thrombocytopenia). 
8.6 
Permitted Concomitant Medications and Procedures 
For patients with platelet count ≤10,000/μL prophylactic platelet transfusion per guidelines may 
be considered (except Cycle 1). 
8.7 
Precautions and Restrictions 
8.7.1 Pregnancy and Contraception 
It is not known what effects niraparib has on human pregnancy or development of the embryo or 
fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and 
male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below. 
Female patients must meet 1 of the following: 
• Postmenopausal for at least 1 year before the screening visit (natural amenorrhea, not due to 
other medical reasons), or 
• Surgically sterile, or 
• If they are of childbearing potential*, agree to practice 1 highly effective method and 1 
additional effective (barrier) method of contraception** at the same time, from the time of 
signing of the informed consent form (ICF) through 180 days after the last dose of study 
drug. 
• Agree to practice true abstinence from the time of signing of the informed consent form 
through 180 days after the last dose of study drug, when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], condoms only, withdrawal, spermicides only, and lactational 
amenorrhea are not acceptable methods of contraception.) 
Male patients, even if surgically sterilized (ie, vasectomy) must agree to 1 of the following: 
• Agree to practice 1 highly effective method and 1 additional effective barrier contraception** 
from the time of signing of the informed consent form through 120 days after the last dose of 
study drug. If the female partner of a male subject is of child bearing potential, it should also 
be advised to use a highly effective method of contraception**. 
• Agree to practice true abstinence from the time of signing of the informed consent form 
through 120 days after the last dose of study drug, when this is in line with the preferred and 
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods of the female partner], condoms only, withdrawal, spermicides only, 
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and lactational amenorrhea are not acceptable methods of contraception. Female and male 
condoms should not be used together.) 
*Women of childbearing potential is defined as any sexually active female subjects who meet 
both of the following criteria: 
• Those who have not undergone hysterectomy or bilateral oophorectomy. 
• Those who have not had natural menopause for 12 consecutive months or longer. 
Note: A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient. 
**Examples of highly effective contraception methods are listed below: 
• Hormonal birth control pills. 
• Intrauterine device. 
• Intrauterine hormone-releasing system. 
8.7.2 Other Precautions and Restrictions 
• Patients who are blood donors should not donate blood during the study and for 90 days after 
the last dose of study treatment. 
8.8 
Management of Clinical Events 
Detailed niraparib dose modification and prevention/prophylaxis guidelines for specific clinical 
events are provided in the following sections. General guidelines for niraparib interruption, dose 
reduction and discontinuation are provided in Section 8.4.1. 
8.8.1 Hematologic Toxicities 
Hematologic adverse reactions (thrombocytopenia, anemia, neutropenia), including clinical 
diagnoses and/or laboratory findings, have been reported in patients treated with niraparib. In 
patients who have experienced hematologic toxicities after niraparib administration, study 
medication must be interrupted until platelet, hemoglobin and neutrophil levels have returned to 
the levels specified in Table 8.c (Section 8.4.1). 
If deemed clinically necessary, supportive therapy with platelet or RBC transfusion and 
supportive therapy with hematopoietic growth factors (G-CSFs) may be considered for these 
hematologic toxicities. Generally, G-CSFs should not be administered in the first cycle of the 
study; however if the patient experiences a DLT, G-CSFs can be administered thereafter. 
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After the toxicity has resolved, CBCs should be tested weekly for the first month, followed by 
testing as a part of clinical laboratory evaluation on study visits to monitor for clinically 
significant changes in any hematologic parameter during treatment. 
If a patient develops severe persistent hematologic toxicity that does not resolve within 28 days 
following interruption, niraparib should be discontinued (Section 8.4.1). 
Due to the risk of thrombocytopenia, anticoagulant and antiplatelet drugs should be used with 
caution (Section 8.5) 
8.8.2 Myelodysplastic Syndrome/Acute Myeloid Leukemia 
MDS/AML, including cases with fatal outcome, have been reported in a small number of 
patients who received niraparib or placebo. If MDS and/or AML are confirmed while on 
treatment with niraparib, then niraparib should be permanently discontinued (See Section 8.4.1). 
8.8.3 Hypertension, Including Hypertensive Crisis 
Hypertension, including hypertensive crisis, has been reported with the use of niraparib. Blood 
pressure should be monitored periodically on study visits during treatment with niraparib. 
Hypertension should be medically managed with antihypertensive medications as well as 
adjustment of the niraparib dose, if necessary. 
8.8.4 Diarrhea 
Diarrhea should be treated promptly with appropriate supportive care, including administration 
of an anti-diarrheal agent according to standard practice guidelines. Anti-diarrheal agents should 
not be taken prophylactically. Subjects should be instructed to begin taking anti-diarrheal 
medication at the first sign of: 
1. Poorly formed or loose stool. 
2. Occurrence of more bowel movements than usual in one day. 
3. Unusually high volume of stool. 
Anti-diarrheal agents should be deferred if blood or mucus is present in the stool or if diarrhea is 
accompanied by fever. In this setting, appropriate diagnostic microbiologic specimens should be 
obtained to exclude an infectious etiology. Subjects should also be advised to have sufficient oral 
fluid intake to prevent dehydration. 
8.8.5 Nausea and/or Vomiting 
Nausea and vomiting should be treated proactively, according to standard institutional practice, 
including administration of prophylactic antiemetic therapy. Subjects should be strongly 
encouraged to maintain sufficient oral fluid intake. 
8.9 
Blinding and Unblinding 
This is an open-label study. 
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8.10 
Description of Investigational Agents 
Niraparib capsule contains 100 mg of niraparib (free form). The hard capsules have a white body 
with a printed black bar, and a purple cap with a printed white bar. 
8.11 
Preparation, Reconstitution, and Dispensation 
Detailed instructions for dispensing niraparib tablets are provided in the Pharmacy Manual. 
Niraparib is an anticancer drug, and as with other potentially toxic compounds, caution should be 
exercised when handling niraparib. 
8.12 
Packaging and Labeling 
Niraparib capsules are packaged in a high-density polyethylene (HDPE) white bottle with a two-
piece, pulp-backed, heat-induction-foil inner seal, tamper-proof cap. Each bottle contains 93 
capsules. The label text of the study drug will comply with the national legislation to meet all 
requirements in Japan. 
8.13 
Storage, Handling, and Accountability 
Investigational study drug must be stored in accordance with the Pharmacy Manual instructions 
and package labeling. Until dispensed to the patients and returned to the sponsor or its designated 
disposal vendor, the study treatment will be stored in a securely locked area, accessible to 
authorized personnel only. 
All investigational study drug supplies in the US must be stored at 20°C to 25°C (68°F to 77°F); 
excursions are permitted between 15°C to 30°C (59°F to 86°F) (see USP Controlled Room 
Temperature) and investigation study drug supplies in the EU must be stored below 30°C. Refer 
to the Pharmacy Manual for further details. 
8.14 
Other Protocol-Specified Materials 
Not applicable. 
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9.0 
STUDY CONDUCT 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guidelines. 
9.1 
Study Personnel and Organizations 
The contact information for the sponsor’s medical monitor for this study, other third-party 
vendors, and the list of investigators may be found in the protocol annex or the Study Manual. 
9.2 
Arrangements for Recruitment of Patients 
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator or subinvestigator’s local practice or referrals from other physicians. If 
advertisements become part of the recruitment strategy, they will be reviewed by the institutional 
review board (IRB). 
9.3 
Treatment Group Assignments 
This phase 1 study includes 2 cohorts, consisting of Cohort 1 (200 mg QD) and Cohort 2 
(300 mg QD), and each subject will be assigned to either one of the cohorts based on the Dose 
Escalation Rules described in Section 8.3. 
A subject identification code will be assigned to each patient after he/she signed the ICF. 
Patient eligibility will be confirmed by the sponsor’s Medical Monitor (or designee) before 
enrollment by the investigator or subinvestigator into the study. If a subject discontinues the 
study, the subject identification code will not be reused. 
9.4 
Study Procedures 
Refer to the Schedule of Events (Appendix A) for the timing of assessments. Additional details 
are provided as necessary in the sections that follow. 
9.4.1 Informed Consent 
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient's standard care. 
9.4.2 Patient Demographics 
The date of birth, race and sex of each subject are to be recorded during the Screening period. If 
available, the data on whether individual subjects have BRCA mutations will also be collected. 
9.4.3 Medical History 
During the Screening period, all concurrent conditions will be collected for each subject. Also, 
medical history that are considered to be clinically useful by the investigator will be collected. 
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As the information about the underlying disease, the following data will be collected and 
recorded specifically: the date of initial diagnosis, the type of tumor, the stage of disease at the 
initial diagnosis, the results of histology at diagnosis, grade and recent biopsy results (if 
performed). 
During screening, the following medications are to be recorded as prior medications based on 
hearing from the subjects: 
– All non-chemotherapeutic medications given to subjects within 14 days before Cycle 1 
Day 1. 
– All chemotherapeutic agents and treatment given to subjects after the initial diagnosis: 
drug used in the first treatment and its start and end dates, drugs used in subsequent 
treatments and their start and end dates, and the best response to each treatment. 
9.4.4 Physical Examination 
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events (Appendix A). 
9.4.5 Patient Height and Weight 
Height will be measured at Screening only. Weight will be measured at the times specified in the 
Schedule of Events (Appendix A). 
9.4.6 Vital Signs 
Vital signs include diastolic and systolic blood pressure, pulse rate and body temperature 
(axillary) measured at the times specified in the Schedule of Events (Appendix A). Subjects must 
be resting in a sitting position for 10 minutes prior to obtaining vital signs. This measurement 
method will be used throughout the study. To determine the effects of niraparib on the 
cardiovascular system, blood pressure will be measured prior to obtaining blood samples. 
If blood pressure exceeds 150/100 mmHg or diastolic blood pressure exceeds 20 mmHg from 
baseline despite the subject has no history of hypertension, blood pressure must be re-measured 
within 10 minutes for confirmation. 
If there was a change in blood pressure from prior to study drug administration, which was 
judged by the investigator as an AE, such change will be recorded in the eCRF. 
9.4.7 ECOG 
ECOG performance status will be assessed and recorded according to Appendix E at the times 
specified in the Schedule of Events (Appendix A). 
The investigator will evaluate the performance status. 
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9.4.8 Pregnancy Test 
A serum pregnancy test will be performed for women of childbearing potential (defined in 
Section 8.7.1) within 7 days before Cycle 1 Day 1, and negative results must be obtained. 
Subsequently, urine pregnancy tests will be performed predose on Day 1 of Cycle 2 and 
thereafter, and negative results must be obtained before the study drug administration. 
9.4.9 Concomitant Medications and Procedures 
Medications used by the subject and therapeutic procedures completed by the subject will be 
recorded in the eCRF from the time of signing the informed consent through 28 days after the 
last dose of study drug. See Section 8.5 and Section 8.6 for medications and therapies that are 
prohibited or allowed during the study. 
All medications other than the study drug (including Chinese herbal medicine and other non-
traditional remedies) used by subjects as concomitant drugs during the study period should be 
investigated and recorded by hearing from the subjects. For each medication, the nonproprietary 
name, the start and end date and the purpose of use will be recorded. 
9.4.10 Adverse Events 
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified 
in the Schedule of Events (Appendix A). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of AEs and serious AEs (SAEs). 
9.4.11 
Enrollment 
A subject is considered to be enrolled in the study when the sponsor sends an enrollment sheet 
back to the investigational site. Procedures for completion of the enrollment information are 
described in the Study Manual. 
9.4.12 
Electrocardiogram 
A 12-lead ECG will be performed at time points specified in the Schedule of Events (Appendix 
A) and Detailed Schedule of PK Sample Collection and 12-lead ECG in Cycle 1 (Appendix B) , 
and the results of 12-lead ECG will be evaluated at each study site. The heart rate, RR, PR, QRS, 
QT, and corrected QT (QTcF) intervals will be recorded in the eCRF. 
An additional ECG measurement may be performed as clinically indicated. 
9.4.13 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will be performed locally before administration of the study drug. 
9.4.13.1 Clinical Chemistry, Hematology, and Urinalysis 
Blood samples for analysis of the clinical chemistry and hematological parameters shown in 
Table 9.a and urine samples for analysis of the parameters shown in Table 9.b will be obtained 
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on the same day, before administration of the study drug, as specified in the Schedule of Events 
(Appendix A). 
Table 9.a 
Clinical Chemistry and Hematology Tests 
Hematology 
Serum Chemistry 
 Erythrocyte 
 Hematocrit 
 Hemoglobin 
 Leukocytes with differential 
(ANC, basophil count, eosinophil 
count, absolute lymphocyte count, 
monocyte count) 
 Platelet count 
 MCV 
 Albumin 
 ALP 
 ALT 
 Amylase 
 AST 
 Total bilirubin 
 Urea nitrogen 
 Calcium 
 Bicarbonate 
 Creatinine 
 Chloride 
 GGT 
 Glucose (fasted) 
 LDH 
 Magnesium 
 Inorganic phosphate 
 Potassium 
 Sodium 
 Protein (total protein) 
Blood coagulation test 
Pregnancy test (serum, urine) 
 
 aPTT 
 PT 
 INR 
 hCG 
 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANC, absolute neutrophil count; aPTT, 
activated partial thromboplastin time; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; 
hCG, human chorionic gonadotropin; INR, international normalized ratio; LDH, lactate dehydrogenase; MCV, mean 
cell volume; PT, prothrombin time. 
Table 9.b 
Clinical Urinalysis Tests 
Urinalysis 
 Bilirubin 
 Glucose 
 Ketone body 
 Nitrite 
 Occult blood 
 Protein 
 Specific gravity 
 Urobilinogen 
 Leukocyte esterase 
 
If creatinine clearance is to be estimated, the Cockcroft-Gault formula will be employed as 
follows: 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 
=  [(140 −𝐴𝐴𝐴𝐴𝐴𝐴) ∗𝑊𝑊𝑊𝑊𝑊𝑊𝑔𝑔ℎ𝑡𝑡(𝑘𝑘𝑘𝑘) ] / [72 ∗𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐(𝑚𝑚𝑚𝑚/𝑑𝑑𝑑𝑑)] 
For female subjects, the result of the formula above should be multiplied by 0.85. 
9.4.13.2 HIV and Hepatitis Testing 
HIV and hepatitis testing will be performed during the screening period. 
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HBsAg, HBsAb and HBcAb will be tested to screen HBV. For patients who are HBsAg negative 
but HBsAb and/or HBcAb positive, hepatitis B viral load (HBV-DNA) will also be assessed at 
Screening. Patients who are HBsAg-negative but HBsAb and/or HBcAb-positive may be eligible 
if they have an undetectable HBV-DNA. 
HCVAb will also be tested for hepatitis C at Screening. Patients who are positive for HCVAb 
will also be tested for hepatitis C viral load (HCV-RNA) at Screening. Patients who are positive 
for HCVAb may be eligible if they have an undetectable HCV-RNA. 
Patients who were positive for serum virus tests and had an undetectable HBV-DNA or HCV-
RNA may be enrolled in this study, but they should be measured for viral load (HBV-DNA or 
HCV-RNA) and monitored at Day 1 of each cycle, at the end of the treatment (EOT) and at the 
Follow-up visit 28 days after the last dose. If HBV-DNA or HCV-RNA is detected, the patient 
would be withdrawn from the study and treated according to the institutional guidelines. In this 
case, a consultation with a hepatologist should be considered. 
9.4.14 
Disease Assessment 
Subjects will undergo computed tomography (CT) with contrast as appropriate to monitor and 
assess PD, using modified RECIST criteria (Version 1.1) (Appendix F) [14]. Specific disease 
sites that cannot be adequately imaged by CT with contrast may be documented by magnetic 
resonance imaging (MRI). Bone scans may be performed on subjects with bone metastases rather 
than contrast enhanced CT or MRI. 
During the study, anatomical measurements will be collected for each target lesion using an 
imaging modality consistent with that used at Screening. The same method (CT with contrast, 
MRI or bone scan) must be consistently used on a subject throughout the study. 
Objective assessments will be performed at each time point as described in the Schedule of 
Events (Appendix A) as long as there is no evidence of early PD. When possible, the same 
qualified physician will interpret the results to reduce variability. 
Diagnostic imaging/tumor assessment performed within 42 days before the first dose of the study 
drug may be used as screening assessment. Appropriate imaging evaluation at screening should 
include a CT/MRI of the chest, abdomen and pelvis. Imaging evaluations of other body parts are 
not necessary unless clinically indicated. 
The sizes of visible lesions will be recorded using a ruler. The sizes of palpable lesions will be 
recorded in the subject's source documents at the physical examination. The tumor status will be 
compared with that at screening, using physical findings, imaging results and ECOG 
performance status. 
Radiographic images will be maintained at each site, and test results and physicians’ findings 
will be filed in subject's source documents. The sponsor may request electronic images for those 
subjects who demonstrate tumor reduction. 
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9.4.15 Pharmacokinetic Measurements 
Blood samples for PK analysis of niraparib will be serially collected at the time points specified 
in the Pharmacokinetic Sample Breakdown table (Appendix A) and Detailed Schedule of PK 
Sample Collection and 12-lead ECG in Cycle 1 (Appendix B). The exact dates and times of 
administration of niraparib before collection of the blood sample for PK analysis and the exact 
dates and times of collection of the blood sample for PK analysis will be recorded on the eCRF. 
9.4.16 Hospitalization 
Subjects will receive niraparib under inpatient hospitalization (from Cycle 1 Day 1 to Cycle 1 
Day 8 will be mandatory) during Cycle 1. If a subject wishes to return home temporarily and the 
investigator or subinvestigator confirms that the subject's symptoms are stable based on the 
available data, then the subject may return home temporarily, except from Cycle 1 Day 1 to 
Cycle 1 Day 8, provided this does not interfere with the study assessments. The investigator or 
subinvestigator must document the confirmation record that there is no problem in the subject’s 
safety in the medical records before the patient's temporary leave. 
9.4.17 Dosing Compliance (Patient Diary) 
Subjects will be provided a patient diary to confirm their dosing compliance with niraparib 
treatment, and record each dose they take in their diary every day. The investigator will check 
the patient diary on their visits. 
9.5 
Documentation of Screen Failure 
Investigators must account for all subjects who sign the ICF. 
Even if the subject is found to be not eligible prior to the first dose of the study drug, the 
investigator or subinvestigator should complete the applicable eCRF. 
The primary reason for subject failure is recorded in the eCRF using the following categories: 
• Death 
• Adverse event 
• Screen failure (failed inclusion criteria or did meet exclusion criteria) 
• Protocol deviation 
• Lost to Follow-up 
• Withdrawal by subject 
• Study terminated by sponsor 
Subject identification codes assigned to subjects who fail screening should not be reused. 
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9.6 
Completion of Investigational Product Administration / Study Treatment (for 
Individual Patients) 
Patients will be considered to have completed treatment if they discontinue treatment with study 
drug for any of the reasons outlined in Section 9.8. 
Treatment will continue until PD, unacceptable toxicities, or withdrawal due to other reasons. 
9.7 
Completion of Study (for Individual Patients) 
Patients will be considered to have completed the study if they discontinue the treatment and 
complete the 28-day safety follow-up. 
9.8 
Discontinuation of Treatment With Study Drug 
Treatment with study drug may be discontinued for any of the following reasons: 
• Adverse event 
• Protocol deviation 
• PD 
• Study terminated by sponsor 
• Withdrawal by subject 
• Death 
• Lost to follow-up 
• Pregnancy 
• Other 
The sponsor should be notified of all discontinuations of study drug as soon as possible. The 
primary reason for study drug discontinuation will be recorded in the eCRF. 
Once the study drug has been discontinued, all study procedures outlined for the Early 
Termination will be completed as specified in the Schedule of Events (Appendix A). All subjects 
will be followed until 28 days after the last dose of study drug, unless the subject withdraws 
consent to participate in the study. 
If a subject did not receive at least 80% of planned doses of study drug in Cycle 1 due to reasons 
other than study drug-related toxicity, the subject may be replaced. 
9.9 
Withdrawal of Subjects From Study 
A subject may be withdrawn from the study for any of the following reasons. However, subjects 
may withdraw their consent to participate in the study at any time without prejudice. 
• Lost to follow-up 
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• Study terminated by sponsor 
• Withdrawal by subject 
• Death 
• Other 
The sponsor should be notified of all subject withdrawals from the study as soon as possible. If a 
subject withdraws consent to participate in the study, no study data will be collected or data 
added to the database for this subject thereafter. However, every effort will be made to follow all 
subjects for safety. 
9.10 
Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision of 
the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of study drug receipt and dispensing. 
Subjects will receive a sufficient quantity of study drugs for each treatment cycle and provided a 
diary where the date of study drug administration will be recorded. The study site staff will 
check the patient diary versus the subject's supply of remaining niraparib at each study visit to 
ensure proper compliance with dosing. Subjects who are not compliant with the dosing schedule 
may be withdrawn from the study. 
Tests and procedures should be performed on schedule. However, except Cycle 1 Day 1, Cycle 2 
Day 1, Early Termination and follow-up 28 days after the last dose, occasional changes are 
allowable within a 3-day window for holidays, vacations, and other administrative reasons. If 
extenuating circumstances prevent a subject from beginning treatment or completing a planned 
procedure or assessment within 3 days of the scheduled time, the subject may continue the study 
at the discretion of the investigator and after consultation with the sponsor's medical monitor or 
designee. However, the timing of PK assessment as specified in the Schedule of Events 
(Appendix A) and Detailed Schedule of PK Sample Collection and 12-lead ECG in Cycle 1 
(Appendix B) is not flexible. 
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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse Event Definition 
AE means any untoward medical occurrence in a subject or subject who has signed informed 
consent to participate in a study; it does not necessarily have to have a causal relationship with 
this treatment (including an investigational product). An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom or disease temporally 
associated with the use of a medicinal (investigational) product whether or not it is related to the 
medicinal product. This includes any newly occurring event, or a previous condition that has 
increased in severity or frequency since the administration of study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator or subinvestigator to be a clinically significant change from 
baseline. 
10.1.2 Serious Adverse Event Definition 
SAE means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the subject was at risk of death at the time of 
the event. It does not refer to an event which hypothetically might have caused death if it was 
more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
Section 10.2 for planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person's ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event. It may be considered serious when, an AE may not result in 
death or immediately life threatening or require hospitalization, but may jeopardize the 
subject, or require medical or surgical intervention to prevent one of the outcomes listed 
above, or involves suspected transmission via a medicinal product of an infectious agent, 
based on appropriate medical judgment. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
disorders or convulsions that do not result in hospitalization, or the development of drug 
dependence or drug abuse; any microorganism, virus, or infectious particle (eg, prion protein 
transmitting transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent. 
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In this study, intensity of each AE including any lab abnormality will be determined using the 
NCI CTCAE, Version 4.03 (effective date: 14 June 2010) [15]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the 
terms serious and severe are NOT synonymous. The general term “severe” is often used to 
describe the intensity (severity) of a specific event; the event itself, however, may be of 
relatively minor medical significance (such as a Grade 3 headache), so that this is NOT the same 
as serious. “Serious” is based on patient/event outcome or action criteria described above, and is 
usually associated with events that pose a threat to a subject’s life or ability to function. A severe 
AE (Grade 3 or 4) does not necessarily need to be considered serious. For example, a white 
blood cell count of 1000/mm3 to less than 2000/mm3 is considered Grade 3 (severe), but may not 
be considered serious. Seriousness (not intensity) serves as a guide for defining regulatory 
reporting obligations. 
10.2 
Procedures for Recording and Reporting Adverse Events and Serious Adverse 
Events 
All AEs spontaneously reported by the subject and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). 
Any clinically relevant deterioration in laboratory assessments or other clinical finding is 
considered an AE. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as 1 comprehensive event. 
Regardless of causality, SAEs must be reported (see Section 10.3 for the period of observation) 
by the investigator or subinvestigator to the Takeda Global Pharmacovigilance Department or 
designee (contact information provided below). This should be done by faxing, calling or e-
mailing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to the clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE may be requested 
by Takeda. SAE report information must be consistent with the data provided on the eCRF. 
SAE Reporting Contact Information 
BI Medical, Inc. 
 
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
the subject was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (eg, surgery was performed earlier or later 
than planned). 
For both serious and nonserious AEs, the investigator or subinvestigator must determine both the 
severity (toxicity grade) of the event and the relationship of the event to study drug 
administration. 
PPD
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Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 4.03, effective on 14 June 2010 [15]. 
A relationship of the event to study drug administration (ie, its causality) will be determined by 
the investigator or subinvestigator responding “Yes” (related) or “No” (unrelated) to the 
following question: “Is there a reasonable possibility that the AE is associated with the study 
drug?” 
10.3 
Monitoring of Adverse Events and Period of Observation 
AEs, both nonserious and serious, will be monitored throughout the study as follows: 
• AEs will be reported from the signing of informed consent through 28 days after 
administration of the last dose of study drug and recorded in the eCRFs. 
• SAEs 
– Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of study drug through 
28 days after administration of the last dose of study drug and recorded in the eCRF. 
After this period, only related SAEs must be reported to the Takeda Global 
Pharmacovigilance department or designee. SAEs should be monitored until they are 
resolved or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es). 
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator or subinvestigator immediately and permanently discontinue 
study drug. The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). The 
pregnancy must be followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every 
effort should be made to follow the pregnancy for the final pregnancy outcome. 
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) 
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or e-mail address provided below, or immediately contact the study monitor. 
A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
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underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or e-mail address provided below, contact the 
study monitor, and record the event in the Overdose page of the eCRF. 
Product 
Call center 
Phone number 
E-mail 
Fax 
All other 
molecules 
DLSS 
 
 
 
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, 
an SAE form should be completed and sent to BI Medical, Inc. (refer to Section 10.2). 
10.6 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, IRBs, and the 
head of the institution, as applicable, in accordance with national regulations in the countries 
where the study is conducted. Relative to the first awareness of the event by/or further provision 
to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory authorities as 
an expedited report within 7 days for fatal and life-threatening events and 15 days for other 
serious events, unless otherwise required by national regulations. The sponsor will also prepare 
an expedited report for other safety issues where these might materially alter the current benefit-
risk assessment of an investigational medicinal product or that would be sufficient to consider 
changes in the investigational medicinal product’s administration or in the overall conduct of the 
trial. 
PPD
PPD
PPD
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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study. 
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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary. 
12.1 
eCRFs 
Completed eCRFs are required for each subject who signs an ICF. 
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor, contract 
research organization (CRO) partners, and regulatory authorities. Investigative sites must 
complete eCRFs in English. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator, subinvestigator, or appropriate site personnel. Corrections to eCRFs are recorded in 
an audit trail that captures the old information, the new information, identification of the person 
making the correction, the date the correction was made, and the reason for change. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor. 
12.2 
Record Retention 
The investigator and the head of the institution agree to keep the records stipulated in 
Section 12.1 and those documents that include (but are not limited to) the study-specific 
documents, the identification log of all participating subjects, medical records, temporary media 
such as thermal sensitive paper, source worksheets, all original signed and dated ICFs, subject 
authorization forms regarding the use of personal health information (if separate from the ICFs), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
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International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) E6 Section 4.9.5 requires the investigator and the head of the institution to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or until at 
least 2 years after the investigation is discontinued and regulatory authorities are notified. In 
addition, ICH E6 Section 4.9.5 states that the study records should be retained until an amount of 
time specified by applicable regulatory requirements or for a time specified in the Clinical Study 
Site Agreement between the investigator and/or the head of the institution and sponsor. 
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. 
The investigator and the head of the institution should contact and receive written approval from 
the sponsor before disposing of any such documents. 
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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
In this study, statistical analyses will be primarily descriptive and graphical in nature. No formal 
statistical hypothesis testing will be performed. 
13.1.1 Analysis Sets 
Analysis sets will include the following: 
• Safety analysis set: patients who receive at least 1 dose of study drug. 
• PK analysis set: patients with sufficient dosing and PK data to reliably estimate 1 or more PK 
parameters. 
• DLT-evaluable set: patients who have received at least 80% of planned doses of niraparib in 
Cycle 1 (for at least 17 days out of 21 days) unless interrupted by study drug-related 
toxicities and have sufficient follow-up data considered by sponsor and investigator to 
determine whether DLT occurred. 
• Response-evaluable set: patients who receive at least 1 dose of study drug, have sites of 
measurable disease at baseline, and have at least 1 postbaseline disease assessment. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by dose cohort using the 
safety analysis set. 
13.1.3 Efficacy Analysis 
ORR and its two-sided 95% confidence interval based on binominal distribution will be provided 
by dose cohort using the response-evaluable set. The two-sided 95% confidence interval will be 
calculated based on binominal distribution. 
13.1.4 Pharmacokinetic Analysis 
All PK analyses will be performed using the PK analysis set. 
Plasma niraparib concentrations obtained from Cycle 1 will be summarized by descriptive 
statistics according to nominal (scheduled) time postdose and day for each cohort. Mean and 
individual plasma niraparib concentration data from Cycle 1 will be plotted over time for each 
day (Days 1 and 21) for each cohort. All plasma concentration data will be listed by cohort. The 
same analyses will be applied for the major metabolite M1 obtained from Cycle 1. 
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PK parameters will be calculated on Cycle 1 Days 1 and 21 for niraparib by noncompartmental 
analysis as permitted by the data. These parameters will include, but will not be limited to, Cmax, 
Tmax, and AUC. PK parameters will be summarized using descriptive statistics for each cohort 
and day. Individual PK parameters will be listed by cohort. The same analyses will be applied for 
the major metabolite M1. 
13.1.5 Safety Analysis 
The number of cases and incidence of DLTs during Cycle 1 will be tabulated using DLT-
evaluable set. 
Safety analyses for TEAE will be performed by dose levels using the safety analysis set. TEAE 
is defined as adverse events that occur after administration of the first dose of study drug and 
through 28 days after the last dose of study drug. TEAEs will be coded using the MedDRA 
dictionary, and will be tabulated by system organ class and preferred terms. 
• TEAEs 
• Drug-related TEAEs 
• Grade 3 or higher TEAEs 
• Grade 3 or higher drug-related TEAEs 
• Serious TEAEs 
• TEAEs leading to study drug discontinuation 
Shift tables based on changes in NCI CTCAE grade from baseline to the worst postbaseline 
value for laboratory parameters will be generated using the safety analysis set. Of the laboratory 
parameters, platelet count at each time point and changes from baseline will be summarized 
using descriptive statistics by dose level. 
Additional safety analyses may be performed to more clearly enumerate rates of toxicities and to 
further define the safety profile of niraparib QD. 
13.2 
Interim Analysis and Criteria for Early Termination 
No formal interim analysis is planned. 
13.3 
Determination of Sample Size 
Expected number of subjects: 6 to 12 patients (3 to 6 patients per Cohort) 
This study will use a 3+3 design. In the study, 2 ascending dose cohorts (3 to 6 patients per 
Cohort) are planned and approximately 6 to 12 DLT evaluable patients will be enrolled. 
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator guarantee access to source documents by the sponsor or its designee (CRO) and 
by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee, including but not limited to the Investigator’s Binder, study medication, subject 
medical records, informed consent documentation, and review of eCRFs and associated source 
documents. It is important that the investigator, subinvestigator, and other study personnel are 
available during the monitoring visits and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator or subinvestigator can deviate and change from the protocol for any medically 
unavoidable reason, for example, to eliminate an immediate hazard to study subjects, without a 
prior written agreement with the sponsor or a prior approval from IRB. In the event of a 
deviation or change, the principal investigator should notify the sponsor and the head of the site 
of the deviation or change as well as its reason in a written form, and then retain a copy of the 
written form. When necessary, the principal investigator may consult and agree with the sponsor 
on a protocol amendment. If the protocol amendment is appropriate, the amendment proposal 
should be submitted to the head of the site as soon as possible and an approval from IRB should 
be obtained. 
The investigator or subinvestigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the Food and Drug Administration [FDA], the 
United Kingdom Medicines and Healthcare products Regulatory Agency [MHRA], the 
Pharmaceuticals and Medical Devices Agency [PMDA] of Japan). If the study site is contacted 
for an inspection by a regulatory body, the sponsor should be notified immediately. The 
investigator and institution guarantee access for quality assurance auditors to all study documents 
as described in Section 14.1. 
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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix 
C. The principles of Helsinki are addressed through the protocol and through appendices 
containing requirements for informed consent and investigator responsibilities. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable local requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of 
members who make up the respective IRB. If any member of the IRB has direct participation in 
this study, written notification regarding his or her abstinence from voting must also be obtained. 
Those American sites unwilling to provide names and titles of all members due to privacy and 
conflict of interest concerns should instead provide a Federal Wide Assurance Number or 
comparable number assigned by the Department of Health and Human Services. 
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the ICF, 
and, if applicable, subject recruitment materials and/or advertisements and other documents 
required by all applicable laws and regulations, must be submitted to a central or local IRB for 
approval. The IRB’s written approval of the protocol and subject informed consent must be 
obtained and submitted to the sponsor or designee before commencement of the study (ie, before 
shipment of the sponsor-supplied drug). The IRB approval must refer to the study by exact 
protocol title, number, and version date; identify versions of other documents (eg, ICF) 
reviewed; and state the approval date. The sponsor will notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives 
notification no protocol activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the ICF, recruitment materials 
intended for viewing by subjects, local safety reporting requirements, reports and updates 
regarding the ongoing review of the study at intervals specified by the respective IRB, and 
submission of the investigator’s final status report to IRB. All IRB approvals and relevant 
documentation for these items must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
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applicable laws and regulations. The ICF describes the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF further explains the nature of the study, its objectives, and potential risks and 
benefits, as well as the date informed consent is given. The ICF will detail the requirements of 
the participant and the fact that he or she is free to withdraw at any time without giving a reason 
and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the ICF. The 
ICF, must be approved by both the IRB and the sponsor prior to use. 
The ICF must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator or subinvestigator to explain the detailed elements of the ICF to 
the subject. Information should be given in both oral and written form whenever possible and in 
the manner deemed appropriate by the IRB. 
The subject must be given ample opportunity to: (1) inquire about details of the study and 
(2) decide whether or not to participate in the study. If the subject determines he or she will 
participate in the study, then the ICF must be signed and dated by the subject at the time of 
consent and prior to the subject entering into the study. The subject should be instructed to sign 
using their legal names, not nicknames, using blue or black ballpoint ink. The investigator and 
subinvestigator must also sign and date the ICF at the time of consent and prior to subject 
entering into the study. 
Once signed, the original ICF will be stored in the investigator’s site file. The investigator or 
subinvestigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed ICF shall be given to the subject. 
All revised ICFs must be reviewed and signed by relevant subjects in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised ICF. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor or designee requires the investigator to permit its monitor or designee’s monitor, 
representatives from any regulatory authority (eg, FDA, MHRA and PMDA), the sponsor’s 
designated auditors, and the appropriate IRBs to review the subject’s original medical records 
(source data or documents), including, but not limited to, laboratory test result reports, ECG 
reports, admission and discharge summaries for hospital admissions occurring during a subject’s 
study participation, and autopsy reports. Access to a subject’s original medical records requires 
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the specific authorization of the subject as part of the informed consent process (see Section 
15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators, subinvestigators or to regulatory agencies, 
except as required by law or regulation. Except as otherwise allowable in the clinical study site 
agreement, any public disclosure (including publicly accessible websites) related to the protocol 
or study results, study recruitment materials and/or advertisements, is the sole responsibility of 
the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document. All publications and presentations must be prepared in 
accordance with this section and the Clinical Study Site Agreement. In the event of any 
discrepancy between the protocol and the Clinical Study Site Agreement, the Clinical Study Site 
Agreement will prevail. 
15.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, the sponsor will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites on or before start of study, as defined in Takeda Policy/Standard. 
The sponsor’s contact information, along with facility name, investigator’s city, state (for 
Americas investigators), country, and recruiting status will be registered and available for public 
viewing. 
15.4.3 Clinical Trial Results Disclosure 
The sponsor will post the results of clinical trials on ClinicalTrials.gov or other publicly 
accessible websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations. 
15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
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sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
subjects. Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator or subinvestigator has questions 
regarding this policy, he or she should contact the sponsor or sponsor’s designee. 
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16.0 
REFERENCES 
1. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients 
with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244-250. 
2. Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor 
olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-
of-concept trial. Lancet. 2010;376(9737):245-251. 
3. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors 
from BRCA mutation carriers. N Engl J Med. 2009;361(2):123-134. 
4. Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade 
serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, 
multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12(9):852-861. 
5. Kummar S, Ji J, Morgan R, et al. A phase I study of veliparib in combination with 
metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin 
Cancer Res. 2012;18(6):1726-1734. 
6. Turner NC, Ashworth A. Biomarkers of PARP inhibitor sensitivity. Breast Cancer Res Treat. 
2011;127(1):283-286. 
7. Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility 
gene BRCA2. Nature. 1995;378(6559):789-792. 
8. Chen JJ, Silver D, Cantor S, Livingston DM, Scully R. BRCA1, BRCA2, and Rad51 operate 
in a common DNA damage response pathway. Cancer Res. 1999;59(7 Suppl):1752s-1756s. 
9. Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev 
Cancer. 2004;4(10):814-819. 
10. Kaelin WG, Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat 
Rev Cancer. 2005;5(9):689-698. 
11. Kang J, D'Andrea AD, Kozono D. A DNA repair pathway-focused score for prediction of 
outcomes in ovarian cancer treated with platinum-based chemotherapy. J Natl Cancer Inst. 
2012;104(9):670-681. 
12. Konstantinopoulos PA, Spentzos D, Karlan BY, et al. Gene expression profile of BRCAness 
that correlates with responsiveness to chemotherapy and with outcome in patients with 
epithelial ovarian cancer. J Clin Oncol. 2010;28(22):3555-3561. 
13. Stefansson OA, Jonasson JG, Johannsson OT, et al. Genomic profiling of breast tumours in 
relation to BRCA abnormalities and phenotypes. Breast Cancer Res. 2009;11(4):R47. 
14. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009;45(2):228-47. 
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15. Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services  Series v4.03. 
June 14, 2010. Publication No. 09-5410. 
16. Schiffer CA, Anderson KC, Bennett CL, et al. Platelet transfusion for patients with cancer: 
clinical practice guidelines of the American Society of Clinical Oncology. 2001;19(5):1519-
1538. 
17. Slichter SJ. Evidence-based platelet transfusion guidelines. 2007:172-178. 
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CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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CCI
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SAP_001.pdf: 
Title: A Phase 1, Open-label Study of Niraparib as Single Agent in Patients 
With Advanced Solid Tumors 
NCT Number: NCT03497429 
Statistical analysis plan Approve Date: 03-APR-2019 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered
confidential information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners,
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: Niraparib-1001 
A Phase 1, Open-label Study of Niraparib as Single Agent in Patients 
With Advanced Solid Tumors 
PHASE 1 
Version: 2nd 
Date: 03 April 2019 
Prepared by: 
Based on: 
Protocol Version: Initial version 
Protocol Date: 18 January 2018 
PPD
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1.1 
Approval Signatures 
Electronic signatures can be found on the last page of this document. 
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2.0 
TABLE OF CONTENTS 
1.1 
Approval Signatures ...................................................................................................... 2 
2.0 
TABLE OF CONTENTS .................................................................................................... 3 
3.0 
LIST OF ABBREVIATIONS ............................................................................................. 5 
4.0 
OBJECTIVES ...................................................................................................................... 6 
4.1 
Primary Objectives ........................................................................................................ 6 
4.2 
Secondary Objectives .................................................................................................... 6 
4.3 
Additional Objectives .................................................................................................... 6 
4.4 
Study Design .................................................................................................................. 6 
5.0 
ANALYSIS ENDPOINTS .................................................................................................. 7 
5.1.1 Primary Endpoints ................................................................................................... 7 
5.1.2 Secondary Endpoints ............................................................................................... 7 
5.1.3 Additional Endpoints ............................................................................................... 7 
6.0 
DETERMINATION OF SAMPLE SIZE ............................................................................ 8 
7.0 
METHODS OF ANALYSIS AND PRESENTATION ....................................................... 9 
7.1 
General Principles .......................................................................................................... 9 
7.1.1 Study Definitions ..................................................................................................... 9 
7.1.2 Definition of Study Visit Windows ......................................................................... 9 
7.1.3 Conventions for Missing Adverse Event Dates ..................................................... 10 
7.1.4 Conventions for Missing Concomitant Medication Dates .................................... 10 
7.2 
Analysis Sets ................................................................................................................ 10 
7.3 
Disposition of Subjects ................................................................................................ 11 
7.3.1 Study Information .................................................................................................. 11 
7.3.2 Screen Failures ...................................................................................................... 11 
7.3.3 Subject Eligibility .................................................................................................. 11 
7.3.4 Disposition of Subjects .......................................................................................... 12 
7.3.5 Protocol Deviations and Analysis Sets .................................................................. 12 
7.4 
Demographic and Other Baseline Characteristics ....................................................... 13 
7.5 
Medical History and Concurrent Medical Conditions ................................................. 14 
7.6 
Medication History and Concomitant Medications ..................................................... 15 
7.7 
Study Drug Exposure and Compliance ....................................................................... 15 
7.8 
Efficacy Analysis ......................................................................................................... 16 
7.8.1 Primary Efficacy Endpoint(s) ................................................................................ 16 
7.8.2 Secondary Efficacy Endpoint(s) ............................................................................ 16 
7.8.3 Additional Efficacy Endpoint(s) ............................................................................ 16 
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7.8.4 Statistical/Analytical Issues ................................................................................... 16 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis............................................................. 17 
7.9.1 Pharmacokinetic Analysis ..................................................................................... 17 
7.9.2 Pharmacodynamic Analysis .................................................................................. 18 
7.10 
Other Outcomes ........................................................................................................... 18 
7.11 
Safety Analysis ............................................................................................................ 19 
7.11.1 Adverse Events ...................................................................................................... 19 
7.11.2 Clinical Laboratory Evaluations ............................................................................ 22 
7.11.3 Vital Signs and Weight .......................................................................................... 23 
7.11.4 12-Lead ECGs ....................................................................................................... 23 
7.11.5 Other Observations Related to Safety ................................................................... 23 
7.12 
Interim Analysis .......................................................................................................... 23 
7.13 
Changes in the Statistical Analysis Plan ...................................................................... 23 
8.0 
REFERENCES .................................................................................................................. 25 
 
LIST OF IN-TEXT TABLES 
Table 7.a 
Visit Window of Clinical Laboratory Test ............................................................ 10 
 
LIST OF IN-TEXT FIGURES 
Figure 4.a 
Schematic of Study Design ...................................................................................... 6 
 
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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloblastic leukemia 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC24 
area under the plasma concentration-time curve 
BRCA 
breast cancer (gene) 
C24 
plasma concentration at 24 hrs after last dose 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration at multiple dose 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
FDA 
(United States) Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HCVAb 
hepatitis C virus antibody 
HIV 
human immunodeficiency virus 
HRD 
homologous recombination deficiency 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
MedDRA 
Medical Dictionary for Regulatory Activities 
ORR 
overall response rate 
R(AUC24) 
accumulation ratio based on AUC24 
R(Cmax) 
accumulation ratio based on Cmax 
Tmax 
time of first occurrence of Cmax 
TEAE 
treatment-emergent adverse event 
 
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5.0 
ANALYSIS ENDPOINTS 
5.1.1 Primary Endpoints 
• The number and percentage of subjects with DLTs during Cycle 1. 
• The number and percentage of subjects with TEAEs. 
• The number and percentage of subjects with Grade 3 or higher TEAEs. 
• The number and percentage of subjects with serious TEAEs. 
• The number and percentage of subjects who discontinued the study drug because of TEAEs. 
5.1.2 Secondary Endpoints 
• PK parameters of niraparib on Cycle 1 Day 1 and Day 21: Cmax, Tmax and AUC24. 
5.1.3 Additional Endpoints 
• Overall response rate (ORR) (complete response [CR] + partial response [PR]) as measured 
by the RECIST guidelines. 
• Laboratory safety assessments, Eastern Cooperative Oncology Group (ECOG) performance 
status, electrocardiograms (ECGs) and vital signs. 
• PK parameters of a metabolite, M1, on Cycle 1 Day 1 and Day 21: Cmax, Tmax and AUC24. 
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6.0 
DETERMINATION OF SAMPLE SIZE 
Expected number of subjects: 6 to 12 patients (3 to 6 patients per Cohort). 
This study will use a 3+3 design. In the study, 2 ascending dose cohorts (3 to 6 patients per 
Cohort) are planned and approximately 6 to 12 DLT evaluable patients will be enrolled. 
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7.0 
METHODS OF ANALYSIS AND PRESENTATION 
7.1 
General Principles  
7.1.1 Study Definitions 
The following definitions and calculation formulas will be used. 
• Treatment-emergent adverse event (TEAE): Adverse events that occur after administration of 
the first dose of study drug and through 28 days after the last dose of study drug. 
• Pretreatment event (PTE): Any untoward medical occurrence in a clinical investigation 
subject who has signed informed consent to participate in a study but prior to administration 
of study drug. 
• Descriptive statistics: Number of subjects, mean, standard deviation, maximum, minimum, 
and quartiles 
• Dose: Initial dose level of 200 mg for Niraparib, Initial dose level of 300 mg for Niraparib. 
• Group: Initial dose level of 200 mg for Niraparib, Initial dose level of 300 mg for Niraparib.  
• Coefficient of variation (CV) (%): Standard deviation / mean * 100.  
7.1.2 Definition of Study Visit Windows 
When calculating Study Day relative to a reference date (ie, date of first dose [Day 1]), if the 
date of the observation is on the same date or after the reference date, it will be calculated as: 
date of observation - reference date + 1; otherwise, it will be calculated as: date of observation - 
reference date. Hence, reference day is always Day 1 and there is no Day 0. 
All evaluable data (ie, non-missing data) will be handled according to the following rules. 
For each visit, observation obtained in the corresponding time interval will be used. If more than 
one observation lies within the same visit window, the observation with the closest Study Day to 
the scheduled Study Day will be used. If there are two observations equidistant to the scheduled 
Study Day, the later observation will be used. 
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7.3 
Disposition of Subjects 
7.3.1 Study Information 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variable(s): 
Date First Subject Signed Informed Consent Form 
Date of Data Cutoff 
MedDRA Version 
WHO Drug Version 
SAS Version Used for Creating the Datasets 
Analytical Method(s): 
(1) Study Information 
Study information shown in the analysis variables section will be provided. 
7.3.2 Screen Failures 
Analysis Set: 
All Subjects Who Did Not Enter the Treatment Period 
Analysis Variable(s): 
Age (years) 
Gender 
[Male, Female] 
Analytical Method(s): 
(1) Screen Failures 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided. 
7.3.3 Subject Eligibility 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variable(s): 
Eligibility Status 
[Eligible for Entrance into the Treatment Period, Not Eligible for Entrance into 
the Treatment Period] 
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Primary Reason for Subject Not Being Eligible 
[Death, Adverse Event, Protocol Deviation, Study Terminated by Sponsor, 
Withdrawal by Subject, Lost to Follow-up, Screen Failure, Other] 
Analytical Method(s): 
(1) Eligibility for Entrance into the Treatment Period 
Frequency distributions will be provided. When calculating percentages for the 
primary reasons for subject not being eligible, the total number of ineligible subjects 
will be used as the denominator. 
7.3.4 Disposition of Subjects 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Study Drug Administration Status 
[Ongoing, Discontinued] 
Reason for Discontinuation of Study Drug Administration 
[Death, Adverse Event, Protocol Deviation, Progressive Disease, Study 
Terminated by Sponsor, Pregnancy, Withdrawal by Subject, Lost to Follow-up, 
Other] 
Analytical Method(s): 
(1) Disposition of Subjects 
Frequency distributions will be provided by dose and overall. When calculating 
percentages for the reasons for discontinuation, the total number of subjects who 
discontinued treatment will be used as the denominator. 
7.3.5 Protocol Deviations and Analysis Sets 
7.3.5.1 Protocol Deviations 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Significant Protocol Deviation 
[Entry Criteria, Concomitant Medication, Procedure Not Performed Per Protocol, 
Study Medication, Withdrawal Criteria, Major GCP Violations] 
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Analytical Method(s): 
(1) Protocol Deviations 
Frequency distribution will be provided by dose and overall for each deviation 
category. A subject who has several deviations will be counted once in each 
appropriate category. A subject who has several deviations that can be classified into 
the same category will be counted only once. 
7.3.5.2 Analysis Sets 
Analysis Set: 
All Subjects Who Entered the Treatment Period 
Analysis Variable(s): 
Handling of Subjects 
[Categories are based on the specifications in Subject Evaluability List] 
Analysis Sets 
Safety Analysis Set 
[Included] 
Pharmacokinetic Analysis Set 
[Included] 
DLT-evaluable Set 
[Included] 
Response-evaluable Set 
[Included] 
Analytical Method(s): 
(1) Subjects Excluded from Analysis Sets 
(2) Analysis Sets 
Frequency distributions will be provided by dose for (1), and by dose and overall for 
(2). For (1), a subject who has several reasons for exclusion will be counted once in 
each appropriate category. A subject who has several reasons for exclusion that can 
be classified into the same category will be counted only once. 
7.4 
Demographic and Other Baseline Characteristics 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Age (years) 
 
Gender 
[Male, Female] 
Height (cm)  
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Weight (kg)  
BMI (kg/m2)  
Race 
[American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White] 
ECOG performance status 
[0, 1, 2, 3, 4] 
Diagnosis 
[Adrenal cancer, Breast cancer, Cervical cancer, Colorectal cancer, 
Endometrial cancer, Gastric cancer, Head and neck cancer, Liver cancer, Malignant 
melanoma, Non small cell lung cancer, Ovarian cancer, Pancreatic cancer, Prostatic 
cancer, Small cell lung cancer, Other] 
Prior Surgery/Procedure 
[Yes, No] 
Prior Radiation Therapy 
[Yes, No] 
BRCA1 Mutant 
[Yes, No, Unknown] 
BRCA2 Mutant 
[Yes, No, Unknown] 
Analytical Method(s): 
(1) Summary of Demographics and Baseline Characteristics 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided by dose and overall. 
7.5 
Medical History and Concurrent Medical Conditions 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Medical History 
Concurrent Medical Conditions 
Analytical Methods: 
(1) Medical History by System Organ Class and Preferred Term 
(2) Concurrent Medical Conditions by System Organ Class and Preferred Term 
Frequency distributions will be provided by dose and overall. MedDRA dictionary 
will be used for coding. Summaries will be provided using SOC and PT, where SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency. A subject 
with multiple occurrences of medical history or concurrent medical condition within 
a SOC will be counted only once in that SOC. A subject with multiple occurrences of 
medical history or concurrent medical condition within a PT will be counted only 
once in that PT. 
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7.6 
Medication History and Concomitant Medications 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Prior Anticancer Drug Therapy 
Concomitant Medications 
Analytical Methods: 
(1) Prior Anticancer Therapy by Preferred Medication Name. 
(2) Concomitant Medications That Started and Stopped Prior to Baseline by Preferred 
Medication Name. 
(3) Concomitant Medications That Started Prior to and Were Ongoing at Baseline as 
well as Those That Started After Baseline by Preferred Medication Name. 
Frequency distributions will be provided by dose and overall. WHO Drug dictionary 
will be used for coding. Summaries will be provided using preferred medication 
names and sorted in decreasing frequency based on the number of reports. A subject 
who has been administered several medications with the same preferred medication 
name will be counted only once for that preferred medication name. 
7.7 
Study Drug Exposure and Compliance 
Analysis Set: 
DLT-evaluable Set 
Safety Analysis Set  
Analysis Variable(s): 
Treatment Compliance at Cycle1 (%) 
[Min<= - <80, 80<= - <=Max] 
Days on Treatment 
Number of Cycles 
Analytical Method(s): 
(1) Study Drug Exposure and Compliance 
Frequency distributions and descriptive statistics for continuous variables will be 
provided by dose and overall. 
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7.8 
Efficacy Analysis 
7.8.1 Primary Efficacy Endpoint(s) 
Not applicable. 
7.8.2 Secondary Efficacy Endpoint(s) 
Not applicable. 
7.8.3 Additional Efficacy Endpoint(s) 
Analysis Set: 
Response-Evaluable Analysis Set 
Analysis Variables: 
ORR  
Overall Response  
[CR, PR, SD, PD, NE] 
Analytical Methods: 
(1) Primary Analysis 
For ORR, point estimate and the 2-sided 95% exact CI will be provided by dose. 
(2) Summary of Overall Response 
For overall response, frequency distributions will be provided by dose. 
7.8.4 Statistical/Analytical Issues 
7.8.4.1 Adjustments for Covariates 
Not applicable. 
7.8.4.2 Handling of Dropouts or Missing Data 
Missing test results will not be used for estimations.  
For plasma concentrations and laboratory test results, values below the lower limit of 
quantification will be treated as zero when calculating the descriptive statistics. For laboratory 
test results, values above the upper limit of quantification will be treated as the upper limit value 
when calculating the descriptive statistics. 
7.8.4.3 Multicenter Studies 
Not applicable. 
7.8.4.4 Multiple Comparison/Multiplicity 
Not applicable. 
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7.8.4.5 Use of an “Efficacy Subset” of Subjects 
Not applicable. 
7.8.4.6 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
Not applicable. 
7.8.4.7 Examination of Subgroups 
Not applicable. 
7.9 
Pharmacokinetic/Pharmacodynamic Analysis 
7.9.1 Pharmacokinetic Analysis 
7.9.1.1 Plasma Concentrations 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis Variable(s): 
Plasma Concentrations of Niraparib and M1 
Visit: 
Cycle 1 Day 1/Day 21: Predose, 1, 1.5, 2, 3, 4, 6, 8, 10, 24* hours postdose 
Cycle 1 Day 1/Day 3/Day 5/Day 8/Day 15 and Day 21: Predose  
* Corresponding to predose at Cycle 1 Day 2 and Cycle 2 Day 1 for Cycle 1 Day 1 and 
Cycle 1 Day 21, respectively. 
Analytical Method(s): 
The following summaries will be provided by dose.  
(1) Summary of Plasma Concentrations by Visit 
Descriptive statistics will be provided by visit. 
(2) Mean and Standard Deviation Plot of Plasma Concentrations on Cycle 1 Day 1 and 
Cycle 1 Day 21 
Mean and standard deviation will be plotted. Relative nominal time since last dose 
(numerical) will be plotted on the horizontal axis and each of the analysis variables 
will be plotted on the vertical axis for Cycle 1 Day 1 and Cycle 1 Day 21, separately. 
The vertical axis will be a normal scale. 
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(3) Mean Plot of Plasma Concentrations on Cycle 1 Day 1 and Cycle 1 Day 21 
Mean will be plotted. Relative nominal time since last dose (numerical) will be 
plotted on the horizontal axis and each of the analysis variables will be plotted on the 
vertical axis for Cycle 1 Day 1 and Cycle 1 Day 21, separately. The vertical axis will 
be a common logarithmic scale. 
(4) Plot of Individual Plasma Concentrations on Cycle 1 Day 1 and Cycle 1 Day 21 
Individual plasma concentrations will be plotted. Relative actual time since last dose 
(numerical) will be plotted on the horizontal axis and each of the analysis variables 
will be plotted on the vertical axis for Cycle 1 Day 1 and Cycle 1 Day 21, separately. 
The vertical axis will be normal scale. 
7.9.1.2 Pharmacokinetic Parameters 
Analysis Set: 
Pharmacokinetic Analysis Set 
Analysis Variable(s): 
Pharmacokinetic parameters of Niraparib and M1 
Cycle 1 Day 1 
Cmax, Tmax, AUC24 
Cycle 1 Day 21 
Cmax, Tmax, AUC24, Cmin, R(AUC24), R(Cmax) 
Visit: 
Cycle 1 Day 1 and Cycle 1 Day 21 
Analytical Method(s): 
The following summaries will be provided by dose.  
(1) Summary of Pharmacokinetic Parameters by Visit 
For Tmax, descriptive statistics will be provided. For other parameters, descriptive 
statistics, geometric mean, and CV will be provided. 
7.9.2 Pharmacodynamic Analysis 
Not applicable. 
7.10 
Other Outcomes 
Not applicable. 
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7.11 
Safety Analysis 
In this study, safety will be evaluated as the primary endpoint. 
7.11.1 Adverse Events 
7.11.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
TEAE 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
Analytical Method(s): 
The following summaries will be provided by dose. 
(1) Overview of Treatment-Emergent Adverse Events 
1) All Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects). 
2) Relationship of Treatment-Emergent Adverse Events to study drug (number of 
events, number and percentage of subjects). 
3) Grade 3 or higher Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects). 
4) Grade 3 or higher Drug-Related Treatment-Emergent Adverse Events (number of 
events, number and percentage of subjects). 
5) Treatment-Emergent Adverse Events leading to study drug discontinuation 
(number of events, number and percentage of subjects). 
6) Serious Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects). 
7) Relationship of serious Treatment-Emergent Adverse Events to study drug 
(number of events, number and percentage of subjects). 
8) Serious Treatment-Emergent Adverse Events leading to study drug 
discontinuation (number of events, number and percentage of subjects). 
9) Treatment-Emergent Adverse Events resulting in death (number of events, 
number and percentage of subjects). 
TEAEs will be counted according to the rules below. Percentages will be based on the 
number of subjects in the safety analysis set. 
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Number of subjects 
• Summaries for 2) and 7)  
A subject with occurrences of TEAE in both categories (ie, Related and Not Related) 
will be counted once in the Related category. 
• Summaries other than 2) and 7)  
A subject with multiple occurrences of TEAE will be counted only once. 
Number of events 
For each summary, the total number of events will be calculated. 
7.11.1.2 Frequency of Subjects with DLTs during Cycle 1 
Analysis Set: 
DLT-evaluable Set 
Analysis Variable(s): 
DLTs during Cycle 1 
Analytical Method(s): 
The number and percentage of Subjects with DLTs will be provided by dose. 
7.11.1.3 Displays of Treatment-Emergent Adverse events 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
TEAE 
Categories: 
Toxicity Grade 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5] 
Analytical Method(s): 
The following summaries will be provided using frequency distribution by dose. 
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT. 
SOC will be sorted alphabetically and PT will be sorted in decreasing frequency for 
tables provided by SOC and PT. SOC and PT will be sorted in decreasing frequency for 
tables provided by System Organ Class only or PT only. 
(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term. 
(2) Treatment-Emergent Adverse Events by System Organ Class. 
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(3) Treatment-Emergent Adverse Events by Preferred Term. 
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term. 
(5) Toxicity Grade of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term. 
(6) Toxicity Grade of Drug-Related Treatment-Emergent Adverse Events by System 
Organ Class, and Preferred Term. 
(7) Treatment-Emergent Adverse Events Leading to Study Drug Dose Reduction by 
System Organ Class and Preferred Term (number of events, number and percentage 
of subjects). 
(8) Treatment-Emergent Adverse Events Leading to Study Drug Dose Interruption by 
System Organ Class and Preferred Term (number of events, number and percentage 
of subjects). 
(9) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term (number of events, number and percentage 
of subjects). 
(10) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term. 
The frequency distribution will be provided according to the rules below. Percentages 
will be based on the number of subjects in the safety analysis set. 
Number of subjects 
• Summary tables other than (5) and (6) 
A subject with multiple occurrences of TEAE within a SOC will be counted only once 
in that SOC. A subject with multiple occurrences of TEAE within a PT will be 
counted only once in that PT. 
• Summary tables for (5) and (6)  
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted 
only once for the TEAE with the maximum toxicity grade. 
7.11.1.4 Displays of Pretreatment Events 
Analysis Set: 
All Subjects Who Signed the Informed Consent Form 
Analysis Variable(s): 
PTE 
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Analytical Method(s): 
The following summaries will be provided using frequency distribution. 
PTEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency. 
(1) Pretreatment Events by System Organ Class and Preferred Term 
(2) Serious Pretreatment Events by System Organ Class and Preferred Term 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
A subject with multiple occurrences of PTE within a SOC will be counted only once in 
that SOC. A subject with multiple occurrences of PTE within a PT will be counted only 
once in that PT. 
7.11.2 Clinical Laboratory Evaluations 
7.11.2.1 Hematology and Serum Chemistry 
Analysis Set: 
Safety Analysis Set 
Analysis Variable(s): 
Hematology 
Erythrocytes, Hemoglobin, Hematocrit, Platelet Count, Leukocytes with 
Differentials (ANC, Eosinophils Count, Basophils Count, Absolute Lymphocytes 
Count, Monocyte Count), MCV 
Serum Chemistry 
Amylase, Protein (Total Protein), Albumin, ALP, Urea Nitrogen, Creatinine, 
Magnesium, Total Bilirubin, Sodium, Potassium, Chloride, Calcium, Bicarbonate, 
Inorganic Phosphate, AST, ALT, LDH, GGT, Glucose (fasted) 
Categories: 
Toxicity Grade 
[Grade 0, Grade 1, Grade 2, Grade 3, Grade 4] 
Visit: 
 
Cycle 1: Day 1(Predose), Day 8, Day 15 
Cycle 2: Day 1, Day 8, Day 15 
Cycle 3 and Thereafter: Day 1, Day 8 
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Analytical Method(s): 
For each variables other than Platelets Count, The following summary (3) will be 
provided by dose. 
For Platelets Count, The following summaries (1) ~ (3) will be provided by dose. 
(1) Summary of Laboratory Test Results and Change from Baseline by Visit 
Descriptive statistics for observed values and changes from baseline (each postdose 
visit - Predose) will be provided by visit. 
(2) Case Plots of Laboratory Test Results 
Plots over time for each subject will be presented. 
(3) Summary of Shifts of Laboratory Test Results 
Shift tables showing the number of subjects in each category of baseline grade and 
post-baseline maximum grade for laboratory abnormalities will be provided. 
Shift tables showing the number of subjects in each category at Predose and each 
postdose visit will be provided. 
For each laboratory test, the laboratory values will be classified as “Low”, “Normal” 
or “High” relative to the normal reference range. The shift tables will be based on 
these classifications. 
7.11.2.2 Urinalysis 
Not applicable. 
7.11.3 Vital Signs and Weight 
Not applicable. 
7.11.4 12-Lead ECGs 
Not applicable. 
7.11.5 Other Observations Related to Safety 
Not applicable. 
7.12 
Interim Analysis 
Not applicable. 
7.13 
Changes in the Statistical Analysis Plan  
From the SAP version 1.0, the following parts were updated. In section 7.1.2, the visit window of 
clinical laboratory test was modified as below. 
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8.0 
REFERENCES 
Not applicable. 
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