Conditions: Ovarian Cancer Fallopian Tube Cancer Primary Peritoneal Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of niraparib in Japanese participants with platinum-sensitive, relapsed ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who achieved complete response (CR) or partial response (PR) in the last chemotherapy containing platinum-based anticancer agents.

Detailed description:
The drug being tested in this study is called niraparib. Niraparib is being tested to treat people who have platinum-sensitive, relapsed ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. This study will look at the safety and efficacy of niraparib in Japanese participants.

The study will enroll approximately 15 participants. Participants will be enrolled to one group and after that will be asked to take niraparib capsules at the same time each day throughout the study:

\- Niraparib 300 mg

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 28 months. Participants will make multiple visits to the clinic in the treatment period, and the post-treatment period including follow-up assessments after the last dose of the study drug.

Arms:
arm 1: Niraparib 300 mg, capsules, orally, once daily on Days 1 to 28 of each 28-day treatment cycle (up to 51 cycles).

Interventions: intervention 1: Niraparib
Intervention descriptions: intervention 1: Niraparib capsule

Protocol document:
Prot_002.pdf: 
 
 
Clinical Study Protocol 
 
NCT Number: NCT03759587 
Title: A Phase 2, Multicenter, Open-label, Single-arm Study to Evaluate the Safety of 
Niraparib in Japanese Patients With Platinum-sensitive, Relapsed Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer Who Achieved CR or PR in the Last Chemotherapy 
Containing Platinum-based Anticancer Agents 
Study Number: Niraparib-2001 
Document Version and Date: Amendment 3 / 09-Nov-2021 
 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
 
A summary of changes to previous protocol versions is appended to the end of the 
document. 
 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


PROTOCOL
A Phase 2, Multicenter, Open-label, Single-arm Study to Evaluate the Safety of Niraparib in 
Japanese Patients With Platinum-sensitive, Relapsed Ovarian, Fallopian Tube, or Primary 
Peritoneal Cancer Who Achieved CR or PR in the Last Chemotherapy Containing 
Platinum-based Anticancer Agents
Japan Phase 2 Study of Niraparib (Maintenance Therapy) in Patients With Relapsed 
Ovarian Cancer
Sponsor:
Takeda Pharmaceutical Company Limited.
4-1-1 Doshomachi, Chuo-ku, Osaka 540-8645
Study Number:
Niraparib-2001
EudraCT Number:
Not Applicable
Compound:
Niraparib (MK-4827)
Date:
09 November 2021
(English translation:
09 November 2021)
Amendment Number:
03
Amendment History:
Date
Amendment Number
Region
05 October 2018
(English translation: 
16 November 2018)
Initial version
All sites
14 November 2018
(English translation: 
22 January 2019)
Amendment 01
All sites
18 January 2019
(English translation: 
12 March 2019)
Amendment 02
All sites
09 November 2021
(English translation: 
09 November 2021)
Amendment 03
All sites
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event (SAE) 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 Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP):
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.
Date
Date
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1.3
Protocol Amendment 03 Summary of Changes
The primary purpose of this amendment is to change a frequency of imaging for tumor assessment 
due to consideration for effect of long-term radiation on subject.
Other minor text changes related to imaging were added for clarification.
Full details on changes are given in Appendix H.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 03 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................10
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Principal Investigator...............................................................................................15
3.3
List of Abbreviations ...............................................................................................16
4.0
INTRODUCTION.........................................................................................................18
4.1
Background .............................................................................................................18
4.1.1
Nonclinical Studies .....................................................................................19
4.1.2
Clinical Studies...........................................................................................19
4.1.3
Benefit-Risk of Niraparib............................................................................22
4.2
Rationale for the Proposed Study.............................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................24
5.1
Objectives................................................................................................................24
5.1.1
Primary Objectives......................................................................................24
5.1.2
Secondary Objectives..................................................................................24
5.1.3
Additional Objectives..................................................................................24
5.2
Endpoints.................................................................................................................24
5.2.1
Primary Endpoints.......................................................................................24
5.2.2
Secondary Endpoints...................................................................................24
5.2.3
Safety Endpoints.........................................................................................25
5.2.4
Additional Endpoints ..................................................................................25
6.0
STUDY DESIGN..........................................................................................................26
6.1
Overview of Study Design.......................................................................................26
6.2
Number of Patients ..................................................................................................27
6.3
Duration of Study ....................................................................................................27
6.3.1
Duration of an Individual Patient’s Study Participation ...............................27
6.3.2
End of Study/Study Completion Definition and Planned Reporting.............27
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures..28
6.3.4
Total Study Duration...................................................................................28
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6.3.5
Posttrial Access...........................................................................................29
7.0
STUDY POPULATION................................................................................................30
7.1
Inclusion Criteria .....................................................................................................30
7.2
Exclusion Criteria ....................................................................................................31
8.0
STUDY DRUG .............................................................................................................34
8.1
Study Drug Administration......................................................................................34
8.2
Dose Modification Guidelines..................................................................................34
8.2.1
Criteria for Dose Reduction, Interruption, and Discontinuation ...................34
8.2.2
Re-Escalation After Dose Reduction ...........................................................36
8.2.3
Criteria for Beginning or Delaying a Subsequent Treatment Cycle..............36
8.3
Excluded Concomitant Medications and Procedures ................................................36
8.4
Permitted Concomitant Medications and Procedures................................................37
8.5
Precautions and Restrictions ....................................................................................37
8.5.1
Pregnancy and Contraception......................................................................37
8.5.2
Other Precautions and Restrictions..............................................................38
8.6
Blinding and Unblinding..........................................................................................38
8.7
Description of Investigational Agents ......................................................................38
8.8
Preparation, Reconstitution, and Dispensation..........................................................39
8.9
Packaging and Labeling...........................................................................................39
8.10
Storage, Handling, and Accountability.....................................................................39
8.11
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 .............................................................................................41
9.4.6
Vital Signs ..................................................................................................41
9.4.7
ECOG Performance Status..........................................................................41
9.4.8
Pregnancy Test............................................................................................41
9.4.9
Concomitant Medications and Procedures...................................................42
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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
ORR............................................................................................................45
9.4.16
PFS (Definition of PD)................................................................................45
9.4.17
OS...............................................................................................................46
9.4.18
Pharmacokinetic Measurements ..................................................................46
9.5
Records of Patients who Discontinued the Study After Enrollment and Before the 
First Administration of Study Drug..........................................................................46
9.6
Completion of Study Treatment (for Individual Patients) .........................................47
9.7
Completion of Study (for Individual Patients)..........................................................47
9.8
Discontinuation of Treatment With Study Drug and Patient Replacement................47
9.9
Withdrawal of Patients From Study .........................................................................48
9.10
Study Compliance....................................................................................................48
9.11
Thirty Days Follow-up After the Last Dose..............................................................49
9.12
Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival)..................................................................................................................49
10.0
ADVERSE EVENTS ....................................................................................................51
10.1
Definitions...............................................................................................................51
10.1.1
AE Definition..............................................................................................51
10.1.2
SAE Definition ...........................................................................................51
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................52
10.3
Monitoring of AEs and Period of Observation .........................................................53
10.4
Adverse Events of Special Interest...........................................................................53
10.5
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........53
10.6
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................54
10.7
Safety Reporting to Investigators, IRBs, and Regulatory Authorities........................54
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................55
12.0
DATA HANDLING AND RECORDKEEPING............................................................56
12.1
eCRFs......................................................................................................................56
12.2
Record Retention .....................................................................................................56
13.0
STATISTICAL METHODS..........................................................................................58
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13.1
Statistical and Analytical Plans ................................................................................58
13.1.1
Analysis Sets...............................................................................................58
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................58
13.1.3
Efficacy Analysis........................................................................................58
13.1.4
Pharmacokinetic Analysis ...........................................................................59
13.1.5
Safety Analysis ...........................................................................................59
13.2
Interim Analysis and Criteria for Early Termination ................................................60
13.3
Determination of Sample Size..................................................................................60
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................61
14.1
Study-Site Monitoring Visits ...................................................................................61
14.2
Protocol Deviations..................................................................................................61
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................61
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................62
15.1
IRB Approval ..........................................................................................................62
15.2
Subject Information, Informed Consent, and Subject Authorization .........................62
15.3
Subject Confidentiality ............................................................................................63
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................64
15.4.1
Publication..................................................................................................64
15.4.2
Clinical Trial Registration...........................................................................64
15.4.3
Clinical Trial Results Disclosure .................................................................65
15.5
Insurance and Compensation for Injury....................................................................65
16.0
REFERENCES..............................................................................................................66
LIST OF IN-TEXT TABLES
Table 4.a
Progression-Free Survival in the Primary Efficacy Cohorts (ITT Population, N 
= 553) ................................................................................................................20
Table 4.b
Grade 3/4 Treatment Emergent Adverse Events Reported in ≥5% of Patients in 
Either Treatment Arm (Safety Population, N = 546)...........................................21
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................28
Table 8.a
Dose Reductions for Non-Hematologic Toxicities..............................................35
Table 8.b
Dose Interruption, Resume or Reduction for Hematologic Toxicities .................35
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................43
Table 9.b
Clinical Urinalysis Tests ....................................................................................43
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LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................67
Appendix B
Responsibilities of the Investigator.....................................................................70
Appendix C
Investigator Consent to Use of Personal Information..........................................72
Appendix D
ECOG Scale for Performance Status ..................................................................73
Appendix E
Response Evaluation Criteria In Solid Tumors (RECIST), Amendment V1.1.....74
Appendix F
Substrate Drugs Known to be Affected by Inhibition or Induction by CYP 
Enzymes ............................................................................................................78
Appendix G
Drugs Associated With QT Prolongation and Torsades de Pointes .....................79
Appendix H
Detailed Description of Amendments to Text.....................................................80
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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 2, Multicenter, Open-label, Single-arm Study to 
Evaluate the Safety of Niraparib in Japanese Patients With
Platinum-sensitive, Relapsed Ovarian, Fallopian Tube, or 
Primary Peritoneal Cancer Who Achieved CR or PR in the 
Last Chemotherapy Containing Platinum-based Anticancer 
Agents
EudraCT No.:
Not Applicable
Study Number: Niraparib-2001
Phase: 2
Study Design:
The study is a phase 2, multicenter, open-label, single-arm study to evaluate the safety of niraparib in Japanese patients 
with platinum-sensitive, relapsed ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, who achieved 
complete response (CR) or partial response (PR) in the last chemotherapy containing platinum-based anticancer 
agents.
The eligible patients must have received at least 2 platinum-based regimens with the last regimen prior to study 
enrollment; had a response assessed by a physician of CR or PR to their last regimen; must not have any measurable 
lesion >2 cm, and must have normal cancer antigen (CA)-125 equal to or less than the upper limit of the normal range,
or >90% decrease following their last treatment and which was stable for at least 7 days. The study will evaluate the 
safety of niraparib as a maintenance therapy based on a primary endpoint of the incidence of Grade 3 or 4 
thrombocytopenia occurring within 30 days after initial administration of niraparib in this population.
Eligible subjects will receive 300 mg/day of the study drug orally QD continuously (in 28-day cycles), and the 
treatment will continue until the patient meet a discontinuation criteria specified in the study protocol.
Dose interruption (no longer than 28 days) and dose reductions (maximum reduction to 100 mg/day) will be allowed. 
Dose interruption and/or reduction may be implemented at any time for any grade toxicity considered intolerable by 
the patient. The timing of efficacy or safety evaluations should not be affected by dose interruptions or reductions.
Clinic visits will be weekly during Cycle 1 and then every 4 weeks (±3 days) for subsequent cycles.
All AEs will be collected and recorded for each patient from the day of signing the informed consent form (ICF) until 
30 days after last dose of study treatment administration, or beginning of subsequent anticancer therapy, whichever 
comes first. All AEs and SAEs experienced by a patient, irrespective of the suspected causality, will be monitored 
until the AE or SAE has resolved, any abnormal laboratory values have returned to baseline or normalized, until there 
is a satisfactory explanation for the changes observed, until the patient is lost to follow-up, or until the patient has died. 
The Adverse Events of Special Interest (AESIs) for this study are MDS, AML, secondary cancers (new primary 
malignancies other than MDS/AML), pneumonitis, and embryo-fetal toxicity. AESIs must be reported to the Sponsor 
as soon as the investigator becomes aware of them.
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 will be used for tumor assessment via a 
computed tomography (CT) or magnetic resonance imaging (MRI) scan of abdomen/pelvis and clinically indicated 
areas, which is required at the end of every 2 cycles (8 weeks with a window of ±7 days from date of visit) through 
Cycle 14, then at the end of every 3 cycles (12 weeks with a window of ±7 days) until Cycle 38, and at the end of every 
6 cycles (24 weeks with a window of ±7 days) until progression. Cycle timing will not be delayed for treatment 
interruptions, and tumor assessment should occur according to this schedule regardless of whether study treatment is 
interrupted. If a patient discontinues treatment for clinical progression and does not meet the criteria specified in the 
protocol, scans and CA-125 testing should continue at the specified intervals in the protocol until progression is 
confirmed or until the start of subsequent anticancer treatment.
Blood samples for measurements of plasma levels of niraparib will be obtained on Cycle 1 Day 1 predose and 2 hours 
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postdose, Cycle 2 Day 1 predose and 2 hours postdose, and Cycle 4 Day 1 predose.
Primary Objectives:
To evaluate the safety of niraparib in Japanese patients with platinum-sensitive, relapsed ovarian cancer, fallopian 
tube cancer, or primary peritoneal cancer, who achieved CR or PR in the last chemotherapy containing platinum-based 
anticancer agents.
Secondary Objectives:
To evaluate the efficacy of niraparib in Japanese patients with platinum-sensitive, relapsed ovarian cancer, fallopian 
tube cancer, or primary peritoneal cancer, who achieved CR or PR in the last chemotherapy containing platinum-
based anticancer agents.
Subject Population: Japanese adult patients with platinum-sensitive, relapsed ovarian cancer, fallopian tube cancer, 
or primary peritoneal cancer, who achieved CR or PR in the last chemotherapy containing platinum-based anticancer 
agents
Number of Subjects:
15 subjects
Number of Sites:
Approximately 30 sites in Japan
Dose Level(s):
The study drug will be administered at 300 mg QD, orally,
continuously, in 28-day cycles, and the treatment will 
continue until the patient meet a discontinuation criteria 
specified in the study protocol.
Route of Administration:
Oral
Duration of Treatment: Subjects may receive study drug 
until they experience objective PD, experience 
unacceptable toxicity, withdrawal of consent or until study 
discontinuation due to any other reasons specified in the 
study protocol.
Period of Evaluation: The estimated time frame for 
study completion (screening, study drug administration 
and follow-up period) is approximately 28 months.
Main Criteria for Inclusion:
1.
Japanese female patients aged 20 years or older on the day of signing informed consent.
2.
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.
3.
Patient must have a histologically diagnosed ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.
4.
Patient must have a high-grade (or Grade 3) serous or high-grade predominantly serous histology or known to
have gBRCAmut.
5.
Patients must have completed at least 2 previous lines of platinum-containing therapy:
Note: The last platinum regimen did not necessarily have to immediately follow the next-to-last (penultimate)
platinum regimen. For example, if a patient received a non-platinum regimen between the penultimate platinum
regimen and last platinum regimen, she could have been eligible as long as she met all entry criteria.
a
For the penultimate platinum-based chemotherapy prior to study enrollment, patients must have had
platinum-sensitive disease after this treatment, defined as achieving a response (CR or PR) and disease 
progression (PD) >6 months after completion of her last dose of platinum therapy (documented 6 to 12 
months or >12 months). Source documentation was required.
b
For the last line of platinum-based chemotherapy prior to study enrollment:
i.
Patients must have received a platinum-containing regimen for a minimum of 4 cycles.
ii.
Patients must have achieved a partial or complete tumor response.
iii.
Following the last regimen, patients must have had either:
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1.
CA-125 equal to or less than the upper limit of the normal range.
2.
CA-125 decrease by more than 90% during the last platinum regimen, and which was stable for at least
7 days (ie, no increase >15%).
iv.
Following the last regimen, patients could not have had any measurable lesion >2 cm at the time of
study enrollment.
c
Patients must have been enrolled within 8 weeks after completion of their final dose of the platinum-
containing regimen.
6.
Patients must have performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) Performance
Status Scale.
7.
Patients must have adequate organ function as indicated by the following laboratory values:
a
Absolute neutrophil count (ANC) ≥1,500/μL.
b
Platelet count ≥100,000/μL.
c
Hemoglobin ≥9 g/dL.
d
Serum creatinine ≤1.5× institutional upper limit of normal (ULN) OR calculated creatinine clearance
≥50 mL/minute, using the Cockcroft-Gault equation.
e
Total bilirubin ≤1.5×ULN OR direct bilirubin ≤1×ULN.
f
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN unless liver metastases
were present, in which case they had to be ≤5×ULN.
8.
Patients must be able to take oral medications.
9.
Female patients of childbearing potential must be negative for pregnancy test (β-hCG) within 7 days prior to
receiving the first dose of study treatment.
10.
Female patients who:
a
Are postmenopausal for at least 1 year before the screening visit, OR
b
Are surgically sterile, OR
c
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
d
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.)
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Main Criteria for Exclusion:
1.
Patients who have had drainage of ascites during last 2 cycles of last chemotherapy.
2.
Patients who have had palliative radiotherapy encompassing >20% of the bone marrow within 1 week of the first
dose of study treatment.
3.
Patients who have persistent Grade ≥3 toxicity from last cancer therapy.
4.
Patients who have symptomatic, uncontrolled brain or leptomeningeal metastases. To be considered
“controlled,” central nervous system (CNS) disease must have undergone treatment (eg, radiation or
chemotherapy) at least 1 month prior to study enrollment. The patient must not have had any new or progressive
signs or symptoms related to the CNS disease and must have been taking a stable dose of steroids or no steroids
(as long as these were started at least 4 weeks prior to enrollment] or no steroids). A scan to confirm the absence
of brain metastases at baseline was not required. Patients with spinal cord compression might have been
considered if they had received definitive treatment for this and evidence of clinically stable disease for 28 days.
5.
Patients who have known hypersensitivity to the components of niraparib.
6.
Patients who have had prior treatment with a known PARP inhibitor.
7.
Patient who have had treatment with any investigational products within 28 days or 5 half-lives (whichever was
longer) before the first dose.
8.
Patients who have had major surgery per investigator judgment within 3 weeks of the first dose. Patient must
have recovered from any effects of any major surgery.
9.
Patients who have diagnosis, detection, or treatment of invasive second primary malignancy other than ovarian
cancer ≤24 months prior to study enrollment (except basal or squamous cell carcinoma of the skin that was
definitively treated). Note: Patients must not have any known history or current diagnosis of myelodysplastic
syndrome (MDS) or acute myeloid leukemia (AML), irrespective of the time for disease history.
10.
Patients who are considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant
systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled
ventricular arrhythmia, recent (within 90 days of the first dose) myocardial infarction, uncontrolled major seizure
disorder, unstable spinal cord compression, superior vena cava syndrome, small bowel obstruction or other
serious gastrointestinal disorder, or any psychiatric disorder that prohibits obtaining informed consent.
11.
Patients who have received a transfusion (platelets or red blood cells) within 4 weeks of the first dose of study
treatment.
12.
Patients who have received a live virus and bacterial vaccines within 4 weeks of the first dose of study treatment.
13.
Patients who have a history or current evidence of any condition, therapy, or lab abnormality (including active or
uncontrolled myelosuppression [ie, anemia, leukopenia, neutropenia, thrombocytopenia]) 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
14.
Patients who are regular user (including “recreational use”) of any illicit drugs at the time of signing informed
consent or have a recent history (within the past year) of drug or alcohol abuse.
15.
Patients who are pregnant or breast-feeding, or expecting to conceive within the planned duration of the study.
NOTE: If a breast-feeding woman discontinue breast-feeding, she may be enrolled in the study.
16.
Patients who are immunocompromised (patients with splenectomy are allowed).
17.
Patients who have known HIV positive.
18.
Patients who have 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:
•
The subject incidence of Grade 3 or 4 thrombocytopenia occurring within 30 days after initial administration of
niraparib.
Secondary:
•
The safety of niraparib, including:
-
The subject incidence of TEAEs.
-
The subject incidence of Grade 3 or higher TEAEs.
-
The subject incidence of serious TEAEs
-
The subject incidence of TEAEs leading to drug discontinuation because of TEAEs.
-
The subject incidence of TEAEs leading to dose interruption because of TEAEs.
-
The subject incidence of TEAEs leading to dose reduction because of TEAEs.
•
Progression free survival (PFS).
•
Overall survival (OS).
•
Overall response rate (ORR).
Statistical Considerations:
In this study, patients who receive at least 1 dose of study drug will be defined as safety analysis set. The subject 
incidence of Grade 3 or 4 thrombocytopenia within 30 days after the initial dose of niraparib is calculated as a primary 
endpoint using safety analysis set.
In addition, the following adverse events are coded by MedDRA and the subject incidence is calculated by SOC and 
PT using safety analysis set: TEAE, Grade 3 or above TEAE, serious TEAE, TEAE leading to treatment 
discontinuation, TEAE leading to dose interruption and TEAE leading to dose reduction.
In this study, patients who receive at least 1 dose of study drug will be defined as full analysis set (FAS). PFS and OS 
will be analyzed using Kaplan-Meier method to provide quartiles and progression/survival rate at specified points with 
95% CI using FAS. The Kaplan-Meier plot for PFS and OS will also be provided.
ORR and its two-sided 95% confidence interval (CI) based on binominal distribution will be provided using the FAS. 
The two-sided 95% CI will be calculated based on binominal distribution.
Sample Size Justification:
To evaluate safety of niraparib in Japanese patients, the incidence of Grade 3 or 4 thrombocytopenia within 30 days 
after the initial dose of niraparib will be compared between Japanese and non-Japanese patients to make a certain level 
of evaluation that the incidence in Japanese patients is not obviously higher than that in non-Japanese patients. Fifteen 
patients can be evaluable sample size for the rationale.
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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
clinical supplier list in the study manual. The identified vendors will perform specific 
study-related activities either in full or in partnership with the sponsor.
3.2
Principal Investigator
Takeda will select a signatory coordinating investigator 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, and study participation. The signatory coordinating investigator will be required to 
review and sign the clinical study report (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
AESI
adverse event of special interest
ALT
alanine aminotransferase
AML
acute myeloblastic leukemia
AST
aspartate aminotransferase
ATM
ataxia telangiectasia mutated
β-hCG
beta human chorionic gonadotropin
BRCA
breast cancer (gene)
CR
complete response
CRO
contract research organization
CSR
clinical study report
CT
computed tomography
CYP
cytochrome P450
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
EU
European Union
eCRF
electronic case report form
FAS
full analysis set
FDA
(United States) Food and Drug Administration
FPI
first patient in
FSH
follicle stimulating hormone
gBRCA
germline breast cancer gene
GCIG
Gynecologic Cancer Intergroup
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
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
HDPE
high-density polyethylene
HIV
human immunodeficiency virus
HRD
homologous recombination deficiency/deficient
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
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IRB
institutional review board
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
OS
overall survival
PARP
poly (adenosine diphosphate [ADP]-ribose) polymerase
PBMC
peripheral blood mononuclear cells
PD
progressive disease (disease progression)
PFS
progression-free survival
P-gp
P-glycoproetein
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PR
partial response
PT
preferred term
QTc
QT interval corrected for heart rate
QTcF
Fridericia’s corrected QT interval
RECIST
Response Evaluation Criteria in Solid Tumors
SD
stable disease
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
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4.0 
INTRODUCTION
4.1 
Background
Niraparib is an orally available, potent, and highly selective PARP1 and PARP2 inhibitor. 
Niraparib was originated by 
 and developed by 
 for the treatment of a variety of 
cancer types.
DNA repair is accomplished by serval mechanisms in healthy cells including, but not limited to, 
homologous recombination, base excision repair, and nonhomologous end-joining. Some cells are 
incapable of homologous recombination due to the inactivation of genes such as BRCA1, BRCA2, 
ataxia telangiectasia mutated (ATM), and others. In the absence of homologous recombination, 
these cells must rely on alternative DNA repair mechanisms.
A complete loss of function or inactivation of both BRCA alleles occurs commonly in women who 
are carriers of a gBRCAmut. A loss of BRCA function compromises the repair of double-strand 
DNA breaks via the homologous recombination pathway resulting in the use of an alternative 
DNA repair pathway such as NHEJ. Reliance on mechanisms such as NHEJ contributes 
significantly to the accumulation of mutations in ovarian cells and may ultimately promote the 
development of ovarian tumors.[1][2]
PARP1 and PARP2 are zinc-finger DNA-binding proteins that detect damaged DNA and promote 
DNA repair by several mechanisms. After detecting DNA damage, PARP activates the BER 
pathway via an intracellular signaling mechanism. Conversely, PARP inhibitors block DNA repair 
by the BER pathway. In cells incapable of DNA repair via homologous recombination (eg, BRCA1 
and BRCA2 mutations), PARP inhibition leads to irreparable DSB, collapsed replication forks, and 
an increased use of the NHEJ pathway. These disruptions result in genomic instability and 
ultimately cell death. The synergy between cellular defect and drug-induced effect is referred to as 
synthetic lethality.[3] Treatment with PARP inhibitors represents an opportunity to selectively kill 
cancer cells with deficiencies in homologous recombination and other DNA repair mechanisms. 
Recently, it has been reported that, breast cancer gene (BRCA) mutation-negative, wild-type 
tumors, can result in a BRCA1/2 mutation-like state as a result of deficiency in repair of DNA 
double-strand breaks by homologous recombination due to other factors. It is anticipated that 
PARP inhibitors may induce synthetic lethality against such tumor.[4] In ovarian cancer, the 
homologous recombination deficiency (HRD) score has been found useful as an indicator of HRD, 
including such genomic instability.[5]
Based on the results of a 
sponsored overseas phase 3 pivotal study (NOVA study), 
niraparib has been approved in the in March 2017 and in Europe in November 2017, as a 
maintenance therapy for adult patients with relapsed epithelial ovarian, fallopian tube, or primary 
peritoneal cancer who achieved complete response (CR) or partial response (PR) to a 
chemotherapy containing platinum-based anticancer agents.
Nonclinical and clinical study result summaries are shown below. For further details, refer to the 
current Investigator’s Brochure and package inserts in regions/countries where niraparib is 
approved.
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4.1.1 Nonclinical Studies
In animal models, maximal in vivo efficacy was achieved in mutant breast cancer susceptibility 
gene (BRCA) 1 (BRCA1mut) ovarian tumor models with once daily (QD) oral administration of 
niraparib at a dose sufficient to suppress approximately 90% of the PARP-enzymatic activity in 
the tumor at 8 hours postdose. The same dose translated to a >50% inhibition of PARP activity in 
peripheral blood mononuclear cells (PBMCs) at 8 hours postdose.
Data from nonclinical experiments demonstrate that tumors containing BRCA mutations or that are 
otherwise positive by commercially available homologous recombination deficiency (HRD) tests 
regressed in response to niraparib treatment. Moreover, tumor growth inhibition was observed in a 
subset of HRD-negative (HRDneg) models, suggesting that 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
Niraparib clinical studies have been conducted in Japan and overseas countries, and the safety and 
tolerability of niraparib has been evaluated in over 1214 patients with advanced cancer who have 
received at least 1 dose of niraparib. The highest dose studied in the overseas Phase 1 trials was 
400 mg QD, and the dose-limiting toxicity at this dose was thrombocytopenia. The recommended 
phase 2 dose for niraparib monotherapy was 300 mg QD, and this dose was subsequently approved 
for the treatment of ovarian cancer (OC) in the United States (US) and European Union (EU), 
based on the result of overseas phase 3 study.
4.1.2.1 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
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.
In NOVA study, niraparib 300 mg was administered to patients with platinum-sensitive, relapsed 
ovarian cancer who responded to the last chemotherapy containing platinum-based anticancer 
agents once daily in a double-blind manner to compare with the placebo group. Consequently, 
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) (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
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.
In NOVA study, niraparib 300 mg was tolerable. The most commonly observed TEAEs (all 
grades) of niraparib were nausea (niraparib: 73.6%, placebo: 35.2%), anaemia (48.5%, 6.7%), 
thrombocytopenia (46.0%, 3.4%), fatigue (45.8%, 32.4%) and constipation (39.8%, 20.1%). Of 
these, Grade 3 or 4 TEAEs were thrombocytopenia (28.3%, 0.6%), anaemia (24.8%, 0%) and 
neutropenia (11.2%, 0.6%).
The most common Grade 3 or 4 adverse events that were reported in the niraparib group were 
thrombocytopenia (28.3%), anemia (24.8%), and neutropenia (11.2%), which were managed with 
dose modifications (Table 4.b). Most patients achieved their individual MTD by the third month. 
The average dose of niraparib during the study was 206 mg. Only 14.7% patients had dose 
discontinued due to adverse events.
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Table 4.b
Grade 3/4 Treatment Emergent Adverse Events Reported in ≥5% of Patients 
in Either Treatment Arm (Safety Population, N = 546)
MedDRA Preferred Term
Niraparib
(N = 367)
n (%)
Placebo
(N = 179)
n (%)
Any CTCAE Grade 3/4 TEAE
272 (74.1)
41 (22.9)
Thrombocytopenia
104 (28.3)
1 (0.6)
Anaemia
91 (24.8)
0
Neutropenia
41 (11.2)
1 (0.6)
Neutrophil count decreased
32 (8.7)
2 (1.1)
Hypertension
30 (8.2)
4 (2.2)
Platelet count decreased
27 (7.4)
0
Fatigue
21 (5.7)
0
Source: PR-30-5011-C (NOVA Main Study) Clinical Study Report
NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Event; MedDRA, Medical 
Dictionary for Regulatory Activities
4.1.2.2 Study Niraparib-1001 (Japanese Phase 1 Study)
Study Niraparib-1001 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. In this study, dose-escalation will proceed according to a 3+3 design. A total of 6 patients 
were treated with 200 mg QD (Cohort 1) or 300 mg QD (Cohort 2) of niraparib. Niraparib was 
administered QD, continuously for 21-day in cycle. The starting dose was not to be adjusted 
depending on the baseline body weight or platelet count.
The enrollment was completed and the total of 9 patients were enrolled to Cohort 1 or Cohort 2 of 
the study. In Cycle 1 of Cohort 1(niraparib 200 mg QD), no dose limiting toxicity (DLT) was 
observed. In Cycle 1 of Cohort 2 (niraparib 300 mg QD), DLT was observed in 1 of 6 subjects, and 
niraparib 300 mg was deemed tolerable in Japanese patients with advanced solid tumors.
The observed DLT was Grade 4 thrombocytopenia. According to the preliminary data of the 
TEAEs reported as of 31 October 2018, the TEAEs reported in more than 1 subject were vomiting 
and thrombocytopenia/platelet count decreased (4 subjects each), nausea and anorexia (3 subjects 
each), and diarrhoea, alkaline phosphatase increased, creatinine increased, leukopenia/white blood 
cell count decreased, neutrophil count decreased/febrile neutropenia and fatigue/malaise (2 
subjects each).
As of 14 November 2018, the study drug administration is ongoing in 4 subjects.
4.1.2.3 Identification of Factors for Thrombocytopenia
A further review of the results of clinical studies indicated that the patient body weight and platelet 
count at baseline effect on the occurrence of thrombocytopenia. In NOVA study, the incidence of 
Grade 3 or 4 thrombocytopenia in the first 30 days after the initial dose of niraparib was higher in 
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patients with baseline body weight of <77 kg or baseline platelet count of <150,000/μL (34.6%, 
97/280 subjects) than in those with body weight of ≥77 kg and platelet count of ≥150,000/μL 
(11.8%, 10/85 subjects). In addition, the incidence of Grade 3 or 4 treatment-related 
thrombocytopenia during the first 30 days after the initial dose of niraparib was higher in patients 
with baseline body weight of <77 kg or baseline platelet count of <150,000/μL (49.6%, 139/280 
subjects; 45.7%, 128/280 subjects) than in those with body weight of ≥77 kg and platelet count of 
≥150,000/μL (31.8%, 27/85 subjects; 27.1%, 23/85 subjects) as well. In addition, dose reductions 
did not lead to a decrement in efficacy for the patients who are dose reduced to achieve their 
individual maximum tolerated dose in NOVA study.
4.1.3 Benefit-Risk of Niraparib
The NOVA trial demonstrated that niraparib maintenance therapy results in a statistically 
significant and clinically meaningful delay in time to cancer progression or death in patients with 
platinum-sensitive recurrent OC regardless of BRCA mutation or HRD tumor status. Patient 
reported outcome data from validated survey tools indicate that niraparib-treated subjects reported 
no significant difference from placebo in measures associated with symptom-specific and general 
quality of life. Niraparib treatment did not reduce the effectiveness of subsequent therapies and 
continued to show beneficial treatment effect in the secondary efficacy measure of PFS.
The most common adverse drug reactions occurring in approximately 20% of the subjects in 
clinical trials were as follows: nausea, fatigue, anemia, vomiting, constipation, thrombocytopenia, 
decreased appetite, headache, insomnia, and abdominal pain. The occurrence of these events is 
consistent with niraparib’s mechanism of action and readily manageable with dose modifications. 
No additional safety information has been received from clinical trials with regard to other safety 
issues such as pregnancy, overdose, and lack of efficacy.
There have been no reports of risks associated with the investigational or diagnostic procedures 
included in the clinical trials, no reports of risks that might be associated with insufficient quality 
of the IMP, and no significant reports of lack of efficacy with niraparib.
4.2 
Rationale for the Proposed Study
This Japan phase 2 study is designed to assess a primary endpoint of the incidence of Grade 3 or 4 
thrombocytopenia within 30 days after the initial dose of niraparib to evaluate safety of niraparib 
in Japanese patients comparable to the population in NOVA study.
In an overseas phase 3 study (NOVA study), niraparib 300 mg was administered to patients with 
platinum-sensitive, relapsed OC who responded to the last chemotherapy containing 
platinum-based anticancer agents once daily in a double-blind manner to compare with the placebo 
group. The results showed a significant reduction in the risk of progression or death (primary 
endpoint of PFS) in all three pre- specified primary analysis populations (gBRCAmut cohort, 
HRD-positive patients in the non-gBRCAmut cohort and the entire non-gBRCAmut cohort), 
supporting the efficacy and safety of niraparib as a maintenance therapy for patients with 
platinum-sensitive, relapsed OC. There is no clear difference in treatment system of OC between 
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Japan and overseas countries. No obvious differences were observed in the PK of niraparib among 
races. Therefore, it could be possible to extrapolate the results of NOVA study into Japanese 
patients. 
Meanwhile, as mentioned above, a further review of the results of clinical studies indicated the 
patient body weight and platelet count at baseline effect on the occurrence of thrombocytopenia. In 
NOVA study, the incidence of Grade ≥3 TEAEs, SAEs, and TEAEs leading to dose modification 
or treatment discontinuation occurred more commonly in the <77 kg cohort than in the ≥77 kg 
cohort.
In the Japan phase 1 study, the tolerability of niraparib at up to 300 mg was determined in Japanese 
patients with advanced solid tumors who were treated with niraparib 200 mg or 300 mg (dosed 
QD, orally, continuously in 21-day cycles). The observed DLT was Grade 4 thrombocytopenia.
In this situation, Takeda plan to evaluate the safety of niraparib in Japanese patients, using the 
subject incidence of Grade 3 or 4 thrombocytopenia occurring within 30 days after initial 
administration of niraparib (the valuable used for initial dose consideration in overseas studies) as 
a primary endpoint.
In this study, the initial dose of niraparib is determined as 300 mg, based on the maximum dose at 
which tolerability was observed in Japanese patients. Given the overseas clinical data that the 
patient body weight can affect the occurrence of study drug-related TEAEs, it is important to 
examine the safety of niraparib in Japanese patients because the body weight of Japanese patients 
is generally lower than that of patients in US or EU.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objectives
To evaluate the safety of niraparib in Japanese patients with platinum-sensitive, relapsed ovarian 
cancer, fallopian tube cancer, or primary peritoneal cancer, who achieved CR or PR in the last 
chemotherapy containing platinum-based anticancer agents.
5.1.2
Secondary Objectives
To evaluate the efficacy of niraparib in Japanese patients with platinum-sensitive, relapsed ovarian 
cancer, fallopian tube cancer, or primary peritoneal cancer, who achieved CR or PR in the last 
chemotherapy containing platinum- based anticancer agents.
5.1.3
Additional Objectives
To evaluate the pharmacokinetics of niraparib in Japanese patients with platinum-sensitive, 
relapsed ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, who achieved CR or 
PR in the last chemotherapy containing platinum-based anticancer agents.
5.2
Endpoints
5.2.1
Primary Endpoints

The subject incidence of Grade 3 or 4 thrombocytopenia occurring within 30 days after initial
administration of niraparib.
5.2.2
Secondary Endpoints

Safety of niraparib, including
–
The subject incidence of TEAEs.
–
The subject incidence of Grade 3 or higher TEAEs.
–
The subject incidence of serious TEAEs
–
The subject incidence of TEAEs leading to drug discontinuation.
–
The subject incidence of TEAEs leading to dose interruption because of TEAEs.
–
The subject incidence of TEAEs leading to dose reduction because of TEAEs.

Progression free survival (PFS)

Overall survival (OS)

Overall response rate (ORR)
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5.2.3
Safety Endpoints

Laboratory values

Vital signs

ECOG performance status

Electrocardiograms (ECGs)
5.2.4
Additional Endpoints

Plasma concentrations of niraparib for population pharmacokinetics
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6.0 
STUDY DESIGN
6.1 
Overview of Study Design
The study is a phase 2, multicenter, open-label, single-arm study to evaluate the safety of niraparib 
in Japanese patients with platinum-sensitive, relapsed ovarian cancer, fallopian tube cancer, or 
primary peritoneal cancer, who achieved CR or PR in the last chemotherapy containing 
platinum-based anticancer agents.
The eligible patients must have received at least 2 platinum-based regimens with the last regimen 
prior to study enrollment; had a response assessed by a physician of CR or PR to their last regimen; 
must not have any measurable lesion >2 cm, and must have normal cancer antigen (CA)-125 equal 
to or less than the upper limit of the normal range, or >90% decrease following their last treatment 
and which was stable for at least 7 days. The study will evaluate the safety of niraparib as a 
maintenance therapy based on a primary endpoint of the incidence of Grade 3 or 4 
thrombocytopenia occurring within 30 days after initial administration of niraparib in this 
population.
Eligible subjects will receive 300 mg/day of the study drug orally QD continuously (in 28-day 
cycles), and the treatment will continue until the patient meet a discontinuation criteria specified in 
the study protocol.
Dose interruption (no longer than 28 days) and dose reductions (maximum reduction to 
100 mg/day) will be allowed. Dose interruption and/or reduction may be implemented at any time 
for any grade toxicity considered intolerable by the patient. The timing of efficacy or safety 
evaluations should not be affected by dose interruptions or reductions.
Clinic visits will be weekly during Cycle 1 and then every 4 weeks (±3 days) for subsequent 
cycles.
All AEs will be collected and recorded for each patient from the day of signing the informed 
consent form (ICF) until 30 days after last dose of study treatment administration, or beginning of 
subsequent anticancer therapy, whichever comes first. All AEs and SAEs experienced by a patient, 
irrespective of the suspected causality, will be monitored until the AE or SAE has resolved, any 
abnormal laboratory values have returned to baseline or normalized, until there is a satisfactory 
explanation for the changes observed, until the patient is lost to follow-up, or until the patient has 
died. The Adverse Events of Special Interest (AESIs) for this study are MDS, AML, secondary 
cancers (new primary malignancies other than MDS/AML), pneumonitis, and embryo-fetal 
toxicity. AESIs must be reported to the Sponsor as soon as the investigator becomes aware of 
them.
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 will be used for tumor 
assessment via a computed tomography (CT) or magnetic resonance imaging (MRI) scan of 
abdomen/pelvis and clinically indicated areas, which is required at the end of every 2 cycles 
(8 weeks with a window of ±7 days from date of visit) through Cycle 14, then at the end of every 
3 cycles (12 weeks with a window of ±7 days) until Cycle 38, and at the end of every 6 cycles 
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(24 weeks with a window of ±7 days) until progression. Cycle timing will not be delayed for 
treatment interruptions, and tumor assessment should occur according to this schedule regardless 
of whether study treatment is interrupted. If a patient discontinues treatment for clinical 
progression and does not meet the criteria specified in the protocol, scans and CA-125 testing 
should continue at the specified intervals in the protocol until progression is confirmed or until the 
start of subsequent anticancer treatment.
Blood samples for measurements of plasma levels of niraparib will be obtained on Cycle 1 Day 1 
predose and 2 hours postdose, Cycle 2 Day 1 predose and 2 hours postdose, and Cycle 4 Day 1 
predose.
6.2 
Number of Patients
Approximately 15 patients will be enrolled in this study from approximately 30 study centers in 
Japan. Enrollment is defined as the time when the sponsor sends an enrollment sheet back to the 
investigational site (see Section 9.4.11).
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 9.8. The OS follow-up should be 
performed until any of reason for withdrawal of patients from study (described in Section 9.9) 
including death occur.
6.3.2 End of Study/Study Completion Definition and Planned Reporting
End of study is defined as a date that last patient complete post treatment assessments.
Primary Analysis
The final analyses (primary analysis) for the primary endpoint will be conducted 30 days or more 
after initial dose for last enrolled patient. The estimated time frame for primary analysis is 
approximately 6 to 8 months from first patient enrollment.
Other Planned Analyses
If follow-up assessment continues after the final analyses for the primary endpoint, a CSR safety 
addendum is planned for when all enrolled patients have had the opportunity to complete 
follow-up assessment.
Study Completion
The estimated time frame for study completion (screening, study drug administration and 
follow-up period) is approximately 28 months.
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6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame
Primary:
• The subject incidence of Grade 3 or 4
thrombocytopenia occurring within 30
days after initial administration of
niraparib.
-
30 days after initial dose 
for last enrolled patient
Approximately 6 to 8
months
Secondary:
• Safety and tolerability
-
−
The number and percentage of subjects
with TEAEs (a)
The number and percentage of subjects with
TEAEs in the safety analysis set.
Approximately 28 months
−
The number and percentage of subjects
with Grade 3 or higher TEAEs (a)
The number and percentage of subjects with
Grade 3 or higher TEAEs in the safety 
analysis set.
Approximately 28 months
−
The number and percentage of subjects
with serious TEAEs (a)
The number and percentage of subjects with
serious TEAEs in the safety analysis set.
Approximately 28 months
−
The number and percentage of subjects
with TEAEs leading to drug
discontinuation (a)
The number and percentage of subjects with 
TEAEs leading to drug discontinuation in 
the safety analysis set.
Approximately 28 months
−
The number and percentage of subjects
with TEAEs leading to dose
interruption (a)
The number and percentage of subjects with 
TEAEs leading to dose interruption in the 
safety analysis set.
Approximately 28 months
−
The number and percentage of subjects
with TEAEs leading to dose reduction
(a)
The number and percentage of subjects with
TEAEs leading to dose reduction in the 
safety analysis set.
Approximately 28 months
• Progression-free survival
The time from the date of enrollment to the 
earlier date of progression assessed by the 
investigator per RECIST (v.1.1) or clinical 
criteria, or death by any cause.
Approximately 28 months
• Overall survival
The time from the date of enrollment to the 
date of death by any cause.
Approximately 28 months
• Overall response rate
The proportion of patients achieving CR or 
PR in the FAS.
Approximately 28 months
CR: complete response; FAS: full analysis set; PR: partial response; RECIST: Response Evaluation Criteria in Solid 
Tumors; TEAE: treatment-emergent adverse event.
(a) 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 will be completed approximately 2 months from the 
enrollment of the first patient into the study.
It is anticipated that this study will last for approximately 28 months.
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6.3.5
Posttrial Access
The study will be continued until last patient complete post treatment assessments.
After a marketing approval of niraparib is obtained in Japan before the study 
completion/withdrawal, this study will be continued as a post-marketing clinical study in 
compliance with the GCP and the Good Post-marketing Study Practice.
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7.0
STUDY POPULATION
The study will be conducted in Japanese patients with platinum-sensitive, relapsed ovarian cancer, 
fallopian tube cancer, or primary peritoneal cancer, who achieved CR or PR in the last 
chemotherapy containing platinum-based anticancer agents.
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Japanese female patients aged 20 years or older on the day of signing informed consent.
2. 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.
3. Patient must have a histologically diagnosed ovarian cancer, fallopian tube cancer, or primary
peritoneal cancer.
4. Patient must have a high-grade (or Grade 3) serous or high-grade predominantly serous
histology or known to have gBRCAmut.
5. Patients must have completed at least 2 previous lines of platinum-containing therapy:
Note: The last platinum regimen did not necessarily have to immediately follow the
next-to-last (penultimate) platinum regimen. For example, if a patient received a non-platinum
regimen between the penultimate platinum regimen and last platinum regimen, she could have
been eligible as long as she met all entry criteria.
a. For the penultimate platinum-based chemotherapy prior to study enrollment, patients must
have had platinum-sensitive disease after this treatment, defined as achieving a response
(CR or PR) and disease progression >6 months after completion of her last dose of platinum
therapy (documented 6 to 12 months or >12 months). Source documentation was required.
b. For the last line of platinum-based chemotherapy prior to study enrollment:
i.
Patients must have received a platinum-containing regimen for a minimum of 4
cycles.
ii.
Patients must have achieved a partial or complete tumor response.
iii.
Following the last regimen, patients must have had either.
1. CA-125 equal to or less than the upper limit of the normal range.
2. CA-125 decrease by more than 90% during the last platinum regimen, and which
was stable for at least 7 days (ie, no increase >15%).
iv.
Following the last regimen, patients could not have had any measurable lesion >2 cm
at the time of study enrollment.
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c. Patients must have been enrolled within 8 weeks after completion of their final dose of the
platinum- containing regimen.
6. Patients must have performance status of ≤1 on the Eastern Cooperative Oncology Group
(ECOG) Performance Status Scale.
7. Patients must have adequate organ function as indicated by the following laboratory values:
a. Absolute neutrophil count (ANC) ≥1,500/μL.
b. Platelet count ≥100,000/μL.
c. Hemoglobin ≥9 g/dL.
d. Serum creatinine ≤1.5× institutional upper limit of normal (ULN) OR calculated creatinine
clearance ≥50 mL/minute, using the Cockcroft-Gault equation.
e. Total bilirubin ≤1.5×ULN OR direct bilirubin ≤1×ULN.
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN unless
liver metastases were present, in which case they had to be ≤5×ULN.
8. Patients must be able to take oral medications.
9. Female patients of childbearing potential must be negative for pregnancy test (β-hCG) within 7
days prior to receiving the first dose of study treatment.
10. Female patients who:
a. Are postmenopausal for at least 1 year before the screening visit, OR
b. Are surgically sterile, OR
c. 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
d. 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.)
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Patients who have had drainage of ascites during last 2 cycles of last chemotherapy.
2. Patients who have had palliative radiotherapy encompassing >20% of the bone marrow within
1 week of the first dose of study treatment.
3. Patients who have any persistent Grade ≥3 toxicity from last cancer therapy.
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4. Patients who have symptomatic, uncontrolled brain or leptomeningeal metastases. To be
considered “controlled,” central nervous system (CNS) disease must have undergone
treatment (eg, radiation or chemotherapy) at least 1 month prior to study enrollment. The
patient must not have had any new or progressive signs or symptoms related to the CNS
disease and must have been taking a stable dose of steroids or no steroids (as long as these were
started at least 4 weeks prior to enrollment] or no steroids). A scan to confirm the absence of
brain metastases at baseline was not required. Patients with spinal cord compression might
have been considered if they had received definitive treatment for this and evidence of
clinically stable disease for 28 days.
5. Patients who have known hypersensitivity to the components of niraparib.
6. Patients who have had prior treatment with a known PARP inhibitor.
7. Patient who have had treatment with any investigational products within 28 days or 5 half-lives
(whichever was longer) before the first dose.
8. Patients who have had major surgery per investigator judgment within 3 weeks of the first
dose. Patient must have recovered from any effects of any major surgery.
9. Patients who have diagnosis, detection, or treatment of invasive second primary malignancy
other than ovarian cancer ≤24 months prior to study enrollment (except basal or squamous cell
carcinoma of the skin that was definitively treated). Note: Patients must not have any known
history or current diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia
(AML), irrespective of the time for disease history.
10. Patients who are considered a poor medical risk due to a serious, uncontrolled medical
disorder, non-malignant systemic disease, or active, uncontrolled infection. Examples include,
but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days of the first
dose) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord
compression, superior vena cava syndrome, small bowel obstruction or other serious
gastrointestinal disorder, or any psychiatric disorder that prohibits obtaining informed consent.
11. Patients who have received a transfusion (platelets or red blood cells) within 4 weeks of the
first dose of study treatment.
12. Patients who have received a live virus and bacterial vaccines within 4 weeks of the first dose
of study treatment.
13. Patients who have a history or current evidence of any condition, therapy, or lab abnormality
(including active or uncontrolled myelosuppression [ie, anemia, leukopenia, neutropenia,
thrombocytopenia]) 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
14. Patients who are regular user (including “recreational use”) of any illicit drugs at the time of
signing informed consent or have a recent history (within the past year) of drug or alcohol
abuse.
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15. Patients who are pregnant or breast-feeding, or expecting to conceive within the planned
duration of the study. NOTE: If a breast-feeding woman discontinue breast-feeding, she may
be enrolled in the study.
16. Patients who are immunocompromised (patients with splenectomy are allowed).
17. Patients who have known HIV positive.
18. Patients who have 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
The study drug will be administered at 300 mg QD, orally continuously, in 28-day cycles. 
Niraparib will be administered until subjects experience objective PD, experience unacceptable 
toxicity, withdrawal of consent or until study discontinuation due to any other reasons specified in 
the study protocol.
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.
Patients will be provided dosing diary and instructed to record any dose of study drug and the time 
of administration in their dosing diary in study treatment period.
8.2 
Dose Modification Guidelines
8.2.1 Criteria for Dose Reduction, Interruption, and Discontinuation
Dose interruption and/or reduction may be implemented at any time for any grade toxicity if the 
investigator or subinvestigator deems that the toxicity is intolerable by the patient.
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).
(1) Dose Modifications for Non-Hematologic Toxicities
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 the Grade 3 or 4 non-hematologic toxicity is appropriately resolved to baseline or 
Grade 1 or less within 28 days following interruption, the patient may restart treatment with 
niraparib at the same dose level. However, if prophylaxis is not considered feasible, treatment with 
niraparib should be restarted with a dose level reduction according to Table 8.a. After the restart, if 
the event recurs at the same or worse grade, treatment should be interrupted again and, upon 
resolution, treatment with niraparib should be restarted with a dose level reduction according to 
Table 8.a.
Dose reductions to 200 mg/day and subsequently to 100 mg/day will be allowed. No further dose 
reduction will be allowed. 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 the maximum dose reductions, the patient must permanently 
discontinue study treatment.
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Table 8.a
Dose Reductions for Non-Hematologic Toxicities
Event
Dose(a)
Initial dose
300 mg QD
1st dose reduction for NCI CTCAE Grade 3 or 4 treatment-related SAEs/AEs
where prophylaxis with medication is not considered feasible.
200 mg QD
2nd dose reduction for NCI CTCAE Grade 3 or 4 treatment-related 
SAEs/AEs where prophylaxis with medication is not considered feasible.
100 mg QD
Continued NCI CTCAE Grade 3 or 4 treatment-related SAEs/AEs ≥28 days.
Discontinue study medication
AE: adverse event; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; QD:
once daily; SAE: serious adverse event.
(a) Dose not to be decreased below 100 mg QD.
(2) Dose Modification for Hematologic Toxicities
The dose interruption/modification criteria for hematologic parameters will be based on blood 
counts and are outlined in Table 8.b.
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 reduction(s), the 
patient must permanently discontinue treatment with niraparib.
Table 8.b
Dose Interruption, Resume or Reduction for Hematologic Toxicities
Finding
Modification
Platelet count 
75,000-99,999/μL
(1st occurrence)
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.
Platelet count 
75,000-99,999/μL
(2nd occurrence after 
resolution)
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 ≥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.
CBC: complete blood cell count.
*For patients with platelet count ≤10,000/μL prophylactic platelet transfusion per guidelines may be considered. For 
patients taking anticoagulation or antiplatelet drugs consider of interrupting these drugs and/or prophylactic 
transfusion at an alternate threshold, such as ≤20,000/μL (before platelet count decreased ≤10,000/μL).
If dose interruption or modification is required at any point on study because of hematologic 
toxicity, weekly blood draws for CBC will be monitored until the AE resolves. When the treatment 
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is re-started after the AE resolution, weekly blood draws for CBC will be also required for an 
additional 4 weeks to ensure safety of the restarted dose. Monitoring every 4 weeks may resume
thereafter.
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 interruption with sufficient supportive care. If a 
diagnosis of myelodysplastic syndrome (MDS)/acute myeloblastic leukemia (AML) is confirmed 
by a hematologist, the patient must permanently discontinue study treatment.
(3) Other
If a secondary cancer (new malignancies other than MDS/AML) is diagnosed while on study, the 
patient must permanently discontinue study treatment.
For major surgery while on treatment, up to 28 days of drug interruption is allowed.
8.2.2
Re-Escalation After Dose Reduction
Once the dose of study treatment has been reduced, any re-escalation must be discussed with the
medical monitor.
8.2.3
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 8.2.1.
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.
8.3
Excluded Concomitant Medications and Procedures
The following medications, procedures and foods are prohibited from the time of signing the 
informed consent through the treatment discontinuation visit:

Other anticancer therapies other than study treatment, with the exception as follows:
–
The patient can receive a stable dose of corticosteroids during the study as long as these
were started at least 4 weeks prior to enrollment for the treatment of brain or
leptomeningeal metastases or other diseases (Section 7.2, Exclusion Criteria 4).
Temporary steroid use will be permitted for treatment of AEs or for prophylaxis. Of note,
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topical steroids such as intraarticular, intranasal, eye-drops, and inhalation are permitted 
without limitation.
–
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.

Conventional chemotherapy drugs, live virus and bacterial vaccines increased risk of infection
have been observed. Effects with niraparib are unknown and therefore they should not be
administered to patients 4 weeks before initial administration of niraparib and during the study.

Prophylactic cytokine (granulocyte colony-stimulating factor [GCSF]) administration should
not be given in Cycle 1. 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
treatment period:

Drugs that are substrates for cytochrome P450 (CYP) 1A2 (Appendix F) (niraparib is a
CYP1A2 inducer).

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).

Drugs associated with QT interval (QTc) prolongation (Appendix G) (Niraparib has been
associated with QT prolongation when co-administered with medications known to cause QTc
prolongation.)
8.4
Permitted Concomitant Medications and Procedures
For patients with platelet count ≤10,000/μL prophylactic platelet transfusion per guidelines may
be considered.
8.5
Precautions and Restrictions
8.5.1
Pregnancy and Contraception
Niraparib is clastogenic and is expected to exhibit embryo-fetal toxicity based on the mechanism 
of action. Therefore, female patients participating in this study should avoid becoming pregnant. 
Nonsterilized female patients of reproductive age group 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, or

Surgically sterile, or
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
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 ICF through 180 days after the last dose of study drug, or

Agree to practice true abstinence from the time of signing of the ICF 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. Female and male condoms should not be used together.)
*Women of childbearing potential are 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.
8.5.2 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.
8.6 
Blinding and Unblinding
This is an open-label study.
8.7 
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.
Refer to the Investigator’s Brochure for further details.
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8.8 
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.
8.9 
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.
8.10 
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.
Niraparib capsules must be stored at 2°C to 25°C. Refer to the Pharmacy Manual for further 
details.
8.11 
Other Protocol-Specified Materials
Not applicable.
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9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, GCP, applicable regulatory 
requirements, and 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
Not applicable.
9.4
Study Procedures
Refer to the Schedule of Events (Appendix A) for 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 histories that are considered to be clinically useful by the investigator will be collected.
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 and grade.
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.
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
All chemotherapeutic agents and treatment given to subjects after the initial diagnosis, its start
and end dates and the best response to each treatment.

All prior surgeries for the underlying disease.
In addition, CA-125 values at start and complete date of the last platinum-based regimens.
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
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 Performance Status
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.
9.4.8 Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential (defined in 
Section 8.5.1) within 7 days before Cycle 1 Day 1, and negative results must be obtained before 
the first dose of study drug. Subsequently, serum or urine pregnancy tests will be performed every 
three cycles during the study treatment, and negative results must be obtained before the study 
drug administration.
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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 30 days after the last 
dose of study drug or the start of subsequent antitumor therapy, whichever comes first. See 
Section 8.3 and Section 8.4 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) and treatment used by subjects 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).
For any suspected case of MDS/AML or second primary malignancies other than MDS/AML 
reported while a patient is receiving treatment or being followed for post-treatment assessments, 
bone marrow aspirate and biopsy testing must be completed by a local hematologist. Testing 
completed as part of standard of care is sufficient as long as the methods are acceptable to the 
Sponsor's Medical Monitor. The study site must receive a copy of the hematologist’s report of 
aspirate/biopsy findings, which must include a classification according to World Health 
Organization (WHO) criteria, and other sample testing reports related to MDS/AML or secondary 
cancer (new malignancies other than MDS/AML).
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.
Initial dose of niraparib must be administered within 5 days of the patient enrollment.
9.4.12 Electrocardiogram
A 12-lead ECG will be performed at time points specified in the Schedule of Events (Appendix A) 
and the results 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.
9.4.13 Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally before administration of the study drug.
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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 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 (optional) (a)
•
Albumin
•
ALP
•
ALT
•
Amylase
•
AST
•
Total bilirubin
Direct bilirubin
•
Urea nitrogen
•
Calcium
•
Creatinine
•
Chloride
•
GGT
•
Glucose
•
LDH
•
Magnesium
•
Inorganic phosphate
•
Potassium
•
Sodium
•
Protein (total protein)
Blood coagulation test
Pregnancy test (serum, urine)
•
aPTT
•
INR
•
β-hCG
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANC: absolute neutrophil count; aPTT: activated partial 
thromboplastin time; AST: aspartate aminotransferase; GGT: gamma-glutamyl transpeptidase; β-hCG: human 
chorionic gonadotropin; INR: international normalized ratio; LDH: lactate dehydrogenase; MCV: mean cell volume; 
PT: prothrombin time.
(a) Although mean platelet volume collection is optional, it is highly encouraged, especially for patients with
high-grade thrombocytopenia.
Table 9.b
Clinical Urinalysis Tests
Urinalysis
•
Bilirubin
•
Glucose
•
Ketones
•
Nitrite
•
Occult blood
•
Protein
•
Specific gravity
•
Urobilinogen
•
Leukocyte esterase
If creatinine clearance is to be estimated, the Cockroft-Gault formula will be employed as follows:
	
 
	
 
		
 ( 
	
 	
) 
=  [(140 −
) ∗	() ] / [72 ∗
$ 
	
(/%)] ∗0.85
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9.4.13.2 Serum CA-125 Assessment
Blood samples for analysis of the serum CA-125 assessment will be obtained on the same day, 
before administration of the study drug, as specified in the Schedule of Events (Appendix A).
If CA-125 samples for screening assessment are collected within 72 hours prior to the first dose on 
Cycle 1 Day 1, repeat testing is not required for Cycle 1 Day 1. CA-125 levels must be normal at 
screening or have a >90% decrease, and which was stable for at least 7 days (ie, no increase >15%) 
compared to baseline prior to their last platinum-based chemotherapy course.
Abnormal CA-125 levels on-study do not represent disease progression; however, they may 
prompt imaging if clinically indicated. For determination of CA-125 progression, at least 2 
CA-125 values at least 1 week apart are required for confirmation.
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). 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). When possible, the same qualified physician will interpret the results to reduce 
variability.
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.
If the chest CT/MRI is clear at screening, repeat chest imaging is not required in the absence of 
lesions to be followed or in the absence of clinical indication requiring follow-up.
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.
In this study, confirmation of complete or partial response is required. Complete or partial 
responses may be claimed only if the criteria for each are met 4 weeks or more later.
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 ORR
ORR is defined as the proportion of patients achieving CR or PR as assessed by the investigator 
per RECIST (v.1.1) (Appendix E).
9.4.16 PFS (Definition of PD)
PFS is defined as the time from the date of enrollment to the earlier date of progression assessed by 
the investigator per RECIST (v.1.1) (Appendix E) or clinical criteria, or death by any cause.
PFS will be determined based on a tumor assessment by the investigator and the criteria of CA-125 
progression. The date of progressive disease (PD) will be determined based on imaging 
assessment according to RECIST v.1.1 (Appendix 2, Table 5) criteria, preferentially. Because of 
the pelvic location of the primary tumor and the frequent occurrence of peritoneal disease, imaging 
may not always be reliable for documentation of PD.
Criteria other than RECIST may be applicable to define PD. PD will be determined if at least 1 of 
the following criteria is met:
1. Tumor assessment by CT/MRI unequivocally shows PD according to RECIST v.1.1 criteria
(Appendix E)
a. If a patient had a CT/MRI of the abdomen/pelvis and clinically indicated areas within the
28-day screening window before Cycle 1 Day 1 but prior to signing the main ICF, the
patient is not required to complete an additional CT/MRI scan for study screening. CT/MRI
scans completed during screening prior to signing the ICF must have been performed under
same condition during the study and be able to be submitted.
2. Additional diagnostic tests (eg, histology/cytology, ultrasound techniques, endoscopy,
positron emission tomography) identify new lesions or determine existing lesions qualify for
unequivocal PD AND CA-125 progression according to Gynecologic Cancer Intergroup
(GCIG)-criteria (below).
3. Definitive clinical signs and symptoms of PD unrelated to non-malignant or iatrogenic causes
([1] intractable cancer-related pain; [2] malignant bowel obstruction/worsening dysfunction;
or [3] unequivocal symptomatic worsening of ascites or pleural effusion) AND CA-125
progression according to GCIG criteria (below).
PD will not be diagnosed in case of CA-125 progression in the absence of at least 1 of the criteria 
defined above.
The investigator will describe why PD was diagnosed in the eCRF. The date of PD is defined as 
the earliest time point when one of the PD criteria is met. When required to determine progression, 
CA-125 levels should be evaluated ±2 weeks from the primary PD assessments (ie, diagnostic test 
or clinical parameters) and must be confirmed by a second determination ≥7 days later. In case 
assessments of CA-125 levels occur greater than 2 weeks from the primary PD assessments, the 
date of the primary assessment of PD will be used to define the date of PD. GCIG criteria for 
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CA-125 progression are as follows: (Note: CA-125 progression alone will not be considered 
disease progression.)
CA-125 progression according to GCIG criteria
1. Patients with elevated CA-125 pretreatment and normalization of CA-125 must show evidence
of CA-125 ≥2 x ULN on 2 occasions at least 1 week apart, OR
2. Patients with elevated CA-125 pretreatment, which never normalizes must show evidence of
CA-125 ≥2 x the nadir value on 2 occasions at least 1 week apart, OR
3. Patients with CA-125 in the normal range pretreatment must show evidence of CA-125 ≥2 x
ULN on 2 occasions at least 1 week apart.
If CT/MRI shows existing (baseline) lesions which only equivocally suggest PD and additional 
diagnostic tests are required to determine unequivocal PD, the official date of PD will be the date 
PD was unequivocally determined. Alternatively with new lesions (except ascites and effusions) 
that are initially equivocal that are later unequivocally determined, the date of progression will be 
the date the lesion was initially identified.
Note: If the investigator determines clinical PD, they can consult an imaging clinician at the 
investigational site prior to receiving results from the central reader. Pursuant to consultation with 
the clinician, the investigator can keep the patient on study treatment as long as it is considered 
safe, or the investigator can discontinue the patient.
9.4.17 OS
OS is defined as the time from the date of enrollment to the date of death by any cause. Following 
the treatment discontinuation visit, survival status will be collected for all patients using 
acceptable means including telephone contact. New malignancy information will also be collected 
as part of this assessment.
9.4.18 Pharmacokinetic Measurements
Blood samples for PK analysis of niraparib will be serially collected at the time points specified in 
the Schedule of Events (Appendix A). 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.
9.5 
Records of Patients who Discontinued the Study After Enrollment and Before the 
First Administration of Study Drug
The investigator or subinvestigator is responsible for documenting the records of all patients who 
signed the ICF.
The investigator or subinvestigator is responsible for the eCRF data entry, even if the patient 
turned out to be ineligible after enrollment and before the first administration of study drug.
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The primary reason of study discontinuation after enrollment and before the first administration of 
study drug will be recorded in the eCRF, under the following categories:

Death.

Adverse event.

Screen failure (the subject did not meet the inclusion criteria or did meet the exclusion criteria).

Protocol deviation.

Lost to follow-up.

Consent withdrawal by patient.

Termination of the whole study by sponsor.
The subject identification number of the patient who discontinued the study before the first study 
drug administration will not be reused.
9.6
Completion of 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 based on the patient being followed until a 
specific event, eg, death or until study termination, and complete the safety follow-up.
9.8
Discontinuation of Treatment With Study Drug and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons:

AE.
–
Any treatment-related NCI CTCAE (ver. 4.03) Grade 3 or 4 non-hematologic toxicity that
have not reverted to CTCAE Grade 1 or better within 28 days of dose interruption.
–
Any hematologic toxicity that have not retreated to the pre-specified level within 28 days
following study drug interruption.
–
Any treatment emergent adverse event that lead to study drug interruption and restart with
dose reduction occurred in a patient who has already received a minimum dose of niraparib
(100 mg QD) after prior study drug interruption due to adverse event.

Protocol deviation.

PD.
–
Definition of PD (Section 9.4.16) as judged by the investigator or subinvestigator.
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
Pregnancy.

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Other.
Once study drug has been discontinued, all study procedures outlined for the end-of-treatment visit 
will be completed as specified in the Schedule of Events (Appendix A). The primary reason for 
study drug discontinuation will be recorded on the eCRF.
Note that some patients may discontinue study drug for reasons other than progressive disease 
before completing the full treatment course; these patients will remain in the study for 
posttreatment assessments as outlined in the Schedule of Events until disease progression occurs.
9.9
Withdrawal of Patients 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.

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.
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Tests and procedures should be performed on schedule. However, except Cycle 1 Day 1, Cycle 2
Day 1, Early Termination and follow-up 30 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) is not flexible.
The observation and test specified in the Study Treatment Discontinuation visit will be conducted 
within 7 days after last dose of niraparib. The observation and test specified in the 30 days after the 
last dose visit will be conducted at 30 days (+7 days) after the last dose of study drug
administration, or beginning of subsequent anticancer therapy, whichever comes first, and the 
follow-up assessments will be conducted every 90 days (±7 days) from the termination day of the 
study drug administration.
9.11
Thirty Days Follow-up After the Last Dose
All AEs (including laboratory data specified in the schedule) and concomitant medications will be 
collected and recorded for each patient from the day of signing the ICF until 30 days (+7 days) 
after last dose of study treatment administration, or beginning of subsequent anticancer therapy, 
whichever comes first.
All AEs and SAEs which occurred until the visit of 30 days follow-up after the last dose will be
recorded and monitored appropriately.
9.12
Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival)
If a patient discontinues treatment for the reason other than PD, withdrawal by subject, and lost to
follow-up, scans and CA-125 testing will continue to be collected for PFS evaluation.
The PFS evaluation after study treatment discontinuation will be performed at the protocol 
specified intervals (ie, same as an interval during study treatment) from study treatment 
discontinuation until progression is confirmed or until the start of subsequent anticancer treatment.
If a patient discontinues treatment for PD, follow-up information will continue to be collected for 
OS assessment. The OS assessment will be performed every 90 days (±7 days) following study 
treatment discontinuation. Following the treatment discontinuation visit, survival status will be 
collected for all patients using acceptable means (ie, hospital visit is not mandatory). New 
malignancy information will also be collected as part of this assessment.
The following information will be collected in the Post Treatment Assessments:

MDS, AML, and secondary cancers (new malignancies other than MDS/AML) which
occurred after study treatment discontinuation

Treatment-related death
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–
The death must be reported by the investigator or subinvestigator to the Takeda Global
Pharmacovigilance Department or designee, same as during study treatment period
(Section 10.2).

Outcome of adverse event that occurred during the study
–
All AEs experienced by a patient will be monitored until the AE has resolved, any
abnormal laboratory values have returned to baseline or normal levels, until there is a
satisfactory explanation for the changes observed, until the patient is lost to follow-up, or
until the patient has died.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 AE Definition
AE means any untoward medical occurrence in a patient or subject who has been enrolled in a 
study; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. 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 to be a clinically significant change from baseline.
10.1.2 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient 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 were
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see
Section 10.2 on 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. This refers to an AE that may not result in death, be
immediately life-threatening, or require hospitalization, but may be considered serious when,
on the basis of appropriate medical judgment, it may jeopardize the patient, 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. Examples of such medical events
include allergic bronchospasm requiring intensive treatment in an emergency room or at home,
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the
development of drug dependency or drug abuse; any organism, 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 for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective 14 June 2010 [6]. 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). This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above and is usually associated with events that 
pose a threat to a patient’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 AEs and SAEs
All AEs spontaneously reported by the patient 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 a single comprehensive event.
Regardless of causality, SAEs must be reported by the investigator or subinvestigator to the 
Takeda Global Pharmacovigilance Department or designee (contact information provided below)
(see Section 10.3 for the period of observation). 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. SAE report information must be consistent with the data
provided on the eCRF.
SAE Reporting Contact Information
If information not available at the time of the first report becomes available at a later date, then the 
investigator or subinvestigator will transmit a follow-up SAE report or provide other 
documentation immediately within 24 hours of receipt. Copies of any relevant data from the 
hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent 
to the addressee, if requested.
All SAEs should be followed up by the investigator or subinvestigator until resolution or 
permanent outcome of the event. The timelines and procedure for follow-up reports are the same 
as those for the initial report.
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Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient 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.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective 14 June 2010 [6].
Relationship of the event to study drug administration (ie, its causality) will be determined by the 
investigator responding yes (related) or no (unrelated) to this question: “Is there a reasonable 
possibility that the AE is associated with the study drug?”
10.3
Monitoring of AEs 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 30 days after
administration of the last dose of study drug, whichever comes first, and recorded in the
eCRFs.

SAEs will be reported to the Takeda Global Pharmacovigilance department or designee from
the signing of informed consent through 30 days after administration of the last dose of study
drug, whichever comes first, 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 
Adverse Events of Special Interest
MDS, AML, secondary cancers (new malignancies other than MDS/AML), pneumonitis, and 
embryo-fetal toxicity are Adverse of Special Interest (AESIs) of niraparib. AESIs must be reported 
to the sponsor and recorded as such on the eCRF and on an SAE form; the SAE form must be 
submitted within 24 hours of the investigator becoming aware (Section 10.2). AESI monitoring 
must occur during the study, during follow-up and after study discontinuation.
10.5 
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 investigator or subinvestigator must also be contacted immediately by sending 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.
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10.6
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
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.
Call Center
Phone Number
Email
Fax
Product complaints and medication errors in and of themselves are not AEs. If a product complaint 
or a medication error results in an SAE, the SAE should be reported. 
10.7 
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, and 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 
expedited reports within 7 days for fatal and life-threatening events and within 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.
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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 has been enrolled in the study.
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, 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 designee) 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 the 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 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 copies of eCRFs including the audit trails, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities and the sponsor or 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, ICH 
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E6 Section (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, if an application is 
not approved, 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 for 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.
13.1.1 Analysis Sets
In this study, the following 4 analysis sets are defined: safety analysis set, full analysis set, 
response-evaluable analysis set, and PK analysis set. The details of the definition will be provided 
in the SAP.
The sponsor will review the definition of any analysis set and the data handling rule and add any 
issue handling rule specified after study initiation, with consultation with medical expert if 
necessary, then the SAP will be finalized before database lock.
13.1.1.1 Safety Analysis Set
Safety analysis set is defined as patients who receive at least 1 dose of study drug.
13.1.1.2 Full Analysis Set
Full analysis set is defined as patients who receive at least 1 dose of study drug.
13.1.1.3 Response-evaluable Analysis Set
Response-evaluable analysis set is defined as patients who receive at least 1 dose of study drug and 
have at least one measurable disease at baseline.
13.1.1.4 PK Analysis Set
PK analysis set is defined as patients who receive at least 1 dose of study drug and have at least 1 
concentration data of niraparib.
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized by dose cohort using the 
FAS, the safety analysis set and the PK analysis set.
13.1.3 Efficacy Analysis
PFS and OS will be analyzed using Kaplan-Meier method to provide quartiles and 
progression/survival rate at specified points with 95% CI using FAS. The Kaplan-Meier plot for 
PFS and OS will also be provided.
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ORR and its two-sided 95% confidence interval will be provided using the response-evaluable 
analysis 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.
Population PK analyses will be conducted using the PK data of niraparib collected in this study.
These population PK analyses may additionally include data collected in other niraparib clinical 
studies. The plan for the population PK analysis will be defined separately and the results reported 
separately.
13.1.5 Safety Analysis
13.1.5.1 Primary Endpoint analysis
The subject incidence of Grade 3 or 4 thrombocytopenia within 30 days after the initial dose of 
niraparib will be calculated using safety analysis set.
13.1.5.2 Secondary Endpoints analysis
The following analyses will be performed using the safety analysis set.
TEAE is defined as adverse events that occur after administration of the first dose of study drug. 
TEAEs will be coded using the MedDRA dictionary, and will be tabulated by preferred terms (PT) 
and system organ class (SOC).

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

Serious TEAEs.

TEAEs leading to study drug discontinuation.

TEAEs leading to study drug interruption.

TEAEs leading to study drug reduction.
13.1.5.3 Other Endpoints Analysis
For laboratory tests, vital sign, ECG and ECOG performance status, shift tables based on changes 
in NCI CTCAE grade from baseline to the worst postbaseline value will be generated using the 
safety analysis set. For continuous variable, value at each time point and changes from baseline 
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will be summarized using descriptive statistics. Case plots over time for each subject will be 
presented.
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 interim analysis is planned.
13.3 
Determination of Sample Size
The incidence of thrombocytopenia in non-Japanese patients was estimated to be 35% based on an 
overseas clinical study, and the incidence of thrombocytopenia in subject population in this study 
was estimated to be 46% (the rationale for each incidence is shown below). The sample size in this 
study is set to be 15, because the probability that the point estimate of the incidence of 
thrombocytopenia will be ≥35% is 76%, with which a certain level of evaluation is expected to be 
achievable.
Rationale for Threshold of 35% for the Incidence of Thrombocytopenia
In the analysis of clinical data versus baseline body weight and platelet count in the NOVA study, 
the incidence of Grade 3 or 4 thrombocytopenia during the first 30 days after the initial dose of 
niraparib was higher in patients with baseline body weight of <77 kg or baseline platelet count of 
<150,000/μL (34.6%, 97/280 subjects) than in those with body weight of ≥77 kg and platelet count 
of ≥150,000/μL (11.8%, 10/85 subjects), as described in Section 1.3.2.5. Therefore, the threshold 
for the incidence of thrombocytopenia is considered as 35%.
Rationale for Threshold of 46% for the Expected Incidence of Thrombocytopenia
According to the results of minimum platelet count by baseline body weight during the first 30 
days after the initial dose of niraparib in the NOVA study, the incidence of platelet count decreased 
to 50,000/μL, which is almost equal to or more than Grade 3 thrombocytopenia, was 46% in 
patients with baseline body weight of <58 kg.
According to the body weight distribution in ovarian cancer patients in Japan, based on the 
research by 
 using prescription information as data source, ≥77% patients had 
body weight of ≤59 kg. Therefore, the expectation of the incidence of thrombocytopenia in subject 
population in this study was considered as 46%.
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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 
(as long as blinding is not jeopardized), 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 prior 
written agreement with the sponsor or 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 and 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 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 United States [US] Food and Drug Administration [FDA], 
the United Kingdom [UK] Medicines and Healthcare products Regulatory Agency [MHRA], the 
Pharmaceuticals and Medical Devices Agency of Japan [PMDA]). 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 B. 
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.
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 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 its 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 the 
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 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 
applicable laws and regulations. The ICF describe the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
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the study. The ICF further explain the nature of the study, its objectives, and potential risks and 
benefits, and 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 the IRB and the sponsor before 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 to participate in the study. If the subject determines that he or she will participate in 
the study, then the ICF and subject authorization form (if applicable) must be signed and dated by 
the subject, at the time of consent and before the subject enters into the study. The subject should 
be instructed to sign using their legal names, not nicknames, using a ballpoint pen with either blue 
or black ink. The investigator or subinvestigator must also sign and date the ICF at the time of 
consent and before the subject enters 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 be linked to the 
sponsor’s clinical study database or documentation only via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age and 
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 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, UK MHRA, Japan 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 the specific authorization 
of the subject as part of the informed consent process (see Section 15.2).
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Copies of any subject source documents that are provided to the sponsor must have certain 
identifying personal information removed, (eg, 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 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, other 
than study recruitment materials and 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
To ensure that information on clinical trials reaches the public in a timely manner and to comply 
with applicable laws, regulations, and guidance, Takeda 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 by Takeda policy/standards. Takeda 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.
As needed, Takeda and investigator/site contact information may be made public to support 
participant access to trials via registries. In certain situations/registries, Takeda may assist 
participants or potential participants in finding a clinical trial by helping them locate trial sites 
closest to their homes by providing the investigator name, address, and phone number via 
email/phone or other methods preferred by callers requesting trial information. Once subjects 
receive investigator contact information, they may call the site requesting enrollment into the trial. 
The investigative sites are encouraged to handle the trial inquiries according to their established 
subject screening process. If the caller asks additional questions beyond the topic of trial 
enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site.
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15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov, and other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
policy/standards, applicable laws, and/or regulations.
Data Sharing
The sponsor is committed to responsible sharing of clinical data with the goal of advancing 
medical science and improving patient care. Qualified independent researchers will be permitted 
to use data collected from patients during the study to conduct additional scientific research, which 
may be unrelated to the study drug or the patient’s disease. The data provided to external 
researchers will not include information that identifies patients personally.
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 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 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, Audeh MW, Friedlander M, Balmana J, et
al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
J Clin Oncol 2015;33(3):244-50.
[2] Watkins JA, Irshad S, Grigoriadis A, Tutt AN. Genomic scars as biomarkers of homologous
recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res
2014;16(3):211.
[3] Kaelin WG, Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev
Cancer 2005;5(9):689-98.
[4] Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer
2004;4(10):814-9.
[5] Abkevich V, Timms KM, Hennessy BT, Potter J, Carey MS, Meyer LA, et al. Patterns of
genomic loss of heterozygosity predict homologous recombination repair defects in epithelial
ovarian cancer. Br J Cancer 2012;107(10):1776-82.
[6] 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.
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(i)
CA-125 levels must be normal at screening or >90% decrease, and which was stable for at least 7 days (ie, no increase >15%) as compared with baseline prior
to last platinum-based chemotherapy course. Abnormal CA-125 levels during study do not represent disease progression; however, they may prompt imaging if
clinically indicated. If CA-125 samples for screening are collected within 72 hours prior to the first dose on Cycle 1 Day 1, repeated testing is not required for
Cycle 1 Day 1.
(j)
For determination of CA-125 progression, at least 2 CA-125 values at least 1 week apart are required for confirmation.
(k) Urinalysis parameters must include: specific gravity, leukocyte esterase, nitrite, blood, protein, glucose, ketones, urobilinogen, and bilirubin.
(l)
Chest CT/MRI will be performed if not done as part of RECIST tumor assessment at Screening. If the chest CT/MRI is clear at screening, repeat chest imaging
is not required in the absence of lesions to be followed or in the absence of clinical indication requiring follow-up.
(m) For any suspected MDS/AML, and secondary cancers (new primary malignancies other than MDS/AML) case reported while a patient is receiving treatment or
being followed for post-treatment assessments, bone marrow aspirate and biopsy testing must be completed by a local hematologist. A whole blood sample will also
be collected for cytogenetic analysis (mutations of select myeloid-associated genes). Testing completed as part of standard of care is sufficient as long as the
methods are acceptable to the Sponsor's Medical Monitor. The study site must receive a copy of the hematologist's report of aspirate/biopsy findings (which must
include a classification according to WHO criteria and other sample testing results related to MDS/AML, and secondary cancers (new primary malignancies other
than MDS/AML).
(n) All AEs (excluding MDS, AML, and secondary cancers [new primary malignancies other than MDS/AML]) will be recorded for each patient from the day of
signing the ICF until 30 days after last dose of study treatment administration, or beginning of subsequent anticancer therapy, whichever comes first.
(o) RECIST tumor assessment via CT or MRI scan of abdomen/pelvis and clinically indicated areas required at baseline, then after every 2 cycles (ie, 8 weeks with
a window of ±7 days from date of visit) through Cycle 14 (56 weeks) (ie, Day 1 of Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11, Cycle 13, and Cycle 15), then after
every 3 cycles (12 weeks with a window of ±7 days) until Cycle 38 (ie, Day 1 of Cycle 18, Cycle 21, Cycle 24, …, and Cycle 39), and after every 6 cycles (24 weeks
with a window of ±7 days) until progression (ie, Day 1 of Cycle 45, Cycle 51, … ); at this point (ie, progression), a final follow-up set of imaging is required.
PET/CT may be used according to RECIST guidelines. Cycle timing will not be delayed for treatment interruptions, and tumor assessment should occur according
to this schedule regardless of whether study treatment is interrupted. If a patient discontinues treatment for clinical progression and does not meet the criteria
specified in the protocol, scans and CA-125 testing should continue at the specified intervals in the protocol until progression is confirmed or until the start of
subsequent anticancer treatment. 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.
(p) If a patient had a CT/MRI of the abdomen/pelvis and clinically indicated areas within the 28-day screening window before Cycle 1 Day 1 but prior to signing
the ICF, the patient is not required to complete an additional CT/MRI scan for study screening. CT/MRI scans completed during screening prior to signing the ICF
must have been performed and be able to be submitted per the Sponsor-specified method.
(q) Every 90 days (±7 days) following study treatment discontinuation.
(r) Blood samples for PK collected on Cycle 1 Day 1 and Cycle 2 Day 1 collected predose (within 30 minutes) and 2 hours postdose (±15 minutes). Additional
blood samples for PK on Cycle 4 Day 1 will be collected at predose within 30 minutes only. In addition, the exact time of the PK blood draw will be recorded.
(s) No new capsules dispensed (collection only).
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Appendix B
Responsibilities of the Investigator
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the subinvestigators and other staff who will assist in the
protocol.
3. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel)
screening assessments, are NOT performed on potential subjects before the receipt of written
approval from relevant governing bodies/authorities.
4. Ensure that all subinvestigators, colleagues and employees assisting in the conduct of the study
are informed of these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB that conform to ICH
and local regulatory requirements.
6. Ensure that the IRB will be responsible for initial review, continuing review, and approval of
the protocol. Promptly report to the IRB all changes in research activity and all anticipated
risks to subjects. Make at least yearly reports on the progress of the study to the IRB, and issue
a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are
met.
8. Obtain valid informed consent from each subject who participates in the study, and document
the date of consent in the subject’s medical chart. Valid ICF is the most current version
approved by the IRB. Each ICF should contain a section that describes the uses and disclosures
of a subject’s personal information (including personal health information) that will take place
in connection with the study. If an ICF does not include such a section on the uses and
disclosures of a subject’s personal information, then the investigator must obtain a separate
subject authorization form from each subject or the subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of
2 years following notification by the sponsor that all investigations have been discontinued or
that the regulatory authority has approved the marketing application. The investigator should
contact and receive written approval from the sponsor before disposing of any such
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential
documents.
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor. This responsibility lies on
the appropriate individual, designated by the site in Japan.
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12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to
regulatory agencies relating to other medications used in other clinical studies that may contain
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria 
of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology 1982;5(6):649-55.
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Appendix E
Response Evaluation Criteria In Solid Tumors (RECIST), Amendment V1.1
These criteria are adapted from Eisenhauer EA, Therasse P, Bogaerts J, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45:228-247.
Measurability of Tumor at Baseline
Measureable
Tumor lesions
Must be accurately measured in at least one dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness recommended to be no greater than 5 mm. For a
study site which defines that the slice thickness greater than 5 mm is medically acceptable, the
minimum size for a measurable lesion at baseline should be twice the slice thickness used for
imaging).

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured
with calipers should be recorded as non-measurable).

20 mm by chest X-ray.
Malignant lymph nodes
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short 
axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than
5 mm). At baseline and in follow-up, only the short axis will be measured and followed.
Non-measurable
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered truly 
non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Tumor Response Evaluation
Target lesions

When more than one measurable lesion is present at baseline, all lesions up to a maximum of
five lesions total (and a maximum of two lesions per organ) representative of all involved
organs should be identified as target lesions and will be recorded and measured at baseline (this
means, for instance, where patients have only one or two organ sites involved a maximum of
two and four lesions, respectively, will be recorded).
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
Target lesions should be selected on the basis of their size (lesions with the longest diameter),
be representative of all involved organs, but in addition should be those that lend themselves to
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion
does not lend itself to reproducible measurement in which circumstance the next largest lesion
which can be measured reproducibly should be selected

Pathological nodes which are defined as measurable and may be identified as target lesions
must meet the criterion of a short axis of ≥15 mm by CT scan. Only the short axis of these
nodes will contribute to the baseline sum.

A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all
target lesions will be calculated and reported as the baseline sum diameters.
Non-target lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present”, “absent”, or in rare cases “unequivocal 
progression”.
Response Criteria
Evaluation of target lesions

CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or
non-target) must have reduction in short axis to <10 mm.

PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference
the baseline sum diameters.

PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the
smallest sum on study (this includes the baseline sum if that is the smallest on study). In
addition, the sum must also demonstrate an absolute increase of at least 5 mm.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to
qualify for PD, taking as reference the smallest sum diameters while on study.
Evaluation of non-target lesions

CR: Disappearance of all non-target lesions and normalization of tumor marker level. All
lymph nodes must be non-pathological in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of
tumor marker level above the normal limits.

PD: Appearance of unequivocal progression of existing non-target lesions. Unequivocal
progression should not normally trump target lesion status. It must be representative of overall
disease status change, not a single lesion increase.
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New lesions

There are no specific criteria for the identification of new radiographic lesions; however, the
finding of a new lesion should be unequivocal.

A lesion identified on a follow-up study in an anatomical location that was not scanned at
baseline is considered a new lesion and will indicate PD.

If a new lesion is equivocal, for example, because of its small size, continued therapy and
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there
is definitely a new lesion, then progression should be declared using the date of the initial scan.
Evaluation of Best Overall Response

The best overall response is the best response recorded from the start of the study treatment
until the end of treatment taking into account any requirement for confirmation.

The patient’s best overall response assignment will depend on the findings of both target and
non-target disease and will also take into consideration the appearance of new lesions.

The best overall response across all time points is determined once all the data for the patient is
known.

In this study, confirmation of complete or partial response is required. Complete or partial
responses may be claimed only if the criteria for each are met 4 weeks or more later (Table 1).
In this circumstance, the best overall response can be interpreted as in Table 3.

When SD is believed to be best response, SD criteria must be met within 4 weeks or more from
baseline (minimum time interval).
Table 1 Overall Response: Patients with Target (+/-Non-target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
Confirmation
CR
CR
No
CR
≥4 weeks
CR
Non-CR/non-PD
No
PR
≥4 weeks
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
documented at 
least once 
≥4 weeks. from 
baseline
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
no prior SD, PR or 
CR
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; NE, not evaluable.
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Table 2 Overall Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD(a)
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR, complete response; PD, progressive disease; NE, not evaluable.
Table 3. Best Overall Response When Confirmation of CR and PR Required
Overall response
First time point
Overall response
Subsequent time point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD or PR(a)
CR
SD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise NE
NE
NE
NE
CR, complete response; PD, progressive disease; NE, not evaluable; SD, stable disease.
(a) If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the first
time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.

The duration of overall response is measured from the time measurement criteria are first met
for CR/PR until the first date that recurrent or progressive disease is objectively documented as
assessed per RECIST (v.1.1) or clinical criteria (taking as reference for progressive disease the
smallest measurements recorded on study).
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Appendix F
Substrate Drugs Known to be Affected by Inhibition or Induction by CYP 
Enzymes
P450 Isozyme
Substrate Drugs
CYP1A2
caffeine, tizanidine
CYP, cytochrome P450.
Source: MHLW DDI Guidance.
This list is not intended to be exhaustive, but is to show examples of drugs whose metabolism is significantly 
influenced by CYP enzyme.
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Appendix G
Drugs Associated With QT Prolongation and Torsades de Pointes
Antiarrhythmics
Antimicrobials
Antidepressants
Antipsychotics
Others (including 
Selected Antiemetics)
Amiodarone
Sotalol
Quinidine
Procainamide
Dofetilide
Ibutilide
Levofloxacin
Ciprofloxacin
Gatifloxacin
Moxifloxacin
Clarithromycin
Erythromycin
Ketoconazole*
Itraconazole
Amitriptyline
Doxepin
Haloperidol
Droperidol
Quetiapine
Thioridazine
Ziprasidone
Cisapride
Sumatriptan
Zolmitriptan
Arsenic
Dolasetron
Methadone
Source: Huang X, Venet F, Wang YL, et al. PD-1 expression by macrophages plays a pathologic role in altering 
microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A. 
2009;106(15):6303-6308.
Funk KA, Bostwick JR. A comparison of the risk of QT prolongation among SSRIs. Ann Pharmacother. 
2013;47(10):1330-1341.
*Topical use only allowed for ketoconazole.
This list is not intended to be exhaustive, but is to show examples of representative drugs.
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Appendix H Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment 03.
The existing texts are shown with italics and underlines, and revised text are represented with bold 
letters.
Page 10, Section 2.0 STUDY SUMMARY – Study Design
Page 26, Section 6.1 Overview of Study Design
Existing Text
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 will be used for tumor 
assessment via a computed tomography (CT) or magnetic resonance imaging (MRI) scan of 
abdomen/pelvis and clinically indicated areas, which is required at the end of every 2 cycles (8 
weeks with a window of ±7 days from date of visit) through Cycle 14, then at the end of every 3 
cycles (12 weeks with a window of ±7 days) until progression. Cycle timing will not be delayed 
for treatment interruptions, and tumor assessment should occur according to this schedule 
regardless of whether study treatment is interrupted. If a patient discontinues treatment for clinical 
progression and does not meet the criteria specified in the protocol, scans and CA-125 testing 
should continue at the specified intervals in the protocol until progression is confirmed or until the 
start of subsequent anticancer treatment.
Revised Text
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 will be used for tumor 
assessment via a computed tomography (CT) or magnetic resonance imaging (MRI) scan of 
abdomen/pelvis and clinically indicated areas, which is required at the end of every 2 cycles 
(8 weeks with a window of ±7 days from date of visit) through Cycle 14, then at the end of every 
3 cycles (12 weeks with a window of ±7 days) until Cycle 38, and at the end of every 6 cycles 
(24 weeks with a window of ±7 days) until progression. Cycle timing will not be delayed for 
treatment interruptions, and tumor assessment should occur according to this schedule regardless 
of whether study treatment is interrupted. If a patient discontinues treatment for clinical 
progression and does not meet the criteria specified in the protocol, scans and CA-125 testing 
should continue at the specified intervals in the protocol until progression is confirmed or until the 
start of subsequent anticancer treatment.
Rationale for Amendment
Changed a frequency of imaging for tumor assessment due to consideration for effect of long-term 
radiation on subject.
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Page 67, Appendix A Schedule of Events
Existing Text
(o) RECIST tumor assessment via CT or MRI scan of abdomen/pelvis and clinically indicated 
areas required at baseline, then after every 2 cycles (ie, 8 weeks with a window of ±7 days from 
date of visit) through Cycle 14 (56 weeks), then after every 3 cycles (12 weeks with a window of
±7 days) until study treatment discontinuation; at this point, a final follow-up set of imaging is 
required. PET/CT may be used according to RECIST guidelines. Cycle timing will not be delayed 
for treatment interruptions, and tumor assessment should occur according to this schedule 
regardless of whether study treatment is interrupted. If a patient discontinues treatment for clinical 
progression and does not meet the criteria specified in the protocol, scans and CA-125 testing 
should continue at the specified intervals in the protocol until progression is confirmed or until the 
start of subsequent anticancer treatment. 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.
Revised Text
(o) RECIST tumor assessment via CT or MRI scan of abdomen/pelvis and clinically indicated 
areas required at baseline, then after every 2 cycles (ie, 8 weeks with a window of ±7 days from 
date of visit) through Cycle 14 (56 weeks) (ie, Day 1 of Cycle 3, Cycle 5, Cycle 7, Cycle 9, 
Cycle 11, Cycle 13, and Cycle 15), then after every 3 cycles (12 weeks with a window of ±7 days) 
until Cycle 38 (ie, Day 1 of Cycle 18, Cycle 21, Cycle 24, …, and Cycle 39), and after every 6 
cycles (24 weeks with a window of ±7 days) until progression (ie, Day 1 of Cycle 45, Cycle 51,
… ); at this point (ie, progression), a final follow-up set of imaging is required. PET/CT may be 
used according to RECIST guidelines. Cycle timing will not be delayed for treatment 
interruptions, and tumor assessment should occur according to this schedule regardless of whether 
study treatment is interrupted. If a patient discontinues treatment for clinical progression and does 
not meet the criteria specified in the protocol, scans and CA-125 testing should continue at the 
specified intervals in the protocol until progression is confirmed or until the start of subsequent 
anticancer treatment. 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.
Rationale for Amendment
Changed a frequency of imaging for tumor assessment due to consideration for effect of long-term 
radiation on subject.
Clarified the process for imaging.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


Document History 
 
Version 
Date 
Comments 
original version 
2018/10/05 
New document 
2nd version 
2018/11/14 
The primary purpose of this amendment is to revise the starting 
dose of niraparib in each subject, based on the tolerability results 
of niraparib in the local phase 1 study (Niraparib-1001 study). 
3rd version 
2019/01/18 
The primary purpose of this amendment is to correct 
typographical errors in the Sample Size Justification, and thereby 
demonstrate the appropriateness of the sample size. 
4th version 
2021/11/09 
The primary purpose of this amendment is to change a frequency 
of imaging for tumor assessment due to consideration for effect 
of long-term radiation on subject. 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

SAP_001.pdf: 
 
 
Title: A Phase 2, Multicenter, Open-label, Single-arm Study to Evaluate the Safety of 
Niraparib in Japanese Patients With Platinum-sensitive, Relapsed Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer Who Achieved CR or PR in the Last Chemotherapy 
Containing Platinum-based Anticancer Agents 
 
NCT Number: NCT03759587 
Statistical analysis plan Approve Date: 03-JUN-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). 
 


1.0 
TITLE PAGE 
 
STATISTICAL ANALYSIS PLAN 
STUDY NUMBER: Niraparib-2001 
A Phase 2, Multicenter, Open-label, Single-arm Study to Evaluate the Safety of Niraparib 
in Japanese Patients With Platinum-sensitive, Relapsed Ovarian, Fallopian Tube, or 
Primary Peritoneal Cancer Who Achieved CR or PR in the Last Chemotherapy 
Containing Platinum-based Anticancer Agents 
PHASE 2 
Version: 2nd 
Date: 03 June 2019 
 
 
 
Prepared by:  
 
 
 
 
 
Based on: 
Protocol Version: Amendment 2 
Protocol Date: 18 January 2019 
 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda. 
PPD
PPD


Niraparib-2001 
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03 June 2019
 
CONFIDENTIAL 
1.1 
Approval Signatures 
Electronic signatures can be found on the last page of this document. 


Niraparib-2001 
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CONFIDENTIAL 
2.0 
TABLE OF CONTENTS 
1.0 
TITLE PAGE .................................................................................................................. 1 
1.1 
Approval Signatures .................................................................................................. 2 
2.0 
TABLE OF CONTENTS ................................................................................................ 3 
List of In-Text Tables ........................................................................................................... 5 
3.0 
LIST OF ABBREVIATIONS .......................................................................................... 6 
4.0 
OBJECTIVES ................................................................................................................. 7 
4.1 
Primary Objectives .................................................................................................... 7 
4.2 
Secondary Objectives ................................................................................................ 7 
4.3 
Additional Objectives ................................................................................................ 7 
4.4 
Study Design ............................................................................................................. 7 
5.0 
ANALYSIS ENDPOINTS .............................................................................................. 9 
5.1.1 Primary Endpoint................................................................................................. 9 
5.1.2 Secondary Endpoints ........................................................................................... 9 
5.1.3 Safety Endpoints .................................................................................................. 9 
5.1.4 Additional Endpoints ........................................................................................... 9 
6.0 
DETERMINATION OF SAMPLE SIZE ....................................................................... 10 
7.0 
METHODS OF ANALYSIS AND PRESENTATION .................................................. 11 
7.1 
General Principles ................................................................................................... 11 
7.1.1 Study Definitions ............................................................................................... 11 
7.1.2 Definition of Study Days ................................................................................... 12 
7.1.3 Definition of Study Visit Windows .................................................................... 12 
7.1.4 Significance Level and Confidence Coefficient .................................................. 14 
7.1.5 Conventions for Missing Adverse Event Dates .................................................. 14 
7.1.6 Conventions for Missing Concomitant Medication Dates ................................... 14 
7.2 
Analysis Sets ........................................................................................................... 14 
7.3 
Disposition of Subjects ............................................................................................ 14 
7.3.1 Study Information .............................................................................................. 14 
7.3.2 Screen Failures .................................................................................................. 15 
7.3.3 Subject Eligibility .............................................................................................. 15 
7.3.4 Number of Subjects Who Were Enrolled by Site................................................ 15 
7.3.5 Disposition of Subjects ...................................................................................... 15 
7.3.6 Protocol Deviations and Analysis Sets ............................................................... 16 
7.3.6.1 Protocol Deviations ...................................................................................... 16 
7.3.6.2 Analysis Sets ............................................................................................... 16 


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CONFIDENTIAL 
7.4 
Demographic and Other Baseline Characteristics ..................................................... 17 
7.5 
Medical History and Concurrent Medical Conditions............................................... 19 
7.6 
Medication History and Concomitant Medications .................................................. 19 
7.7 
Study Drug Exposure and Compliance .................................................................... 20 
7.8 
Study Drug Modification ......................................................................................... 20 
7.9 
Efficacy Analysis .................................................................................................... 21 
7.9.1 Primary Efficacy Endpoint(s)............................................................................. 21 
7.9.2 Secondary Efficacy Endpoint(s) ......................................................................... 21 
7.9.2.1 Progression Free Survival ............................................................................ 21 
7.9.2.2 Overall Survival ........................................................................................... 21 
7.9.2.3 Overall Response Rate ................................................................................. 22 
7.9.3 Additional Efficacy Endpoint(s) ........................................................................ 22 
7.9.3.1 Time to First Subsequent Therapy ................................................................ 22 
7.9.4 Statistical/Analytical Issues ............................................................................... 22 
7.9.4.1 Adjustments for Covariates .......................................................................... 22 
7.9.4.2 Handling of Dropouts or Missing Data ......................................................... 22 
7.9.4.3 Multicenter Studies ...................................................................................... 23 
7.9.4.4 Multiple Comparison/Multiplicity ................................................................ 23 
7.9.4.5 Use of an “Efficacy Subset” of Subjects ....................................................... 23 
7.9.4.6 Active-Control Studies Intended to Show Equivalence or Non-Inferiority .... 23 
7.9.4.7 Examination of Subgroups ........................................................................... 23 
7.10 
Pharmacokinetic/Pharmacodynamic Analysis .......................................................... 23 
7.10.1 Pharmacokinetic Analysis .................................................................................. 23 
7.10.2 Pharmacodynamic Analysis ............................................................................... 23 
7.11 
Other Outcomes ...................................................................................................... 23 
7.12 
Safety Analysis........................................................................................................ 23 
7.12.1 Adverse Events .................................................................................................. 23 
7.12.1.1 
The Subject Incidence of Grade 3 or 4 Thrombocytopenia Occurring 
within 30 Days after Initial Administration of Niraparib............................... 23 
7.12.1.2 
The Subject Incidence of Toxicity Grade of Thrombocytopenia 
Occurring within 30 Days after Initial Administration of Niraparib. ............. 24 
7.12.1.3 
Overview of Treatment-Emergent Adverse Events ................................. 24 
7.12.1.4 
Displays of Treatment-Emergent Adverse events ................................... 26 
7.12.1.5 
Displays of Pretreatment Events ............................................................. 27 
7.12.2 Clinical Laboratory Evaluations ......................................................................... 28 
7.12.2.1 
Hematology and Serum Chemistry ......................................................... 28 


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CONFIDENTIAL 
7.12.2.2 
Urinalysis ............................................................................................... 29 
7.12.3 Vital Signs and Weight ...................................................................................... 29 
7.12.4 12-Lead ECGs ................................................................................................... 30 
7.12.5 Other Observations Related to Safety................................................................. 30 
7.12.5.1 
ECOG Performance Status ..................................................................... 30 
7.13 
Interim Analysis ...................................................................................................... 30 
7.14 
Changes in the Statistical Analysis Plan................................................................... 30 
8.0 
REFERENCES ............................................................................................................. 33 
9.0 
APPENDIX................................................................................................................... 34 
 
LIST OF IN-TEXT TABLES 
Table 7.a 
Visit Window of Hematology ............................................................................ 13 
Table 7.b 
Visit Window of Serum Chemistry, Coagulation ............................................... 13 
Table 7.c 
Visit Window of Serum CA-125 and ECOG Performance Status ....................... 13 
Table 7.d 
Visit Window of Vital Signs and Weight ........................................................... 14 
 


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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BRCA 
breast cancer (gene) 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
ECGs 
electrocardiograms 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
full analysis set 
FUACT 
follow-up anti-cancer treatment 
GGT 
γ-glutamyl transferase 
INR 
international normalized ratio 
LDH 
lactate dehydrogenase 
MCV 
mean cell volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPV 
mean platelet volume 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NE 
inevaluable 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease (disease progression) 
PFS 
progression-free survival 
PR 
partial response 
PT 
preferred term 
PTE 
pretremtent event 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TFST 
time to first subsequent therapy 
WHO Drug 
World Health Organization Drug Dictionary 
 


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4.0 
OBJECTIVES 
4.1 
Primary Objectives 
To evaluate the safety of niraparib in Japanese patients with platinum-sensitive, relapsed ovarian 
cancer, fallopian tube cancer, or primary peritoneal cancer, who achieved CR or PR in the last 
chemotherapy containing platinum-based anticancer agents. 
4.2 
Secondary Objectives 
To evaluate the efficacy of niraparib in Japanese patients with platinum-sensitive, relapsed 
ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, who achieved CR or PR in 
the last chemotherapy containing platinum- based anticancer agents. 
4.3 
Additional Objectives 
To evaluate the pharmacokinetics of niraparib in Japanese patients with platinum-sensitive, 
relapsed ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, who achieved CR or 
PR in the last chemotherapy containing platinum-based anticancer agents. 
4.4 
Study Design 
The study is a phase 2, multicenter, open-label, single-arm study to evaluate the safety of 
niraparib in Japanese patients with platinum-sensitive, relapsed ovarian cancer, fallopian tube 
cancer, or primary peritoneal cancer, who achieved CR or PR in the last chemotherapy 
containing platinum-based anticancer agents. 
The eligible patients must have received at least 2 platinum-based regimens with the last regimen 
prior to study enrollment; had a response assessed by a physician of CR or PR to their last 
regimen; must not have any measurable lesion >2 cm, and must have normal cancer antigen 
(CA)-125 equal to or less than the upper limit of the normal range, or >90% decrease following 
their last treatment and which was stable for at least 7 days. The study will evaluate the safety of 
niraparib as a maintenance therapy based on a primary endpoint of the incidence of Grade 3 or 4 
thrombocytopenia occurring within 30 days after initial administration of niraparib in this 
population. 
Eligible subjects will receive 300 mg/day of the study drug orally QD continuously (in 28-day 
cycles), and the treatment will continue until the patient meet a discontinuation criteria specified 
in the study protocol. 
Dose interruption (no longer than 28 days) and dose reductions (maximum reduction to 
100 mg/day) will be allowed. Dose interruption and/or reduction may be implemented at any 
time for any grade toxicity considered intolerable by the patient. The timing of efficacy or safety 
evaluations should not be affected by dose interruptions or reductions. 
Clinic visits will be weekly during Cycle 1 and then every 4 weeks (±3 days) for subsequent 
cycles. 


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All AEs will be collected and recorded for each patient from the day of signing the informed 
consent form (ICF) until 30 days after last dose of study treatment administration, or beginning 
of subsequent anticancer therapy, whichever comes first. All AEs and SAEs experienced by a 
patient, irrespective of the suspected causality, will be monitored until the AE or SAE has 
resolved, any abnormal laboratory values have returned to baseline or normalized, until there is a 
satisfactory explanation for the changes observed, until the patient is lost to follow-up, or until 
the patient has died. The Adverse Events of Special Interest (AESIs) for this study are MDS, 
AML, secondary cancers (new primary malignancies other than MDS/AML), pneumonitis, and 
embryo-fetal toxicity. AESIs must be reported to the Sponsor as soon as the investigator 
becomes aware of them. 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 will be used for tumor 
assessment via a computed tomography (CT) or magnetic resonance imaging (MRI) scan of 
abdomen/pelvis and clinically indicated areas, which is required at the end of every 2 cycles 
(8 weeks with a window of ±7 days from date of visit) through Cycle 14, then at the end of every 
3 cycles (12 weeks with a window of ±7 days) until progression. Cycle timing will not be 
delayed for treatment interruptions, and tumor assessment should occur according to this 
schedule regardless of whether study treatment is interrupted. If a patient discontinues treatment 
for clinical progression and does not meet the criteria specified in the protocol, scans and CA-
125 testing should continue at the specified intervals in the protocol until progression is 
confirmed or until the start of subsequent anticancer treatment. 
Blood samples for measurements of plasma levels of niraparib will be obtained on Cycle 1 Day 1 
predose and 2 hours postdose, Cycle 2 Day 1 predose and 2 hours postdose, and Cycle 4 Day 1 
predose. 


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5.0 
ANALYSIS ENDPOINTS 
5.1.1 Primary Endpoint 
• The subject incidence of Grade 3 or 4 thrombocytopenia occurring within 30 days after initial 
administration of niraparib. 
5.1.2 Secondary Endpoints 
• The safety of niraparib, including 
– The subject incidence of TEAEs. 
– The subject incidence of Grade 3 or higher TEAEs. 
– The subject incidence of serious TEAEs 
– The subject incidence of TEAEs leading to drug discontinuation. 
– The subject incidence of TEAEs leading to dose interruption because of TEAEs. 
– The subject incidence of TEAEs leading to dose reduction because of TEAEs. 
• Progression free survival (PFS). 
• Overall survival. 
• Overall response rate. 
5.1.3 Safety Endpoints 
• Laboratory values. 
• Vital signs. 
• ECOG performance status. 
• Electrocardiograms (ECGs). 
5.1.4 Additional Endpoints 
• Plasma concentrations of niraparib for population pharmacokinetics. 


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6.0 
DETERMINATION OF SAMPLE SIZE 
The incidence of thrombocytopenia in non-Japanese patients was estimated to be 35% based on 
an overseas clinical study, and the incidence of thrombocytopenia in subject population in this 
study was estimated to be 46% (the rationale for each incidence is shown below). The sample 
size in this study is set to be 15, because the probability that the point estimate of the incidence 
of thrombocytopenia will be ≥35% is 76%, with which a certain level of evaluation is expected 
to be achievable. 
Rationale for Threshold of 35% for the Incidence of Thrombocytopenia 
In the analysis of clinical data versus baseline body weight and platelet count in the NOVA 
study, the incidence of Grade 3 or 4 thrombocytopenia during the first 30 days after the initial 
dose of niraparib was higher in patients with baseline body weight of <77 kg or baseline platelet 
count of <150,000/μL (34.6%, 97/280 subjects) than in those with body weight of ≥77 kg and 
platelet count of ≥150,000/μL (11.8%, 10/85 subjects). Therefore, the threshold for the incidence 
of thrombocytopenia is considered as 35%. 
Rationale for Threshold of 46% for the Expected Incidence of Thrombocytopenia 
According to the results of minimum platelet count by baseline body weight during the first 30 
days after the initial dose of niraparib in the NOVA study, the incidence of platelet count 
decreased to 50,000/μL, which is almost equal to or more than Grade 3 thrombocytopenia, was 
46% in patients with baseline body weight of <58 kg. 
According to the body weight distribution in ovarian cancer patients in Japan, based on the 
research by Ipsos Healthcare using prescription information as data source, ≥77% patients had 
body weight of ≤59 kg. Therefore, the expectation of the incidence of thrombocytopenia in 
subject population in this study was considered as 46%. 


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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): An adverse event whose date of onset occurs on 
or after the start of study drug and within 30 days after the date of last dose. 
• Pretreatment event (PTE): Any untoward medical occurrence in a clinical investigation 
subject who were enrolled in a study but prior to administration of study drug. 
• Descriptive statistics: Number of subjects, mean, standard deviation, maximum, minimum, 
and quartiles. 
• Dose Level: 300 mg, 200 mg, 100 mg. 
• Total Study Duration (days): Last visit date or date of death - Enrollment date + 1. 
• Overall Treatment Exposure (days): Date of last dose - date of first dose + 1. 
• Duration of exposure to study drug (days): Date of last dose - date of first dose minus any 
skipped or interrupted + 1. 
• Dose intensity (mg/day): Sum of the total daily doses ingested divided by Overall treatment 
exposure. 
• Relative Dose Intensity (%): Dose intensity (mg/day) divided by intended dose intensity 
(mg/day) multiplied by 100, where intended dose intensity is 300 (mg/day). 
• Dose reduction regardless of causality: Dose consumed is less than prescribed for any reason. 
• Dose reduction due to AE: Dose consumed is less than prescribed due to AE. 
• Dose interruptions regardless of causality: Dose consumed is 0 mg for any reason (includes 
missed doses). 
• Dose interruptions due to AE: Dose consumed is 0 mg due to AE. 
• Initial dose level for each cycle: Dose level on the first date when dose is not 0 mg for each 
cycle.  
• PFS: The time from the date of enrollment to the earlier date of progression assessed by the 
Investigator per RECIST (v.1.1) or clinical criteria, or death by any cause. Progression-free 
survival (months) will be calculated as: (PD/Death date - enrollment date + 1) / 30.4375 
General censoring rules for the analysis of PFS will be as follows: 
– No adequate post-baseline radiological assessments; therefore PFS is censored at the date 
of enrollment unless death occurred within 17 weeks of enrollment (in which case the 
death is an event) or clinical PD is determined. 


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– Patients known to be alive and known not to have started new (non-protocol) anti-cancer 
treatment, who are progression-free, and who have a baseline and at least 1 post-dosing 
radiological assessment, are censored at the date of the last radiological assessment that 
verified lack of PD. 
– Patients starting new anti-cancer treatment prior to progression or death are censored at 
the date of last radiological assessment documenting no progression prior to the new 
treatment. 
– Documentation of progression or death after an unacceptably long interval (>17 weeks, 
ie, 2 consecutive missed or indeterminate overall response assessments) since the last 
radiological assessment will be censored at the date of last radiological assessment 
documenting no progression. 
• OS: The time from the date of enrollment to the date of death by any cause. Patients known 
to be alive will be censored at the last known survival follow-up date. The OS (months) will 
be calculated as: (Death date - enrollment date + 1) / 30.4375. 
• TFST: The date of enrollment to the earlier of the start date of first follow-up anti-cancer 
treatment (FUACT) or death. Patients alive and not starting a first FUACT will be censored 
at the date last known to be alive. TFST (months) will be calculated as: (Start date of first 
FUACT – enrollment date + 1) / 30.4375. 
• TEAE leading to study drug modification: Any TEAE leading to dose reduction, dose 
interruption or dose discontinuation. 
7.1.2 Definition of Study Days 
The following definitions and calculation formulas will be used. 
• Study Day: The day before the first dose of the study drug will be defined as Study Day -1 
and the day of the first dose will be defined as Study Day 1. If the date of the observation is 
on the same date or after the day of the first dose, Study Day will be calculated relative to 
Study Day 1. Otherwise, Study Day will be calculated relative to Study Day -1. 
• Follow-up Day: The day after the last dose of the study drug will be defined as Follow-up 
Day 1. Follow-up Day will be calculated relative to Day 1. 
7.1.3 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.  
When calculating Follow-up Day relative to a reference date (ie, date of last dose [Follow-up 
Day 0]), it will be calculated as: date of observation - reference date. Hence, reference day is 
always Follow-up Day 0. 


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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 earlier observation will be used. 
Table 7.a 
Visit Window of Hematology 
Visit 
Scheduled Study Day 
(days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Baseline 
Study Day: 
1 
-28 - 1 
 
Cycle 1, Day 8 
Study Day: 
8 
5 - 11 
 
Cycle 1, Day 15 
Study Day: 
15 
12 - 18 
 
Cycle 1, Day 22 
Study Day: 
22 
19 - 25 
 
Cycle (n) (Cycle 2 and 
thereafter), Day 1 
Study Day: 
28(n - 1) + 1 
28(n - 1) - 2 to 28 
(n - 1) + 4 
<38 
 
Table 7.b 
Visit Window of Serum Chemistry, Coagulation  
Visit 
Scheduled Study Day 
(days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Baseline 
Study Day: 
1 
-28 - 1 
 
Cycle 1, Day 15 
Study Day: 
15 
12 - 18 
 
Cycle (n) (Cycle 2 and 
thereafter), Day 1 
Study Day: 
28(n - 1) + 1 
28(n - 1) - 2 to 28 
(n - 1) + 4 
<38 
 
Table 7.c 
Visit Window of Serum CA-125 and ECOG Performance Status 
Visit 
Scheduled Study Day 
(days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Baseline 
Study Day: 
1 
-28 - 1 
 
Cycle (n) (Cycle 2 and 
thereafter), Day 1 
Study Day: 
28(n - 1) + 1 
28(n - 1) - 2 to 28 
(n - 1) + 4 
<38 
 


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Table 7.d 
Visit Window of Vital Signs and Weight 
Visit 
Scheduled Study Day 
(days) 
Time Interval (days) 
Study Day 
Follow-up Day 
Baseline 
Study Day: 
1 
-28 - 1 
 
Cycle 1, Day 15 
Study Day: 
15 
12 - 18 
 
Cycle (n) (Cycle 2 and 
thereafter), Day 1 
Study Day: 
28(n - 1) + 1 
28(n - 1) - 2 to 28 
(n - 1) + 4 
<38 
 
7.1.4 Significance Level and Confidence Coefficient 
• Confidence coefficient: 95% (two-sided). 
7.1.5 Conventions for Missing Adverse Event Dates 
Not applicable. 
7.1.6 Conventions for Missing Concomitant Medication Dates 
Not applicable. 
7.2 
Analysis Sets 
• Safety Analysis Set: 
All subjects who received at least one dose of study drug. 
• Full Analysis Set: 
All subjects who received at least one dose of study drug. 
• Response-evaluable Analysis Set: 
Response-evaluable analysis set is defined as patients who receive at least 1 dose of study 
drug and have at least one measurable disease at baseline. 
7.3 
Disposition of Subjects 
7.3.1 Study Information 
Analysis Set: 
All Subjects Who Were Enrolled 
Analysis Variables: 
Date First Subject Signed Informed Consent Form 
Date of Data Cutoff 
MedDRA Version 
WHO Drug Version 


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SAS Version Used for Creating the Datasets 
Analytical Methods: 
(1) Study Information 
Study information shown in the analysis variables section will be provided. 
7.3.2 Screen Failures 
Not applicable. 
7.3.3 Subject Eligibility 
Not applicable. 
7.3.4 Number of Subjects Who Were Enrolled by Site 
Analysis Set: 
All Subjects Who Were Enrolled 
Analysis Variables: 
Status of Enrollment [Enrolled] 
Stratum: 
Site 
[Site numbers will be used as categories] 
Analytical Methods: 
(1) Number of Subjects Who Were Enrolled by Site 
Frequency distribution will be provided for each stratum. 
7.3.5 Disposition of Subjects 
Analysis Set: 
All Subjects Who Were Enrolled 
Analysis Variables: 
Study Drug Administration Status 
[Enrolled but Not Treated] 
Reason for Not Being Treated 
[Death, Adverse Event, Protocol Deviation, Study Terminated by Sponsor, 
Withdrawal by Subject, Lost to Follow-up, Screen Failure, Other] 
Study Drug Completion Status 
[Ongoing, Discontinued Study Drug] 


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Reason for Discontinuation of Study Drug 
[Death, Adverse Event, Protocol Deviation, Progressive Disease, Pregnancy, 
Study Terminated by Sponsor, Withdrawal by Subject, Lost to Follow-up, Other] 
Analytical Methods: 
(1) Disposition of Subjects. 
Frequency distributions will be provided. When calculating percentages for the 
reasons for not being treated, the total number of subjects not treated by the study 
drug will be used as the denominator. When calculating percentages for the reasons 
for discontinuation, the total number of subjects who discontinued the study drug 
will be used as the denominator. 
7.3.6 Protocol Deviations and Analysis Sets 
7.3.6.1 Protocol Deviations 
Analysis Set: 
All Subjects Who Were Enrolled 
Analysis Variables: 
Significant Protocol Deviation 
[Entry Criteria, Concomitant Medication, Procedure Not Performed Per Protocol, 
Study Medication, Withdrawal Criteria, Major GCP Violations] 
Analytical Methods: 
(1) Protocol Deviations. 
Frequency distribution will be provided 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. 
7.3.6.2 Analysis Sets 
Analysis Set: 
All Subjects Who Were Enrolled 
Analysis Variables: 
Handling of Subjects 
[Categories are based on the specifications in Subject Evaluability List] 
Analysis Sets 
Full Analysis Set 
[Included] 


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Safety Analysis Set 
[Included] 
Response-evaluable Set 
[Included] 
Analytical Methods: 
(1) Subjects Excluded from Analysis Sets. 
(2) Analysis Sets. 
Frequency distributions will be provided. 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 Variables: 
Age (years) 
[18<= - <=64, 65<= - <=74, 75<= - <=Max] 
Gender 
[Male, Female] 
Height (cm)  
Weight (kg) 
[Min<= - <58, 58<= - <77, 77<= - <=Max] 
BMI (kg/m2) 
Race [American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White] 
BRCA1 Mutant 
[Yes, No, Unknown] 
BRCA2 Mutant 
[Yes, No, Unknown] 
Time to Progression after the Penultimate (Next to Last) Platinum Therapy 
[6-12 Month, More Than 12 Month, Other, Unknown] 
Best Response during the Last Platinum Regimen  [CR, PR] 
Time from Last Platinum Therapy to Start of Study Drug (days) 
ECOG Performance Status 
[0, 1, 2, 3, 4] 
Primary Tumor Site  
[Ovarian, Primary Peritoneal, Fallopian Tube] 
Duration since Initial Diagnosis of Primary Cancer (years) 
Cancer Stage at time of Initial Diagnosis 
[I, IA, IB, IC, II, IIA, IIB, IIC, III, IIIA, IIIB, IIIC, IV, Unknown, Other] 


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Sites of Metastatic Disease   
[Ascites or pleural effusion, CNS, Liver, Lung, Gastrointestinal, Genitourinary, 
Peritoneum, Lymph nodes, Bone or muscle, Other] 
Number of Metastatic Sites [Min<= - <3, 3<= - <=Max] 
Prior Radiation Therapy 
[Yes, No] 
Prior Surgery/Procedure 
[Yes, No] 
Prior Chemotherapy  
[Yes, No] 
Number of Prior Surgery/Procedure for Study Indication 
[Missing, 1, 2, 3<= - <=Max] 
Prior History of Myelosuppression 
[Yes, No, Unknown] 
Any Prior Myelosuppression 
Prior Thrombocytopenia 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5, Unknown]  
Prior Leukopenia 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5, Unknown]  
Prior Anemia 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5, Unknown]  
Prior Neutropenia 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5, Unknown]  
Baseline Platelet Count (10^9/L) 
Ovarian Cancer Pathology 
Histological 
Histologic Subtype  
[Serous, Endometrioid, Mucinous, Other] 
Tumor Grade  
[Low Grade, Grade 1, Grade 2, Grade 3, High Grade, Not Assessable]  
Analytical Methods: 
(1) Summary of Demographics and Baseline Characteristics. 
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided. 


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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. 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. 
7.6 
Medication History and Concomitant Medications 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Medication History (not Included Ovarian Cancer Treatment) 
Prior Ovarian Cancer Treatment 
Concomitant Medications 
Analytical Methods: 
(1) Medication History (not Included Ovarian Cancer Treatment) by Preferred 
Medication Name. 
(2) Prior Ovarian Cancer Treatment 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. 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 


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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: 
Safety Analysis Set 
Analysis Variables: 
Number of Cycles Started 
[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 <= - <= Max] 
Total Study Duration (days) 
Overall Treatment Exposure (days)  
Duration of Exposure to Study Drug (days) 
Dose Intensity (mg/days) 
Relative Dose Intensity (%) 
Initial Dose Level for Each Cycle 
Analytical Methods: 
(1) Study Drug Exposure and Compliance. 
For initial dose level for each cycle, frequency distributions will be provided by dose 
level and overall by visit for each cycle. Composite bar chart will be plotted by visit 
for each cycle. 
For other than initial dose level for each cycle, frequency distributions for categorical 
variables and descriptive statistics for continuous variables will be provided. 
7.8 
Study Drug Modification 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Dose Reductions 
Dose Reduction for Any Reason 
Dose Reduction due to AE 
Dose Interruptions 
Dose Interruption for Any Reason 
Dose Interruption Due to AE 


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Analytical Methods: 
(1) Study Drug Modification. 
Frequency distributions will be provided by 4 weeks for the first 48 weeks, and by 24 
weeks thereafter. 
7.9 
Efficacy Analysis 
7.9.1 Primary Efficacy Endpoint(s) 
Not applicable. In this study, safety will be evaluated as the primary endpoint. 
7.9.2 Secondary Efficacy Endpoint(s) 
7.9.2.1 Progression Free Survival 
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
PFS 
Analytical Methods: 
(1) PFS.  
For PFS, breakdown of the number of subjects who were censored and who 
experienced an event will be summarized. Quartiles of PFS and the two-sided 95% 
confidence intervals will be estimated using the Kaplan-Meier method. 
Kaplan-Meier estimate of PFS proportion at specified points will also be provided. 
The Kaplan-Meier plot of PFS will be presented. The definition of PFS refers to 
section 7.1.1. 
7.9.2.2 Overall Survival 
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
OS 
Analytical Methods: 
(1) OS. 
For OS, the same analyses as those for PFS in the section 7.9.2.1 will be conducted 
using the FAS. The definition of OS refer to section 7.1.1. 


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7.9.2.3 Overall Response Rate 
Analysis Set: 
Response-Evaluable Analysis Set 
Analysis Variables: 
ORR  
Overall Response  
[CR, PR, SD, PD, NE] 
Analytical Methods: 
(1) ORR. 
For ORR, point estimate and the 2-sided 95% exact CI will be provided. 
(2) Summary of Overall Response. 
For overall response, frequency distributions will be provided. 
7.9.3 Additional Efficacy Endpoint(s) 
7.9.3.1 Time to First Subsequent Therapy  
Analysis Set: 
Full Analysis Set 
Analysis Variables: 
TFST 
Analytical Methods: 
(1) TFST. 
For TFST, the same analyses as those for PFS will be conducted using the FAS. The 
definition of TFST refers to section 7.1.1. 
7.9.4 Statistical/Analytical Issues 
7.9.4.1 Adjustments for Covariates 
Not applicable. 
7.9.4.2 Handling of Dropouts or Missing Data 
Missing test results will not be used for hypothesis testing and estimations.  
Values less than or equal to the lower limit of quantification will be treated as zero when 
calculating the descriptive statistics. Values greater than or equal to the upper limit of 
quantification will be treated as the upper limit value when calculating the descriptive statistics. 


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7.9.4.3 Multicenter Studies 
Not applicable. 
7.9.4.4 Multiple Comparison/Multiplicity 
Not applicable. 
7.9.4.5 Use of an “Efficacy Subset” of Subjects 
Not applicable. 
7.9.4.6 Active-Control Studies Intended to Show Equivalence or Non-Inferiority 
Not applicable. 
7.9.4.7 Examination of Subgroups 
Not applicable. 
7.10 
Pharmacokinetic/Pharmacodynamic Analysis 
7.10.1 Pharmacokinetic Analysis 
Not applicable. 
7.10.2 Pharmacodynamic Analysis 
Not applicable. 
7.11 
Other Outcomes 
Not applicable. 
7.12 
Safety Analysis 
7.12.1 Adverse Events 
7.12.1.1 The Subject Incidence of Grade 3 or 4 Thrombocytopenia Occurring within 30 Days 
after Initial Administration of Niraparib. 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Grade 3 or 4 Thrombocytopenia Occurring within 30 days after Initial Administration of 
Niraparib 


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Analytical Methods: 
The number and percentage of Subjects with Thrombocytopenia will be provided using 
frequency distribution. 
7.12.1.2 The Subject Incidence of Toxicity Grade of Thrombocytopenia Occurring within 
30 Days after Initial Administration of Niraparib. 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Thrombocytopenia Occurring within 30 days after Initial Administration of Niraparib 
Categories: 
Toxicity Grade 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5] 
Analytical Methods: 
The number and percentage of Subjects with Thrombocytopenia will be provided using 
frequency distribution. A subject with multiple occurrences of Thrombocytopenia will be 
counted once for the Thrombocytopenia with the maximum toxicity grade. 
7.12.1.3 Overview of Treatment-Emergent Adverse Events 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
TEAE 
Categories: 
Relationship to Study Drug 
[Related, Not Related] 
Toxicity Grade 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5] 
Analytical Methods: 
The following summaries will be provided. 
(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). 


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4) Grade 3 or higher Drug-Related Treatment-Emergent Adverse Events (number of 
events, number and percentage of subjects). 
5) Toxicity Grade of Treatment-Emergent Adverse Events (number of events, 
number and percentage of subjects). 
6) Treatment-Emergent Adverse Events leading to study drug discontinuation 
(number of events, number and percentage of subjects). 
7) Treatment-Emergent Adverse Events leading to study drug reduction (number of 
events, number and percentage of subjects). 
8) Treatment-Emergent Adverse Events leading to study drug interruption (number 
of events, number and percentage of subjects). 
9) Treatment-Emergent Adverse Events leading to study drug modification (number 
of events, number and percentage of subjects). 
10) Serious Treatment-Emergent Adverse Events (number of events, number and 
percentage of subjects). 
11) Relationship of serious Treatment-Emergent Adverse Events to study drug 
(number of events, number and percentage of subjects). 
12) Serious Treatment-Emergent Adverse Events leading to study drug 
discontinuation (number of events, number and percentage of subjects). 
13) Treatment-Emergent Adverse Events resulting in death (number of events, 
number and percentage of subjects). 
TEAEs will be counted according to the rules below. 
Number of subjects 
• Summaries for 2) and 11).  
A subject with occurrences of TEAE in both categories (ie, Related and Not Related) 
will be counted once in the Related category. 
• Summary for 5). 
A subject with multiple occurrences of TEAE will be counted once for the TEAE with 
the maximum toxicity grade. 
• Summaries other than 2), 5) and 11).  
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. 


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7.12.1.4 Displays of Treatment-Emergent Adverse events 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
TEAE 
Categories: 
Toxicity Grade 
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5] 
Analytical Methods: 
The following summaries will be provided using frequency distribution. 
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. 
(3) Treatment-Emergent Adverse Events by Preferred Term. 
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term. 
(5) Grade 3 or higher Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term. 
(6) Grade 3 or higher Drug-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term. 
(7) Toxicity Grade of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term. 
(8) Toxicity Grade of Drug-Related Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term. 
(9) Treatment-Emergent Adverse Events Leading to Study Drug Dose Reduction by 
System Organ Class and Preferred Term. 
(10) Treatment-Emergent Adverse Events Leading to Study Drug Interruption by System 
Organ Class and Preferred Term. 
(11) Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term. 


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(12) Treatment-Emergent Adverse Events Leading to Death by System Organ Class and 
Preferred Term. 
(13) Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred 
Term. 
(14) Treatment-Emergent Adverse Events of Special Interest by System Organ Class and 
Preferred Term. 
(15) Grade 3 or higher Treatment-Emergent Adverse Events of Special Interest by System 
Organ Class and Preferred Term. 
(16) Serious Treatment-Emergent Adverse Events of Special Interest by System Organ 
Class and Preferred Term. 
(17) Drug-Related Treatment-Emergent Adverse Events of Special Interest by System 
Organ Class and Preferred Term. 
The frequency distribution will be provided according to the rules below. 
Number of subjects 
• Summary tables other than (7) and (8). 
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. Percentages will be based on the number of subjects in 
the safety analysis set. 
• Summary tables for (7) and (8).  
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. Percentages will be based 
on the number of subjects in the safety analysis set. 
7.12.1.5 Displays of Pretreatment Events 
Analysis Set: 
All Subjects Who Were Enrolled 
Analysis Variables: 
PTE 
Analytical Methods: 
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. 


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(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. 
7.12.2 Clinical Laboratory Evaluations 
7.12.2.1 Hematology and Serum Chemistry 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Hematology 
Erythrocytes, Hematocrit, Hemoglobin, Leukocytes, ANC, Basophils, 
Eosinophils, Lymphocytes/Leukocytes, Monocytes/Leukocytes, Platelets count, 
MCV, MPV  
Serum Chemistry 
Albumin, ALP, ALT, Amylase, AST, Total bilirubin, Direct bilirubin, Blood Urea 
Nitrogen, Calcium, Creatinine, Chloride, Gamma Glutamyl Transferase (GGT), 
Glucose, LDH, Magnesium, Phosphorus, Potassium, Sodium, Protein 
Coagulation 
INR, aPTT 
Serum CA-125 
Serum CA-125 
Visit: 
Hematology 
Cycle 1: Baseline, Day 8, Day 15, Day 22 
Cycle 2 and Thereafter: Day 1 
Serum Chemistry, Coagulation 
Cycle 1: Baseline, Day 15 
Cycle 2 and Thereafter: Day 1 


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Serum CA-125 
Cycle 1: Baseline 
Cycle 2 and Thereafter: Day 1 
Analytical Methods: 
For each variable, summaries (1) to (3) will be provided. 
(1) Summary of Laboratory Test Results and Change from Baseline by Visit. 
Descriptive statistics for observed values and changes from baseline (each postdose 
visit - Baseline) will be provided for each visit. 
(2) Case Plots. 
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 at baseline and each 
post-baseline visit will be provided. 
Shift tables showing the number of subjects in each category of baseline grade and 
post-baseline maximum grade for laboratory abnormalities will be provided. 
7.12.2.2 Urinalysis 
Not applicable. 
7.12.3 Vital Signs and Weight 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
Systolic Blood Pressure 
Diastolic Blood Pressure 
Pulse Rate 
Weight 
Temperature 
Visit: 
Cycle 1: Baseline, Day 15 
Cycle 2 and Thereafter: Day 1 


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Analytical Methods: 
For each variable, summaries (1) and (2) will be provided. 
(1) Summary of Vital Signs Parameters and Change from Baseline by Visit. 
Descriptive statistics for observed values and changes from baseline (each postdose 
visit - Baseline) will be provided for each visit. 
(2) Case Plots. 
Plots over time for each subject will be presented. 
7.12.4 12-Lead ECGs 
Not applicable. 
7.12.5 Other Observations Related to Safety 
7.12.5.1 ECOG Performance Status 
Analysis Set: 
Safety Analysis Set 
Analysis Variables: 
ECOG Performance Status 
Analytical Methods: 
(1) Summary of Shift of ECOG Performance Status. 
Shift table showing the number of subjects in each category at baseline and the worst 
post-baseline result will be provided. 
7.13 
Interim Analysis 
Not applicable. 
7.14 
Changes in the Statistical Analysis Plan  
From the SAP version 1.0, the following parts were updated. In section 7.1.1, the definition of 
the dose intensity was modified and units for some analysis variables were added for clarity as 
below. 
Before the change 
Section 7.1.1 Study Definitions 
Total Study Duration: Last visit date or date of death - Enrollment date + 1. 
Duration of exposure to study drug: Date of last dose - date of first dose minus any skipped or 
interrupted + 1. 


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Dose intensity (mg/day): Sum of the total daily doses ingested divided by Duration of exposure 
to study drug. 
 
After the change 
Section 7.1.1 Study Definitions 
Total Study Duration (days): Last visit date or date of death - Enrollment date + 1. 
Duration of exposure to study drug (days): Date of last dose - date of first dose minus any 
skipped or interrupted + 1. 
Dose intensity (mg/day): Sum of the total daily doses ingested divided by Overall treatment 
exposure. 
 
Reason for the change 
The definition of the dose intensity was modified to be consistent with that of NOVA study. 
 
Before the change 
Section 7.4 Demographic and Other Baseline Characteristics 
Analysis Variables: 
Time from Last Platinum Therapy to Start of Study Drug 
 
After the change 
Section 7.4 Demographic and Other Baseline Characteristics 
Analysis Variables: 
Time from Last Platinum Therapy to Start of Study Drug (days) 
 
Reason for the change 
Text was added for clarity 
 
Before the change 
Section 7.7 Study Drug Exposure and Compliance 
Analysis Variables: 
Total Study Duration 


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Relative Dose Intensity 
 
After the change 
Section 7.7 Study Drug Exposure and Compliance 
Analysis Variables: 
Total Study Duration (days) 
Relative Dose Intensity (%) 
 
Reason for the change 
Text was added for clarity. 


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8.0 
REFERENCES 
Not applicable. 


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9.0 
APPENDIX 
Not applicable.