Clinical trial NCT02657889
Conditions: Neoplasms Triple Negative Breast Cancer Ovarian Cancer Breast Cancer Metastatic Breast Cancer Advanced Breast Cancer Stage IV Breast Cancer Fallopian Tube Cancer Peritoneal Cancer
Keywords: PARP inhibitor PD-1 Niraparib Pembrolizumab Keynote TOPACIO
Sponsor: Tesaro, Inc.
Start date: 2016-04-15; Completion date: 2021-09-17
Enrollment: 122 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This Phase 1/2 study will evaluate the safety and efficacy of combination treatment with niraparib and pembrolizumab (MK-3475) in patients with advanced or metastatic triple-negative breast cancer or recurrent ovarian cancer. (KEYNOTE-162)

Detailed description:

Arms: arm 1: Phase 1: Dose-escalation: ascending doses of niraparib up to 300mg/day orally (PO) on Days 1-21 and pembrolizumab 200mg intravenously (IV) on Day 1 of each 21-day cycle

Phase 2: niraparib (recommended Phase 2 dose) in combination with pembrolizumab 200mg IV on Day 1 of each 21-day cycle
Interventions: intervention 1: niraparib intervention 2: pembrolizumab
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE 
 
Phase 1/2 Clinical Study of Niraparib in Combination with Pembrolizumab in Patients 
with Advanced or Metastatic Triple-Negative Breast Cancer and  
in Patients with Recurrent Ovarian Cancer 
Sponsor: 
TESARO, Inc. 
1000 Winter Street 
Suite 3300 
Waltham, MA 02451 
+1 339 970 0900 
TESARO UK, Limited 
55 Baker Street. 
London W1U7EU,  
United Kingdom 
+44 1753 910398 
Medical Monitor: 
 
Senior Medical Director 
 
Clinical Research Organization: 
Pharmaceutical Research Associates, Inc. 
 
 
Sponsor Protocol No.: 
3000-PN162-01-001 
IND No(s).: 
100,996 and 117,580 
EudraCT No.: 
2015-003398-14 
Study Drug Names: 
Niraparib capsules/pembrolizumab for injection 
Development Phase: 
1/2 
Date of Original Protocol: 
Date of Protocol Amendment 1: 
Date of Protocol Amendment 2: 
19 October 2015 
28 July 2016 
01 March 2017 
Version of Protocol: 
3.0 
 
The study will be conducted according to the protocol and in compliance with Good Clinical Practice 
(GCP), with the Declaration of Helsinki, and with other applicable regulatory requirements. 
 
Confidentiality Statement 
All information contained in this document is privileged and confidential to TESARO. Any 
distribution, copying, or disclosure is strictly prohibited without prior written approval by 
TESARO. 


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SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
 
Title: Phase 1/2 Clinical Study of Niraparib in Combination with Pembrolizumab in 
Patients with Advanced or Metastatic Triple-Negative Breast Cancer and in Patients with 
Recurrent Ovarian Cancer 
 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
products as well as with the moral, ethical, and scientific principles governing clinical research 
as set out in the Declaration of Helsinki and the guidelines on Good Clinical Practice. 
 
 
_____________________________________ 
_____________________ 
 
Date 
Senior Medical Director 
TESARO, Inc. 


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INVESTIGATOR SIGNATURE PAGE 
 
Declaration of the Principal Investigator 
 
Title: Phase 1/2 Clinical Study of Niraparib in Combination with Pembrolizumab in 
Patients with Advanced or Metastatic Triple-Negative Breast Cancer and in Patients with 
Recurrent Ovarian Cancer 
 
I have read this study protocol, including all appendices. By signing this protocol, I agree to 
conduct the clinical study, following approval by an Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB), in accordance with the study protocol, the current 
International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), 
and applicable regulatory requirements. I will ensure that all personnel involved in the study 
under my direction will be informed about the contents of this study protocol and will receive all 
necessary instructions for performing the study according to the study protocol. 
 
Principal Investigator 
 
 
_____________________________________ 
_____________________ 
Name:  
Date 
Title:  
Institution:  


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SYNOPSIS 
Name of Sponsor/Company: TESARO, Inc. 
Name of Investigational Product: niraparib and pembrolizumab 
Name of Active Ingredient: niraparib and pembrolizumab 
Title of Study: Phase 1/2 Clinical Study of Niraparib in Combination with Pembrolizumab in 
Patients with Advanced or Metastatic Triple-Negative Breast Cancer and in Patients with 
Recurrent Ovarian Cancer 
Study Center(s): Phase 1: approximately 6 centers in the United States; Phase 2: 
approximately 40 centers in the United States 
Study Period (years):  
Estimated date first patient enrolled: April 2016 
Estimated date last patient completed: November 
2019 
Phase of Development: 1/2 
Objectives: 
Primary objectives: 
 Phase 1: To evaluate dose-limiting toxicities (DLTs) of combination treatment with 
niraparib and pembrolizumab during the first cycle of treatment, and to establish a 
recommended Phase 2 dose (RP2D) and schedule  
 Phase 2: To estimate the clinical activity of combination treatment with niraparib 
and pembrolizumab in terms of objective response rate (ORR) as assessed by the 
Investigators using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
separately for the triple-negative breast cancer (TNBC) and ovarian cancer (OC) 
cohorts.  
Secondary objectives: 
 Phase 1 and Phase 2: To evaluate the safety and tolerability of combination 
treatment with niraparib and pembrolizumab using Common Terminology Criteria 
for Adverse Events (CTCAE, v.4.03)  
 Phase 2: To evaluate additional measures of clinical benefit as assessed by the 
Investigators, including: 
 ORR by immune-related RECIST (irRECIST) 
 Duration of response (DOR) by RECIST v1.1 and irRECIST; 
 Disease control rate (DCR) by RECIST v1.1 and irRECIST; 


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 Progression-free survival (PFS) by RECIST v1.1 and by irRECIST; 
 Overall survival (OS). 
 Phase 1 and 2: To evaluate the pharmacokinetics (PK) of niraparib and associated 
major metabolite M1 during combination treatment. 
Exploratory objectives (both phases): 
 To identify the biomarker-based patient population that would derive benefit from 
the combination treatment based on the tumor tissue molecular profile, molecular 
profile of tumor-infiltrating lymphocytes (TILs), and circulating biomarkers. 
 To correlate homologous recombination deficiency (HRD) status with other 
immune-related biomarkers and with efficacy outcomes. 
Methodology: 
Overall 
This is a multicenter, open-label, single-arm Phase 1/2 study evaluating the safety and efficacy 
of combination treatment with niraparib and pembrolizumab in patients with previously treated 
TNBC or OC. Specifically, patients eligible for this study are those with: 
 Advanced or metastatic TNBC (in Phase 1 patients may have received up to 4 lines 
of cytotoxic therapy for advanced/metastatic disease or in Phase 2, up to 2 lines of 
cytotoxic therapy for advanced/metastatic disease); or 
 Advanced, recurrent epithelial (for Phase 1: any serous, endometroid, mucinous, 
clear cell; for Phase 2: high-grade serous or endometroid) ovarian, fallopian tube, or 
primary peritoneal cancer who are currently platinum-resistant but previously 
experienced a response lasting for at least 6 months to first-line platinum-based 
therapy (in Phase 1 patients may have received up to 5 lines of cytotoxic therapy or 
in Phase 2, up to 4 lines of cytotoxic therapy). Study treatment should be considered 
an appropriate option by the Investigator.  
The study will be conducted in 2 parts. The Phase 1 portion of the study will be a dose-
escalation evaluation to determine the RP2D and schedule of niraparib to be administered in 
combination with the recommended dose of pembrolizumab, and the Phase 2 portion will 
further evaluate the RP2D and schedule in 2 cohorts of approximately 48 patients each with 
TNBC or OC as described above. 
The study will be conducted in conformance with Good Clinical Practice (GCP). The study 
schema is provided below.  


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Abbreviations: AE = adverse event; d = day(s); DL = dose level; DLT = dose-limiting toxicity; OC = ovarian cancer; PK = 
pharmacokinetics; N = niraparib; P = pembrolizumab; RP2D = recommended Phase 2 dose; q21d = every 21 days; TNBC = 
triple-negative breast cancer. 
Phase 1 Dose Escalation 
At Dose Level 1, a cohort of 6 patients with either TNBC or OC will be enrolled. After all 
patients in Dose Level 1 who are evaluable for safety have completed Cycle 1 of combination 
treatment, the next higher dose level (Dose Level 2) will be open for enrollment if less than 
one-third of patients (ie, < 2 of 6 patients or < 4 of 12 patients) in Dose Level 1 experience a 
DLT during Cycle 1 (see DLT definition below).  
Based on current single-agent niraparib experience (see niraparib Investigator’s Brochure), 
hematological laboratory abnormalities are expected in a significant proportion of patients. If 2 
of 6 initially enrolled patients in a cohort experience hematologic DLTs, a lower dose level will 
be evaluated. If, however, the 2 observed DLTs include 1 hematologic DLT and 1 non-
hematologic DLT or 2 non-hematologic DLTs, a cohort may be expanded up to approximately 
12 patients to better characterize the safety of the combination treatment. 
Once Dose Level 1 is determined to be safe, a cohort of 6 patients with either TNBC or OC will 
be enrolled in Dose Level 2. No further dose escalation will be considered if Dose Level 2 is 
reached. 
The maximum tolerated dose (MTD) will be defined as the highest dose with DLTs observed in 
less than one-third of patients (ie, < 2 of 6 patients or < 4 of 12 patients) during Cycle 1 of 
combination treatment. If one-third or more of the evaluable patients experiences a DLT, then 
this dose will be considered to exceed the MTD and a lower dose level may be opened for 
enrollment if not yet evaluated. Alternative dosing schedules may be explored. 
Additional cohorts of 6 patients may be opened to evaluate Dose Level (-1) or Dose Level (-2), 
which will explore lower niraparib dose intensity, for example, by introducing an alternative 
dosing schedule following agreement by the Investigators and Sponsor.  
The RP2D will be determined following discussion and agreement between Investigators and 
the Sponsor (see Section 9.12) based on an evaluation of multiple endpoints, which may include 
the DLT rate in first and subsequent cycles of combination treatment, the rate of dose 
modifications for non-DLT adverse events (AEs), the ability to manage toxicities, PK, niraparib 
N: 200mg d1-21; q21d
P: 200mg d1; q21d
N: 300mg d1-21; q21d
P: 200mg d1; q21d
<1/3 DLT
N: 200mg or 300mg; d1-14; q21d
P: 200mg d1; q21d
≥1/3 DLT
DL2: 6 patients 
DL1: 6 patients 
DL(-1): 6 patients
RP2D
Consider:
DLT rate,
dose 
modifications,
dose intensity,
PK, AE rate
Phase 2 
OC: n=48
TNBC: n=48
Phase 1 
OC and TNBC: up to 36 patients
DL(-2): 6 patients
N: 200mg or 300mg; d1-7; q21d
P: 200mg d1; q21d
Starting
≥1/3 DLT


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dose intensity, and signs of clinical efficacy. The goal will be to identify the dose/regimen of 
niraparib with the greatest dose intensity that can be safely combined with the recommended 
dose/regimen of pembrolizumab. 
In the Phase 1 portion of this study, 14 patients with advanced TNBC or OC were enrolled in 
Dose Level 1 or Dose Level 2. Twelve patients were eligible for DLT evaluation. In Dose Level 
1, 1 of 6 DLT-eligible patients experienced multiple DLTs including Grade 3 anemia, Grade 4 
neutropenia, and Grade 4 thrombocytopenia. In Dose Level 2, 1 of 6 DLT-eligible patients 
experienced 1 DLT, Grade 4 thrombocytopenia; an additional patient experienced an adverse 
event that was deemed to be a DLT-equivalent; the patient had epistaxis on C1D17 and Grade 4 
thrombocytopenia on C2D1.   
DLT criteria (as assessed during Cycle 1, ie, during the first 21 days of treatment - Day 1 
through Day 21): 
 Any treatment-related Grade ≥ 3 non-hematologic clinical (non-laboratory) AE 
 Any treatment-related Grade 3 or Grade 4 non-hematologic laboratory abnormality 
if: 
 Medical intervention is required to treat the patient, or 
 The abnormality leads to hospitalization, or 
 The abnormality persists for ≥ 7 days. 
 Any treatment-related hematologic toxicity specifically defined as:  
 Thrombocytopenia Grade 4 for ≥ 7 days, or Grade 3 or 4 associated with 
bleeding or requiring platelet transfusion;  
 Neutropenia Grade 4 for ≥ 7 days, or Grade 3 or 4 associated with infection or 
febrile neutropenia;  
 Anemia Grade 4, or Grade 3 or 4 requiring blood transfusion 
 Any treatment-related AE leading to niraparib dose interruption per the following 
criteria:  
 A dose interruption per dose modification rules (see Section 5.4.1, Table 3) for a 
non-DLT laboratory abnormality (eg, for Grade 2 or 3 thrombocytopenia or for 
Grade 3 anemia or neutropenia) lasting ≥ 14 days  
 A dose interruption per dose modification rules (see Section 5.4.1, Table 2 ) for 
non-hematologic AE leading to < 80% of an intended dose being administered 
(eg, niraparib dose interruption for > 4 days within Cycle 1). 
Note that niraparib dosing has been safely managed with dose interruptions and/or adjustments 
for AEs, including laboratory abnormalities, while maintaining activity in the single-agent 
setting (see Section 5.4.1, Table 3 and niraparib Investigator’s Brochure). Therefore, niraparib 
dose interruption and/or reduction for an AE that does not meet a DLT definition as described 
above will be considered a non-DLT modification. The non-DLT dose modifications will not be 
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intensity and RP2D. 
Phase 2: Efficacy Phase 
The Phase 2 portion of the study will commence after the RP2D is determined during the 
Phase 1 portion. Two cohorts of approximately 48 patients each with advanced or metastatic 
TNBC or recurrent OC as outlined above will be enrolled.  
Patients in this phase of the study will receive the RP2D dose: niraparib 200 mg/day PO on 
days 1-21 and pembrolizumab 200 mg IV on day 1 of each 21-day cycle; niraparib dose may be 
escalated on or after C3D1 from 200 mg daily to 300 mg daily if hemoglobin ≥ 9 g/dL, platelets 
≥ 100,000/µL and neutrophils ≥ 1500/µL for all labs performed during the first two cycles after 
discussion with Medical Monitor or Designee. 
Pembrolizumab/niraparib combination treatment may continue for up to 2 years or until disease 
progression, unacceptable toxicity, patient withdrawal, Investigator’s decision, or death. 
Continued treatment with niraparib beyond 2 years may be considered following discussion 
between the Sponsor and Investigator. 
General Study Conduct: Phase 1 and 2 
All patients will begin treatment with niraparib and pembrolizumab on Cycle 1/Day 1; 
additional on-treatment assessments will be conducted on Days 8 and 15 of Cycle 1 and on Day 
1 of all subsequent cycles. Safety assessments conducted throughout the treatment period 
include symptom-directed physical examination, vital signs, ECGs, ECOG performance status, 
and clinical laboratory assessments (complete blood count [CBC], coagulation [Phase 1 only], 
chemistry, thyroid stimulating hormone [TSH], triiodothyronine [T3] or free T3 [FT3], free 
thyroxine [FT4], urinalysis, cancer antigen-125 [CA-125] [OC patients only], and pregnancy 
testing). Radiographic evaluations (computed tomography/magnetic resonance imaging 
[CT/MRI] of chest [all TNBC patients and OC patients with abnormal screening scan or with 
clinical indication], abdomen, and pelvis) to assess extent of disease will be conducted every 9 
weeks (63 days ±7 days) while on study treatment independent of cycle delays and/or dose 
interruptions, and/or at any time when progression of disease is suspected. Brain scan will be 
conducted if clinically indicated; bone scans will be conducted per standard of care. After 1 
year of radiographic assessments, patients will have imaging performed every 12 weeks (84 ±7 
days). If a patient discontinues treatment for a reason other than progression or death, 
withdrawal of consent, or loss to follow-up, scans and CA-125 testing (OC patients only) 
should continue at the specified intervals (ie, every 9 weeks for the first year and every 12 
weeks thereafter). All radiographic images/scans will be sent to a central imaging vendor upon 
acquisition and archived for potential future evaluation. Per RECIST v1.1, complete response 
(CR) or partial response (PR) should be confirmed; tumor imaging for confirmation of response 
may be performed at the earliest 4 weeks after the first indication of response, or at the next 
scheduled scan (ie, 9 weeks later), whichever is clinically indicated. Blood sampling for PK and 
biomarker evaluations will be conducted for patients in both Phase 1 and Phase 2. 
In patients who consent to fresh biopsies, serial fresh biopsies will be obtained for exploratory 
biomarker analysis at 3 time points: during the screening period, 1 to 3 days before or on C3D1 
prior to pembrolizumab infusion and, whenever possible, at the time of disease progression 
(note: although the biopsy is voluntary, it is highly encouraged). The serial biopsies at different 


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time points should preferably be on the same lesion. A core biopsy is recommended (details are 
provided in the Study Manual); if an excisional or incisional biopsy is to be performed, it must 
be conducted on a non-target lesion. If a patient has had a biopsy within 12 weeks prior to 
entering screening, that biopsy may be accepted in lieu of the screening biopsy. Blood samples 
will also be obtained for biomarker analysis predose on Day 1 of Cycle 1 and Cycle 2, as well 
as at the end of treatment (EOT). 
All patients will undergo an EOT visit within 7 days of the last dose of study treatment and a 
safety follow-up visit conducted 30 days (+7 days) post-treatment. Thereafter, all patients will 
enter the post-treatment period for telephone assessment of survival status and the occurrence of 
any new malignancies every 90 days (±14 days). 
All AEs will be collected and recorded for each patient from the day of signing the informed 
consent form until 30 days after last study drug administration; serious adverse events (SAEs) 
and Events of Clinical Interest (ECI) (see Section 6.1.6) are required to be captured through 
90 days after cessation of study treatment (or to a minimum of 30 days post treatment if the 
patient starts alternate anticancer therapy), and any pregnancies that occur within 120 days post-
treatment are to be captured. All AEs and SAEs experienced by a patient, irrespective of the 
suspected causality, will be monitored until the AE or SAE has resolved, until 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.  
Number of Patients (Planned):  
Phase 1: A total of approximately 18 patients (up to 36 patients may be included) 
Phase 2: A total of approximately 96 patients (ie, approximately 48 patients enrolled into each 
cohort of TNBC and OC patients) 
Criteria for Inclusion: 
To be considered eligible to participate in this study, all of the following requirements must be 
met: 
1. Patient is male or female, at least 18 years of age. Male patients are only for TNBC and 
not OC. 
2. Patient has histologically proven advanced (unresectable) or metastatic cancer as 
outlined below according to study phase and disease type: 
a. Phase 1 patients (breast or ovarian cancer) 
 Patients with advanced or metastatic breast cancer must have disease that is 
HER2-negative, estrogen receptor-negative, and progesterone receptor-negative 
(ie, TNBC). Patients with disease recurrence or progression following 
neoadjuvant or adjuvant therapy are eligible. Patients with advanced or 
metastatic disease may have up to 4 lines of cytotoxic therapy. Neoadjuvant and 
adjuvant therapies are not counted towards lines of therapy. Targeted small 
molecules (eg, tyrosine kinase inhibitors), hormonal agents and monoclonal 


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antibodies that inhibit angiogenesis (eg, bevacizumab, afilbercept) are not 
counted in the number of lines of therapy. 
 Patients must have any epithelial (ie, serous, endometroid, mucinous, clear cell) 
ovarian, fallopian tube, or primary peritoneal cancer. Patients must have 
experienced a response lasting at least 6 months to first-line platinum-based 
therapy but currently considered to have platinum-resistant disease per 
investigator’s assessment (e.g, patient is not eligible for further platinum 
containing treatment). Patients may have received up to 5 lines of cytotoxic 
therapy for advanced or metastatic cancer. Neoadjuvant and adjuvant therapies 
are not counted towards lines of therapy. Treatment with small molecules (eg, 
tyrosine kinase inhibitors), hormonal agents and monoclonal antibodies that 
inhibit angiogenesis (eg, bevacizumab, aflibercept) are not counted in the 
number of lines of therapy.  
b. Phase 2 patients (breast or ovarian cancer) 
 Patients with advanced or metastatic breast cancer must have TNBC. Patients 
with disease recurrence or progression following neoadjuvant or adjuvant 
therapy are eligible. Patients with advanced or metastatic disease may have 
received up to 2 lines of cytotoxic therapy. Adjuvant and/or neoadjuvant 
therapies are not counted in the number of lines of therapy. Targeted small 
molecules (eg, tyrosine kinase inhibitors), hormonal agents and monoclonal 
antibodies that inhibit angiogenesis (eg, bevacizumab, afilbercept) are not 
counted. TNBC patients who have previously received platinum chemotherapy 
in the metastatic setting are allowed to enroll in the study as long as they did not 
progress while on or within 8 weeks from the day of the last platinum 
administration. 
 Patients must have with high-grade serous or endometroid ovarian, fallopian 
tube, or primary peritoneal cancer. Patients must have experienced a response 
lasting at least 6 months to first-line platinum-based therapy but currently 
considered to have platinum-resistant disease per investigator’s assessment (e.g, 
patient is not eligible for further platinum containing treatment).  Patients may 
have had up to 4 lines of cytotoxic therapy for advanced or metastatic cancer. 
Neoadjuvant, adjuvant, and the combination of both will be considered as one 
line of therapy. Treatment with small molecules (eg, tyrosine kinase inhibitors), 
hormonal agents and monoclonal antibodies that inhibit angiogenesis (eg, 
bevacizumab, aflibercept) are not counted in the number of lines of therapy.  
3. Patient has archival tumor tissue available that is formalin-fixed and paraffin-embedded.  
a. For patients who do not have archival tissue, tissue from a fresh biopsy must be 
obtained prior to study treatment initiation.  
b. Serial fresh tumor tissue samples will be collected in patients with lesions amenable 
for a biopsy who consent to such a procedure. 
4. Patient has measurable lesions by RECIST v1.1. 


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5. Patient has an ECOG performance status of 0 to 1. 
6. Patient has adequate organ function, defined as (Note: complete blood count [CBC] test 
should be obtained without transfusion or receipt of colony stimulating factors before 2 
weeks of obtaining sample): 
a. Absolute neutrophil count (ANC) ≥ 1500/µL 
b. Platelets ≥ 100,000/µL 
c. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 
d. Serum creatinine ≤ 1.5× upper limit of normal (ULN) or calculated creatinine 
clearance ≥ 60 mL/min using Cockcroft-Gault equation for patients with creatinine 
levels > 1.5× institutional ULN 
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 are present, in which case they must be ≤ 5× ULN 
g. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5× ULN unless 
patient is receiving anticoagulant therapy as long as PT or partial thromboplastin 
time (PTT) is within therapeutic range of intended use of anticoagulants 
h. Activated partial thromboplastin time (aPTT) ≤ 1.5× ULN unless patient is receiving 
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
7. Patient is able to take oral medications. 
8. Female patient has a negative serum pregnancy test within 72 hours prior to taking study 
medication if of childbearing potential, or agrees to abstain from activities that could 
result in pregnancy from enrollment through 120 days after the last dose of study 
treatment, or be of non-childbearing potential. Non-childbearing potential is defined as 
(by other than medical reasons): 
a. ≥ 45 years of age and has not had menses for >1 year 
b. Amenorrheic for < 2 years without a hysterectomy and oophorectomy and a follicle-
stimulating hormone (FSH) value in the postmenopausal range upon pre-study 
(screening) evaluation 
c. Post hysterectomy, bilateral oophorectomy or tubal ligation. Documented 
hysterectomy or oophorectomy must be confirmed with medical records of the 
actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed 
with medical records of the actual procedure, otherwise the patient must be willing 
to use 2 adequate barrier methods throughout the study, starting with the screening 
visit through 120 days after the last dose of study therapy. See Section 5.7.2 for a list 
of acceptable birth control methods. Information must be captured appropriately 
within the site's source documents. 
Note: Abstinence is acceptable if this is the established and preferred contraception 
for the patient. 
9. Male patient agrees to use an adequate method of contraception (please see 
Section 5.7.2 for a list of acceptable birth control methods) starting with the first dose of 
study therapy through 120 days after the last dose of study therapy. 


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Note: Abstinence is acceptable if this is the established and preferred contraception for 
the patient.   
10. Patient agrees to blood samples during screening and at the end of treatment for 
cytogenetic analysis. 
Criteria for Exclusion: 
Patients will not be eligible for study entry if any of the following criteria are met: 
1. Patients with primary platinum refractory ovarian cancer (ie, progressive disease on or 
within 6 months of first-line platinum therapy) are not eligible in Phase 1 or Phase 2 of 
this study.  
2. Patient has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  
Note: Patients with previously treated brain metastases may participate provided they 
are stable (without evidence of progression by imaging [using the identical imaging 
modality for each assessment, either MRI or CT scan] for at least 4 weeks prior to the 
first dose of study treatment and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases, and have not been using steroids 
for at least 7 days prior to study treatment. Carcinomatous meningitis precludes a patient 
from study participation regardless of clinical stability. 
3. Patient has a known additional malignancy that progressed or required active treatment 
within the last 2 years. Exceptions include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin that has undergone potentially curative therapy, or in situ 
cervical cancer. 
4. Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, 
nonmalignant systemic disease or active infection that requires systemic therapy. 
Specific examples include, but are not limited to, history of (non-infectious) 
pneumonitis that required steroids or current pneumonitis; uncontrolled ventricular 
arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure 
disorder; unstable spinal cord compression; superior vena cava syndrome; or any 
psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the study (including obtaining informed consent).  
5. Patient has a condition (such as transfusion dependent anemia or thrombocytopenia), 
therapy, or laboratory abnormality that might confound the study results, or interfere 
with the patient’s participation for the full duration of the study treatment. Patients who 
received colony-stimulating factors (eg, granulocyte colony stimulating factor [G-CSF], 
granulocyte macrophage colony-stimulating factor [GM-CSF] or recombinant 
erythropoietin) within 2 weeks prior to the first dose of study treatment are not eligible. 
6. Patient is pregnant or breastfeeding, or expecting to conceive children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of study treatment. 
7. Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or 


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any other form of immunosuppressive therapy within 7 days prior to the first dose of 
study treatment.  
8. Patient has a known history of human immunodeficiency virus (HIV) (HIV 1/2 
antibodies). 
9. Patient has known active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) 
or hepatitis C (eg, hepatitis C virus ribonucleic acid [HCV RNA] [qualitative] is 
detected). 
10. Patient has an active autoimmune disease that has required systemic treatment in the 
past 2 years (ie, with use of disease-modifying agents, corticosteroids, or 
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. 
11. Patient has not recovered (ie, to ≤Grade 1 or to baseline) from cytotoxic therapy-induced 
AEs. Note: Patient with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia is an exception to 
this criterion and may qualify for the study. 
12. Patient is currently participating and receiving study therapy or has participated in a 
study of an investigational agent and received study therapy or used an investigational 
device within 4 weeks of the first dose of treatment.  
13. Patient has had a prior cytotoxic therapy, anticancer targeted small molecules (eg, 
tyrosine kinase inhibitors), hormonal agents within 5 half-lives, or monoclonal 
antibodies (mAb) within 5 half-lives or 4 weeks (whichever is shorter) of that treatment 
prior to study Day 1 or radiation therapy encompassing > 20% of the bone marrow 
within 2 weeks or any radiation therapy within 1 week prior to study Day 1. 
14. Patient has not recovered adequately from AEs and/or complications from any major 
surgery prior to starting therapy. 
15. Patient has received prior therapy with an anti-programmed death-1 (anti-PD-1), anti-
PD-1-ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD-L2) agent or the patient has 
previously participated in Merck MK-3475 (pembrolizumab) clinical studies. 
16. Patient has received a live vaccine within 30 days of planned start of study therapy. 
17. Patient has undergone prior treatment with a known poly(ADP-ribose) polymerase 
(PARP) inhibitor. 
18. Patient has a heart-rate corrected QT interval (QTc) prolongation > 470 msec at 
screening. 
Note: If a patient has a prolonged QT interval and the prolongation is deemed to be due 
to a pacemaker upon Investigator evaluation (ie, the patient otherwise has no cardiac 
abnormalities), the patient may be eligible to participate in the study following 
discussion with the Medical Monitor. 
19. Patient has a known hypersensitivity to niraparib or pembrolizumab components or 
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20. Known history or current diagnosis of myelodysplastic syndrome (MDS) or acute 
myeloid leukemia (AML). 
Investigational Product, Dosage, and Mode of Administration: 
Niraparib 
Niraparib will be administered orally (PO) throughout the 21-day cycle at the assigned dose and 
schedule. On Day 1 of each cycle, a niraparib dose will be administered upon completion of 
pembrolizumab infusion. Depending on dose schedule, 1, 2, or 3 capsules of 100 mg strength 
niraparib will be taken at each dose administration (total dose 100 mg, 200 mg, or 300 mg per 
dose schedule, respectively). Patients will be instructed to take their niraparib dose at the same 
time each day, preferably in the morning. Patients must swallow and not chew all capsules. The 
consumption of water and food is permissible.  
Niraparib will be dispensed to patients on Day 1 of every cycle (every 21 days) thereafter until 
the patient discontinues study treatment. The Pharmacy Manual contains descriptions of the 
packaging of niraparib and instructions for the preparation and administration of niraparib.  
Pembrolizumab 
Pembrolizumab will be administered at a dose of 200 mg intravenously (IV) using a 30-minute 
IV infusion on Day 1 of each 21-day treatment cycle after all procedures and assessments have 
been completed as detailed in Table 6. Sites should make every effort to target infusion timing 
to be as close to 30 minutes as possible. Given the variability of infusion pumps from site to 
site, however, a window between -5 minutes and +10 minutes is permitted. 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of the infusion solution. 
Duration of Treatment and Study Conduct: 
Treatment duration for individual patient: Patients may continue the pembrolizumab/niraparib 
combination treatment for up to 2 years or until disease progression, unacceptable toxicity, 
patient withdrawal, Investigator’s decision, or death. Continued treatment with niraparib 
beyond 2 years may be considered following discussion between the Sponsor and Investigator. 
Long-term follow-up: Every 3 months (90 days), via telephone. 
Planned study conduct duration: the first data cutoff will occur at approximately 18 months (ie, 
time from first patient enrolled/when responder or discontinuation status for all patients is 
known/approximately 6 months after last patient is enrolled). The final analysis of primary and 
secondary endpoints will be conducted at approximately 12 months after the last patient is 
enrolled). 
Criteria for Evaluation: 
Safety 
 Dose-limiting toxicities during the first cycle (ie, during the first 21 days of 
treatment/ Cycle 1/Day 1 through Cycle 1/Day 21) (Phase 1 only) 


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 Incidence of treatment-emergent AEs (TEAEs) during the first cycle compared to 
the second and subsequent cycles  
 Incidence of TEAEs occurring while patients are on treatment or up to 30 days after 
the last dose of study drug 
 Incidence of serious adverse events (SAEs) and events of clinical interest (ECI) 
occurring while patients are on treatment or up to 90 days after the last dose of study 
drug 
 Changes in clinical laboratory parameters (hematology, chemistry, coagulation, 
thyroid function, urinalysis), vital signs, ECOG performance status, ECG 
parameters, physical examinations, and usage of concomitant medications 
 Whole blood samples will be collected prior to the start of the study drug and at 
treatment discontinuation for cytogenetic analysis 
Efficacy 
 Primary endpoint: ORR, defined as the proportion of patients who have achieved CR 
or PR, evaluated using RECIST v1.1 based on Investigator assessment 
 The following secondary endpoints will also be evaluated based on Investigator 
assessment: 
 ORR by irRECIST 
 Duration of response, defined as the time from first documentation of response 
(CR or PR) until the time of first documentation of disease progression by 
RECIST v1.1 and by irRECIST 
 Disease control rate defined as the percentage of patients who have achieved CR, 
PR, or stable disease (SD) per RECIST v1.1 and irRECIST 
 Progression-free survival, defined as the time from first dose to the earlier date 
of assessment of progression, or death by any cause in the absence of 
progression, by RECIST v1.1 and by irRECIST 
 Overall survival as measured from the date of first dose to the date of death by 
any cause 
Pharmacokinetics 
Samples for PK determination will be collected from patients in both Phase 1 (plasma and 
serum) and Phase 2 (plasma only) and the plasma will be analyzed using liquid chromatography 
with mass spectroscopic detection (LC-MS-MS) for niraparib and major metabolite M1. The 
serum may be analyzed for pembrolizumab using enzyme-linked immunosorbent assay 
(ELISA). Model predicted area under the concentration × time curves (AUCs) will be derived. 
Parameters of interest are AUC, minimum concentration (Cmin), maximum concentration (Cmax), 
clearance after oral administration (CL/F) and volume of distribution after oral administration 
(Vz/F), AUC at steady state (AUCss), Cmin at steady state (Cmin,ss), Cmax at steady state (Cmax,ss). 
Biomarkers 


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Biomarker classifiers will be evaluated in archival and fresh tumor samples obtained during 
screening; in addition, in the subset of patients who undergo serial biopsies, biomarkers will be 
evaluated in fresh tumor samples obtained 1 to 3 days before or on C3D1 prior to 
pembrolizumab infusion and, whenever possible, at the time of disease progression. Blood 
samples for biomarker analysis will be obtained predose on Day 1 of Cycle 1 and Cycle 2, as 
well as at the EOT visit. Tumor and blood markers, including mutations in homologous 
recombination genes, such as breast cancer gene 1 and 2 (BRCA1 and 2) mutations, may be 
explored. The magnitude of homologous recombination deficiency (HRD) positivity and tumor 
immune microenvironment may be evaluated. Programmed death ligand-1 (PD-L1) expression 
and other related markers in tumor and tumor-infiltrating immune cells may be explored. 
HRD status and other biomarkers may be correlated with efficacy outcomes. 
Statistical Methods: 
Sample Size Considerations 
Phase 1: A total sample size of approximately 18 patients is estimated for the Phase 1 portion of 
the study to provide initial comparison of incidence of DLTs and safety profiles of the 
combination treatment between dose schedules in each patient population. More patients could 
be enrolled (eg, if the Dose Level -2 is explored or if expansion at any dose level is required to 
better understand safety and tolerability); up to a total of 36 patients may be enrolled. 
Phase 2: A total of approximately 96 evaluable patients (approximately 48 patients in each 
tumor type) will be enrolled to ensure understanding of the activity of the combination 
treatment and to obtain adequate representation of different molecular cancer subtypes and 
biomarkers. 
Analysis Populations 
Three analysis populations will be defined as follows: 
 Safety Population: All patients who receive any amount of study drug. The 
assessment of DLTs in Phase 1 will include only those patients completing the first 
cycle of therapy, unless the patient discontinued study drug due to a DLT. 
 Full Analysis Set (FAS): All patients who receive any amount of study drug. The 
primary analysis of efficacy endpoints will be performed on the FAS population. 
 Per-Protocol Population: All patients who receive at least two cycles of study drug 
andhave at least one protocol-required post-baseline disease assessments and have 
no major protocol violations that would impact efficacy evaluations. Supportive 
analyses of efficacy endpoints will be performed on the per-protocol population. 
General Methods 
All analyses will include summary statistics, including number and percentage for categorical 
variables and number of patients, mean, standard deviation, median, minimum, and maximum 
for continuous variables. Time-to-event analyses will be performed using Kaplan-Meier 
methods. As the Phase 2 portion of the study is single-arm, any statistical analysis to be 
performed among subgroups is for descriptive and future study purposes. Further detail will be 


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provided in the study statistical analysis plan. 
Safety 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) for purposes of summarization. All AEs occurring during the study will be included 
in by-patient data listings and tabulated by MedDRA system organ class and preferred term. 
Safety endpoints for AEs include the following: incidence of DLTs, TEAEs, ECI, TEAEs 
leading to death, SAEs and AEs leading to discontinuation; tabulations will be produced by 
MedDRA system organ class and preferred term. Tabulations of TEAEs will also be produced 
by severity and by relationship to study drug.  
Additional safety summaries will be provided for clinical laboratory tests, vital signs, ECOG 
performance status, and ECGs. 
Results of cytogenetic analysis, including incidence of cytogenetic abnormalities at end of study 
treatment, will be summarized. 
Efficacy 
ORR and DCR will be summarized using descriptive statistics including number, percentage 
and 1-sided 90% CI. 
Duration of response, PFS, and OS will be summarized using Kaplan-Meier analysis, including 
number and percentage of events, number and percentage of censored patients, and 25th, 50th, 
and 75th percentiles of times to event with 95% CIs. 
Pharmacokinetics 
Pharmacokinetic parameters will be summarized by study phase and dose schedule using 
descriptive statistics.  
Biomarkers 
The incidence of biomarkers will be summarized using descriptive statistics. Comparisons of 
efficacy endpoints between biomarker subpopulations may be performed.  
Interim Analysis 
To minimize the risk of exposing patients to an ineffective treatment, a series of response 
assessments will be performed when 6, 12, and 18 of 48 Phase 2 patients from each cancer type 
have at least 2 post-baseline tumor assessments. A formal decision regarding futility, which 
could result in stopping the study early, will be conducted separately for the TNBC and OC 
cohorts and will only be made from the analysis of 24 patients within each cohort. The earlier 
response assessments, however, will inform the conduct of the formal interim analysis as 
follows: If no responder is observed in all three response assessments from 6, 12, and 18 
patients, then enrollment will be suspended after 24 patients have been enrolled, and no further 
patients will be enrolled until the result of the formal interim analysis of 24 patients is known. If 
≥1 responder is observed in any single response assessment from 6, 12, or 18 patients, then 
enrollment will not be curtailed. The decision rule regarding the formal interim analysis at 
N=24 is as follows: If there are fewer than 3 responders out of 24, enrollment may be closed 
and the corresponding cohort may be stopped for futility. Otherwise, the study will continue to 


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the planned enrollment of approximately 48 patients.  


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
INVESTIGATOR SIGNATURE PAGE .........................................................................................3 
SYNOPSIS ......................................................................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................25 
1. 
INTRODUCTION ......................................................................................................29 
1.1. 
Background .................................................................................................................29 
1.1.1. 
PARP and Homologous Recombination Deficiency ..................................................29 
1.1.2. 
Immune Surveillance and PD-1 Inhibitors .................................................................30 
1.2. 
Study Treatments ........................................................................................................31 
1.2.1. 
Niraparib .....................................................................................................................31 
1.2.2. 
Pembrolizumab ...........................................................................................................34 
1.3. 
Rationale for Current Study ........................................................................................34 
2. 
STUDY OBJECTIVES ..............................................................................................36 
2.1. 
Primary Objective .......................................................................................................36 
2.2. 
Secondary Objectives .................................................................................................36 
2.3. 
Exploratory Objectives ...............................................................................................36 
3. 
INVESTIGATIONAL PLAN .....................................................................................37 
3.1. 
Overall Study Design and Plan ...................................................................................37 
3.1.1. 
Overview .....................................................................................................................37 
3.1.2. 
Phase 1 Dose Escalation .............................................................................................38 
3.1.2.1. 
Recommended Phase 2 Dose ......................................................................................39 
3.1.3. 
Phase 2 Expansion ......................................................................................................40 
3.1.4. 
General Study Conduct: Phase 1 and 2.......................................................................40 
4. 
STUDY POPULATION .............................................................................................42 
4.1. 
Inclusion Criteria ........................................................................................................42 
4.2. 
Exclusion Criteria .......................................................................................................44 
4.3. 
Patient Withdrawal and Replacement .........................................................................46 
4.3.1. 
Discontinuation from Treatment .................................................................................46 
4.3.2. 
Discontinuation from the Study ..................................................................................47 
4.3.3. 
Replacement of Patients .............................................................................................47 


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4.4. 
Patient Identification and Randomization ..................................................................47 
4.4.1. 
Patient Identification ...................................................................................................47 
4.4.2. 
Randomization Scheme ..............................................................................................47 
5. 
STUDY MEDICATION .............................................................................................48 
5.1. 
Identity ........................................................................................................................48 
5.1.1. 
Niraparib .....................................................................................................................48 
5.1.2. 
Pembrolizumab ...........................................................................................................48 
5.2. 
Administration ............................................................................................................48 
5.2.1. 
Niraparib .....................................................................................................................48 
5.2.2. 
Pembrolizumab ...........................................................................................................48 
5.3. 
Dose-Limiting Toxicity ..............................................................................................49 
5.4. 
Dose Modification ......................................................................................................49 
5.4.1. 
Niraparib .....................................................................................................................50 
5.4.2. 
Pembrolizumab ...........................................................................................................52 
5.5. 
Packaging, Labeling, and Storage ..............................................................................56 
5.6. 
Drug Accountability ...................................................................................................56 
5.7. 
Previous and Concomitant Medications .....................................................................56 
5.7.1. 
Prohibited Medications ...............................................................................................57 
5.7.2. 
Contraception ..............................................................................................................57 
5.7.3. 
Rescue Medications and Supportive Care Guidelines During Treatment with 
Pembrolizumab ...........................................................................................................58 
5.7.4. 
Other Study Restrictions .............................................................................................62 
6. 
ENDPOINTS AND METHODS OF ASSESSMENT ...............................................63 
6.1. 
Safety Endpoints .........................................................................................................63 
6.1.1. 
Definitions ..................................................................................................................63 
6.1.2. 
Assessment of Adverse Events ...................................................................................64 
6.1.2.1. 
Intensity ......................................................................................................................64 
6.1.2.2. 
Causality .....................................................................................................................64 
6.1.3. 
Collecting and Recording Adverse Events .................................................................65 
6.1.4. 
Reporting Disease Progression ...................................................................................66 
6.1.5. 
Serious Adverse Events ..............................................................................................66 
6.1.5.1. 
Reporting of Serious Adverse Events .........................................................................66 


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6.1.5.2. 
Submission and Distribution of Adverse Events/Serious Adverse Events .................67 
6.1.6. 
Events of Clinical Interest ..........................................................................................67 
6.1.6.1. 
Pembrolizumab ...........................................................................................................67 
6.1.6.2. 
Niraparib .....................................................................................................................67 
6.1.7. 
Pregnancy Reporting and Follow-up ..........................................................................68 
6.1.8. 
Clinical Laboratory Assessments ...............................................................................69 
6.1.9. 
Physical Examination and Vital Signs ........................................................................70 
6.1.10. 
Eastern Cooperative Oncology Group Performance Status ........................................70 
6.1.11. 
Additional Safety Assessments...................................................................................70 
6.2. 
Demographics and Baseline Characteristics ...............................................................71 
6.2.1. 
Patient Eligibility ........................................................................................................71 
6.2.2. 
Patient Demography ...................................................................................................71 
6.2.3. 
Disease History ...........................................................................................................71 
6.2.4. 
Medical and Surgical History .....................................................................................71 
6.2.5. 
Previous and Concomitant Medications .....................................................................72 
6.3. 
Efficacy Endpoint(s) ...................................................................................................72 
6.3.1. 
Evaluation of Tumor Response ..................................................................................72 
6.3.1.1. 
Overview .....................................................................................................................72 
6.3.1.2. 
Timing of Radiographic Evaluations ..........................................................................72 
6.3.1.3. 
Assessment of Response by RECIST .........................................................................73 
6.3.1.4. 
Assessment of Response by Immune-Related RECIST .............................................73 
6.3.2. 
Efficacy Endpoints ......................................................................................................75 
6.3.2.1. 
Objective Response Rate ............................................................................................75 
6.3.2.2. 
Duration of Response .................................................................................................75 
6.3.2.3. 
Disease Control Rate ..................................................................................................75 
6.3.2.4. 
Progression-Free Survival ..........................................................................................75 
6.3.2.5. 
Overall Survival ..........................................................................................................75 
6.4. 
Pharmacokinetics ........................................................................................................75 
6.4.1. 
Phase 1 ........................................................................................................................76 
6.4.2. 
Phase 2 ........................................................................................................................76 
6.4.3. 
Determination of Pharmacokinetic Parameters ..........................................................76 
6.5. 
Biomarkers ..................................................................................................................76 


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7. 
STUDY CONDUCT ...................................................................................................78 
7.1. 
Schedule of Procedures ...............................................................................................78 
7.2. 
Procedures by Visit .....................................................................................................90 
7.2.1. 
Screening (Day -21 to Day -1) ....................................................................................90 
7.2.2. 
Cycle 1/Day 1 .............................................................................................................91 
7.2.3. 
Cycle 1/Day 2 (Phase 1 Patients Only) .......................................................................92 
7.2.4. 
Cycle 1/Day 8 .............................................................................................................92 
7.2.5. 
Cycle 1/Day 15 ...........................................................................................................93 
7.2.6. 
Day 1, Subsequent Cycles ..........................................................................................93 
7.2.7. 
Cycle 2, Day 2 (Phase 1 Patients Only) ......................................................................95 
7.2.8. 
End of Treatment (within 7 days of last dose) ............................................................95 
7.2.9. 
Safety Follow-up (30 days [+ 7 days] Post-treatment) ...............................................96 
7.2.10. 
Follow-up Assessments ..............................................................................................96 
7.2.11. 
Unscheduled Assessments ..........................................................................................97 
8. 
STATISTICAL METHODS .......................................................................................98 
8.1. 
Study Populations .......................................................................................................98 
8.2. 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications .................................................................................................................98 
8.3. 
Safety Analyses ..........................................................................................................98 
8.4. 
Pharmacokinetic Analyses ..........................................................................................99 
8.5. 
Post-Treatment Analyses ............................................................................................99 
8.6. 
Efficacy Analyses .......................................................................................................99 
8.6.1. 
Primary Efficacy Parameter ......................................................................................100 
8.6.2. 
Secondary Efficacy Parameter(s) .............................................................................100 
8.7. 
Biomarker Analyses ..................................................................................................100 
8.8. 
Probability of Dose Escalation .................................................................................100 
8.9. 
Interim Analyses .......................................................................................................103 
8.10. 
Determination of Sample Size ..................................................................................103 
9. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ..................................105 
9.1. 
Data Quality Assurance ............................................................................................105 
9.2. 
Access to Source Data/Documents ...........................................................................105 
9.3. 
Archiving Study Documents .....................................................................................106 


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9.4. 
Good Clinical Practice ..............................................................................................106 
9.5. 
Informed Consent .....................................................................................................106 
9.6. 
Protocol Approval and Amendment .........................................................................106 
9.7. 
Patient Confidentiality and Data Protection .............................................................107 
9.8. 
Study Monitoring ......................................................................................................107 
9.9. 
Audits and Inspections ..............................................................................................107 
9.10. 
Ethical Considerations ..............................................................................................107 
9.11. 
Publication Policy .....................................................................................................108 
9.12. 
Study Committee ......................................................................................................108 
10. 
REFERENCE LIST ..................................................................................................109 
APPENDIX A. ASCO TNBC GUIDANCE 2010(70)................................................................115 
APPENDIX B. DRUGS KNOWN TO INHIBIT OR INDUCE CYP1A2 OR ARE 
SUBSTRATES OF CYP1A2 ...................................................................................116 
APPENDIX C. DRUGS THAT ARE SUBSTRATES OR INHIBITORS OF P-
GLYCOPROTEIN ....................................................................................................117 
APPENDIX D. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST), V1.1 ........................................................................................................118 
APPENDIX E. IMMUNE-RELATED RESPONSE EVALUATION CRITERIA IN 
SOLID TUMORS (IRRECIST) ...............................................................................120 
APPENDIX F. ASSESSMENT OF RESPONSE IN OVARIAN CANCER BY 
GYNECOLOGIC CANCER INTERGROUP (GCIG) CRITERIA .........................121 
APPENDIX G. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .....................................................................................122 
 
 


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LIST OF TABLES 
Table 1 
Progression-Free Survival in Ovarian Cancer Patients in NOVA ...............................32 
Table 2 
Niraparib Dose Reductions for Non-Hematologic Toxicity .......................................50 
Table 3 
Management of Hematologic Toxicities* ..................................................................52 
Table 4 
Pembrolizumab Dose Modifications for Non-hematologic Toxicities .......................54 
Table 5 
Pembrolizumab Infusion Reaction Treatment Guidelines ..........................................61 
Table 6 
Schedule of Events .....................................................................................................79 
Table 7 
Schedule of Events - Phase 2 Only .............................................................................83 
Table 8 
Pharmacokinetic Sampling and Electrocardiogram Schedule – Phase 1 ....................87 
Table 9 
Pharmacokinetic Sampling and Electrocardiogram Schedule – Phase 2 ....................88 
Table 10 
Niraparib Administration – Phase 1 ...........................................................................88 
Table 11 
Niraparib Administration – Phase 2 ...........................................................................89 
Table 12 
Dose Escalation Decision Rules ...............................................................................101 
Table 13 
RECIST Response for Patients with Measurable Disease (ie, Target Disease) .......119 
Table 14 
RECIST Response for Patients with Non-Measurable Disease (ie, Non-Target 
Disease) .....................................................................................................................119 
Table 15 
Imaging and Treatment after First Radiologic Evidence of Progressive Disease ....120 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema .............................................................................................................38 
Figure 2 
Probability of Dose Escalation in a 6 + 6 Design .....................................................102 
Figure 3 
Probability of Dose Escalation in a 6 + 6 Design versus 3 + 3 Design at a Fixed 
Rate of 0.05 for Non-hematologic DLTs ..................................................................103 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
activities of daily living 
ADP 
adenosine diphosphate 
AE 
adverse event 
ALT 
alanine aminotransferase 
alt-NHEJ 
alternative nonhomologous end-joining 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATM 
ataxia telangiectasia mutated 
ATR 
ATM and Rad3-related 
AUC 
area under the concentration × time curve 
AUCss 
area under the concentration × time curve at steady state 
BCG 
bacille Calmette-Guerin 
BER 
base excision repair 
BP 
blood pressure 
BRCA 
breast cancer (gene) 
CA-125 
cancer antigen 125 
CBC 
complete blood count 
CHK 
check point kinases 
CI 
confidence interval 
CL/F 
clearance after oral administration 
Cmax 
maximum concentration 
Cmax,ss 
maximum concentration at steady state 
Cmin 
minimum concentration 
Cmin,ss 
minimum concentration at steady state 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 


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Abbreviation 
Definition 
DCR 
disease control rate 
DKA 
diabetic ketoacidosis 
DL 
dose level 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECI 
events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EOT 
end of treatment 
ER 
estrogen receptor 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone 
gBRCAmut 
germline breast cancer gene mutation 
GCIG 
Gynecologic Cancer Intergroup 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
HBsAg 
hepatitis B surface antigen 
HCV RNA 
hepatitis C virus ribonucleic acid 
HER2 
human epidermal growth factor receptor 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRD 
homologous recombination deficiency 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IgG 
immunoglobulin G 
INR 
international normalized ratio 


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Abbreviation 
Definition 
IRB 
Institutional Review Board 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
ITIM 
immunoreceptor tyrosine-based inhibition motif 
ITSM 
immunoreceptor tyrosine-based switch motif 
IV 
intravenous(ly) 
KM 
Kaplan-Meier 
LC-MS-MS 
liquid chromatography with mass spectroscopic detection 
mAb 
monoclonal antibody 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MMR 
mismatch repair deficiency 
NBS1 
Nijmegen breakage syndrome 1 
NER 
nucleotide excision repair 
NHEJ 
nonhomologous end-joining 
OC 
primary peritoneal ovarian cancer 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly(ADP-ribose) polymerase 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1 
programmed death ligand-1 
PD-L2 
programmed death ligand-2 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetics 
PO 
oral(ly) 
PR 
partial response 
PR 
progesterone receptor 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 


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Abbreviation 
Definition 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
T3 
triiodothyronine 
TEAE 
treatment-emergent adverse event 
TIL 
tumor-infiltrating lymphocytes 
TNBC 
triple-negative breast cancer 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
V-type 
variable-type 
Vz/F 
volume of distribution after oral administration 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
PARP and Homologous Recombination Deficiency 
Poly(ADP-ribose) polymerases (PARP)1 and PARP2 are zinc-finger deoxyribonucleic acid 
(DNA)-binding enzymes that play a crucial role in DNA repair.(1) Upon formation of DNA breaks, 
PARP binds at the end of broken DNA strands, a process that activates its enzymatic activity. 
Activated PARP catalyzes the addition of long polymers of adenosine diphosphate (ADP)-ribose 
onto PARP and several other proteins associated with chromatin, including histones and various 
DNA repair proteins. This results in chromatin relaxation, fast recruitment of DNA repair proteins, 
and efficient repair of DNA breaks. In this manner, PARP plays a key role in sensing DNA damage 
and converting it into intracellular signals that activate the base excision repair (BER) and single-
strand break repair pathways.(1, 2) 
Normal cells repair up to 10,000 DNA defects daily, and single-strand breaks are the most common 
form of DNA damage. Cells that are unable to repair this burden of DNA damage, such as those 
with defects in the homologous recombination or BER pathways, are at risk for accumulating 
multiple lesions that will ultimately trigger apoptosis. They enter the S phase (DNA replication) of 
the cell cycle with unrepaired single- and double-strand breaks. Pre-existing single-strand breaks 
are converted to double-strand breaks as the replication machinery passes.(1) Accumulated double-
strand breaks present during S phase are repaired by homologous recombination . Homologous 
recombination is the preferred repair pathway because it is associated with a much lower error rate 
than other forms of repair. Cells unable to perform DNA repair via homologous recombination (eg, 
due to inactivation of genes required for homologous recombination, such as breast cancer gene 
[BRCA]1- or BRCA2-mutated cells) are at risk for accumulating multiple lesions that will 
ultimately trigger apoptosis. These cells accumulate stalled replication forks during S phase and are 
more likely to use the error-prone nonhomologous end-joining (NHEJ) or alternative (alt)-NHEJ 
pathways to repair double-strand breaks in DNA. Accumulation of errors in DNA by NHEJ 
contributes to mutation burden that promotes the development of cancer. Over time, the buildup of 
excessive DNA errors in combination with the inability to complete S phase (because of stalled 
replication forks) contributes to cell death. 
Treatment with PARP inhibitors could represent a novel opportunity to selectively kill a subset of 
cancer cells with deficiencies in DNA repair pathways. For example, a tumor arising in a patient 
with a germline BRCA mutation (gBRCAmut) has a defective homologous recombination DNA 
repair pathway and would be increasingly dependent on NHEJ, alt-NHEJ, and BER for 
maintenance of genomic integrity. PARP inhibitors block alt-NHEJ and BER, forcing tumors with 
BRCA deficiencies to use the error-prone NHEJ to fix double-strand breaks.(1) Non-BRCA 
deficiencies in homologous recombination DNA repair genes could also enhance tumor cell 
sensitivity to PARP inhibitors.(3) The rationale for anticancer activity in a subset of non-gBRCAmut 
tumors is that they share distinctive DNA repair defects with gBRCAmut carriers, a phenomenon 
broadly described as “BRCAness.”(4) DNA repair defects can be caused by germline or somatic 
alterations to the homologous recombination DNA repair pathway. In a recent analysis of 


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approximately 500 high-grade serous ovarian adenocarcinoma tumors, approximately 50% 
contained homologous recombination defects.(5) A subset of these tumors had biologically plausible 
molecular alterations that may make them sensitive to PARP inhibition by niraparib. A similar 
analysis of triple-negative breast cancer (TNBC) indicates up to 40% of these patients have tumors 
with homologous recombination defects.(6) 
Homologous recombination is a complex pathway, and several genes other than BRCA1 and 
BRCA2 are required either to sense or repair DNA double-strand breaks via the homologous 
recombination pathway. Therefore, PARP inhibitors are also selectively cytotoxic for cancer cells 
with deficiencies in DNA repair proteins other than BRCA1 and BRCA2, including RecA 
homologs (RAD51 and RAD54), X-ray repair complementing defective repair in Chinese hamster 
cells (XRCC2 and XRCC3), DSS1, replication protein A1 (RPA1), ataxia telangiectasia mutated 
(ATM), ATM and Rad3-related (ATR), check point kinases (CHK1, CHK2), Nijmegen breakage 
syndrome 1 (NBS1), and the components of the Fanconi anemia repair pathway.(1, 4, 7) 
Clinical studies have shown that PARP inhibitors are active for recurrent ovarian cancer (OC).(1-3, 8-
11) Clinical anticancer activity has been observed in patients with and without gBRCAmut and in 
patients who are platinum-sensitive and platinum-resistant. PARP inhibition appears to be most 
active in patients with gBRCAmut platinum-sensitive disease.(3, 9) Additionally, maintenance therapy 
in patients with relapsed, platinum-sensitive OC appears promising.(10) Of patients with a BRCA 
mutation, median progression-free survival (PFS) was significantly longer in the PARP inhibitor 
group than in the placebo group (11.2 months vs. 4.3 months; hazard ratio: 0.18; p< 0.0001). 
Similar findings were noted for patients with wild-type BRCA, although the difference between 
groups was smaller (7.4 months vs. 5.5 months; hazard ratio: 0.54; p = 0.007).  
Recent clinical studies also have shown PARP inhibitors to be active in breast and ovarian cancer. 
Clinical anticancer activity with PARP inhibitors has been seen in both patients with gBRCAmut and 
without gBRCAmut; however, activity is more robust in patients with the germline mutation.(1, 3, 8, 10-
12) 
In summary, treatment with PARP1/2 inhibitors represents a novel opportunity to selectively kill a 
subset of cancer cell types by exploiting their deficiencies in DNA repair. Human cancers exhibit 
genomic instability and an increased mutation rate due to underlying defects in DNA repair. These 
deficiencies render cancer cells more dependent on the remaining DNA repair pathways, and 
targeting these pathways is expected to have a much greater impact on the survival of the tumor 
cells than on normal cells. 
1.1.2. 
Immune Surveillance and PD-1 Inhibitors 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation 
has been known for decades.(13) Accumulating evidence shows a correlation between tumor-
infiltrating lymphocytes (TILs) in cancer tissue and prognosis in various malignancies.(14-26) In 
particular, the presence of CD8+ T cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory T 
cells seem to correlate with improved prognosis and long-term survival in many solid tumors.(22, 27-
33) 
The programmed death-1 (PD-1) receptor-ligand interaction is a major pathway hijacked by tumors 
to suppress immune control.(34) The normal function of PD-1, expressed on the cell surface of 
activated T cells under healthy conditions, is to down-modulate unwanted or excessive immune 


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responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to CD28 and CTLA-4, which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-
L2). The structures of murine PD-1 alone (35) and in complex with its ligands were first resolved (36, 
37), and more recently the nuclear magnetic resonance-based structure of the human PD-1 
extracellular region and analyses of its interactions with its ligands were also reported.(38) PD-1 and 
family members are type I transmembrane glycoproteins containing an Ig variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail, which is responsible for the binding 
of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based 
switch motif (ITSM). Following T cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 
and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules, such as CD3ζ, PKCθ and ZAP70, which are involved in the CD3 T cell 
signaling cascade.(39) The mechanism by which PD-1 down-modulates T cell responses is similar 
to, but distinct from, that of CTLA-4.(40) PD-1 was shown to be expressed on activated 
lymphocytes, including peripheral CD4+ and CD8+ T cells, B cells, T regs, and natural killer 
cells.(41) Expression has also been shown during thymic development on CD4-/CD8- (double-
negative) T cells, (42) as well as subsets of macrophages (43) and dendritic cells.(44) The ligands for 
PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell 
types.(45) PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is predominantly expressed on antigen-presenting 
cells found in lymphoid tissue or chronic inflammatory environments.(45) Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and 
short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 
inhibits T cell activation triggered through the T cell receptor. PD-L2 is thought to control immune 
T cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T cell function 
in peripheral tissues. Although healthy organs express little (if any) PD-L1, a variety of cancers 
were demonstrated to express abundant levels of this T cell inhibitor, (46, 47) which, via its 
interaction with the PD-1 receptor on tumor-specific T cells, plays a critical role in immune evasion 
by tumors.(48) As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in cancer.(49) 
1.2. 
Study Treatments 
1.2.1. 
Niraparib 
Niraparib is a potent, orally active PARP1 and PARP2 inhibitor being developed as a treatment for 
patients with tumors that harbor defects in the homologous recombination DNA repair pathway or 
that are driven by PARP-mediated transcription factors. 
Nonclinical data on niraparib are discussed in detail in the Investigator’s Brochure. Briefly, in 
nonclinical models, niraparib has been observed to inhibit normal DNA repair mechanisms and 
induce synthetic lethality when administered to cells with homologous recombination defects. In a 
BRCA1-mutant xenograft study, niraparib dosed orally caused tumor regression, which was 
mirrored by > 90% reduction in tumor weight compared with control. In a BRCA2-mutant 
xenograft study, niraparib-dosed mice showed 55% to 60% growth inhibition, both by tumor 
volume and weight. 


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Niraparib displayed strong antitumor activity in in vivo studies with BRCA1-mutant breast cancer 
(MDA-MB-436), BRCA2-mutant pancreatic cancer (CAPAN-1), ATM-mutant mantle cell 
lymphoma (GRANTA-519), serous OC (OVCAR3), and colorectal cancer (HT29 and DLD-1) 
xenograft models and with patient-derived Ewing sarcoma mice models. Utilizing patient-derived 
ovarian and breast cancer xenograft models, niraparib demonstrated response in both BRCA 
mutation and BRCA wild-type tumors.  
Niraparib clinical data are discussed in detail in the niraparib Investigator’s Brochure. In the Phase 
1 clinical program, niraparib, as a monotherapy or in combination with chemotherapy, has been 
administered to 144 patients.  
In the Phase 1 program (n=144), the most common (> 20.0% of patients) adverse events (AEs), 
were fatigue (58.3%), nausea (54.9%), anemia (50.7%), constipation (39.6%), thrombocytopenia 
(37.5%), vomiting (36.8%), decreased appetite (31.9%), neutropenia (28.5%), headache (26.4%), 
diarrhea (21.5%), dyspnea (21.5%), cough (20.8%), and leukopenia (20.8%). 
In the randomized, double-blind, Phase 3 NOVA trial (Niraparib Maintenance Therapy in Platinum-
Sensitive, Recurrent Ovarian Cancer), a total of 553 patients were randomized at 107 centers 
worldwide. Patients were categorized according to the presence or absence of a germline BRCA 
mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were 
randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary 
end point was progression-free survival. The study enrolled 203 patients in the gBRCAmut cohort 
and 350 patients in the non-gBRCAmut cohort. Among the 350 patients in the non-gBRCAmut 
cohort, 162 had tumors that were defined as HRDpos and 134 had tumors that were HRD negative 
(HRDneg). HRD status was not determined (HRDnd) for 54 patients.  
Demographic and baseline characteristics were well balanced. Table 1 shows the results for the PFS 
primary endpoint for each of the 3 primary efficacy populations (ie, gBRCAmut cohort, HRDpos 
cohort, and overall non-gBRCAmut cohort). In addition, median PFS in patients with HRD 
negative (HRDneg) tumors was 6.9 months (95% CI: 5.6, 9.6) in the niraparib arm, versus 3.8 
months (95% CI: 3.7, 5.6) in the placebo arm, with a hazard ratio (HR) of 0.58 (95% CI: 0.361, 
0.922) (p=0.0226). 
Table 1 
Progression-Free Survival in Ovarian Cancer Patients in NOVA 
 
gBRCAmut Cohort 
non-gBRCAmut Cohort 
(regardless of HRD status) 
HRDpos 
(within non-gBRCAmut cohort) 
Niraparib 
(N=138) 
Placebo 
(N=65) 
Niraparib 
(N=234) 
Placebo  
(N=116) 
Niraparib 
(N=106) 
Placebo  
(N=56) 
PFS Median 
(95% CI)a 
21.0 
(12.9, NR) 
5.5 
(3.8, 7.2) 
9.3 
(7.2, 11.2) 
3.9 
(3.7, 5.5) 
12.9 
(8.1, 15.9) 
3.8 
(3.5, 5.7) 
p-value 
<0.0001 
<0.0001 
<0.0001 


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gBRCAmut Cohort 
non-gBRCAmut Cohort 
(regardless of HRD status) 
HRDpos 
(within non-gBRCAmut cohort) 
Niraparib 
(N=138) 
Placebo 
(N=65) 
Niraparib 
(N=234) 
Placebo  
(N=116) 
Niraparib 
(N=106) 
Placebo  
(N=56) 
Hazard Ratio 
(Nir:Plac) 
(95% CI) 
0.27 
(0.173, 0.410) 
0.45 
(0.338, 0.607) 
0.38 
(0.243, 0.586) 
Progression-free survival is defined as the time in months from the date of randomization to progression or death. 
The primary data to support the safety of treatment with niraparib are derived from the NOVA main 
study in which a total of 546 patients received study treatment. 
All 367 patients who received niraparib and 171 (96%) of 179 patients who received placebo 
experienced at least 1 treatment-emergent adverse event (TEAE). The high rate of TEAEs in the 
placebo group indicates the burden of prior chemotherapy and the patient’s underlying ovarian 
cancer. Review of the data across study cohorts for TEAE incidence showed that, in general, the 
results were similar in the gBRCAmut and non-gBRCAmut cohorts. In the overall safety population, 
for the niraparib versus placebo treatment arms, the incidences of Grade 3/4 TEAEs (74% vs. 23%), 
serious adverse events (SAEs) (30% vs. 15%), TEAEs leading to treatment interruption (69% vs. 
5%), TEAEs leading to dose reduction (67% vs. 15%), and TEAEs leading to treatment 
discontinuation (15% vs 2%) were higher for niraparib. There were no on-treatment deaths 
reported.  
The most commonly observed non-hematologic TEAEs (all grades) observed in niraparib-
compared to placebo-treated patients were nausea (74% vs. 35%), fatigue (46% vs. 32%), 
constipation (40% vs. 20%), and vomiting (34% vs. 16%). The majority of the non-hematological 
TEAEs were mild to moderate in severity. The most commonly observed hematologic TEAEs (all 
grades) of niraparib were anemia (49%), thrombocytopenia (46%), and neutropenia (18%). 
Although Grade 3/4 hematologic laboratory events were common at the initiation of treatment, no 
severe clinical sequelae were observed, and relatively few patients discontinued due to these AEs. 
Dose adjustment based on individual tolerability during the first 3 cycles substantially reduced the 
incidence of these events beyond Cycle 3, indicating the overall effectiveness of the approach to 
dose modification. These TEAEs can be monitored routinely using standard assessments of 
hematological laboratory parameters, as is routine for patients with ovarian cancer receiving anti-
cancer therapies. In the NOVA study, niraparib dose adjustment tended to occur early with most 
patients reaching their individual adjusted dose level at the end of Month 3 (ie Cycle 3) of 
treatment. ~36% pts were kept on 300mg and ~64% pts had dose adjustment after 3 cycles in 
NOVA. However, in the Phase 1 portion of this study (3000-PN162-01-001) no patients were able 
to tolerate the 300 mg dose of niraparib.   
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have been observed in 
patients receiving treatment with olaparib, a PARP inhibitor; given the common mechanism of 
action, MDS and AML therefore represent a potential risk to patients receiving niraparib. In the 
Phase 3 NOVA study, the incidence of MDS/AML in patients who received niraparib (5 of 367; 


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1.4%) was similar to its incidence in patients who received placebo (2 of 179; 1.1%). Guidance on 
monitoring patients for new events of MDS/AML and the follow-up of patients with suspected 
MDS/AML is provided in Section 6.1.8 and Section 7. 
Study PR-30-5011-C1 (NOVA QTc substudy n=26) is an open-label evaluation of the effects of 
niraparib on QTc measurements in patients with histologically diagnosed ovarian cancer, fallopian 
tube cancer, or primary peritoneal cancer. There were no reports of clinically significant abnormal 
electrocardiogram (ECG) changes, including QTc interval prolongation, attributed to niraparib. 
Administration of niraparib at the therapeutic dose did not prolong the QT interval. There was no 
correlation between the exposure level (ie, plasma concentration) of niraparib and QTc changes 
(ie,ΔQTcF). 
Clinical activity data for niraparib administered as monotherapy in patients with OC are available 
from 1 early-phase clinical study. In the Phase 1/2 study PN001, 104 patients with advanced solid 
tumors who had received a median of 5 prior therapies were enrolled; 49 had OC (13 platinum-
sensitive, 35 platinum-resistant, and 1 platinum-refractory).(11) Of the 49 patients, 22 had confirmed 
BRCA1 or BRCA2 mutation, of whom 20 were radiologically assessable. Eight (40%) of these 20 
patients achieved a confirmed partial response (PR) by Response Evaluation Criteria in Solid 
Tumors (RECIST) and cancer antigen (CA)-125 Gynecologic Cancer Intergroup (GCIG) criteria at 
doses ranging from 80 to 400 mg per day. Median response duration was 387 days (range: 159 to 
518 days). Three (33%) of 9 patients with platinum-resistant BRCA-mutant OC had PR by RECIST 
and CA-125 criteria. Additionally, a 50% response rate (5 of 10 evaluable patients) was observed at 
daily doses ranging from 290 to 300 mg among patients with BRCA-mutant OC who had received 
more than 3 lines of prior chemotherapy (data on file).  
1.2.2. 
Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD 1. Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies. 
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a number of 
indications. For more details on specific indications refer to the Investigator brochure. 
1.3. 
Rationale for Current Study 
Current treatment options for patients with advanced or metastatic TNBC and patients with 
recurrent OC are limited, with no approved standard of care.  
Triple-negative breast cancer is an aggressive histologic subtype of breast cancer, clinically defined 
by lack of expression of the estrogen receptor (ER-) and progesterone receptor (PR-) and lack of 
overexpression or amplification of HER2-receptor. The malignancy constitutes an aggressive form 
of the disease regardless of stage at diagnosis, and in patients with metastatic TNBC, there are 
currently no approved therapies or standard of care. 
Similarly for recurrent OC, there are no approved treatments or standard of care. Although the 
National Comprehensive Cancer Network guidelines recommend treatment with single-agent 


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topotecan, doxorubicin, or gemcitabine, the optimal combination and sequence of these agents is 
unclear, and the exact population who would derive the most benefit is not well defined. 
Over recent years, research has revealed the importance of TILs in controlling the clinical 
progression of various cancers and their presence in a tumor is associated with response to immune 
checkpoint inhibitors.(50) Accumulating evidence suggests that basal-type TNBC may be the ER(-) 
breast cancer most regulated by intratumoral T cells and thus the most potentially responsive to 
immunotherapies.(51) In addition, the frequency of BRCA1/2 deficiency, both BRCA mutations and 
silencing of BRCA expression, in TNBC is between 45% and 70%.(6) Similarly in OC, 
intraepithelial CD8+ T-cells correlated with the presence of mutation or loss of expression of 
BRCA1 through promoter methylation.(52) Collectively, metastatic TNBC and OC patient 
populations that were sensitive to agents targeting defects in DNA repair are likely to overlap with 
those tumors with an active yet checkpoint-blocked immune response.  
Despite promising activity of PD-1 inhibitors observed in some types of cancer, including 
melanoma and NSCLC,(53) activity in TNBC (objective response rate [ORR] of 18.5% with 
pembrolizumab) and ovarian cancer (ORR of 11%-12% on pembrolizumab or avelumab) observed 
thus far have been modest.(54-56) Although promising in selected patients with BRCA mutations or 
potentially with homologous recombination deficiency, modest activity of PARP inhibitors in 
unselected ovarian cancer patients with resistant disease has been observed (ORR of 16% with 
niraparib and 0% with olaparib).(3, 11) Synergistic interactions have been observed, however, 
between immune checkpoint inhibitors and PARP inhibitors; nonclinical experiments in syngeneic 
mouse models have shown an increased response rate to the combination of anti-PD-1 and niraparib 
over either agent alone, providing additional support to investigate this combination in patients.(57-
59) Exposure of a tumor in vivo to PARP inhibitor results in increased cancer cell death by 
2 independent mechanisms. First, through the mechanism of synthetic lethality, the PARP inhibitor 
can kill HRD tumors through apoptosis. Second, the PARP inhibitor can increase the number of 
CD8+ T cells and natural killer (NK) cells, as well as their production of IFN-γ and TNF-α, 
resulting in an improved response to checkpoint blockade.(59) Accordingly, the biomarkers for this 
combination clinical study will include a wide range of assays, including the measurement of tumor 
cell death, genomic changes, apoptosis, and immune response. 
Given the unmet medical need of patients with advanced or metastatic TNBC and patients with 
platinum-resistant recurrent OC, the non-overlapping safety and metabolic profile (see the current 
versions of the niraparib Investigator’s Brochure and the pembrolizumab Investigator’s Brochure 
for details), and preclinical data suggesting possible synergistic interaction between immune 
checkpoint inhibitors and PARP inhibitors along with a potential overlap for PD-l- and PARP-
sensitive patient populations, this study is designed to evaluate the combination of niraparib and 
pembrolizumab in these populations. 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objectives of this study, by phase, are as follows: 
 Phase 1: To evaluate dose-limiting toxicities (DLTs) of combination treatment with 
niraparib and pembrolizumab during the first cycle of treatment, and to establish a 
recommended Phase 2 dose (RP2D) and schedule. 
 Phase 2: To estimate the clinical activity of combination treatment with niraparib and 
pembrolizumab in terms of ORR as assessed by the Investigators using RECIST v1.1 
separately for the TNBC and OC cohorts. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are as follows: 
 Phase 1 and Phase 2: To evaluate the safety and tolerability of combination treatment 
with niraparib and pembrolizumab using Common Terminology Criteria for Adverse 
Events (CTCAE, v.4.03). 
 Phase 2: To evaluate additional measures of clinical benefit as assessed by the 
Investigators, including: 
 ORR by immune-related RECIST (irRECIST) 
 Duration of response (DOR) by RECIST v1.1 and by irRECIST; 
 Disease control rate (DCR) by RECIST v1.1 and irRECIST; 
 Progression-free survival (PFS) by RECIST v1.1 and by irRECIST; 
 Overall survival (OS). 
 Phase 1 and Phase 2: To evaluate the pharmacokinetics (PK) of niraparib and associated 
major metabolite M1 during combination treatment. 
2.3. 
Exploratory Objectives 
The exploratory objectives of the study for both phases are as follows: 
 To identify the biomarker-based patient population that would derive benefit from the 
combination treatment based on the tumor tissue molecular profile, molecular profile of 
TILs, and circulating biomarkers. 
 To correlate homologous recombination deficiency (HRD) status with other 
immune-related biomarkers and with efficacy outcomes. 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
3.1.1. 
Overview 
This is a multicenter, open-label, single-arm Phase 1/2 study evaluating the safety and efficacy of 
combination treatment with niraparib and pembrolizumab in patients with previously treated TNBC 
or OC. Specifically, patients eligible for this study are those with: 
 Advanced or metastatic TNBC (in Phase 1 patients may have received up to 4 lines of 
cytotoxic therapy for advanced/metastatic disease or in Phase 2, up to 2 lines of 
cytotoxic therapy for advanced/metastatic disease); or 
 Advanced, recurrent epithelial (for Phase 1: any serous, endometroid, mucinous, clear 
cell; for Phase 2: high-grade serous or endometroid) ovarian, fallopian tube, or primary 
peritoneal cancer who are currently platinum-resistant but previously experienced a 
response lasting for at least 6 months to first-line platinum-based therapy (in Phase 1 
patients may have received up to 5 lines of cytotoxic therapy or in Phase 2, up to 4 lines 
of cytotoxic therapy). 
Study treatment should be considered an appropriate option by the Investigator. The study will be 
conducted in 2 parts. The Phase 1 portion of the study will be a dose-escalation evaluation to 
determine the RP2D and schedule of niraparib to be administered in combination with the 
recommended dose of pembrolizumab, and the Phase 2 portion will further evaluate the RP2D and 
schedule in 2 cohorts of approximately 48 patients each with TNBC or OC as described above. See 
Section 3.1.2.1 for the RP2D.  
Figure 1 presents an overview of the planned study schema. The schedule of events for the study is 
provided in Table 6. 


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Figure 1 
Study Schema 
 
Abbreviations: AE = adverse event; d= day(s); DL = dose level; DLT = dose-limiting toxicity; OC = ovarian cancer; 
PK = pharmacokinetics; q21d = every 21 days; N = niraparib; P = pembrolizumab; RP2D = recommended Phase 2 
dose; TNBC = triple-negative breast cancer. 
The study will be conducted in conformance with Good Clinical Practice (GCP). 
3.1.2. 
Phase 1 Dose Escalation 
The following are the planned dose levels and treatment schedule for the Phase 1 portion of the 
study. Initially, 6 patients will be enrolled within a cohort. Based on current single-agent niraparib 
experience (see niraparib Investigator’s Brochure), hematological laboratory abnormalities are 
expected in a significant proportion of patients; therefore, cohorts may be expanded up to 
approximately 12 patients if needed to better characterize the safety of the combination treatment. 
 Dose Level 1: niraparib 200 mg/day orally (PO) on Days 1-21 and pembrolizumab 200 
mg intravenously (IV) on Day 1 of each 21-day cycle. 
 Dose Level 2: niraparib 300 mg/day PO on Days 1-21 and pembrolizumab 200 mg IV 
on Day 1 of each 21-day cycle. 
 Dose Level (-1): niraparib 200 or 300 mg/day PO on Days 1-14 of each 21-day cycle 
and pembrolizumab 200 mg IV on Day 1 of each 21-day cycle. Schedule of niraparib 
administration will be determined by agreement between Investigators and Sponsor (see 
Section 9.12). 
 Dose Level (-2): niraparib 200 or 300 mg/day PO on Days 1 – 7 of each 21-day cycle 
and pembrolizumab 200 mg IV on Day 1 of each 21-day cycle. Schedule of niraparib 
administration will be determined by agreement between Investigators and Sponsor (see 
Section 9.12).  
Dosing will initiate at Dose Level 1 with a cohort of 6 patients with either TNBC or OC enrolled 
and treated with a combination of niraparib 200 mg PO daily for Days 1-21 and pembrolizumab 
N: 200mg d1-21; q21d
P: 200mg d1; q21d
N: 300mg d1-21; q21d
P: 200mg d1; q21d
<1/3 DLT
N: 200mg or 300mg; d1-14; q21d
P: 200mg d1; q21d
≥1/3 DLT
DL2: 6 patients 
DL1: 6 patients 
DL(-1): 6 patients
RP2D
Consider:
DLT rate,
dose 
modifications,
dose intensity,
PK, AE rate
Phase 2 
OC: n=48
TNBC: n=48
Phase 1 
OC and TNBC: up to 36 patients
DL(-2): 6 patients
N: 200mg or 300mg; d1-7; q21d
P: 200mg d1; q21d
Starting
≥1/3 DLT


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200 mg IV on Day 1 every 21 days. After all patients in Dose Level 1 who are evaluable for safety 
have completed Cycle 1 of combination treatment, a review of the safety of treatment will be 
conducted by the Investigators and Sponsor (see Section 9.12). A patient will be considered non-
evaluable if, for any reason other than safety, the patient is unable to complete the 21-day 
combination treatment DLT observation period or is unable to take > 80% of the intended dose of 
either agent. Patients in Phase 1 considered unevaluable may be replaced after consultation between 
the Sponsor and Principal Investigator. If 2 of 6 initially enrolled patients in a cohort experience 
hematologic DLTs, a lower dose level will be opened. If, however, the 2 observed DLTs include 1 
hematologic DLT and 1 non-hematologic DLT or 2 non-hematologic DLTs, a cohort may be 
expanded up to approximately 12 patients to better characterize the safety of the combination 
treatment. Following the safety review, the next higher dose level (Dose Level 2) will be open for 
enrollment if less than one-third of patients (ie, < 2 of 6 patients or < 4 of 12 patients) in Dose 
Level 1 experience a DLT during Cycle 1 (see Section 5.3 for the definition of DLT).  
Once Dose Level 1 is determined to be safe, a cohort of 6 patients with either TNBC or OC will be 
enrolled in Dose Level 2 and treated with a combination of niraparib 300 mg PO daily for Days 1-
21 and pembrolizumab 200 mg IV on Day 1 every 21 days. No further dose escalation will be 
considered if Dose Level 2 is reached. 
The maximum tolerated dose (MTD) will be defined as the highest dose with DLTs observed in less 
than one-third of patients (ie, < 2 of 6 patients or < 4 of 12 patients) during Cycle 1 of combination 
treatment. If one-third or more of the evaluable patients experiences a DLT, then this dose will be 
considered to exceed the MTD and a lower dose level may be opened for enrollment if not yet 
evaluated. Alternative dosing schedules may be explored. 
Additional cohorts of 6 patients may be opened to evaluate Dose Level (-1) or Dose Level (-2), 
which will explore lower niraparib dose intensity by, for example, introducing an alternative dosing 
schedule, following agreement by the Investigators and Sponsor (see Section 9.12).  
Patients in Phase 1 who complete the 21-day DLT evaluation period may continue the 
pembrolizumab/niraparib combination treatment for up to 2 years unless specific withdrawal 
criteria are met (Section 4.3). Continued treatment with niraparib beyond 2 years may be considered 
following discussion between the Sponsor and Investigator. Appropriate niraparib dose 
modification can be made according to Section 5.4.1. 
3.1.2.1. 
Recommended Phase 2 Dose 
The RP2D was determined following discussion and agreement between Investigators and the 
Sponsor based on evaluation of multiple endpoints, which may include the DLT rate in first and 
subsequent cycles of combination treatment, the rate of dose modifications for non-DLT AEs, the 
ability to manage toxicities, PK, niraparib dose intensity, and signs of clinical efficacy. The goal 
will be to identify the dose/regimen of niraparib with the greatest dose intensity that can be safely 
combined with the recommended dose/regimen of pembrolizumab. 
In the Phase 1 portion of this study, 14 patients with advanced TNBC or OC were enrolled in Dose 
Level 1 or Dose Level 2. Twelve patients were eligible for DLT evaluation. In Dose Level (DL) 1, 
1 of 6 DLT-eligible patients experienced multiple DLTs including Grade 3 anemia, Grade 4 
neutropenia, and Grade 4 thrombocytopenia. In Dose Level 2, 1 of 6 DLT-eligible patients 
experienced 1 DLT, Grade 4 thrombocytopenia; an additional patient experienced an adverse event 


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that was deemed to be a DLT-equivalent; she had epistaxis on C1D17 and Grade 4 
thrombocytopenia on C2D1.  Based on the observed DLTs in DL1 and DL2, the RP2D to be 
implemented in the Phase 2 portion of this study is niraparib 200 mg/day PO on days 1-21 and 
pembrolizumab 200 mg IV on day 1 of each 21-day cycle; niraparib dose may be escalated on or 
after C3D1 from 200 mg daily to 300 mg daily if hemoglobin ≥ 9 g/dL, platelets ≥ 100,000/µL and 
neutrophils ≥ 1500/µL for all labs performed during the first two cycles after discussion with 
Medical Monitor or Designee. 
3.1.3. 
Phase 2 Expansion 
The Phase 2 portion of the study will commence after the RP2D is determined during the Phase 1 
portion. Two cohorts of approximately 48 patients each with advanced TNBC or OC as outlined 
above will be evaluated. 
Patients in this phase of the study will receive the RP2D as described in Section 3.1.2.1.  
Combination pembrolizumab/niraparib treatment may continue for up to 2 years unless specific 
withdrawal criteria are met (Section 4.3). Continued treatment with niraparib beyond 2 years may 
be considered following discussion between the Sponsor and Investigator. 
3.1.4. 
General Study Conduct: Phase 1 and 2 
Following informed consent, all patients in both Phase 1 and Phase 2 will undergo screening 
procedures within 21 days prior to the first dose of study treatment to determine eligibility for study 
entry. Screening procedures include medical, surgical, cancer, and medication history; complete 
physical examination, including vital signs, height, and weight; Eastern Cooperative Oncology 
Group (ECOG) performance status; clinical laboratory tests (complete blood count [CBC], 
coagulation, chemistry, thyroid-stimulating hormone [TSH], triiodothyronine [T3] or free T3 [FT3], 
free thyroxine [FT4], urinalysis, pregnancy test for women of childbearing potential, serum CA-125 
[OC patients only]) and electrocardiogram (ECG). Tumor samples must be available from all 
patients (fresh samples or archived paraffin blocks; see Study Manual for details on sample 
collection and preparation) and will be sent to a centralized laboratory for biomarker testing.  
Radiographic evaluations (computed tomography [CT, preferred method] or magnetic resonance 
imaging [MRI, if clinically indicated]) of the chest, abdomen, and pelvis must be conducted at 
screening to determine extent of disease and confirm presence of measurable disease. Brain scan 
will be conducted if clinically indicated; bone scans will be conducted per standard of care. Scans 
performed prior to the signing of the informed consent form (ICF) as part of routine clinical 
management are acceptable for use as initial tumor imaging if they are of diagnostic quality and are 
performed within 21 days prior to first dose date. 
All patients will begin treatment with niraparib and pembrolizumab on Cycle 1/Day 1; additional 
on-treatment assessments will be conducted on Days 8 and 15 of Cycle 1 and on Day 1 of all 
subsequent cycles. Safety assessments conducted throughout the treatment period include 
symptom-directed physical examination, vital signs, ECGs, ECOG performance status, and clinical 
laboratory assessments (CBC, coagulation [Phase 1 only], chemistry, TSH, T3 or FT3, FT4, 
urinalysis, CA-125 [OC patients only], and pregnancy testing). Radiographic evaluations (CT/MRI 
of chest [all TNBC patients and OC patients with abnormal screening scan or with clinical 
indication], abdomen, and pelvis) to assess extent of disease will be conducted every 9 weeks (63 
days ±7 days) after Cycle 1/Day 1 while on study treatment independent of cycle delays and/or dose 


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interruptions and/or at any time when progression of disease is suspected. The same modality (CT 
or MRI) should be used throughout the study for a given patient. Brain scans will be conducted if 
clinically indicated; bone scans will be conducted per standard of care. After 1 year of radiographic 
assessments, patients will have imaging performed every 12 weeks (84 ±7 days) until disease 
progression. If a patient discontinues treatment for a reason other than progression or death, 
withdrawal of consent, or loss to follow-up, scans and CA-125 testing (OC patients only) should 
continue at the specified intervals (ie, every 9 weeks for the first year and every 12 weeks 
thereafter). All radiographic images/scans will be sent to a central imaging vendor upon acquisition 
and archived for future evaluation if needed. Per RECIST v1.1, patients who achieved complete 
response (CR) or partial response (PR) should have the response confirmed; tumor imaging for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of 
response, or at the next scheduled scan (ie, 9 weeks later), whichever is clinically indicated. Blood 
sampling for PK and biomarker evaluations will be conducted for patients in both Phase 1 and 
Phase 2 (see Section 6.4). 
In patients who consent to fresh biopsies, serial fresh biopsies will be obtained for exploratory 
biomarker analysis at 3 time points: during the screening period, 1 to 3 days before or on C3D1 
prior to pembrolizumab infusion and, whenever possible, at the time of disease progression (note: 
although the biopsy is voluntary, it is highly encouraged). The serial biopsies at different time 
points should be on the same lesion preferably. A core biopsy is recommended (details are provided 
in the Study Manual); if an excisional or incisional biopsy is to be performed, it must be conducted 
on a non-target lesion. If a patient has had a biopsy within 12 weeks prior to entering screening, that 
biopsy may be accepted as the screening biopsy. Blood samples will also be obtained for biomarker 
analysis predose on Day 1 of Cycle 1 and Cycle 2, as well as at the end of treatment (EOT). 
All patients will undergo an EOT visit within 7 days of the last dose of study treatment and a safety 
follow-up visit conducted 30 days (+7 days) post-treatment. Thereafter, all patients will enter the 
post-treatment period for telephone assessment of survival status and the occurrence of any new 
malignancies every 90 days (±14 days). 
All AEs will be collected and recorded for each patient from the day of signing the ICF until 
30 days after last study drug administration; serious adverse events (SAEs) and Events of Clinical 
Interest (ECIs) (see Section 6.1.6) are required to be captured through 90 days after cessation of 
study treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer 
therapy), and any pregnancies are to be captured through 120 days post-treatment. All AEs and 
SAEs experienced by a patient, irrespective of the suspected causality, will be monitored until the 
AE or SAE has resolved, until 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. 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
To be considered eligible to participate in this study, all of the following requirements must be met: 
1. Patient is male or female, at least 18 years of age. Male patients are only for TNBC and not 
OC. 
2. Patient has histologically proven advanced (unresectable) or metastatic cancer as outlined 
below according to study phase and disease type:  
a. Phase 1 patients (breast or ovarian cancer) 
 Patients with advanced or metastatic breast cancer must have disease that is HER2-
negative, estrogen receptor-negative, and progesterone receptor-negative (ie, triple-
negative breast cancer, TNBC). Patients with disease recurrence or progression 
following neoadjuvant or adjuvant therapy are eligible. Patients with advanced or 
metastatic disease may have up to 4 lines of cytotoxic therapy. Neoadjuvant and 
adjuvant therapies are not counted towards lines of therapy. Targeted small 
molecules (eg, tyrosine kinase inhibitors), hormonal agents and monoclonal 
antibodies that inhibit angiogenesis (eg, bevacizumab, afilbercept) are not counted in 
the number of lines of therapy. 
 Patients must have any epithelial (ie, serous, endometroid, mucinous, clear cell) 
ovarian, fallopian tube, or primary peritoneal cancer. Patients must have experienced 
a response lasting at least 6 months to first-line platinum-based therapy but currently 
considered to have platinum-resistant disease per investigator’s assessment (e.g, 
patient is not eligible for further platinum containing treatment). Patients may have 
received up to 5 lines of cytotoxic therapy for advanced or metastatic cancer. 
Neoadjuvant and adjuvant therapies are not counted towards lines of therapy. 
Treatment with small molecules (eg, tyrosine kinase inhibitors), hormonal agents 
and monoclonal antibodies that inhibit angiogenesis (eg, bevacizumab, aflibercept) 
are not counted in the number of lines of therapy.  
b. Phase 2 patients (breast or ovarian cancer) 
 Patients with advanced or metastatic breast cancer must have TNBC. Patients with 
disease recurrence or progression following neoadjuvant or adjuvant therapy are 
eligible. Patients with advanced or metastatic disease may have received up to 2 
lines of cytotoxic therapy. Adjuvant and/or neoadjuvant therapies are not counted in 
the number of lines of therapy. Targeted small molecules (eg, tyrosine kinase 
inhibitors), hormonal agents and monoclonal antibodies that inhibit angiogenesis 
(eg, bevacizumab, afilbercept) are not counted. TNBC patients who have previously 
received platinum chemotherapy in the metastatic setting are allowed to enroll in the 
study as long as they did not progress while on or within 8 weeks from the day of the 
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 Patients must have with high-grade serous or endometroid ovarian, fallopian tube, or 
primary peritoneal cancer. Patients must have experienced a response lasting at least 
6 months to first-line platinum-based therapy but currently considered to have 
platinum-resistant disease per investigator’s assessment  (eg, patient is not eligible 
for further platinum containing treatment). Patients may have had up to 4 lines of 
cytotoxic therapy for advanced or metastatic disease cancer. Neoadjuvant, adjuvant, 
and the combination of both will be considered as one line of therapy. Treatment 
with small molecules (eg, tyrosine kinase inhibitors), hormonal agents and 
monoclonal antibodies that inhibit angiogenesis (eg, bevacizumab, aflibercept) are 
not counted in the number of lines of therapy.  
3. Patient has archival tumor tissue available that is formalin-fixed and paraffin-embedded.  
a. For patients who do not have archival tissue, tissue from a fresh biopsy must be obtained 
prior to study treatment initiation.  
b. Serial fresh tumor tissue samples will be collected in patients with lesions amenable for 
a biopsy who consent to such a procedure. 
4. Patient has measurable lesions by RECIST v1.1. 
5. Patient has an ECOG performance status of 0 to 1. 
6. Patient has adequate organ function, defined as (Note: CBC test should be obtained without 
transfusion or receipt of colony stimulating factors within 2 weeks before obtaining sample): 
a. Absolute neutrophil count (ANC) ≥ 1,500/µL 
b. Platelets ≥ 100,000/µL  
c. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 
d. Serum creatinine ≤ 1.5× upper limit of normal (ULN) or calculated creatinine clearance 
≥ 60 mL/min using Cockcroft-Gault equation for patients with creatinine levels > 1.5× 
institutional ULN 
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 are present, in which case they must be ≤ 5× ULN 
g. International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5× ULN unless 
patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time 
(PTT) is within therapeutic range of intended use of anticoagulants 
h. Activated partial thromboplastin time (aPTT) ≤ 1.5× ULN unless patient is receiving 
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
7. Patient is able to take oral medications. 
8. Female patient has a negative serum pregnancy test within 72 hours prior to taking study 
medication if of childbearing potential, or agrees to abstain from activities that could result 
in pregnancy from enrollment through 120 days after the last dose of study treatment, or be 
of non-childbearing potential. Non-childbearing potential is defined as (by other than 
medical reasons): 
a. ≥ 45 years of age and has not had menses for > 1 year 


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b. Amenorrheic for < 2 years without a hysterectomy and oophorectomy and a 
follicle-stimulating hormone (FSH) value in the postmenopausal range upon pre-study 
(screening) evaluation 
c. Post hysterectomy, bilateral oophorectomy, or tubal ligation. Documented hysterectomy 
or oophorectomy must be confirmed with medical records of the actual procedure or 
confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of 
the actual procedure, otherwise the patient must be willing to use 2 adequate barrier 
methods throughout the study, starting with the screening visit through 120 days after 
the last dose of study therapy. Please see Section 5.7.2 for a list of acceptable birth 
control methods. Information must be captured appropriately within the site's source 
documents. 
 
Note: Abstinence is acceptable if this is the established and preferred contraception for 
the patient. 
9. Male patient agrees to use an adequate method of contraception (please see Section 5.7.2 for 
a list of acceptable birth control methods) starting with the first dose of study therapy 
through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the established and preferred contraception for the 
patient.  
10. Patient agrees to blood samples during screening and at the end of treatment for cytogenetic 
analysis. 
4.2. 
Exclusion Criteria 
Patients will not be eligible for study entry if any of the following criteria are met: 
1. Patients with primary platinum refractory ovarian cancer (ie, progressive disease on or 
within 6 months of first-line platinum therapy) are not eligible in Phase 1 or Phase 2 of this 
study.  
2. Patient has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  
Note: Patients with previously treated brain metastases may participate provided they are 
stable (without evidence of progression by imaging [using the identical imaging modality 
for each assessment, either MRI or CT scan] for at least 4 weeks prior to the first dose of 
study treatment and any neurologic symptoms have returned to baseline), have no evidence 
of new or enlarging brain metastases, and have not been using steroids for at least 7 days 
prior to study treatment. Carcinomatous meningitis precludes a patient from study 
participation regardless of clinical stability. 
3. Patient has a known additional malignancy that progressed or required active treatment 
within the last 2 years. Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical 
cancer.  
4. Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, 
nonmalignant systemic disease or active infection that requires systemic therapy. Specific 


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examples include, but are not limited to, has history of (non-infectious) pneumonitis that 
required steroids or current pneumonitis; uncontrolled ventricular arrhythmia; recent (within 
90 days) myocardial infarction; uncontrolled major seizure disorder; unstable spinal cord 
compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders 
that would interfere with cooperation with the requirements of the study (including 
obtaining informed consent).  
5. Patient has a condition (such as transfusion dependent anemia or thrombocytopenia), 
therapy, or laboratory abnormality that might confound the study results, or interfere with 
the patient’s participation for the full duration of the study treatment. Patients who received 
colony-stimulating factors (eg, granulocyte colony stimulating factor [G-CSF], granulocyte 
macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 2 
weeks prior to the first dose of study treatment are not eligible. 
6. Patient is pregnant or breastfeeding, or expecting to conceive children within the projected 
duration of the study, starting with the screening visit through 120 days after the last dose of 
study treatment. 
7. Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of study 
treatment.  
8. Patient has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). 
9. Patient has known active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or 
hepatitis C (eg, hepatitis C virus ribonucleic acid [HCV RNA] [qualitative] is detected). 
10. Patient has an active autoimmune disease that has required systemic treatment in the past 
2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of 
systemic treatment. 
11. Patient has not recovered (i.e, to ≤Grade 1 or to baseline) from cytotoxic therapy-induced 
AEs. Note: Patient with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia is an exception to this 
criterion and may qualify for the study. 
12. Patient is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device within 
4 weeks of the first dose of treatment.  
13. Patient has had a prior cytotoxic therapy, anticancer targeted small molecules (eg, tyrosine 
kinase inhibitors), hormonal agents within 5 half-lives, or monoclonal antibodies (mAb) 
within 5 half-lives or 4 weeks (whichever is shorter) of that treatment prior to study Day 1or 
radiation therapy encompassing > 20% of the bone marrow within 2 weeks or any radiation 
therapy within 1 week prior to study Day 1. 
14. Patient has not recovered adequately from AEs and/or complications from any major 
surgery prior to starting therapy.  
15. Patient has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or the 
patient has previously participated in Merck MK-3475 (pembrolizumab) clinical studies. 


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16. Patient has received a live vaccine within 30 days of planned start of study therapy. 
17. Patient has undergone prior treatment with a known PARP inhibitor. 
18. Patient has a heart-rate corrected QT interval (QTc) prolongation > 470 msec at screening. 
Note: If a patient has a prolonged QT interval and the prolongation is deemed to be due 
to a pacemaker upon Investigator evaluation (ie, the patient otherwise has no cardiac 
abnormalities), the patient may be eligible to participate in the study following 
discussion with the Medical Monitor. 
19. Patient has a known hypersensitivity to niraparib or pembrolizumab components or 
excipients. 
20. Known history or current diagnosis of MDS or AML. 
4.3. 
Patient Withdrawal and Replacement 
4.3.1. 
Discontinuation from Treatment 
Patients may be discontinued from study treatment at any time. Specific examples of reasons for 
discontinuing all study treatments are given below.  
 Adverse event 
 Disease progression as outlined in Section 6.3 or based on clinical criteria by 
Investigator 
 Risk to patient as judged by the Investigator and/or Sponsor 
 Severe noncompliance with the protocol as judged by the Investigator and/or Sponsor 
 Patient request 
 Patient becomes pregnant 
 Sponsor decision to terminate study 
Details of required niraparib dose modifications, including interruptions, dose reductions, and 
permanent discontinuations, related to toxicity are provided in Section 5.4.1. 
Details of required pembrolizumab dose interruptions and permanent discontinuation related to 
toxicity are provided in Section 5.4.2. 
Note: If a patient is required to be discontinued from one of the study medications in the 
combination, treatment with the other study medication may be continued per decision of the 
Investigator in consultation with Sponsor. 
Discontinuation of treatment may be considered for patients who have attained a confirmed CR, 
have been treated for at least 24 weeks with study treatments, and had at least 2 cycles of treatment 
beyond the date when the initial CR was declared. 
Patients who discontinue from all study treatments will continue to receive follow-up assessments 
(see Table 6) as part of the study unless they are discontinued from the study (Section 4.3.2). 


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4.3.2. 
Discontinuation from the Study 
Patients may be discontinued from the study for any of the following reasons: 
 Withdrawal of consent by the patient, who is at any time free to discontinue their 
participation in the study, without prejudice to further treatment 
 Death from any cause 
 Loss to follow-up 
 Sponsor decision to terminate study 
 Investigator’s decision 
If a patient is lost to follow-up or withdraws from study treatment, attempts should be made to 
contact the patient to determine the reason for discontinuation. For patients who are lost to follow-
up, at least 3 documented attempts, including one via certified mail, should be made to contact the 
patient before considering the patient lost to follow-up. 
4.3.3. 
Replacement of Patients 
After consultation between the Sponsor and the Principal Investigator, enrollment may be extended 
to replace patient(s) that become non-evaluable for safety during Phase 1. 
In Phase 2, if a patient discontinues study treatment prior to the first assessment of disease (either 
scheduled radiological assessment at 9 weeks post treatment initiation or clinically indicated disease 
assessment prior to 9 weeks), the patient should be replaced for the purposes of efficacy analysis 
after consultation between the Sponsor and Principal Investigator. 
4.4. 
Patient Identification and Randomization 
4.4.1. 
Patient Identification 
All patients who enter into the screening period of the study (defined as the point at which the 
patient signs the ICF) will receive a unique patient identification number. This number will be used 
to identify the patient throughout the study and must be used on all study documentation related to 
that patient. A patient will be considered enrolled when the patient has been consented, screened, 
and all eligibility criteria have been confirmed in the electronic case report form (eCRF). The 
patient identification number must remain constant throughout the entire study; it must not be 
changed at the time of enrollment.  
4.4.2. 
Randomization Scheme 
Not applicable, as this is a single-arm study. 


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5. 
STUDY MEDICATION 
5.1. 
Identity 
5.1.1. 
Niraparib 
Niraparib ([3S]-3-[4-{7-(aminocarbonyl)-2H-indazol-2-yl} phenyl] piperidine [tosylate 
monohydrate salt]) is an orally available, potent, highly selective PARP1 and PARP2 inhibitor. The 
excipients for niraparib are lactose monohydrate and magnesium stearate. Niraparib will be 
supplied as 100-mg capsules. 
5.1.2. 
Pembrolizumab 
Pembrolizumab is a potent and highly selective humanized mAb of the IgG4/kappa isotype 
designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
Pembrolizumab Powder for Solution for Infusion is a sterile, non-pyrogenic lyophilized powder for 
IV infusion supplied in single-use Type I glass vial containing 50 mg of pembrolizumab. The 
product is preservative-free, white to off-white powder and free from visible foreign matter. 
5.2. 
Administration 
5.2.1. 
Niraparib 
Niraparib will be supplied as 100-mg capsules and will be administered orally once daily (QD) 
continuously starting on Cycle 1/Day 1. The daily dose to be administered each day (ie, 300 mg as 
3 × 100-mg capsules, 200 mg as 2 × 100-mg capsules, or 100 mg as 1 × 100-mg capsules) will 
depend on the phase of the study, and in Phase 1, the cohort assignment. See Section 3.1.2.1 for the 
RP2D of the combination. Patients will be instructed to take their dose at the same time each day, 
preferably in the morning. Patients must swallow and not chew all capsules. The consumption of 
water and food is permissible.  
Niraparib capsules will be dispensed to patients on Cycle 1/Day 1 and on Day 1 of every cycle (21-
day cycles) thereafter until the patient discontinues study treatment. On Day 1 of each cycle, a 
niraparib dose will be administered at the clinic upon completion of the pembrolizumab infusion. 
Details on the administration of niraparib can be found in the Pharmacy Manual. 
5.2.2. 
Pembrolizumab 
Pembrolizumab will be administered at the study site on Day 1 of each 21-day treatment cycle after 
all procedures and assessments have been completed as detailed in Table 6. Pembrolizumab may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle after Cycle 2 due to 
administrative reasons. 
Pembrolizumab will be administered at a dose of 200 mg IV using a 30-minute IV infusion. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. Given 
the variability of infusion pumps from site to site, however, a window between -5 minutes and +10 
minutes is permitted. 


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See Section 3.1.2.1 for the RP2D of the combination. 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of the infusion solution. 
5.3. 
Dose-Limiting Toxicity 
The following are to be considered DLTs for this study (as assessed during Cycle 1, ie, during the 
first 21 days of treatment, Day 1 through Day 21 during Phase 1): 
 Any treatment-related Grade ≥ 3 non-hematologic clinical (non-laboratory) AE 
 Any treatment-related Grade 3 or Grade 4 non-hematologic laboratory abnormality if: 
 Medical intervention is required to treat the patient, or 
 The abnormality leads to hospitalization, or 
 The abnormality persists for ≥ 7 days. 
 Any treatment-related hematologic toxicity specifically defined as:  
 Thrombocytopenia Grade 4 for ≥ 7 days, or Grade 3 or 4 associated with bleeding or 
requiring platelet transfusion;  
 Neutropenia Grade 4 for ≥ 7 days, or Grade 3 or 4 associated with infection or 
febrile neutropenia;  
 Anemia Grade 4, or Grade 3 or 4 requiring blood transfusion. 
 Any treatment-related AE leading to niraparib dose interruption per the following 
criteria:  
 A dose interruption per dose modification rules (see Section 5.4.1, Table 3) for a 
non-DLT laboratory abnormality (eg, for Grade 2 or 3 thrombocytopenia or for 
Grade 3 anemia or neutropenia) lasting ≥ 14 days. 
 A dose interruption per dose modification rules (see Section 5.4.1, Table 2) for non-
hematologic AE leading to < 80% of an intended dose being administered (eg, 
niraparib dose interruption for > 4 days within Cycle 1). 
Note that niraparib dosing has been safely managed with dose interruptions and/or adjustments for 
AEs, including laboratory abnormalities, while maintaining activity in the single-agent setting (see 
see Section 5.4.1, Table 2 and Table 3, and niraparib Investigator’s Brochure). Therefore, niraparib 
dose interruption and/or reduction for an AE that does not meet a DLT definition as described 
above will be considered a non-DLT modification. The non-DLT dose modifications will not be 
considered in determining the MTD but will be considered in determining the niraparib dose 
intensity and RP2D. 
5.4. 
Dose Modification 
Study treatment dosing interruptions are permitted in the case of medical / surgical events or 
logistical reasons not related to study therapy (eg, surgery, unrelated medical events, patient 


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vacation, and/or holidays). Patients should be placed back on study therapy within 28 days of the 
scheduled interruption, unless otherwise discussed with the Sponsor.  
All treatment interruptions and dose reductions (including any missed doses), and the reasons for 
the reductions/interruptions, are to be recorded in the electronic case report form (eCRF).  
5.4.1. 
Niraparib 
Dose interruption of niraparib may be implemented per the Investigator’s judgement after Cycle 1 
in patients enrolled in Phase 1 and at any time in patients enrolled in Phase 2. See the following 
sections for permitted duration of interruption prior to required discontinuation from treatment. 
Intra-patient Dose Escalation 
For patients in Phase 1, the dose of niraparib may be increased after Cycle 1 to a higher dose level 
that has been found to be safe during the dose escalation phase following discussion with the 
Sponsor. 
See Section 3.1.2.1 for the RP2D.  
Niraparib Dose Modifications for Non-Hematologic Toxicity 
Treatment with niraparib must be interrupted for any treatment-related non-hematologic CTCAE 
Grade 3 or 4 event. Once resolved to Grade ≤ 1, the patient may restart treatment with niraparib 
with a dose level reduction (see Table 2) unless prophylaxis is considered feasible. If the event 
recurs at a similar or worse grade, treatment should be interrupted again and, upon resolution, a 
further dose reduction must be made to a lower dose level, if available, or niraparib dosing should 
be discontinued. If the toxicity requiring dose interruption has not resolved to CTCAE Grade ≤ 1 
during a maximum 4-week (28-day) dose interruption period, and/or the patient has already 
undergone a maximum of 2 dose reductions (to a minimum dose of 100 mg QD), the patient must 
permanently discontinue treatment with niraparib. Once the dose of niraparib has been reduced, any 
re-escalation must be discussed with the Sponsor. Note that treatment with pembrolizumab may 
continue if discontinuation criteria as outlined in Section 5.4.2 have not been met. 
Table 2 
Niraparib Dose Reductions for Non-Hematologic Toxicity 
Event 
Dose
a,b 
Initial dose 
300 mg QD 
1st dose reduction for treatment-related CTCAE Grade 3 or 4 AE or 
SAE where prophylaxis is not considered feasible  
200 mg QD 
2nd dose reduction for treatment-related CTCAE Grade 3 or 4 AE or 
SAE where prophylaxis is not considered feasible  
100 mg QD 
Continued treatment-related CTCAE Grade 3 or 4 AE or SAE 
≥ 28 days  
Discontinue niraparib 
Abbreviations: AE = adverse event; CTCAE = Common Terminology for Adverse Events; QD = once daily; SAE = 
serious adverse event. 
a Dose not to be decreased below 100 mg daily. 
b If initial dose is below 300 mg, the same dose reduction principles will apply with fewer dose modification steps 
available. 


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Niraparib Dose Modifications for Hematologic Toxicity 
The dose interruption/modification criteria for niraparib for hematologic toxicities will be based on 
blood counts and are outlined in Table 3. 
For thrombocytopenia, patients with a platelet count ≥ 25,000 to < 75,000/µL must have niraparib 
interrupted and have blood counts monitored twice weekly until recovery to ≥ 100,000/µL; upon 
recovery, niraparib can be resumed at the same dose for the first occurrence with once weekly 
monitoring for 3 weeks to confirm no recurrence of thrombocytopenia. For a further recurrence of 
platelet count at this level or any occurrence of platelet count < 25,000/µL, dose interruption 
followed by dose reduction upon recovery to ≥ 100,000/µL with subsequent monitoring once 
weekly for 3 weeks to ensure the safety of the new dose level is required (see Table 2).  
For Grade 3 or 4 neutropenia or anemia, treatment with niraparib must be interrupted with blood 
counts monitored twice weekly for neutropenia and once or twice weekly for anemia until recovery 
to ≤ Grade 1. Niraparib dosing should be resumed with a dose level reduction (see Table 2) at that 
time and the patient monitored once weekly for 3 weeks to ensure the safety of the new dose level. 
If clinically indicated, use of G-CSF is allowed according to current American Society of Clinical 
Oncology (ASCO) guidelines.(60) 
If the hematologic toxicity does not recover to the specified level within 4 weeks (28 days) of dose 
interruption and/or the patient has already undergone a maximum of 2 dose reductions (to a 
minimum dose of 100 mg QD), then niraparib should be discontinued.  
Any patient requiring transfusion of platelets or red blood cells (1 or more units) or hematopoietic 
growth factor support must undergo a niraparib dose reduction upon recovery if study treatment is 
resumed. 
It is strongly recommended that the patient be referred to a hematologist for further evaluation (1) if 
transfusions are required on more than 1 occasion or (2) if the treatment-related hematologic 
toxicities have not recovered to CTCAE ≤ Grade 1 within 4 weeks. If a diagnosis of MDS/AML is 
confirmed by a hematologist, the patient must permanently discontinue niraparib. Note that 
treatment with pembrolizumab may continue following discussion with the Sponsor if 
discontinuation criteria as outlined in Section 5.4.2 have not been met. 
The reason for interruption, reduction, or discontinuation of niraparib should be recorded in the 
eCRF. 


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Table 3 
Management of Hematologic Toxicities* 
Laboratory Abnormality 
Intervention 
Platelet count 25,000 to < 75,000/μL  
Niraparib must be interrupted until platelet count is ≥ 100,000/μL 
with twice-weekly CBC monitored until recovery. Niraparib may 
then be resumed at same dose. After recovery, blood counts once 
weekly for 3 weeks. 
Further occurrence of platelet count 
25,000 to < 75,000/μL 
 
Niraparib must be interrupted until platelet count is ≥ 100,000/μL 
with twice-weekly CBCs monitored until recovery. Niraparib may 
then be resumed at a reduced dose (see Table 2 ); after recovery, 
blood counts once weekly for 3 weeks to ensure the safety of the 
new dose level. A further dose reduction
a should be made if an 
additional treatment interruption is needed in less than 3 weeks after 
resuming treatment.  
Platelet count < 25,000/μL
b 
Niraparib must be interrupted until platelet count is ≥ 100,000/μL 
with twice-weekly CBCs monitored until recovery. Niraparib may 
then be resumed at a reduced dosea (see Table 2 ); after recovery, 
blood counts once weekly for 3 weeks to ensure the safety of the 
new dose level. 
Neutrophil < 1,000/μL 
Niraparib must be interrupted until neutrophil counts are ≥ 1,500/μL 
with twice-weekly CBCs monitored until recovery. Niraparib may 
then be resumed at a reduced dosea (see Table 2 ); after recovery, 
blood counts once weekly for 3 weeks to ensure the safety of the 
new dose level. 
Hemoglobin ≤ 8 g/dL 
Niraparib must be interrupted until hemoglobin is ≥ 9 g/dL with 
once- or twice-weekly CBCs monitored until recovery. Niraparib 
may then be resumed at a reduced dosea (see Table 2 
); after 
recovery, blood counts once weekly for 3 weeks to ensure the safety 
of the new dose level. 
Abbreviations: CBC = complete blood count. 
* If blood counts do not recover within 28 days to normal values (ie, platelets ≥ 100,000/μL, hemoglobin ≥ 9 g/dL, 
neutrophils ≥ 1,500/μL) niraparib should be discontinued. 
a Dose not to be decreased below 100 mg daily. 
b For patients with platelet count ≤ 10,000/μL, prophylactic platelet transfusion per guidelines should be considered.(61, 
62) For patients taking anticoagulation or antiplatelet drugs, consider the risk/benefit of interrupting these drugs and/or 
prophylactic transfusion at an alternate threshold, such as ≤ 20,000/μL. 
5.4.2. 
Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These AEs may occur shortly after the first dose or several 
months after the last dose of treatment. Pembrolizumab must be withheld for drug-related toxicities 
and severe or life-threatening AEs per Table 4. See also Section 6.1.6, Events of Clinical Interest 
(ECIs). 
Table 4 provides detailed information for dose interruptions and discontinuations related to toxicity 
for pembrolizumab. No dose reductions of pembrolizumab are permitted. Note that treatment with 


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niraparib may continue following discussion with the Sponsor if discontinuation criteria as outlined 
in Section 5.4.1 have not been met. 
The reason for interruption or discontinuation of pembrolizumab should be recorded in the eCRF. 


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Table 4 
Pembrolizumab Dose Modifications for Non-hematologic Toxicities 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation  
Diarrhea/colitis 
2-3 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
4 
Permanently discontinue. 
Permanently discontinue. 
AST, ALT, or 
increased bilirubin 
2 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue  
(see exception below).
a 
Permanently discontinue. 
Type 1 diabetes 
mellitus (if new 
onset) or 
hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence 
of beta cell failure. 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
4 
Permanently discontinue. 
Permanently discontinue. 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted. 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted. 
Infusion reaction 
2
b 
Toxicity resolves to Grade 0-1. 
Permanently discontinue if toxicity develops despite adequate 
premedication. 
3-4 
Permanently discontinue. 
Permanently discontinue. 


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Table 4 
Pembrolizumab Dose Modifications for Non-hematologic Toxicities (Continued) 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
3-4 or 
Recurrent 2 
Permanently discontinue. 
Permanently discontinue. 
Renal failure or 
nephritis 
2 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
3-4  
Permanently discontinue. 
Permanently discontinue. 
All other drug-
related toxicity
c 
3 or severe 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
4 
Permanently discontinue. 
Permanently discontinue. 
Abbreviations: AE = adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; T1DM=type 1 diabetes mellitus. 
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (eg, from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held until symptoms resolve and the subject should be premedicated  for the next scheduled dose; Refer to Section 5.7.3 
Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 


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5.5. 
Packaging, Labeling, and Storage 
Niraparib 100-mg capsules will be packed in high-density polyethylene bottles with child-
resistant closures.  
Pembrolizumab for injection is supplied as 50-mg lyophilized powder single-use vials. 
The label text of the study treatments will comply with Good Manufacturing Practice and 
national legislation to meet the requirements of the participating countries. The study treatment 
will be open-label and non-patient-specific. 
All study treatment supplies must be stored in accordance with the Pharmacy Manual 
instructions and package labeling. Until dispensed or administered to the patients, the study 
treatment will be stored in a securely locked area, accessible to authorized personnel only. 
5.6. 
Drug Accountability 
The Investigator or designee is responsible for maintaining accurate dispensing records of the 
study treatments throughout the clinical study.  
Details of maintaining drug accountability, including information on the accountability log, will 
be provided in the Pharmacy Manual. 
All dispensation and accountability records will be available for Sponsor review. The study 
monitor will assume the responsibility to reconcile the study treatment accountability log. The 
pharmacist will dispense study treatment for each patient according to the protocol and 
Pharmacy Manual, if applicable. 
5.7. 
Previous and Concomitant Medications 
Any medication the patient takes during the study other than the study treatments, including 
herbal and other nontraditional remedies, is considered a concomitant medication. All 
concomitant medications must be recorded in the eCRF. The following information must be 
recorded in the eCRF for each concomitant medication: generic name, route of administration, 
start date, stop date, dosage, and indication. Any changes in the dosage or regimen of a 
concomitant medication must be recorded in the eCRF. 
At screening, patients will be asked what medications they have taken during the last 30 days. At 
each subsequent study visit, patients will be asked what concomitant medications they are 
currently taking or have taken since the previous visit. 
Niraparib has potential to induce cytochrome P450 (CYP)1A2 and is a substrate for P-
glycoprotein (P-gp); therefore , investigators should be advised to use caution with drugs that are 
sensitive substrates for CYP1A2 (see Appendix A). 
The niraparib safety profile includes risk for thrombocytopenia; therefore, investigators should 
be advised to use caution with anticoagulation and antiplatelet drugs. 


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5.7.1. 
Prohibited Medications 
Patients are prohibited from receiving the following therapies during the screening and treatment 
phase of this study: 
 Antineoplastic systemic chemotherapy or biological therapy 
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than niraparib and pembrolizumab 
 Radiation therapy is prohibited if encompassing > 20% of the bone marrow within 2 
weeks or any radiation therapy within 1 week prior to study Day 1. 
Note: The following may be considered exceptions on a case-by-case basis after 
consultation with the Sponsor: Radiation therapy to pre-existing small areas of 
painful metastases that cannot be managed with local or systemic analgesics 
(excluding palliative radiotherapy encompassing > 20% of the bone marrow) as long 
as no evidence of disease progression is present. The patient must have clear 
measurable disease outside the radiated field. Administration of palliative radiation 
therapy may be considered clinical progression for the purposes of determining PFS. 
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
ECI of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
Note: Inhaled steroids are allowed for the management of asthma. 
 Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, bacille 
Calmette-Guerin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed. Intranasal influenza 
vaccines (eg, Flu-Mist®) are live attenuated vaccines, however, and are not allowed. 
 Prophylactic cytokines (G-CSF) should not be administered in the first cycle of the 
study but may be administered in subsequent cycles according to current ASCO 
guidelines.(60) 
If there is a clinical indication for any medication or vaccination specifically prohibited during 
the study, discontinuation from study therapy may be required. The Investigator should discuss 
any questions regarding this with the Sponsor. The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the patient’s primary physician. The decision to 
continue the patient on study therapy, however, requires the mutual agreement of the 
Investigator, the Sponsor, and the patient. 
5.7.2. 
Contraception 
Pembrolizumab and niraparib are known to have properties that require the patient to use 
contraception. For details on niraparib, please refer to the Investigator’s Brochure.  


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Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. Therefore, 
non-pregnant, non-breastfeeding women may only be enrolled if they are willing to use 2 
methods of birth control or are considered highly unlikely to conceive. Highly unlikely to 
conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥ 45 years 
of age and has not had menses for > 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study. The 2 birth control methods can be either 2 
barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Patients 
should start using birth control from screening throughout the study period up to 120 days after 
the last dose of pembrolizumab.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide per local regulations or guidelines. 
Appropriate hormonal contraceptives will include any registered and marketed contraceptive 
agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, or intramuscular agents). Abstinence is acceptable if this is the established and 
preferred contraception for the patient.  
Patients should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of the 
study and through 120 days after the last study treatment. If there is any question that a patient 
will not reliably comply with the requirements for contraception, that patient should not be 
entered into the study. 
5.7.3. 
Rescue Medications and Supportive Care Guidelines During Treatment with 
Pembrolizumab 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
Investigator. Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined below. Note that several courses of steroid tapering may be 
necessary, as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral 
infection, which might require additional supportive care. The treatment guidelines are intended 
to be applied when the Investigator determines the events to be related to pembrolizumab.  
Note: it may be necessary to perform additional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
The following text details specific guidance by type of AE. 
 Pneumonitis: 
 For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. 
 For Grade 3-4 events, immediately treat with IV steroids. Administer additional 
anti-inflammatory measures, as needed. 


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 Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 Diarrhea/Colitis: 
Patients should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).  
 All patients who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, 
consider gastrointestinal consultation and endoscopy to confirm or rule out colitis. 
 For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
 For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with IV steroids 
followed by high-dose oral steroids.  
 When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis: 
 For Type 1 diabetes mellitus or Grade 3-4 hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 Hypophysitis: 
 For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 


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 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
 Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (eg, propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyronine, is indicated per standard of care. 
 Grade 3-4 hyperthyroidism 
 Treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 Hepatic: 
 For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids. 
 For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
 When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 Renal Failure or Nephritis: 
 For Grade 2 events, treat with corticosteroids. 
 For Grade 3-4 events, treat with systemic corticosteroids. 
 When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 Management of Infusion Reactions: 
Signs and symptoms usually develop during or shortly after drug infusion and 
generally resolve completely within 24 hours of completion of infusion.  
Table 5 shows treatment guidelines for patients who experience an infusion reaction 
associated with administration of pembrolizumab. 


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Table 5 
Pembrolizumab Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at  
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically stable 
in the opinion of the Investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤ 24 hrs 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy may include 
but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically stable 
in the opinion of the Investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/hr to 
50 mL/hr). Otherwise dosing will be held until 
symptoms resolve and the patient should be 
premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study treatment 
administration. 
Patient may be 
premedicated 1.5 hour 
(± 30 minutes) prior to 
infusion of 
pembrolizumab with: 
Diphenhydramine 
50 mg PO (or 
equivalent dose of 
antihistamine). 
Acetaminophen 500-
1000 mg PO (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg, 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically stable 
in the opinion of the Investigator. 
Hospitalization may be indicated. 
Patient is permanently discontinued from further 
study treatment administration. 
No subsequent dosing 
Abbreviations: IV=intravenous; NSAID=nonsteroidal anti-inflammatory; PO=oral. 
Note: Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. 


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5.7.4. 
Other Study Restrictions 
Patients who are blood donors should not donate blood during the study and for 90 days after the 
last dose of study treatment. 
Patients should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea, or vomiting. 


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6. 
ENDPOINTS AND METHODS OF ASSESSMENT 
6.1. 
Safety Endpoints 
Safety parameters evaluated during the conduct of the study include treatment-emergent AEs 
(TEAEs), clinical laboratory values (hematology, chemistry, coagulation, thyroid function, 
urinalysis), vital signs, ECGs, physical examination findings, and use of concomitant 
medications. Additionally, the relationship between cytogenetic abnormalities and safety 
parameters may be explored. 
6.1.1. 
Definitions 
Adverse event: An adverse event is any untoward medical occurrence that occurs in a patient or 
clinical investigation subject administered a pharmaceutical product, and which does not 
necessarily have to have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including clinically significant abnormal laboratory findings), 
symptom, or disease temporally associated with the use of an investigational product, whether or 
not considered related to the product. 
Adverse events may include the onset of new illness and the exacerbation of pre-existing medical 
conditions. An AE can include an undesirable medical condition occurring at any time, including 
baseline or washout periods, even if no study treatment has been administered. 
A treatment-emergent adverse event will be defined as any new AE that begins, or any 
preexisting condition that worsens in severity, after at least 1 dose of study treatment has been 
administered. 
Serious adverse event: A serious adverse event is defined as any untoward medical occurrence 
that, at any dose: 
 Results in death 
 Is life-threatening 
 Note: This means that the patient is at immediate risk of death at the time of the 
event; it does not mean that the event hypothetically might have caused death if it 
were more severe 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Any AE that prolongs hospitalization will be considered an SAE. 
 Exception: Planned hospitalization (eg, for observation, protocol compliance, 
elective procedures, social reasons, etc.) will not be considered an SAE; however, 
the reason for the planned hospitalization should be captured in medical history. 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 


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 Is an important medical event(s) 
 An important medical event may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or require intervention to 
prevent one of the above outcomes. Examples of such events are intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
6.1.2. 
Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to intensity and causality with regard to 
study treatment as outlined in the following sections. 
6.1.2.1. 
Intensity 
Investigators should assess the severity of AEs according to CTCAE. In general, CTCAE (v4.03) 
severity grades are: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). (Instrumental ADL refer 
to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.) 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. (Self-care ADL refer to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden.) 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
A distinction should be made between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria above in Section 6.1.1. For example, a mild degree 
of gastrointestinal bleeding requiring an overnight hospitalization for monitoring purposes may 
be considered an SAE but is not necessarily severe. Similarly, an AE that is severe in intensity is 
not necessarily an SAE. For example, alopecia may be assessed as severe in intensity but may 
not be considered an SAE. 
6.1.2.2. 
Causality 
The Investigator will assess the causality/relationship between the study drug and the AE. One of 
the following categories should be selected based on medical judgment, considering the 
definitions and all contributing factors: 
 Related: A clinical event, including laboratory test abnormality, occurs in a plausible 
time relationship to treatment administration, and which concurrent disease or other 


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drugs or chemicals cannot explain. The response to withdrawal of the treatment 
should be clinically plausible. 
 Possibly related: A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the treatment, unlikely to be attributed 
to concurrent disease or other drugs or chemicals. 
 Unlikely related: A clinical event, including laboratory test abnormality, with a 
temporal relationship to treatment administration which makes a causal relationship 
improbable, or in which other drugs, chemicals or underlying disease provide likely 
explanations. 
 Unrelated: A clinical event, including laboratory test abnormality, with little or no 
temporal relationship with treatment administration. Typically explained by 
extraneous factors (eg, concomitant disease, environmental factors, or other drugs or 
chemicals). 
6.1.3. 
Collecting and Recording Adverse Events 
All AEs, regardless of the source of identification (eg, physical examination, laboratory 
assessment, ECG, reported by patient), must be documented in the eCRF. 
All AEs will be collected and recorded in the eCRF for each patient from the day of signed 
informed consent until 30 days after the last dose of study treatment; SAEs will be monitored 
through 90 days after the last dose of study treatment (or to a minimum of 30 days post-treatment 
if the patient starts alternate anticancer therapy). 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 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. 
If an Investigator becomes aware of an SAE after the specified follow-up period post treatment 
discontinuation and considers the SAE related to investigational product, the Investigator should 
report the SAE to the Sponsor according to timelines for reporting SAEs described in this 
section. 
Adverse events may be volunteered spontaneously by the study patient, or discovered by the 
study staff during physical examinations or by asking an open, non-leading question such as: 
“How have you been feeling since you were last asked?” The Investigator will document the 
nature of AE, date of onset of the AE (and time, if known), date of outcome of the AE (and time, 
if known), severity of the AE, action taken with study drug as a result of the AE, assessment of 
the seriousness of the AE, and assessment of the causal relationship of the AE to study drug 
and/or study procedure. 
All AEs should be recorded individually in the patient’s own words (verbatim) unless, in the 
opinion of the Investigator, the AEs constitute components of a recognized condition, disease, or 
syndrome. In the latter case, the condition, disease, or syndrome should be named rather than 
each individual symptom. 


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Concomitant illnesses that existed before entry into the study will not be considered an AE 
unless the illness worsens during the treatment period. Pre-existing conditions will be recorded in 
the eCRF as well as on the SAE Report Form medical history section. 
6.1.4. 
Reporting Disease Progression 
The event of disease progression is an efficacy criterion and is therefore not considered an AE. 
Disease progression should be reported within the eCRF. If AEs/SAEs occur in relation to 
disease progression, the AEs/SAEs must be reported per AE/SAE reporting requirements 
described in Section 6.1.3 and Section 6.1.5. 
6.1.5. 
Serious Adverse Events 
6.1.5.1. 
Reporting of Serious Adverse Events  
The Investigator must report all SAEs within 24 hours of becoming aware of the initial SAE or 
any follow-up information regarding the SAE using the SAE reporting contact information as 
printed on the SAE forms and in the SAE Completion guidelines. 
For all SAEs, an SAE report form must be completed by the Investigator for all initial and 
follow-up SAEs. A follow-up SAE report must be completed each time an Investigator becomes 
aware of any additional information regarding the SAE. For the follow-up SAE Report Form, the 
following fields must be completed on each form: follow-up number, site number, patient/subject 
number, protocol number, and the SAE term(s) and date of awareness. Additionally, only the 
appropriate field(s) on the SAE Report Form where the Investigator received additional or 
updated information should be completed. Previously provided information does not have to be 
entered on the follow-up SAE Report Form. 
Initial and follow-up SAE reports and any additional supporting documentation (eg, hospital 
reports, consultant reports, death certificates, autopsy reports, etc.) included with the SAE report 
should be sent to the Sponsor (or designee) within 24 hours of the Investigator/site awareness or 
receipt. If supporting documentation is provided, the Investigator should highlight all relevant 
and pertinent information. Also, any additional SAE documentation must be a clear photocopy 
with the patient’s personal identifiers removed. The Investigator must sign and date all SAE 
forms. 
The minimum information required for an initial SAE report is: 
 Name of person sending the report (ie, name, address of Investigator) 
 Patient identification (screening/randomization number, initials [if permitted by local 
data privacy regulations], NOT patient name) 
 Protocol number 
 Description of SAE 
 Causality assessment 
 Seriousness assessment 
In case the Investigator has no ability to either fax or email an SAE (eg, due to technical issues), 
pharmacovigilance can be contacted by phone. If an SAE is reported via phone and during usual 


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business hours, the Sponsor pharmacovigilance (or designee) will capture the information on a 
telephone contact form or similar method. Outside usual business hours, the message will be 
recorded and the required follow-up actions initiated during the next business day. Once 
technical issues are resolved, the Investigator should fax or email the completed SAE form to the 
Sponsor (or designee). 
After receipt of the initial report, the Sponsor (or designee) will review the information and, if 
necessary, contact the Investigator to obtain further information. 
6.1.5.2. 
Submission and Distribution of Adverse Events/Serious Adverse Events 
Per regulatory requirements, if an SAE is required to be submitted to a Regulatory Authority a 
copy of this report (CIOMS or MedWatch 3500A) will be distributed to the Investigators/site. 
The Investigator/site will submit a copy the report to their respective Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC). 
6.1.6. 
Events of Clinical Interest 
Selected non-serious AEs and SAEs are also known as Events of Clinical Interest (ECIs) and 
must be recorded as such on the eCRF and reported within 24 hours to the Sponsor as noted for 
SAEs in Section 6.1.5.1. 
6.1.6.1. 
Pembrolizumab 
Patients are to be monitored through 90 days after the last dose of study treatment for the 
following ECI: 
1. An overdose of pembrolizumab that is not associated with clinical symptoms or abnormal 
laboratory results. For this study, an overdose is defined as a dose ≥ 1000 mg (5 times the 
dose) of pembrolizumab. No specific information is available on the treatment of 
overdose of pembrolizumab. In the event of overdose, the patient should be observed 
closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated 
2. An elevated AST or ALT value that is ≥ 3× ULN concurrent with an elevated total 
bilirubin value that is ≥ 2× ULN and, at the same time, an alkaline phosphatase value that 
is < 2× ULN, as determined by protocol-specified laboratory testing or unscheduled 
laboratory testing. 
Note: These criteria are based upon available regulatory guidance documents.(63) The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent). 
6.1.6.2. 
Niraparib 
Patients are to be monitored through 90 days after the last dose of study treatment for the 
following ECI: 
1. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). ECIs must be 
reported to the Sponsor as soon as the Investigator becomes aware of them. 


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2. An overdose is defined as the accidental or intentional ingestion or infusing of any dose 
of study treatment that exceeds the dose described in the protocol. Overdoses are not 
considered AEs; however, all overdoses should be recorded on a Serious Adverse Event 
Form (Section  6.1.5.1) within 24 hours of becoming aware. An overdose should be 
reported even if it does not result in an AE. Overdoses do not need to be recorded on the 
eCRF; dosing information is recorded on the eCRF. 
3. In conjunction with the survival assessment, new malignancy information will be 
collected for all patients via telephone every 90 (±14) days (Section 7.2.10). Additionally, 
the relationship between cytogenetic abnormalities and safety parameters may be 
explored. 
6.1.7. 
Pregnancy Reporting and Follow-up 
Pregnancies occurring in patients enrolled in a study or in a female partner of a male patient must 
be reported and followed to outcome. If a female patient inadvertently becomes pregnant while 
on study treatment, the patient will immediately be removed from the study. Any pregnancies 
that occur within 120 days following the last dose of study treatment must be captured in the 
eCRF. 
The Investigator should complete the Initial Pregnancy Notification report form and forward it to 
the Sponsor (or designee) within 24 hours of knowledge of the pregnancy. If there is an 
associated serious outcome, then both the Initial Pregnancy Notification report form and SAE 
report form should be completed. 
The site will follow-up with the patient at least monthly and document the patient’s status until 
the pregnancy has been completed or terminated. The Investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the fetus or 
newborn to the Sponsor. The Pregnancy Outcome report form should be completed and 
submitted to the Sponsor within 24 hours after the Investigator becomes aware of the pregnancy 
outcome. 
In the event the pregnancy outcome occurs following the end of the study and database lock, the 
Investigator will report the pregnancy outcome to the Sponsor (or designee) within 24 hours after 
the outcome of the pregnancy is known to the Investigator in accordance with the procedure for 
reporting SAEs (see Section 6.1.5). 
Pregnancy alone is not regarded as an AE unless there is a possibility that the study drug may 
have interfered with the effectiveness of a contraceptive medication. Elective abortions without 
complications should not be considered AEs unless they were therapeutic abortions. 
Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. 
Pregnancy is not considered an SAE unless there is an associated serious outcome. Spontaneous 
abortions should always be reported as SAEs. 
Any SAE that occurs during pregnancy must be recorded on the SAE Report Form (eg, maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, birth defect) and reported within 24 hours in accordance with the procedure 
for reporting SAEs. 


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6.1.8. 
Clinical Laboratory Assessments 
The following laboratory variables will be determined in accordance with the schedule of events 
(Table 6). These tests will be performed by the local laboratory at the clinical site. 
 Complete blood count: 
 Hemoglobin 
 Platelets 
 Mean corpuscular volume 
 Mean platelet volume (optional)* 
 White blood cell count 
 Differential white cell count 
* Note: Although mean platelet volume collection is optional, it is highly encouraged, 
especially for patients with high-grade thrombocytopenia. 
 Coagulation factors: 
 International normalized ratio 
 Activated partial thromboplastin time 
 Serum chemistry: 
 Sodium 
 Amylase 
 Potassium 
 Total bilirubin 
 Calcium 
 Alkaline phosphatase 
 Magnesium 
 Aspartate aminotransferase 
 Chloride 
 Glucose (fasting at baseline) 
 Alanine aminotransferase 
 Total protein 
 Creatinine  
 Albumin  
 Urea or blood urea nitrogen 
 Lactate dehydrogenase  
 Urinalysis: 
 Specific gravity 
 Protein 
 Leukocyte esterase 
 Glucose 
 Nitrite 
 Ketones 
 Blood 
 Urobilinogen 
 Bilirubin 
 
 TSH, T3, or FT3, and FT4 
 Serum CA-125 (OC patients only) 
 Serum pregnancy testing / urine pregnancy testing 


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Any laboratory values assessed as clinically significant should be recorded as an AE. If SAE 
criteria are met or the laboratory abnormality is an ECI (see Section 6.1.6), the event should be 
recorded and reported according to the SAE reporting process (see Section 6.1.5). 
Hematological testing may occur more frequently than is specified in Table 6 when additional 
testing is medically indicated per Investigator judgment or if the event meets the criteria for 
niraparib dose modification (see Section 5.4.1). Additional tests may be performed at a 
laboratory facility other than the study site, but test results must be reported to the study site, the 
study site must keep a copy of test results with the patient’s study file, and the results must be 
entered into the eCRF. 
It is strongly recommended that any suspected MDS/AML case reported while a patient is 
receiving treatment or followed for post-treatment assessments be referred to a local 
hematologist, who must perform bone marrow aspirate and biopsy testing. 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 World Health Organization (WHO),(64) and other sample testing reports related to MDS/AML. 
Report data will be entered in the appropriate eCRF pages and the site must keep a copy of all 
reports with the patient’s study file. 
Whole blood samples will be collected prior to the start of the study drug and at treatment 
discontinuation for cytogenetic analysis. Further details on sample collection and analysis can be 
found in the Study Manual. 
6.1.9. 
Physical Examination and Vital Signs 
Physical examinations, including height (screening only), weight, and vital signs (blood pressure 
[BP], pulse, and temperature), will be performed in accordance with the schedule of events 
(Table 6). 
Any physical examination or vital signs assessed as clinically significant should be recorded as 
an AE or SAE. If SAE criteria are met or the abnormality is an ECI (see Section 6.1.6), the event 
should be recorded and reported according to the SAE reporting process (see Section 6.1.5). 
6.1.10. 
Eastern Cooperative Oncology Group Performance Status 
Performance status will be assessed using the ECOG scale (see Appendix G) in accordance with 
the schedule of events (Table 6). The same observer should assess performance status each time. 
6.1.11. 
Additional Safety Assessments 
All patients will undergo ECGs in accordance with the schedule of events (Table 6). 
Electrocardiograms should be performed prior to blood draws for PK. Patients will be supine and 
rested for approximately 2 minutes before ECGs are recorded. 
Any ECG findings assessed as clinically significant should be recorded as an AE. If SAE criteria 
are met or the abnormality is an ECI (see Section 6.1.6), the event should be recorded and 
reported according to the SAE reporting process (see Section 6.1.5). 


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6.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics consist of those variables that are assessed at 
screening/baseline. 
6.2.1. 
Patient Eligibility 
Compliance with inclusion and exclusion criteria will be assessed as outlined in Section 4.1 and 
Section 4.2. 
6.2.2. 
Patient Demography 
Patient demography consists of age at screening, race, ethnicity, and sex. 
6.2.3. 
Disease History 
For disease history the following will be documented: 
 Date of first diagnosis 
 Tumor type 
 Stage at time of initial diagnosis 
 Histology and grade of disease at diagnosis and most recent biopsy if additional 
biopsy performed 
 Information on first anticancer treatment: 
 Intent (adjuvant, neoadjuvant, curative, palliative) (TNBC patients) 
 Date of start of first treatment 
 Agents used in first treatment 
 Date of last dose of first treatment 
 Information on second and subsequent anticancer treatments: 
 Intent (adjuvant, neoadjuvant, curative, palliative) (TNBC patients) 
 Dates of start of all subsequent treatments 
 Agents in all subsequent treatments 
 Dates of last dose of all subsequent treatments 
 Best response and toxicities (including hematologic events) for each prior anticancer 
treatment 
 Date of recurrence for each prior anticancer treatment 
6.2.4. 
Medical and Surgical History 
Major medical and surgical history (including medication history), including history of 
thrombocytopenia, neutropenia, leukopenia, or anemia, will be collected. Details of any prior 
invasive malignancy will be collected. Medical and surgical history will be obtained by 
interviewing the patient or by reviewing the patient’s medical records. 


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6.2.5. 
Previous and Concomitant Medications 
Previous and concomitant medication will be documented as described in Section 5.7  
Medications will be coded using World Health Organization Anatomical Therapeutic Chemical 
classification. 
6.3. 
Efficacy Endpoint(s) 
6.3.1. 
Evaluation of Tumor Response 
6.3.1.1. 
Overview 
The efficacy of combination treatment with niraparib and pembrolizumab will be evaluated by 
assessment of tumor response to treatment according to RECIST v1.1 (65) and irRECIST (see 
Section 6.3.1.3 and Section 6.3.1.4, respectively) per investigator assessment. Tumor marker 
data (CA-125) will not be used for defining objective responses or disease progression; however 
CA-125 can be used for clinical decisions. Clinical criteria such as the GCIG criteria (66) (see 
Appendix F) will also be considered for management of OC patients with clinical events (eg, 
bowel obstruction) without radiographic evidence of disease progression. The Study Committee 
will adjudicate such cases (see Section 9.12). 
Response to treatment will primarily be based on Investigator evaluation of radiographic images. 
All radiographic images/scans at the time points specified in Table 6, as well as any unscheduled 
images/scans, will be sent by the study sites to the central imaging vendor upon acquisition and 
archived for potential future evaluation. 
The process for image collection and transmission to the central imaging vendor can be found in 
the Site Imaging Manual. 
Tumor imaging (chest, abdomen, and pelvis [plus brain if clinically indicated]) should be 
performed by CT (preferred). Magnetic resonance imaging should only be used when CT is 
contraindicated or for imaging of the brain, but the same imaging technique should be used in a 
patient throughout the study. CT scan is the more commonly used modality and is preferred for 
the majority of patients. An MRI can be utilized if clinically appropriate. Positron emission 
tomography/CT may be used according to RECIST guidelines.  
If the chest (OC patients only) and/or brain (OC and TNBC patients) CT/MRI is clear at 
screening, repeat imaging of these areas is not required in the absence of clinical indication 
requiring follow‐up. 
Bone scans should be conducted per standard of care. 
6.3.1.2. 
Timing of Radiographic Evaluations 
All patients will undergo serial radiographic assessments to assess tumor response. Initial tumor 
imaging at screening must be performed within 21 days prior to the date of the first dose of study 
treatment. Scans performed prior to the signing of the ICF as part of routine clinical management 
are acceptable for use as initial tumor imaging if they are of diagnostic quality and performed 
within 21 days prior to first dose date. 


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The first on-study imaging assessment should be performed at 9 weeks (63 ± 7 days) from the 
date of first dose of study treatment; in the case of progressive disease (PD), a confirmatory 
image will be required 4 weeks later (eg, 13 weeks [91 ±7 days]) (see Section 6.3.1.4). 
Subsequent tumor imaging should be performed every 9 weeks (63 ± 7 days) or more frequently 
if clinically indicated and at the time of suspected disease progression. After 1 year of 
radiographic assessments, patients will have imaging performed every 12 weeks (84 ±7 days). 
Imaging should not be delayed for delays in cycle starts or extension of combination treatment 
cycle intervals. 
Per RECIST v1.1 (see Appendix D), CR or PR should be confirmed by a repeat tumor imaging 
assessment. The tumor imaging for confirmation of response may be performed at the earliest 
4 weeks after the first indication of response, or at the next scheduled scan (ie, 9 weeks later), 
whichever is clinically indicated. 
Continue to perform imaging until whichever of the following occurs: 
 The start of new anticancer treatment 
 Withdrawal of consent 
 Death 
 End of the study (when responder or discontinuation status for all patients is known) 
Patients who discontinue study treatment for reasons other than PD will continue post-treatment 
imaging studies for disease status follow-up at the same frequency as already followed, eg, every 
9 or 12 weeks (± 7 days) depending on the length of treatment with the study combination drugs, 
until disease progression, start of a non–study anticancer treatment, withdrawal of consent to 
study participation, becoming lost to follow-up, death, or end of the study. 
6.3.1.3. 
Assessment of Response by RECIST 
RECIST v1.1 will be used by the Investigator as the primary measure for assessment of tumor 
response, date of disease progression, and as a basis for all protocol guidelines related to disease 
status. Note that irRECIST will be followed in cases of disease progression to assess 
continuation of treatment in clinically stable patients until progression is confirmed (see 
Section 6.3.1.4).  
Details on RECIST v1.1, including evaluation of target and non-target lesions and definitions of 
response are provided in Appendix D. 
6.3.1.4. 
Assessment of Response by Immune-Related RECIST 
RECIST v1.1 will be adapted to account for the unique tumor response characteristics seen 
during treatment with pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses. The 
response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents and can manifest a clinical response after an initial increase 
in tumor burden or even the appearance of new lesions. Standard RECIST v1.1 may, thus, not 
provide an accurate response assessment of immunotherapeutic agents such as pembrolizumab. 
irRECIST will be used by local site Investigators to assess tumor response and progression and 
make treatment decisions. 


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Therefore, RECIST v1.1 will be used with the following adaptations (ie, irRECIST) (see also 
Appendix E). 
 If repeat imaging shows < 20% increase in tumor burden compared with nadir, stable 
or improved previous new lesion (if identified as cause for initial PD), and 
stable/improved non-target disease (if identified as cause for initial PD), treatment 
may be continued / resumed, and the next tumor imaging should be conducted 
according to the protocol schedule of every 9 weeks (63 ± 7 days) (or every 12 weeks 
[84 ± 7 days] if after 1 year). 
 If repeat imaging confirms PD due to any of the scenarios listed below, patients will 
be discontinued from study therapy.  
In determining whether or not the tumor burden has increased or decreased per 
irRECIST, the local site Investigator should consider all target and non-target lesions, 
as well as any incremental new lesion(s). 
If ANY of the following occur by irRECIST on repeat imaging, PD is confirmed: 
 Tumor burden remains ≥ 20% and at least 5-mm absolute increase compared with 
nadir 
 Non-target disease resulting in initial PD is worse (qualitative) 
 New lesion resulting in initial PD is worse (qualitative) 
 Additional new lesion(s) since last evaluation 
 Additional new non-target progression since last evaluation 
In patients who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a patient on study treatment until repeat imaging is obtained. This 
clinical judgment decision should be based on the patient’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data. Patients may receive pembrolizumab 
treatment while waiting for confirmation of PD if they are clinically stable as defined by the 
following criteria: 
 Absence of signs and symptoms indicating clinically significant progression of 
disease, including worsening of laboratory values 
 No decline in ECOG performance status 
 Absence of rapid progression of disease 
 Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
When feasible, patients should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some patients can have a transient tumor flare in the first few months after the 
start of immunotherapy but with subsequent disease response. Patients who are deemed clinically 
unstable are not required to have repeat imaging for confirmation of progressive disease. 


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6.3.2. 
Efficacy Endpoints 
6.3.2.1. 
Objective Response Rate 
The primary efficacy endpoint is ORR, defined as the proportion of patients achieving CR or PR 
as assessed by the Investigator per RECIST (v1.1) (Appendix D). Tumor assessments after the 
initiation of further anticancer therapy are excluded for the assessment of best overall response. 
ORR by irRECIST (Section 6.3.1.4) will also be evaluated as a secondary endpoint. 
6.3.2.2. 
Duration of Response 
Duration of response will be evaluated as a secondary endpoint and is defined as the time from 
first documentation of CR or PR by RECIST v1.1 until: (1) the time of first documentation of 
disease progression per RECIST v1.1 (Appendix D); and (2) the time of first documentation of 
disease progression per irRECIST (Section 6.3.1.4). Note that date of progression based on either 
RECIST v1.1 or irRECIST may be overwritten in patients with OC if clinical criteria 
(Appendix F) indicate earlier progression as adjudicated by the Study Committee (Section 9.12). 
DOR by irRECIST (Section 6.3.1.4) will also be evaluated as a secondary endpoint. 
6.3.2.3. 
Disease Control Rate 
Disease control rate will be assessed as a secondary endpoint and is defined as the proportion of 
patients achieving CR, PR, or stable disease (SD) as assessed by the Investigator per RECIST 
v1.1 (Appendix D) and irRECIST (Section 6.3.1.4). 
6.3.2.4. 
Progression-Free Survival 
Progression-free survival will be assessed as a secondary endpoint and is defined as the time 
from enrollment to the earlier date of assessment of progression or death by any cause in the 
absence of progression based on: (1) the time of first documentation of disease progression per 
RECIST v1.1 (Appendix D); and (2) the time of first documentation of disease progression per 
irRECIST (Section 6.3.1.4). Note that date of progression based on either RECIST v1.1 or 
irRECIST may be overwritten in patients with OC if clinical criteria (Appendix F) indicate 
earlier progression as adjudicated by the Study Committee (Section 9.12).  
6.3.2.5. 
Overall Survival 
Overall survival will be assessed as a secondary endpoint and is defined as the time from date of 
first dose of study treatment to the date of death by any cause. New malignancy information will 
also be collected as part of this assessment (Section 7.2.10).  
6.4. 
Pharmacokinetics 
Pharmacokinetic samples will be collected from patients in both Phase 1 and Phase 2. An 
overview of sampling times for blood for PK analysis and concurrent ECG assessments, see 
Table 8 (Phase 1) and Table 9 (Phase 2).  
For niraparib and major metabolite M1, the plasma samples from both Phase 1 and Phase 2 
patients will be analyzed using liquid chromatography with mass spectroscopic detection 
(LC-MS-MS). For pembrolizumab in Phase 1, serum PK samples will be collected according to 


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the schedule defined in Section 6.4.1, and the samples in an individual patient may be analyzed 
using enzyme-linked immunosorbent assay (ELISA) if required for understanding of AEs. 
The timing of each required sample collection listed in Table 7 and Table 8 for niraparib and 
major metabolite M1, and pembrolizumab for PK blood draws will be recorded.  
Complete instructions for collection, processing, shipping, and handling of samples are detailed 
in the Study Manual. 
6.4.1. 
Phase 1 
For all patients in Phase 1, blood samples for measurements of plasma levels of niraparib and 
M1 will be obtained on Day 1 of Cycles 1 and 2 at the following time points: 0 (predose within 
30 minutes) and 1 hour (±5 minutes), 2 hours (±5 minutes), 4 hours (±5 minutes), 6 hours (±5 
minutes), 8 hours (±10 minutes), and 24 hours (±30 minutes) postdose. 
In addition, blood samples for measurements of drug levels of niraparib and M1 will be obtained 
on Day 1 of Cycles 4 and 8 at the following time points: 0 (predose within 30 minutes) and 2 
hours (±15 minutes) postdose.  
For all patients in Phase 1, blood samples for pembrolizumab will only be analyzed to 
understand an AE in an individual patient. The samples will be collected according to the 
following schedule, stored, and analyzed as needed. Predose blood samples for trough 
measurement of serum levels of pembrolizumab will be obtained at Cycles 1, 2, 4, and 8. All 
predose trough samples should be drawn within 30 minutes (±5 minutes) before infusion of 
pembrolizumab. Additional postdose peak PK serum samples will be drawn within 30 minutes 
after the end of the pembrolizumab infusion at Cycles 1 and 8. An additional single PK serum 
sample should be drawn at 24 hours (±30 minutes) (Day 2), 168 hours (±2 hours) (Day 8), and 
336 hours (±4 hours) (Day 15) after Cycle 1 dosing.  
6.4.2. 
Phase 2 
For patients in Phase 2, blood samples for measurements of plasma levels of niraparib and M1 
will be obtained on Day 1 of Cycles 1, 2, 4, and 8 at the following time points: 0 (predose within 
30 minutes) and 2 hours (±15 minutes) postdose. 
6.4.3. 
Determination of Pharmacokinetic Parameters 
Model predicted area under the concentration × time curves (AUCs) will be derived. Parameters 
of interest are AUC, minimum concentration (Cmin), maximum concentration (Cmax), clearance 
after oral administration (CL/F), volume of distribution after oral administration (Vz/F), AUC at 
steady state (AUCss), Cmin at steady state (Cmin,ss), and Cmax at steady state (Cmax,ss). 
6.5. 
Biomarkers 
Biomarker classifiers will be evaluated in archival OC and TNBC tumor samples obtained 
during screening. In addition, in the subset of patients who undergo serial biopsies, biomarkers 
will be evaluated in fresh tumor samples obtained at screening, 1 to 3 days before or on C3D1 
prior to pembrolizumab infusion and, whenever possible, at the time of disease progression. Core 
biopsies (3 to 6) are preferred; fine needle aspirate, frozen sample, plastic embedded sample, cell 
block, clot, or cytologic specimen will not be acceptable for analysis.  


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Blood samples for biomarker analysis will be obtained predose on Day 1 of Cycles 1 and Cycle 
2, as well as at the EOT visit for analysis of tumor-related circulating biomarkers, such as 
circulating tumor cells and circulating tumor DNA. Biopsy samples will be collected and 
managed centrally, and tumor sections will be distributed to the designated translational research 
laboratories. DNA/RNA will be extracted from samples at a central location and analyzed for 
exploratory biomarkers including HRD mutational status of genes relevant for OC and TNBC,  
and RNA expression. Immunohistochemistry for PD-L1, as well as additional immune 
checkpoint proteins and markers for infiltrating immune cellswill also be performed. Other 
exploratory analyses may be performed with the remaining samples. 
HRD status, PD-L1 positivity and other biomarkers will be correlated with efficacy outcomes. 
Special attention will be devoted to subsets of OC and TNBC which may have distinct 
underlying DNA repair pathway deficiency (homologous recombination, nucleotide excision 
repair (NER), and mismatch repair (MMR) deficiency) and distinct drug responses. 
Details on blood and tissue sample collection and analysis can be found in the Study Manual. 
Samples from blood and tumor will be stored and may be used at a later time for biomarker 
testing, including potential to bridging to candidate companion diagnostic assays.  


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7. 
STUDY CONDUCT 
7.1. 
Schedule of Procedures 
A schedule of study procedures is provided in Table 6 and Table 7. 


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Table 6 
Schedule of Events  
Cycle/Visit: 
Screening 
Cycle 1 
Subsequent Cycles1 
EOT2 
Safety 
Follow-up 
Follow-up 
Assessments 
(every 90 ± 
14 days) via 
telephone 
 
Day: 
Procedure: 
-21 to -1 
1 
23 
84 
15 
Cycle n,  
Day 1 
Cycle 2, 
Day 23 
30 + 7 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical, surgical, cancer, and medication 
history 
X 
 
 
 
 
 
 
 
 
 
Archival tissue5 
X 
 
 
 
 
 
 
 
 
 
Optional serial tumor biopsy6 
X 6,7 
 
 
 
 
X6 
 
X6 
 
 
Blood sample for exploratory biomarkers 
 
X 
 
 
 
X8  
 
X 
 
 
Blood sample for PK9 
 
X 
X3 
X3 
X3 
X 
X3 
 
 
 
Tumor assessment (RECIST and 
irRECIST) 
X7,10 
 
 
 
 
X10 
 
X10 
X10 
X10 
Laboratory assessments: 
 
 
 
 
 
X11 
 
 
X12 
 
CBC13 
X7 
X14 
 
X4 
X 
X 
 
X 
X 
 
Serum chemistry 
X7 
X14 
 
 
X 
X 
 
X 
X 
X15 
Coagulation 
X7 
 
 
 
X3 
X3,16 
 
 
 
 
Pregnancy test 
X7,17 
 
 
 
 
X17 
 
 
X17 
X17 
Serum CA-125 (OC patients only) 
X7 
X14 
 
 
 
X 
 
X18 
X18 
 
Urinalysis 
X7 
X14 
 
 
 
X 
 
X 
X 
 
TSH, T3 or FT3, and FT4 
X7,19 
 
 
 
 
X19 
 
X19 
X19 
 
ECG 
X7,20 
X20 
 
 
 
X20 
 
X20 
 
 
Physical examination 
X7 
 
 
 
 
 
 
X 
 
 


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Cycle/Visit: 
Screening 
Cycle 1 
Subsequent Cycles1 
EOT2 
Safety 
Follow-up 
Follow-up 
Assessments 
(every 90 ± 
14 days) via 
telephone 
 
Day: 
Procedure: 
-21 to -1 
1 
23 
84 
15 
Cycle n,  
Day 1 
Cycle 2, 
Day 23 
30 + 7 days 
Symptom-directed physical examination 
 
X 
 
 
X 
X 
 
 
X 
 
Vital signs, height, and weight21 
X7 
X 
 
X3 
X 
X 
 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
X 
 
X 
 
 
Concomitant medications 
X 
X 
 
X3 
X 
X 
 
X 
X 
 
Adverse event monitoring 
X 
X 
 
X3 
X 
X 
 
X 
X22 
X22 
Pembrolizumab study treatment  
administered23 
 
X 
 
 
 
X 
 
 
 
 
Niraparib study treatment 
dispensed/collected24 
 
X25 
 
 
 
X25 
 
X 
 
 
Survival assessment, including new 
malignancy information 
 
 
 
 
 
 
 
 
 
X 
Sample collection (whole blood) for 
cytogenetic analysis 
X26 
 
 
 
 
 
 
X26 
 
 
Bone marrow aspirate and biopsy and 
sample collection (whole blood) for 
cytogenetic analysis 
 
X27 
 
Abbreviations: AE = adverse event; CBC = complete blood count; CT = computed tomography; ECG = electrocardiogram; ECI = event of clinical interest; 
ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; irRECIST = immune-related RECIST; IV = intravenous; MDS = myelodysplastic 
syndrome; MRI = magnetic resonance imaging; OC = ovarian cancer; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; 
RP2D = recommended Phase 2 dose; SAE = serious adverse event; TNBC = triple-negative breast cancer. 
1 Treatment cycles are 21 days long, with visits on Day 1 of each cycle beyond Cycle 1 unless otherwise specified. Visits for subsequent cycles continue every 21 
days (± 3 days) until study treatment discontinuation. 
2 EOT visit should be completed within 7 days of the last dose of study drug. 
3 Required for Phase 1 patients only. 
4 Patients in Phase 1 are required to have an in-clinic visit on Day 8 with CBC done at the study center’s laboratory. For patients in Phase 2, collection of blood 
for the Cycle 1/Day 8 CBC may be done at the study center’s laboratory or at a laboratory local to the patient, if approved by the Principal Investigator as an 


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adequate laboratory. The laboratory must have the capability to provide results to the Principal Investigator electronically or by fax within 24 hours of blood 
collection. 
5 For patients who do not have archival tissue, tissue from a fresh biopsy must be obtained prior to study treatment initiation. See the Study Manual for details on 
sample collection and processing.  
6 In patients who consent to serial biopsies, fresh tumor sample is to be obtained at screening, 1 to 3 days before or on C3D1 prior to pembrolizumab infusion, 
and when possible, at the time of disease progression. See the Study Manual for details on sample collection and processing. The serial biopsies at different 
time points should be on the same lesion preferably. A core biopsy is recommended; if an excisional or incisional biopsy is to be performed, it must be 
conducted on a non-target lesion. If a patient has had a biopsy within 12 weeks prior to entering screening, that biopsy may be accepted as the screening biopsy. 
7 Standard of care tests/procedures, including biopsy, radiographic scans, laboratory assessments (fasting glucose at baseline), ECG, physical examination, vital 
signs, height, and weight, performed prior to the patient signing the informed consent form can be used as part of the screening assessments as long as the 
tests/procedures meet the protocol-required timelines (ie, within 21 days of first dose for these procedures with the exception of the biopsy, which may have 
been conducted within 12 weeks of first dose, and pregnancy test, which must be conducted within 72 hours of first dose) and any relevant guidelines (eg, 
diagnostic quality for scans). 
8 Required on Day 1 of Cycle 2 only. 
9 Blood samples are to be obtained for niraparib and major metabolite M1, pembrolizumab PK assessments; see Table 8 and Table 9 for the detailed schedule. 
10Tumor assessment per RECIST and irRECIST via CT or MRI (chest, abdomen, and pelvis [brain, only if clinically indicated]) required at screening, every 9 
weeks (63 ±7 days) from Cycle 1/Day 1 for the first year, and then every 12 weeks (84 ±7 days) until progression; at the time of progression, a final follow up 
set of images is required if not done within the last 4 weeks. The same modality (CT or MRI) should be used throughout the study for a given patient. If the 
chest (OC patients only) or brain (OC and TNBC patients) CT/MRI is clear at screening, repeat imaging of these areas is not required in the absence of clinical 
indication requiring follow‐up. Positron emission tomography/CT may be used according to RECIST v1.1 guidelines. Bone scans should be conducted per 
standard of care. Timing of images 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 a reason other than progression or death, withdrawal of consent, or loss to follow-
up, scans and CA-125 testing (OC patients only) should continue at the specified intervals.  
11 May be done within 24 hours prior to the visit. 
12 May be done at the study center’s local laboratory or at a laboratory local to the patient if the laboratory is included on FDA Form 1572. 
13 If dose interruption or modification is required at any point on study because of hematologic toxicity, twice-weekly (thrombocytopenia or neutropenia) or once 
weekly (anemia) blood draws (CBC) will be monitored until the AE resolves, and to ensure safety of the new dose, weekly blood draws for CBC will also be 
required for a subsequent 3 week cycle after the AE has been resolved to the specified levels, after which monitoring every 3 weeks may resume. 
14 If screening laboratory testing (CBC, serum chemistry, CA-125, urinalysis) is performed within 72 hours of first dose of study treatment on Day 1, repeat 
testing is not required. 
15 Serum chemistry to be conducted on Day 90 post-treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy) to 
assess for possible ECI (see Section 6.1.6). The assessment may be done at the study center’s laboratory or at a laboratory local to the patient, if approved by 
the Principal Investigator as an adequate laboratory. This should be the same laboratory as conducted any Cycle 1/Day 8 CBC samples. 
16 Required for Phase 1 patients only. Required on Day 1 of Cycle 2 and Cycle 3 only. 
17 Negative serum pregnancy test required within 72 hours prior to first dose of study treatment on Day 1 for females of childbearing potential; urine pregnancy 
test conducted every 3 cycles for duration of study (ie, Cycle 4, Cycle 7, etc.) and at the 30-day safety follow-up visit. Pregnancy status must be determined 120 
days post treatment. 
18 If a patient discontinues treatment for a reason other than progression or death, withdrawal of consent, or loss to follow-up, CA-125 testing (OC patients only) 
should continue at the intervals specified for tumor assessments. 


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19 Blood samples for TSH, T3 or FT3, and FT4 are to be collected at screening, every 6 weeks from C1D1, and at EOT. Blood samples for TSH, T3 or FT3, and 
FT4 to be collected at 30-day post-treatment safety follow-up only if assessment is clinically indicated. 
20 Patients will undergo ECG monitoring as per Table 8 and Table 9. 
21 Vital signs include blood pressure, pulse, and temperature. Height obtained at screening only. 
22AEs are required to be captured through 30 days after cessation of study treatment, SAEs and ECIs (see Section 6.1.6) are required to be captured through 90 
days after cessation of study treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy), and any pregnancies that 
occur within 120 days post-treatment are to be captured. 
23 Administer pembrolizumab once every 21 days (200 mg IV). Pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of each 
cycle after Cycle 2 due to administrative reasons. 
24 See Table 10 for details of niraparib administration in Phase 1, and Section 3.1.2.1 for the RP2D of the combination. Niraparib dose may be escalated on or 
after C3D1 from 200 mg daily to 300 mg daily if hemoglobin ≥ 9 g/dL, platelets ≥ 100,000/µL and neutrophils ≥ 1500/µL for all labs performed during the first 
two cycles after discussion with Medical Monitor or Designee. 
25 Niraparib dose administered upon completion of pembrolizumab infusion. 
26 Blood samples collected at screening and EOT will be stored for evaluation if the Sponsor's medical monitor finds evaluation necessary for assessing 
niraparib-related risk for MDS/AML (eg, the patient develops MDS/AML). Mutation profile before and after study treatment will be compared to determine 
whether any mutations were present prior to study treatment. Additional details on sample collection and analysis are in the Study Manual. 
27It is strongly recommended that any suspected MDS/AML case reported while a patient is receiving treatment or being followed for post-treatment assessments 
be referred to a local hematologist, who must perform bone marrow aspirate and biopsy testing. 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, (64) and other sample testing results related to MDS/AML. 
 
 
 
 
 
 
 
 
 
 
 


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Table 7 
Schedule of Events - Phase 2 Only 
Cycle/Visit: 
Screening 
Cycle 1 
Subsequent 
Cycles1 
EOT2 
Safety 
Follow-up 
Follow-up 
Assessments 
(every 90 ± 14 days) 
via telephone 
 
Day: 
Procedure: 
-21 to -1 
1 
83 
15 
Cycle n,  
Day 1 
30 + 7 days 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical, surgical, cancer, and medication history 
X 
 
 
 
 
 
 
 
Archival tissue4 
X 
 
 
 
 
 
 
 
Optional serial tumor biopsy5 
X 5,6 
 
 
 
X5 
X5 
 
 
Blood sample for exploratory biomarkers 
 
X 
 
 
X7  
X 
 
 
Blood sample for PK8 
 
X 
 
 
X 
 
 
 
Tumor assessment (RECIST and irRECIST) 
X6,9 
 
 
 
X9 
X9 
X9 
X9 
Laboratory assessments: 
 
 
 
 
X10 
 
X11 
 
CBC12 
X6 
X13 
X3 
X 
X 
X 
X 
 
Serum chemistry 
X6 
X13 
 
X 
X 
X 
X 
X14 
Coagulation 
X6 
 
 
 
 
 
 
 
Pregnancy test 
X6,15 
 
 
 
X15 
 
X15 
X15 
Serum CA-125 (OC patients only) 
X6 
X13 
 
 
X 
X16 
X16 
 
Urinalysis 
X6 
X13 
 
 
X 
X 
X 
 
TSH, T3 or FT3, and FT4 
X6,17 
 
 
 
X17 
X17 
X17 
 
ECG 
X6,18 
X18 
 
 
X18 
X18 
 
 
Physical examination 
X6 
 
 
 
 
X 
 
 
Symptom-directed physical examination 
 
X 
 
X 
X 
 
X 
 


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Cycle/Visit: 
Screening 
Cycle 1 
Subsequent 
Cycles1 
EOT2 
Safety 
Follow-up 
Follow-up 
Assessments 
(every 90 ± 14 days) 
via telephone 
 
Day: 
Procedure: 
-21 to -1 
1 
83 
15 
Cycle n,  
Day 1 
30 + 7 days 
Vital signs, height, and weight19 
X6 
X 
 
X 
X 
X 
X 
 
ECOG performance status 
X 
 
 
 
X 
X 
 
 
Concomitant medications 
X 
X 
 
X 
X 
X 
X 
 
Adverse event monitoring 
X 
X 
 
X 
X 
X 
X20 
X20 
Pembrolizumab study treatment  
administered21 
 
X 
 
 
X 
 
 
 
Niraparib study treatment dispensed/collected22 
 
X23 
 
 
X23 
X 
 
 
Survival assessment, including new malignancy information 
 
 
 
 
 
 
 
X 
Sample collection (whole blood) for cytogenetic analysis 
X24 
 
 
 
 
X24 
 
 
Bone marrow aspirate and biopsy and sample collection (whole 
blood) for cytogenetic analysis 
 
X25 
Abbreviations: AE = adverse event; CBC = complete blood count; CT = computed tomography; ECG = electrocardiogram; ECI = event of clinical interest; 
ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; irRECIST = immune-related RECIST; IV = intravenous; MDS = myelodysplastic 
syndrome; MRI = magnetic resonance imaging; OC = ovarian cancer; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; 
RP2D = recommended Phase 2 dose; SAE = serious adverse event; TNBC = triple-negative breast cancer. 
1 Treatment cycles are 21 days long, with visits on Day 1 of each cycle beyond Cycle 1 unless otherwise specified. Visits for subsequent cycles continue every 21 
days (± 3 days) until study treatment discontinuation. 
2 EOT visit should be completed within 7 days of the last dose of study drug. 
3 For patients in Phase 2, collection of blood for the Cycle 1/Day 8 CBC may be done at the study center’s laboratory or at a laboratory local to the patient, if 
approved by the Principal Investigator as an adequate laboratory. The laboratory must have the capability to provide results to the Principal Investigator 
electronically or by fax within 24 hours of blood collection. 
4 For patients who do not have archival tissue, tissue from a fresh biopsy must be obtained prior to study treatment initiation. See the Study Manual for details on 
sample collection and processing.  
5 In patients who consent to serial biopsies, fresh tumor sample is to be obtained at screening, 1 to 3 days before or on C3D1 prior to pembrolizumab infusion, 
and when possible, at the time of disease progression. See the Study Manual for details on sample collection and processing. The serial biopsies at different 
time points should be on the same lesion preferably. A core biopsy is recommended; if an excisional or incisional biopsy is to be performed, it must be 
conducted on a non-target lesion. If a patient has had a biopsy within 12 weeks prior to entering screening, that biopsy may be accepted as the screening biopsy. 
6 Standard of care tests/procedures, including biopsy, radiographic scans, laboratory assessments (fasting glucose at baseline), ECG, physical examination, vital 
signs, height, and weight, performed prior to the patient signing the informed consent form can be used as part of the screening assessments as long as the 


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tests/procedures meet the protocol-required timelines (ie, within 21 days of first dose for these procedures with the exception of the biopsy, which may have 
been conducted within 12 weeks of first dose, and pregnancy test, which must be conducted within 72 hours of first dose) and any relevant guidelines (eg, 
diagnostic quality for scans). 
7 Required on Day 1 of Cycle 2 only. 
8 Blood samples are to be obtained for niraparib and and major metabolite M1, pembrolizumab PK assessments; see Table 8 and Table 9 for the detailed 
schedule. 
9 Tumor assessment per RECIST and irRECIST via CT or MRI (chest, abdomen, and pelvis [brain, only if clinically indicated]) required at screening, every 9 
weeks (63 ±7 days) from Cycle 1/Day 1 for the first year, and then every 12 weeks (84 ±7 days) until progression; at the time of progression, a final follow up 
set of images is required if not done within the last 4 weeks. The same modality (CT or MRI) should be used throughout the study for a given patient. If the 
chest (OC patients only) or brain (OC and TNBC patients) CT/MRI is clear at screening, repeat imaging of these areas is not required in the absence of clinical 
indication requiring follow‐up. Positron emission tomography/CT may be used according to RECIST v1.1 guidelines. Bone scans should be conducted per 
standard of care. Timing of images 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 a reason other than progression or death, withdrawal of consent, or loss to follow-
up, scans and CA-125 testing (OC patients only) should continue at the specified intervals.  
10 May be done within 24 hours prior to the visit. 
11 May be done at the study center’s local laboratory or at a laboratory local to the patient if the laboratory is included on FDA Form 1572. 
12 If dose interruption or modification is required at any point on study because of hematologic toxicity, twice-weekly (thrombocytopenia or neutropenia) or once 
weekly (anemia) blood draws (CBC) will be monitored until the AE resolves, and to ensure safety of the new dose, weekly blood draws for CBC will also be 
required for a subsequent 3 week cycle after the AE has been resolved to the specified levels, after which monitoring every 3 weeks may resume. 
13 If screening laboratory testing (CBC, serum chemistry, CA-125, urinalysis) is performed within 72 hours of first dose of study treatment on Day 1, repeat 
testing is not required. 
14 Serum chemistry to be conducted on Day 90 post-treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy) to 
assess for possible ECI (see Section 6.1.6). The assessment may be done at the study center’s laboratory or at a laboratory local to the patient, if approved by 
the Principal Investigator as an adequate laboratory. This should be the same laboratory as conducted any Cycle 1/Day 8 CBC samples. 
15 Negative serum pregnancy test required within 72 hours prior to first dose of study treatment on Day 1 for females of childbearing potential; urine pregnancy 
test conducted every 3 cycles for duration of study (ie, Cycle 4, Cycle 7, etc.) and at the 30-day safety follow-up visit. Pregnancy status must be determined 120 
days post treatment. 
16 If a patient discontinues treatment for a reason other than progression or death, withdrawal of consent, or loss to follow-up, CA-125 testing (OC patients only) 
should continue at the intervals specified for tumor assessments. 
17 Blood samples for TSH, T3 or FT3, and FT4 are to be collected at screening, every 6 weeks from C1D1, and at EOT. Blood samples for TSH, T3 or FT3, and 
FT4 to be collected at 30-day post-treatment safety follow-up only if assessment is clinically indicated. 
18 Patients will undergo ECG monitoring as per Table 8 and Table 9. 
19 Vital signs include blood pressure, pulse, and temperature. Height obtained at screening only. 
20AEs are required to be captured through 30 days after cessation of study treatment, SAEs and ECIs (see Section 6.1.6) are required to be captured through 90 
days after cessation of study treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy), and any pregnancies that 
occur within 120 days post-treatment are to be captured. 
21Administer pembrolizumab once every 21 days (200 mg IV). Pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of each 
cycle after Cycle 2 due to administrative reasons. 


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22 See Table 11 for details of niraparib administration in Phase 2. See Section 3.1.2.1 for the RP2D of the combination. Niraparib dose may be escalated on or 
after C3D1 from 200 mg daily to 300 mg daily if hemoglobin ≥ 9 g/dL, platelets ≥ 100,000/µL and neutrophils ≥ 1500/µL for all labs performed during the first 
two cycles after discussion with Medical Monitor or Designee. 
23 Niraparib dose administered upon completion of pembrolizumab infusion. 
24 Blood samples collected at screening and EOT will be stored for evaluation if the Sponsor's medical monitor finds evaluation necessary for assessing 
niraparib-related risk for MDS/AML (eg, the patient develops MDS/AML). Mutation profile before and after study treatment will be compared to determine 
whether any mutations were present prior to study treatment. Additional details on sample collection and analysis are in the Study Manual. 
25It is strongly recommended that any suspected MDS/AML case reported while a patient is receiving treatment or being followed for post-treatment assessments 
be referred to a local hematologist, who must perform bone marrow aspirate and biopsy testing. 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, (64) and other sample testing results related to MDS/AML. 
 


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Table 8 
Pharmacokinetic Sampling and Electrocardiogram Schedule – Phase 1 
Visit/Cycle: 
Screen 
Cycle 1 
Cycle 2 
Cycle 4 
Cycle 8 
EOT 
Study Day: -21 to -1 
1 
2 
8 
15 
1 
2 
1 
1 
 
Assessment: 
Time Point: 
ECG 
ECG 
Blood 
Blood 
Blood 
Blood 
ECG 
Blood 
Blood 
ECG 
Blood 
ECG 
Blood 
ECG 
Anytime 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pre Niraparib dose
a 
 
X 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
Post Niraparib dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 hr (±5 min) 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
2 hr (±5 min) 
 
X 
X 
 
 
 
X 
X 
 
 
X
b 
 
Xb 
 
4 hr (±5 min) 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
6 hr (±5 min) 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
8 hr (±10 min) 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
24 hr (±30 min) 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
Pre Pembrolizumab infusion
c 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
Post Pembrolizumab infusion
d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
30 min (±5 minutes) 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
24 hrs (±30 minutes) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
168 hrs (±2 hours) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
336 hour (±4 hours) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Abbreviations: ECG = electrocardiogram; EOT = end of treatment; hr = hour; min = minute 
a To be obtained within 30 minutes of niraparib dose; ECG should be conducted prior to blood draws. 
b Sample to be obtained 2 hours ±15 minutes post niraparib dose. 
c To be obtained within 30 minutes (±5 minutes) before the start of infusion of pembrolizumab; samples will only be analyzed to understand any AE in an 
individual patient. 
d Samples will only be analyzed to understand an AE in an individual patient. Times are relative to the end of the infusion. 


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Table 9 
Pharmacokinetic Sampling and Electrocardiogram Schedule – Phase 2 
Visit/Cycle: 
Screen 
(Days -21 to -1) 
Cycle 1/Day 1 
Cycle 2/Day 1 
Cycle 4/Day 1 
Cycle 8/ Day 1 
EOT 
 
Assessment: 
Time Point: 
ECG 
ECG 
Blood 
ECG 
Blood 
ECG 
Blood 
ECG 
Blood 
ECG 
Anytime 
X 
 
 
 
 
 
 
 
 
X 
Pre Niraparib dose
a 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Post Niraparib dose 
 
 
 
 
 
 
 
 
 
 
2 hr (±15 min) 
 
X 
X 
X 
X 
 
X 
 
X 
 
Abbreviations: ECG = electrocardiogram; EOT = end of treatment; hr = hour; min = minute 
a To be obtained within 30 minutes of niraparib dose; ECG should be conducted prior to blood draws. 
 
 
Table 10 
Niraparib Administration – Phase 1 
Cycle 
1 
Day 
1 
7 
8 
14 
15 
21 
Niraparib 200 mg QD PO (Dose Level 1)
a 
          X--------------------------------------------------------------------------------------------X 
Niraparib 300 mg QD PO (Dose Level 2)a 
          X--------------------------------------------------------------------------------------------X 
Niraparib 200 or 300 mg QD PO (Dose Level -1)a 
b 
          X--------------------------------------------------------X 
 
 
Niraparib 200 or 300 mg QD PO (Dose Level -2)a b 
          X------------------X 
 
 
 
 
Abbreviations:  PO = oral; QD = once daily 
a For all dose levels, niraparib will be administered during Cycle 1 in combination with pembrolizumab (200 mg IV on Day 1 of the 21-day cycle). 
b Schedule of niraparib administration will be determined by agreement between Investigators and Sponsor (see Section 9.12). 
 
 
 
 


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Table 11 
Niraparib Administration – Phase 2 
Cycle 
N
a 
Day 
1 to 21 
Niraparib 200 mg QD PO Phase 2 
X 
Abbreviations:  PO = oral; QD = once daily 
a The RP2D to be implemented in the Phase 2 portion of this study is niraparib 200 mg/day PO on days 1-21 and pembrolizumab 200 mg IV on day 1 of each 21-
day cycle; niraparib dose may be escalated on or after C3D1 from 200 mg daily to 300 mg daily if hemoglobin ≥ 9 g/dL, platelets ≥ 100,000/µL and neutrophils 
≥ 1500/µL for all labs performed during the first two cycles after discussion with Medical Monitor or Designee. 


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7.2. 
Procedures by Visit 
7.2.1. 
Screening (Day -21 to Day -1) 
Standard of care tests/procedures, including laboratory assessments, ECG, physical examination, 
vital signs, height, and weight, performed prior to the patient signing the informed consent form 
can be used as part of the screening assessments as long as the tests/procedures meet the 
protocol-required timelines (ie, within 21 days of first with the exception of the pregnancy test 
which must be conducted within 72 hours of first dose). Note that source documents must clearly 
identify the standard of care tests/procedures that are used for screening and the results of these 
tests/procedures must be entered in the eCRF. 
At screening, the following procedures/tests will be performed: 
 Obtain written informed consent 
 A single study ICF will be signed before any study procedures 
 Inclusion/exclusion criteria review 
 Demographics 
 Medical/surgical/cancer/medication history 
 Archival tumor sample for biomarker testing 
 For patients who do not have archival tissue, tissue from a fresh biopsy must be 
obtained prior to study treatment initiation. See the Study Manual for details on 
sample collection and processing.  
 Optional tumor biopsy for biomarker testing 
 For patients who consented to serial biopsies. See the Study Manual for details on 
sample collection and processing. If a patient has had a biopsy within 12 weeks 
prior to entering screening, that biopsy may be accepted in lieu of  the screening 
biopsy. 
 Sample collection (whole blood) for cytogenetic analysis. 
 Tumor assessment (CT/MRI) for determination of measurable disease (RECIST v1.1)  
 Chest, abdomen, and pelvis (brain, if clinically indicated) CT (preferred method) 
or MRI (if clinically indicated). If the chest (applies to OC patients only) and/or 
brain (applies to OC and TNBC patients) CT/MRI is clear at screening, repeat 
imaging is not required in the absence of clinical indication requiring follow‐up. 
Positron emission tomography (PET)/CT may be used according to RECIST v1.1 
guidelines. 
 Scans performed prior to informed consent as part of routine clinical management 
are acceptable for use as initial tumor imaging if they are of diagnostic quality and 
are performed within 21 days prior to first dose date. 
 Bone scans performed per standard of care. 


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 Laboratory assessments: 
 Serum pregnancy test for women of childbearing potential within 72 hours of first 
dose of study treatment 
 CBC 
 Serum chemistry 
 TSH, T3 or FT3, and FT4 
 Coagulation 
 Serum CA-125 (OC patients only) 
 Urinalysis 
 ECG 
 Physical examination 
 Vital signs (BP, pulse, and temperature) and weight 
 Height 
 ECOG performance status 
 Concomitant medications 
 AE monitoring 
7.2.2. 
Cycle 1/Day 1 
 Inclusion/exclusion criteria review 
 Laboratory assessments (if screening assessments were performed within 72 hours of 
Day 1, repeat testing is not required): 
 CBC 
 Serum chemistry 
 Serum CA-125 (OC patients only) 
 Urinalysis 
 Symptom-directed physical examination 
 Vital signs (BP, pulse, and temperature) and weight 
 Concomitant medications 
 AE monitoring 
 Blood sample to be obtained predose for exploratory biomarkers 
 Pembrolizumab study treatment administered after other visit procedures are 
completed 


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 Blood samples for pembrolizumab PK assessment 
 Phase 1 patients only: Blood samples will be obtained predose (within 30 
minutes) and within 30 minutes (±5 minutes) after the end of the pembrolizumab 
infusion. 
 Niraparib first dose administered in clinic after completion of pembrolizumab 
infusion 
 ECG 
 ECG monitoring to be conducted prior to the niraparib dose and 2 hours postdose. 
ECGs should be performed prior to PK blood draws. 
 Blood samples for niraparib and M1 PK assessment 
 Phase 1 patients only: Patients at each dose level will undergo intensive 
niraparib and M1 PK evaluation with blood samples obtained at 0 (predose within 
30 minutes) and at 1, 2, 4, and 6 hours (±5 minutes), and 8 hours (±10 minutes) 
postdose. 
 Phase 2 patients: Blood samples for niraparib and M1 PK will be obtained at 0 
(predose within 30 minutes) and 2 hours (±15 minutes) postdose. 
7.2.3. 
Cycle 1/Day 2 (Phase 1 Patients Only) 
 Blood samples for pembrolizumab PK assessment 
 Phase 1 patients only: Obtain blood sample 24 hours (±30 minutes) after the end 
of the pembrolizumab infusion. 
 Blood sample for niraparib PK and M1 assessment 
 Phase 1 patients only: Obtain blood sample 24 hours (±30 minutes) postdose 
following the Cycle 1, Day 1 dose. 
7.2.4. 
Cycle 1/Day 8 
For Phase 1 patients, visit to be conducted at the study site to include: 
 Vital signs (BP, pulse, and temperature) and weight 
 Blood samples for pembrolizumab PK assessment obtained 168 hours (±2 hours) 
Day 8) after the end of the pembrolizumab infusion. 
 CBC 
 Concomitant medications 
 AE monitoring 
For Phase 2 patients: 
 CBC:  may be done at the study center’s local laboratory or at a laboratory local to 
the patient, if approved by the Principal Investigator as an adequate laboratory. The 


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laboratory must have the capability to provide results to the Principal Investigator 
electronically or by fax within 24 hours of blood collection. 
7.2.5. 
Cycle 1/Day 15 
 Laboratory assessments: 
 CBC 
 Serum chemistry 
 Coagulation (Phase 1 patients only) 
 Symptom-directed physical examination 
 Vital signs (BP, pulse, and temperature) and weight 
 Phase 1 patients only: Blood samples for pembrolizumab PK will be obtained 
336 hours (±4 hours) (Day 15) after the end of the pembrolizumab infusion. 
 Concomitant medications 
 AE monitoring 
7.2.6. 
Day 1, Subsequent Cycles 
 Tumor assessment (RECIST v1.1 and irRECIST) 
 Conduct radiographic evaluations of chest (all TNBC patients and OC patients 
with abnormal screening assessment or clinical indication), abdomen, pelvis, and 
brain (if abnormal at screening or clinical indication). The first on-study imaging 
assessment should be performed at 9 weeks (63 ±7 days) from the date of first 
dose of study treatment; in the case of PD, a confirmatory image will be required 
4 weeks later (eg, 13 weeks [91 ±7 days]) (see Section 6.3.1.4). Subsequent tumor 
imaging should be performed every 9 weeks (63 ±7 days) or more frequently if 
clinically indicated and at the time of suspected disease progression. After 1 year 
of radiographic assessments, patients will have imaging performed every 12 
weeks (84 ±7 days). Imaging should not be delayed for delays in cycle starts or 
extension of combination treatment cycle intervals. The same modality (ie, CT or 
MRI) should be used for a given patient throughout the study. PET/CT may be 
used according to RECIST v1.1 guidelines. 
 Patients with CR or PR should have the response confirmed by a repeat tumor 
imaging assessment performed at the earliest 4 weeks after the first indication of 
response, or at the next scheduled scan (ie, 9 weeks later), whichever is clinically 
indicated. 
 Bone scans performed per standard of care. 
 Laboratory assessments: may be done within 24 hours prior to the visit 
 CBC 
 Serum chemistry 


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 Coagulation (Phase 1 patients only; Day 1 of Cycles 2 and 3 only) 
 TSH, T3 or FT3, and FT4 (every 6 weeks) 
 Serum CA-125 (OC patients only) 
 Urinalysis 
 Urine pregnancy test for females of childbearing potential conducted every 3 cycles 
for duration of study (ie, Cycle 4, Cycle 7, etc.). Symptom-directed physical 
examination 
 Vital signs (BP, pulse, and temperature) and weight 
 ECOG performance status 
 Blood sample to be obtained prior to study treatment for exploratory biomarkers on 
Day 1 of Cycle 2 only 
 Pembrolizumab study treatment administered after other visit procedures are 
completed 
 Blood samples for pembrolizumab PK assessment 
 Phase 1 patients (Cycles 2, 4, and 8 only): Blood samples will be obtained 
predose (within 30 minutes). An additional sample will be obtained within 
30 minutes after the end of the pembrolizumab infusion in Cycle 8.  
 Niraparib dose administered in clinic after completion of pembrolizumab infusion 
 ECG 
 Patients will undergo ECG monitoring on Cycle 2/Day 1 prior to the niraparib 
dose and 2 hours postdose and on Cycle 4/Day 1 and Cycle 8/Day 1 predose. 
ECGs should be performed prior to PK blood draws. 
 Blood samples for niraparib and M1 PK assessment 
 Phase 1 patients (Cycle 2 only): Patients at each dose level will undergo 
intensive niraparib and M1 PK evaluation with blood samples obtained at 0 
(predose within 30 minutes) and at 1, 2, 4, and 6 hours (±5 minutes), and 8 hours 
(±10 minutes) postdose. 
 Phase 1 patients (Cycles 4 and 8 only): Blood samples for niraparib and M1 PK 
will be obtained at 0 (predose within 30 minutes) and 2 hours (±15 minutes) 
postdose. 
 Phase 2 patients (Cycles 2, 4, and 8 only): Blood samples for niraparib and M1 
PK will be obtained at 0 (predose within 30 minutes) and 2 hours (±15 minutes) 
postdose.  
 Optional tumor biopsy for biomarker testing 
 Sample to be obtained 1 to 3 days before or on Cycle 3/Day 1 prior to 
pembrolizumab infusion. See the Study Manual for details on sample collection 
and processing. 


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 Concomitant medications 
 AE monitoring 
7.2.7. 
Cycle 2, Day 2 (Phase 1 Patients Only) 
 Blood sample for niraparib and M1 PK assessment 
 Phase 1 patients only: Obtain blood sample 24 hours (±30 minutes) postdose 
following the Cycle 2, Day 1 dose. 
7.2.8. 
End of Treatment (within 7 days of last dose) 
 Optional fresh tumor sample 
 If possible, sample to be obtained at the time of disease progression. See the 
Study Manual for details on sample collection and processing. 
 Sample collection (whole blood) for cytogenetic analysis. 
 Tumor assessment (RECIST and irRECIST) 
 A final set of radiographic images is required at the time of disease progression, if 
not done within the last 4 weeks. 
 If a patient discontinues treatment for a reason other than progression or death, 
withdrawal of consent, or loss to follow-up, radiographic scans/images and CA-
125 testing (OC patients only) should continue every 9 weeks (63 ±7 days) 
through 1 year and every 12 weeks (84 ±7 days) thereafter. 
 ECG 
 Laboratory assessments: 
 CBC 
 Serum chemistry 
 TSH, T3 or FT3, and FT4 
 Serum CA-125 (OC patients only) 
 Urinalysis 
 Physical examination 
 Vital signs (BP, pulse, and temperature) and weight 
 ECOG performance status 
 Concomitant medications 
 AE monitoring 
 Niraparib study treatment collected 


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7.2.9. 
Safety Follow-up (30 days [+ 7 days] Post-treatment) 
 Tumor assessment (RECIST and irRECIST) and serum CA-125 (OC patients only) 
 Patients who discontinue treatment for reasons other than disease progression, 
death, withdrawal of consent, or loss to follow-up will be followed for disease 
assessments, including radiographic scans and CA-125 testing (OC patients only), 
per the specified schedule. 
 Symptom-directed physical examination 
 Laboratory assessments: may be done at the study center’s local laboratory or at a 
laboratory local to the patient if the laboratory is included on FDA Form 1572: 
 CBC 
 Serum chemistry 
 TSH, T3 or FT3, and FT4 (only if clinically indicated) 
 Serum CA-125 (OC patients only) 
 Urine pregnancy test 
 Urinalysis 
 Vital signs (BP, pulse, and temperature) and weight 
 Concomitant medications 
 AE monitoring – AEs are required to be captured through 30 days after cessation of 
study treatment, SAEs, and ECI (see Section 6.1.6) are required to be captured 
through 90 days after cessation of study treatment (or to a minimum of 30 days post-
treatment if the patient starts alternate anticancer therapy), and any pregnancies that 
occur within 120 days post-treatment are to be captured. 
7.2.10. 
Follow-up Assessments 
 Tumor assessment (RECIST and irRECIST) and serum CA-125 (OC patients only) 
 Patients who discontinue treatment for reasons other than disease progression, 
death, withdrawal of consent, or loss to follow-up will be followed for disease 
assessments, including radiographic scans and CA-125 testing (OC patients only), 
per the specified schedule. 
 Serum chemistry to be conducted on Day 90 post-treatment (or to a minimum of 
30 days post-treatment if the patient starts alternate anticancer therapy) to assess for 
possible ECI (see Section 6.1.6). The assessment may be done at the study center’s 
laboratory or at a laboratory local to the patient, if approved by the Principal 
Investigator as an adequate laboratory. This should be the same laboratory as 
conducted any Cycle 1/Day 8 CBC samples (see Section 7.2.4). 
 AE monitoring – SAEs and ECI (see Section 6.1.6) are required to be captured 
through 90 days after cessation of study treatment (or to a minimum of 30 days post-
treatment if the patient starts alternate anticancer therapy) 


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 Subsequent anti-cancer therapy information are required to be captured through post-
treatment if the patient starts alternate anticancer therapy 
 Pregnancy status assessed (through Day 120 post-treatment) 
 Survival/new malignancy assessment 
 Patients will be followed by telephone every 90 days for survival status and the 
occurrence of any new malignancies  
7.2.11. 
Unscheduled Assessments 
 For any patient diagnosed with MDS/AML while on study, a bone marrow aspirate 
and biopsy and sample collection (whole blood) for cytogenetic analysis. See 
Section 6.1.8 for details. 


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8. 
STATISTICAL METHODS 
Details of the statistical analyses presented below will be provided in the study’s statistical 
analysis plan (SAP). A change to the data analysis methods described in the protocol will require 
a protocol amendment only if it alters a principal feature of the protocol. The SAP will be 
finalized prior to database lock. Any changes to the methods described in the plan will be 
described and justified in the final clinical study report.  
8.1. 
Study Populations 
Three analysis populations will be defined as follows: 
 Safety Population: All patients who receive any amount of study drug. The 
assessment of DLTs in Phase 1 will include only those patients completing the first 
cycle of therapy, unless the patient discontinued study drug due to a DLT. 
 Full Analysis Set (FAS): All patients who receive any amount of study drug. The 
primary analysis of efficacy endpoints will be performed on the FAS population. 
 Per-Protocol Population: All patients who receive at least two cycles of study drug, 
have protocol-required post-baseline disease assessments and have no major protocol 
violations that would impact efficacy evaluations. Supportive analyses of efficacy 
endpoints will be performed on the per-protocol population. 
8.2. 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications 
Demographics, baseline characteristics, and medical history information will be summarized by 
dose level for Phase 1, and by indication for Phase 2, for the Safety population using descriptive 
statistics. No formal statistical comparisons will be performed. 
Demographic, baseline characteristics, and medical history data for each patient will be provided 
in data listings. 
8.3. 
Safety Analyses 
The following key safety parameters will be evaluated by study phase, pooled dose schedule 
across phases, by disease type, and overall, unless noted otherwise: 
 Dose-limiting toxicities during the first cycle (ie, during the first 21 days of treatment, 
ie, Cycle 1/Day 1 through Cycle 1/Day 21) for Phase 1 
 Incidence of TEAEs during the first cycle compared to the second and subsequent 
cycles 
 Incidence of TEAEs occurring while patients are on treatment or up to 30 days after 
the last dose of study drug  
 Incidence of SAEs and ECI occurring while patients are on treatment or up to 90 days 
after the last dose of study drug  
 Incidence of any new malignancies 


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 Changes in clinical laboratory parameters (hematology, chemistry, thyroid function, 
coagulation, urinalysis), vital signs, ECOG performance status, ECG parameters, 
physical examinations, and usage of concomitant medications 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
system and displayed in tables and data listings using system organ class and preferred term. 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined per protocol as any AE with onset beginning at the day of 
first administration of study drug, throughout the treatment period until 30 days after the last 
dose of study drug, any SAE or ECI that occurs through 90 days after cessation of study 
treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer 
therapy), or any event that was present at baseline but worsened in intensity or was subsequently 
considered drug-related by the Investigator through the end of the study. DLTs will be tabulated 
by dose level in Phase 1. 
The number and percentage of patients with any TEAE, with any TEAE assessed by the 
Investigator as related to treatment (definite, probable, or possible relationship), and with any 
SAE will be summarized by treatment group and overall. In these tabulations, each patient will 
contribute only once (ie, the most related occurrence or the most intense occurrence) to each of 
the incidence rates in the descriptive analysis, regardless of the number of episodes. No formal 
hypothesis-testing analysis of AE incidence rates will be performed. 
The occurrence of and reasons for any requirement for dose interruption or modification will be 
tabulated, and distinguished as to presumptive causality from niraparib or pembrolizumab, if 
known. 
All AEs occurring on-study will be listed in patient data listings. By-patient listings also will be 
provided for the following: patient deaths, SAEs, and AEs leading to withdrawal. 
8.4. 
Pharmacokinetic Analyses 
All patients who receive at least 1 dose of study drug and have measureable drug concentrations 
will be included in PK analyses. 
Non-compartmental methods will be used to evaluate the PK characteristics of niraparib and its 
major metabolite M1, and pembrolizumab as appropriate. Pharmacokinetic parameters to be 
determined will include AUC, AUCss, Cmin, Cmax, CL/F, Vz/F, Cmin,ss, and Cmax,ss. Plasma 
concentrations and PK parameter estimates will be presented using descriptive statistics by dose 
level. 
8.5. 
Post-Treatment Analyses 
Descriptive summary statistics will be used to summarize post-treatment data (ie, any new 
occurrence of MDS/AML). 
8.6. 
Efficacy Analyses 
All efficacy endpoints will be summarized on the Phase 2 population by disease type; in 
addition, data may be pooled for patients in Phase 1 and Phase 2, by disease type. All analyses 
will include summary statistics, including number and percentage for categorical variables and 


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number of patients, mean, standard deviation, median, minimum, and maximum for continuous 
variables. Two-sided exact 90% confidence intervals (CIs) based on the Clopper-Pearson 
method (67) will be provided where appropriate. Time-to-event analyses will be performed using 
Kaplan-Meier (KM) methods. Comparisons in the Phase 1 portion of the study will be made 
using descriptive statistics. As the Phase 2 portion of the study is single-arm, any statistical 
analysis to be performed among subgroups is for descriptive and future study purposes. 
8.6.1. 
Primary Efficacy Parameter 
The primary efficacy endpoint will be ORR, defined as the achievement of CR or PR using 
RECIST (v1.1), as assessed by the Investigator. Point estimates and 1-sided 95% CI, 
corresponding to the specifications of the sample size calculation will be provided. The primary 
analysis will be performed for each patient cohort and no multiplicity adjustment will be made 
since separate inferences will be drawn for each cohort. 
8.6.2. 
Secondary Efficacy Parameter(s) 
Objective response rate as assessed by the Investigator using irRECIST will be assessed as a 
secondary endpoint. 
Disease control rate will be assessed as a secondary endpoint and is defined as the proportion of 
patients achieving best overall response of CR, PR, or SD as assessed by the Investigator per 
RECIST v1.1 and irRECIST, with point estimates and 2-sided 90% CIs. 
Duration of response, PFS and OS will be presented through use of summary statistics using KM 
methods, to include 25th, 50th (median), and 75th percentiles and associated 2-sided 95% CIs, 
number of events and number of censored observations. DOR and PFS will be defined by both 
RECIST v1.1 and irRECIST criteria, based on the date of PD that will be used to determine 
duration, and will be analyzed separately by both criteria.  
8.7. 
Biomarker Analyses 
For each patient in the study, blood and tumor samples will be prospectively collected, evaluated 
and archived to support exploratory biomarker analysis. PD-L1 expression (retrospective 
analysis), HRD score, immune cell infiltrates, and other exploratory biomarkers will be 
correlated with response. 
8.8. 
Probability of Dose Escalation 
Based on the dose escalation schema planned for the Phase 1 portion of the study as outlined in 
Section 3.1.2, the following decision rules will be used to determine if a dose is or is not 
increased: 


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Table 12 
Dose Escalation Decision Rules 
First 6 Patients 
Second 6 Patients 
Decision 
Number of  
Hematologic DLTs 
Number of  
Non-hematologic DLTs 
Number of  
Hematologic DLTs 
Number of  
Non-hematologic DLTs 
0 
0 
NA 
NA 
Escalate 
1 
0 
NA 
NA 
Escalate 
0 
1 
NA 
NA 
Escalate 
1 
1 
0 
0 
Escalate 
1 
1 
1 
0 
Escalate 
1 
1 
0 
1 
Escalate 
0 
2 
0 
0 
Escalate 
0 
2 
1 
0 
Escalate 
0 
2 
0 
1 
Escalate 
2 
Any 
NA 
NA 
Decrease 
dose 
Abbreviations:  DLT = dos-limiting toxicity; NA = not applicable; second 6 patients are not required to be enrolled. 
To model the probabilities of dose escalation given various rates of true hematological and non-
hematological DLTs, let X = number of hematological DLTs observed and Y = number of non-
hematological DLTs observed. Then the joint distribution of (X,Y) is multinomial (trinomial) 
with parameters: N = number of patients evaluated, PH = true probability of a hematological 
DLT, and PN = true probability of a non-hematological DLT. There are 2 probabilities to 
calculate. First, the probability of escalation based on the first 6 patients enrolled. Second is the 
conditional probability of escalation based on the second 6 patients enrolled, given (X,Y) = (1,1) 
or (0,2) in the first 6 patients. The probability of dose escalation is the sum of these 2 
probabilities. It is assumed that a given patient cannot have more than 1 DLT, and that 
hematologic DLTs take precedence over non-hematologic DLTs. The following graph presents 
the probabilities of dose escalation for ranges of true rates of DLTs, where it is assumed the true 
rates will be approximately 18% (range 12-24%) for hematologic DLTs and 5% (range 3-7%) for 
non-hematologic DLTs. 
As shown in Figure 2, the probability of dose escalation decreases as the DLT rate increases, as 
expected. Over the restricted range of DLT rates, the probabilities are close to a linear 
relationship as the true DLT rates increase. 


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Figure 2 
Probability of Dose Escalation in a 6 + 6 Design 
 
Figure 3 shows the probability of dose escalation for a standard 3+3 escalation design, contrasted 
with the 6 + 6 design, at the fixed rate of 0.05 for non-hematologic DLTs (the anticipated rate). 
As can be seen, the protocol-specified 6 + 6 design has a similar probability of escalation as the 
3+3 design, and is, in fact, somewhat more conservative for hematologic DLT rates >0.15. 
0.400
0.450
0.500
0.550
0.600
0.650
0.700
0.750
0.800
0.850
0.900
0.1
0.12
0.14
0.16
0.18
0.2
0.22
0.24
0.26
Probability of Dose escalation
True Rate for Hematological DLT
0.03
0.04
0.05
0.06
0.07
True Rate for Non-Heme DLT


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Figure 3 
Probability of Dose Escalation in a 6 + 6 Design versus 3 + 3 Design at a 
Fixed Rate of 0.05 for Non-hematologic DLTs 
 
8.9. 
Interim Analyses 
To minimize the risk of exposing patients to an ineffective treatment, a series of response 
assessments will be performed when 6, 12, and18 of 48 Phase 2 patients from each cancer type 
have at least 2 post-baseline tumor assessments. A formal decision regarding futility, which 
could result in stopping the study early, will be conducted separately for the TNBC and OC 
cohorts and will only be made from the analysis of 24 patients within each cohort. The earlier 
response assessments, however, will inform the conduct of the formal interim analysis as 
follows: If no responder is observed in all three response assessments from 6, 12, and 18 
patients, then enrollment will be suspended after 24 patients have been enrolled, and no further 
patients will be enrolled until the result of the formal interim analysis of 24 patients is known. If 
≥1 responder is observed in any single response assessment from 6, 12, or 18 patients, then 
enrollment will not be curtailed. The decision rule regarding the formal interim analysis at N=24 
is as follows: If there are fewer than 3 responders out of 24, enrollment may be closed and the 
corresponding cohortmay be stopped for futility. Otherwise, the study will continue to the 
planned enrollment of 48 patients.  
8.10. 
Determination of Sample Size 
Phase 1: In the Phase 1 portion of this study, 14 patients with advanced TNBC or OC were 
enrolled in Dose Level 1 or Dose Level 2. Twelve patients were eligible for DLT evaluation. In 
Dose Level 1, 1 of 6 DLT-eligible patients experienced multiple DLTs including Grade3 anemia, 
Grade 4 neutropenia, and Grade 4 thrombocytopenia. In Dose Level 2, 1 of 6 DLT-eligible 
patients experienced 1 DLT, Grade 4 thrombocytopenia; an additional patient experienced an 
0.400
0.450
0.500
0.550
0.600
0.650
0.700
0.750
0.800
0.850
0.900
0.1
0.12
0.14
0.16
0.18
0.2
0.22
0.24
0.26
Probability of Dose Escalation
True Rate for Hematological DLT
6+6
 3+3


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adverse event that was deemed to be a DLT-equivalent; the patient had epistaxis on C1D17 and 
Grade 4 thrombocytopenia on C2D1.   
Phase 2: A total of approximately 96 evaluable patients (approximately 48 patients in each tumor 
type) will be enrolled to ensure understanding of the activity of the combination treatment With 
48 patients treated in each cohort, observed 12 responses (CR and/or PR) at the final analysis 
will rule out a 15% response rate. The study has approximately 82%/94% power for each cohort 
to rule out a ≤15% ORR (null hypothesis) when the true ORR is 30%/35% at the 10% type I 
error rate (two-sided). 
The following table shows the two-sided 90% CI for ORR based on 48 subjects for different 
observed response rates. 
Number of Observed Responses 
ORR Estimate 
90% CI for ORR 
8 
16.7% 
(8.6%, 28.1%) 
10 
20.8% 
(11.8%, 32.8%) 
12 
25.0% 
(15.1%, 37.3%) 
14 
29.2% 
(18.6%, 41.8%) 
16 
33.3% 
(22.2%, 46.1%) 
Abbreviations:  CI = confidence interval; ORR = objective response rate 


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9. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1. 
Data Quality Assurance 
The Sponsor (or designee) will conduct a study initiation visit to verify the qualifications of the 
Investigator, inspect the facilities, and inform the Investigator of responsibilities and procedures 
for ensuring adequate and correct documentation. 
The Investigator must prepare and maintain adequate and accurate records of all observations 
and other data pertinent to the clinical study for each study participant. Frequent communication 
between the clinical site and the Sponsor is essential to ensure that the safety of the study is 
monitored adequately. The Investigator will make all appropriate safety assessments on an 
ongoing basis. The Sponsor’s Medical Monitor may review safety information as it becomes 
available throughout the study.  
All aspects of the study will be carefully monitored with respect to GCP and standard operating 
procedures for compliance with applicable government regulations. The Study Monitor will be 
an authorized individual designated by the Sponsor. The Study Monitor will have access to all 
records necessary to ensure integrity of the data and will periodically review the progress of the 
study with the Principal Investigator. 
9.2. 
Access to Source Data/Documents 
An electronic data capture system to manage data collection will be utilized during this study. 
The electronic data capture system is a software tool designed to ensure quality assurance and 
facilitate data capture during clinical studies. The system is fully compliant with Code of Federal 
Regulations 21 Part 11.  
The Investigator will ensure the accuracy, completeness, and timeliness of the data reported to 
the Sponsor. Data collection processes and procedures will be reviewed and validated to ensure 
completeness, accuracy, reliability, and consistency. A complete audit trail will be maintained of 
all data changes. The Investigator or designee will cooperate with the Sponsor’s representative(s) 
for the periodic review of study documents to ensure the accuracy and completeness of the data 
capture system at each scheduled monitoring visit.  
Electronic consistency checks and manual review will be used to identify any errors or 
inconsistencies in the data. This information will be provided to the respective study sites by 
means of electronic or manual queries.  
The Investigator or designee will prepare and maintain adequate and accurate study documents 
(medical records, ECGs, AE, and concomitant medication reporting, raw data collection forms, 
etc.) designed to record all observations and other pertinent data for each patient receiving study 
treatment.  
The Investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the IRB/IEC to have direct access to all documents pertaining to the 
study. 


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9.3. 
Archiving Study Documents 
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected. Master files should be established at the beginning of the study, 
maintained for the duration of the study, and retained according to the appropriate regulations. 
According to International Conference on Harmonisation (ICH) guidelines, essential documents 
should be retained for a minimum of 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the study treatment.  
9.4. 
Good Clinical Practice 
This study will be conducted in accordance with the ICH for good clinical practices (GCPs) and 
the Declaration of Helsinki (Version 2008). The clinical study will also be carried out in 
accordance with national and local regulatory requirement(s).  
9.5. 
Informed Consent 
Before each patient is enrolled in the clinical study, written informed consent will be obtained 
from the patient according to the regulatory and legal requirements of the participating country. 
As part of this procedure, the Investigator must explain orally and in writing the nature, duration, 
and purpose of the study, and the action of the study treatment in such a manner that the patient 
is aware of the potential risks, inconveniences, or AEs that may occur. The patient should be 
informed that he or she is free to withdraw from the study at any time. The patient will receive 
all information that is required by regulatory authorities and ICH guidelines. The Investigator or 
designee will provide the Sponsor with a copy of the IRB/IEC-approved ICF prior to the start of 
the study. 
The ICF must be signed and dated; one copy will be given to the patient and the Investigator will 
retain a copy as part of the clinical study records. The Investigator will not undertake any 
investigation specifically required for the clinical study until written consent has been obtained. 
The terms of the consent and when it was obtained must also be documented.  
If a protocol amendment is required, then the ICF may need to be revised to reflect the changes 
to the protocol. If the ICF is revised, it must be reviewed and approved by the responsible 
IRB/IEC and signed by all patients subsequently enrolled in the clinical study as well as those 
currently enrolled in the clinical study. 
9.6. 
Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/Competent Authorities, in accordance with local legal requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first patient 
is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate). In the United States, following approval, the 
protocol amendment(s) will be submitted to the IND under which the study is being conducted. 


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Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
9.7. 
Patient Confidentiality and Data Protection 
All clinical study findings and documents will be regarded as confidential. Study documents 
(protocols, IBs, and other material) will be stored appropriately to ensure their confidentiality. 
The Investigator and members of his/her research team (including the IRB/IEC) must not 
disclose such information without prior written approval from the Sponsor, except to the extent 
necessary to obtain informed consent from patients who wish to participate in the study or to 
comply with regulatory requirements.  
The anonymity of participating patients must be maintained. Patients will be specified on study 
documents by their enrollment number or birth date, not by name. Documents that identify the 
patient (eg, the signed informed consent document) must be maintained in confidence by the 
Investigator. 
9.8. 
Study Monitoring 
Monitoring and auditing procedures approved by the Sponsor will be followed in order to 
comply with GCP guidelines. On-site checking of the eCRFs for completeness and clarity, cross-
checking with source documents, and clarification of administrative matters will be performed. 
The study will be monitored by the Sponsor or its designee. Monitoring will be done by personal 
visits from a representative of the Sponsor (site monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and by communications (letter, 
telephone, and fax). 
All unused study treatment and other study materials will be returned to the Sponsor after the 
clinical phase of the study has been completed. 
9.9. 
Audits and Inspections 
Regulatory authorities, the IRB/IEC, and/or the Sponsor’s clinical quality assurance group, or its 
designee, may request access to all source documents, eCRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. 
9.10. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the patients. The study will only be conducted at sites where 
IRB/IEC approval has been obtained. The protocol, Investigator Brochure, informed consent, 
advertisements (if applicable), written information given to the patients, safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB/IEC by the 
Investigator. 


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9.11. 
Publication Policy 
Information regarding publication of study results is contained in the Clinical Trial Agreement 
for this study. 
9.12. 
Study Committee 
A Study Committee comprised of Investigators and Sponsor representatives will be established 
to provide review and assessment of the study data on an ongoing basis and to safeguard the 
interest and safety of the participating patients in the study. The details on membership, key 
responsibilities, and corresponding procedures are provided in the Study Committee charter.  


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Disis ML, Patel MR, Pant S, Infante JR, Lockhart AC, K K. Avelumab (MSB0010718C), 
an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian 
cancer:  a phase Ib, open-label expansion trial. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology. 2015;33. 
55. 
Nanda R CL, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Dolled-Filhart M, 
Emancipator K, Gonzalez EJ, Houp J, Pathiraja K, Karantza V, Iannone R, Gause CK, Cheng 
JD, Buisseret L, editor A phase Ib study of pembrolizumab (MK-3475) in patients with advanced 
triple-negative breast cancer. San Antonio Breast Cancer Symposium; 2014 Dec 9-13; San 
Antonio. 
56. 
Varga A P-PS, Ott PA, Mehnert JM, Berton-Rigaud D, Johnson EA. Antitumor activity 
and safety of pembrolizumab in patients (pts) with PD-L1 positive advanced ovarian cancer:  
interim results from a phase Ib study. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology. 2015;33. 
57. 
Data on file at Tesaro. 
58. 
Higuchi T, Flies DB, Marjon NA, Mantia-Smaldone G, Ronner L, Gimotty PA, et al. 
CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient 
Ovarian Cancer. Cancer Immunol Res. 2015. 
59. 
Huang J, Wang L, Cong Z, Amoozgar Z, Kiner E, Xing D, et al. The PARP1 inhibitor 
BMN 673 exhibits immunoregulatory effects in a Brca1 murine model of ovarian cancer. 
Biochemical and biophysical research communications. 2015. 
60. 
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 2006 
update of recommendations for the use of white blood cell growth factors: an evidence-based 
clinical practice guideline. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology. 2006;24(19):3187-205. 


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61. 
Schiffer CA, Anderson KC, Bennett CL, Bernstein S, Elting LS, Goldsmith M, et al. 
Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society 
of Clinical Oncology. Journal of clinical oncology : official journal of the American Society of 
Clinical Oncology. 2001;19(5):1519-38. 
62. 
Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology / the Education 
Program of the American Society of Hematology American Society of Hematology Education 
Program. 2007:172-8. 
63. 
U.S. Department of Health and Human Services. Food and Drug Administration 
Guidance for Industry. Drug-induced Liver Injury:  Premarketing Clinical Evaluation. July 2009. 
64. 
Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 
2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and 
acute leukemia: rationale and important changes. Blood. 2009;114(5):937-51. 
65. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European 
journal of cancer. 2009;45(2):228-47. 
66. 
Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. 
Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 
1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). International journal of 
gynecological cancer : official journal of the International Gynecological Cancer Society. 
2011;21(2):419-23. 
67. 
Clopper C, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934;26:404-13. 
68. 
U.S. Department of Health and Human Services. Food and Drug Administration 
Guidance for Industry. Drug Interaction Studies – Study Design, Data Analysis Implications for 
Dosing and Labeling Recommendations. February 2012. 
69. 
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. 
 
70. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, 
Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller 
K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, 
Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff 
AC, American Society of Clinical Oncology, College of American Pathologists. Arch Pathol Lab 
Med. 2010;134(7):e48. 
 


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APPENDIX A. ASCO TNBC GUIDANCE 2010(70) 
American Society of Clinical Oncology/College of American Pathologists Guideline 
Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in 
Breast Cancer  
Recommendations.—The Panel recommends that ER and PgR status be determined on all 
invasive breast cancers and breast cancer recurrences. A testing algorithm that relies on accurate, 
reproducible assay performance is proposed. Elements to reliably reduce assay variation are 
specified. It is recommended that ER and PgR assays be considered positive if there are at least 
1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of 
internal (normal epithelial elements) and external controls. 


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APPENDIX B. DRUGS KNOWN TO INHIBIT OR INDUCE CYP1A2 OR 
ARE SUBSTRATES OF CYP1A2 
Inhibitors of CYP1A2 
Strong  
≥ 5-fold increase in 
AUC or > 80% 
decrease in CL 
Moderate 
≥ 2 but < 5-fold increase in AUC or 
50%-80% decrease in CL 
Weak  
≥ 1.25 but < 2-fold increase in AUC 
or 20%-50% decrease in CL 
Ciprofloxacin, 
enoxacin, 
fluvoxamine  
 
Methoxsalen, mexiletine, oral 
contraceptives, phenylpropanolamine, 
thiabendazole, vemurafenib, zileuton  
 
Acyclovir, allopurinol, caffeine, 
cimetidine, Daidzein, disulfiram, 
Echinacea, famotidine, norfloxacin, 
propafenone, propranolol, 
terbinafine, ticlopidine, verapamil 
Inducers of CY1A2 
Strong 
80% decrease in AUC 
Moderate 
50%-80% decrease in AUC 
Weak  
20%-50% decrease in AUC 
 
Montelukast, 
phenytoin, smokers 
versus non-smokers 
Moricizine, 
omeprazole, 
phenobarbital 
Substrates of CYP1A2 
Sensitive substrates
a 
Substrates with narrow 
therapeutic range
b 
Alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, 
tizanidine  
Theophylline, tizanidine, warfarin 
Abbreviations: AUC = area under the curve; CL = clearance. 
Source: (68) 
a Sensitive CYP substrates refers to drugs whose plasma AUC values have been shown to increase 5-fold or higher 
when coadministered with a known CYP inhibitor or AUC ratio in poor metabolizers vs. extensive metabolizers is 
greater than 5-fold. 
b CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates that 
small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety 
concerns (eg, Torsades de Pointes). 


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APPENDIX C. DRUGS THAT ARE SUBSTRATES OR INHIBITORS OF 
P-GLYCOPROTEIN 
 
Substrates 
Inhibitors 
Aliskiren 
Amiodarone 
Ambrisentan 
Azithromycin 
Colchicine 
Captopril 
Dabigatran etexilate 
Carvedilol 
Digoxin 
Clarithromycin 
Everolimus 
Conivaptan 
Fexofenadine 
Cyclosporine 
Imatinib 
Diltiazem 
Lapatinib 
Dronedarone 
Maraviroc 
Erythromycin 
Nilotinib 
Felodipine 
Posaconazole 
Itraconazole 
Ranolazine 
Ketoconazole 
Saxagliptin 
Lopinavir and Ritonavir 
Sirolimus 
Quercetin 
Sitagliptin 
Quinidine 
Talinolol 
Ranolazine 
Tolvaptan 
Ticagrelor 
Topotecan 
Verapamil 
Source: (68) 
 


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APPENDIX D. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST), V1.1 
Response Criteria by RECIST v1.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the 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 to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progressions). 
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 
Complete Response (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). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 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. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 


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Table 13 
RECIST Response for Patients with Measurable Disease (ie, Target Disease) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
> 4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
> 4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
documented at least once 
> 4 wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease 
* 
See RECIST v1.1 publication (65) for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should 
be made to document the objective progression even after discontinuation of treatment. 
 
Table 14 
RECIST Response for Patients with Non-Measurable Disease (ie, Non-Target 
Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR = complete response; PD = progressive disease 
*‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not 
advised 
 
 


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APPENDIX E. IMMUNE-RELATED RESPONSE EVALUATION 
CRITERIA IN SOLID TUMORS (irRECIST) 
Immune-related RECIST will be used by local site Investigators to assess tumor response and 
progression and make treatment decisions.  
Table 15 provides a high-level summary of the imaging procedures and treatment decisions to be 
made based on evidence of progression of disease per RECIST v1.1. See also details provided in 
Section 6.3.1.4. 
Table 15 
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease 
Timing of 
Imaging 
Clinically Stable 
Clinically Unstable 
Tumor Imaging 
Treatment 
Tumor Imaging 
Treatment 
1st radiologic 
evidence of PD  
Repeat imaging at 
≥ 4 weeks at site 
to confirm PD 
May continue study 
treatment at the local 
site Investigator’s 
discretion while 
awaiting confirmatory 
tumor imaging 
Repeat imaging at 
≥ 4 weeks to confirm 
PD per physician 
discretion only 
Discontinue treatment 
Repeat tumor 
imaging confirms 
PD  
No additional 
imaging required 
Discontinue treatment  No additional imaging 
required 
N/A 
Repeat tumor 
imaging shows 
SD, PR or CR 
Continue regularly 
scheduled imaging 
assessments  
Continue study 
treatment at the local 
site Investigator’s 
discretion 
Continue regularly 
scheduled imaging 
assessments  
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s 
discretion. 
Abbreviations: CR = complete response; irRECIST = immune-related Response Criteria in Solid Tumors; N/A = not 
applicable; PD = progressive disease; PR = partial response; RECIST = Response Criteria in Solid Tumors; SD = 
stable disease 
 


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APPENDIX F. ASSESSMENT OF RESPONSE IN OVARIAN CANCER 
BY GYNECOLOGIC CANCER INTERGROUP (GCIG) 
CRITERIA 
Because of the pelvic location of the primary tumor in patients with OC and the frequent 
occurrence of peritoneal disease, imaging may not always be reliable for documentation of PD in 
patients with OC. Criteria other than RECIST may be applicable to define PD in these patients. 
For this protocol, the GCIG criteria for disease progression will also be considered for patients 
with OC.(66) Based on these criteria, PD may also be determined if at least 1 of the following 
criteria is met: 
1. 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 GCIG criteria. 
2. Definitive clinical signs and symptoms of PD unrelated to nonmalignant or iatrogenic 
causes ([a] intractable cancer-related pain; [b] malignant bowel obstruction/worsening 
dysfunction; or [c] unequivocal symptomatic worsening of ascites or pleural effusion) 
AND CA-125 progression according to GCIG criteria. 
Abnormal CA-125 levels on-study do not represent disease progression; however, they may 
prompt imaging if clinically indicated. Progressive disease 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 how 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. If 
CT/MRI shows existing (baseline) lesions that 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. 


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APPENDIX G. EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS 
Description 
Grade 
Fully active, able to carry on all pre-disease performance without restriction. 
0 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature, ie, light house work, office work. 
1 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
4 
Source: (69) 
 
 

SAP_001.pdf: 
  
 
  
Sponsor: TESARO, Inc. 
Statistical Analysis Plan 
Protocol no: 3000-PN162-01-001 
Version Date: Final v2.0, 21-Mar-2019 
 
Page 1 of 52 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 Statistical Analysis Plan 
 
Sponsor: 
TESARO, Inc. 
Protocol No: 
3000-PN162-01-001, Amendment 2 
PRA Project Id: 
TSRNIRPD-NIRPD1 
Version No.: 
Protocol v3.0 
 
Title: 
Phase 1/2 Clinical Study of Niraparib in Combination with Pembrolizumab in 
Patients with Advanced or Metastatic Triple-Negative Breast Cancer and in 
Patients with Recurrent Ovarian Cancer 
CRF Version 
No./Date: 
2.135/31-May-2018 
SAP Version Date: 
21-Mar-2019 
SAP No. 
Final v2.0 
 
 Approvals 
Sponsor 
Sponsor Name: 
TESARO, Inc. 
Representative/ Title: 
 MD Senior Medical Director 
Signature /Date: 
 
Sponsor 
Sponsor Name: 
TESARO, Inc. 
Representative/ Title: 
 Statistical Consultant 
Signature /Date: 
 
PRA 
Project Manager/Title: 
 Project Manager 
Signature /Date: 
 
Biostatistician / Title 
(Owner): 
 Principal Biostatistician 
   (Original author: 
 Senior Principal B
Signature /Date: 
 
  
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


  
 
  
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Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Table of Contents 
 Statistical Analysis Plan ....................................................................................................................................................... 1 
 Approvals ................................................................................................................................................................................... 1 
Table of Contents ............................................................................................................................................................................. 2 
 Purpose ....................................................................................................................................................................................... 4 
 Scope ............................................................................................................................................................................................. 4 
 Introduction .............................................................................................................................................................................. 4 
5.1 Changes from Protocol.................................................................................................................................................... 4 
 Study Objectives ...................................................................................................................................................................... 5 
6.1 Phase 1 .................................................................................................................................................................................... 5 
6.1.1 Primary Objectives ................................................................................................................................................... 5 
6.1.2 Secondary Objectives .............................................................................................................................................. 5 
6.2 Phase 2 .................................................................................................................................................................................... 5 
6.2.1 Primary Objective: ................................................................................................................................................... 5 
6.2.2 Secondary Objective:............................................................................................................................................... 5 
6.2.3 Exploratory Objectives........................................................................................................................................... 5 
 Study Design ............................................................................................................................................................................. 6 
7.1 Sample Size Considerations.......................................................................................................................................... 7 
7.2 Randomization .................................................................................................................................................................... 7 
 Study Variables and Covariates ....................................................................................................................................... 7 
8.1 Primary Variables.............................................................................................................................................................. 7 
Phase 1 ....................................................................................................................................................................................... 7 
Phase 2 ....................................................................................................................................................................................... 8 
8.2 Secondary Variables ......................................................................................................................................................... 8 
8.2.1 Efficacy ........................................................................................................................................................................... 8 
8.2.2 Safety .............................................................................................................................................................................. 8 
8.2.3 Exploratory Endpoints ........................................................................................................................................... 9 
8.3 Pharmacokinetic Variables ........................................................................................................................................... 9 
8.3.1 Presentation of Pharmacokinetic Concentrations ................................................................................. 10 
 Definitions ............................................................................................................................................................................... 10 
 Biomarker Definitions .................................................................................................................................................... 14 
 Analysis Sets ........................................................................................................................................................................ 15 
11.1 Screening Analysis Set............................................................................................................................................... 15 
11.2 Full Analysis Set............................................................................................................................................................ 15 
11.3 Pooled OC Full Analysis Set: ................................................................................................................................... 15 
11.4 Safety Analysis Set....................................................................................................................................................... 15 
11.5 DLT Analysis Set ........................................................................................................................................................... 15 
11.6 Efficacy Evaluable (EE) Analysis Set .................................................................................................................. 16 
11.7 Pooled OC EE Analysis Set ....................................................................................................................................... 16 
11.8 Pharmacokinetic (PK) Analysis Set ..................................................................................................................... 16 
 Interim Analyses ............................................................................................................................................................... 16 
 Data Review ......................................................................................................................................................................... 16 
13.1 Data Handling and Transfer ................................................................................................................................... 16 
13.2 Data Cleaning ................................................................................................................................................................. 17 
13.3 Handling of Dropouts or Missing Data .............................................................................................................. 17 
 Statistical Methods ........................................................................................................................................................... 18 
14.1 Patient Disposition ...................................................................................................................................................... 19 


  
 
  
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14.2 Protocol Deviations .................................................................................................................................................... 19 
14.3 Treatments...................................................................................................................................................................... 19 
14.3.1 Extent of Study Treatment Exposure ........................................................................................................ 19 
14.3.2 Prior and Concomitant Medications .......................................................................................................... 21 
14.4 Demographic and Baseline Characteristics .................................................................................................... 22 
14.4.1 Primary Cancer History ................................................................................................................................... 22 
14.4.2 Medical History, Surgical History ................................................................................................................ 22 
14.5 Efficacy Analyses .......................................................................................................................................................... 23 
14.5.1 Primary Endpoints ............................................................................................................................................. 24 
14.5.2 Methods for Handling Dropouts and Missing Data ............................................................................ 24 
14.5.3 Multiplicity ............................................................................................................................................................. 24 
14.5.4 Pooling of Sites ..................................................................................................................................................... 24 
14.5.5 Secondary Endpoints ........................................................................................................................................ 24 
14.5.6 Examination of Subgroups ............................................................................................................................. 25 
14.6 Safety Analyses ............................................................................................................................................................. 27 
14.6.1 Adverse Events..................................................................................................................................................... 27 
14.6.2 Laboratory Data ................................................................................................................................................... 29 
14.6.3 Vital Signs ............................................................................................................................................................... 31 
14.6.4 Physical Examinations and Other Observations Related to Safety ............................................. 31 
14.6.5 ECG ............................................................................................................................................................................. 31 
 Validation ............................................................................................................................................................................. 32 
 References ............................................................................................................................................................................ 33 
 List of Abbreviations ....................................................................................................................................................... 34 
 Appendix 1: Common Terminology Criteria for Adverse Events V4.03 (CTCAE) ............................. 37 
 Appendix 2: Schedule of events ................................................................................................................................. 39 
 Appendix 3 Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 ......................................... 43 
 Appendix 4: Immune-Related response evaluation criteria in solid tumors....................................... 45 
 Appendix 5: Laboratory Standard Units ................................................................................................................ 46 
 Appendix 6: Drugs Excluded from Prior Lines of Therapy ........................................................................... 47 
 Appendix 7: Immune-Related Adverse Events ................................................................................................... 50 
 Document History ............................................................................................................................................................ 52 
 


  
 
  
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Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 Purpose 
The statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under TESARO Inc. Protocol 3000-PN162-01-001. 
 Scope 
This plan is a living document that will be created during the trial start-up. SAP 1 will be drafted within 
three months of final CRF, and maintained throughout the lifecycle of the trial, an email approval of SAP 
1 from the sponsor is sufficient to start programming activities.  The SAP 2 will be finalized prior to 
database lock. SAP 2 will require sign off from the PRA Project Manager and the sponsor.   
The SAP outlines the following: 
x 
Study objectives 
x 
Study design 
x 
Variables analyzed and analysis sets 
x 
Applicable study definitions 
x 
Statistical methods regarding important protocol deviations, study treatment exposure, efficacy 
analysis, concomitant medications, adverse events handling and laboratory data.  
 Introduction 
This SAP describes the statistical methods to be used during the reporting and analyses of data collected 
under TESARO, Inc. Protocol 3000-PN162-01-001. 
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol dated 01-MAR-2017 (Amendment 2) and CRF dated 
31-MAY-2018. Any further changes to the protocol or CRF may necessitate updates to the SAP. 
The SAP is to be developed in two stages. The purpose is to “finalize” an SAP so that we can start 
programming earlier in the process. A final version of the SAP, known as SAP 2, will be issued for 
sponsor approval prior to database lock. Chances made to the SAP after database lock will be documented 
in the Clinical Study Report. 
5.1 Changes from Protocol 
 
The protocol describes a per-protocol population for use in evaluation of supportive analyses of efficacy. 
This population will not be used in this SAP.  
 
The protocol defined evaluation of irRECIST endpoints (objective response rate, duration of response, 
disease control rate and progression free survival).  These endpoints were not consistently collected across 
all patients and therefore cannot formally be evaluated.  All collected data will be listed.  In addition, for 
patients who received study treatment for ≥28 days beyond radiological progression per RECIST v1.1 and 
who have post-progression tumor assessments, the irRECIST evaluations will be listed along-side the 
RECIST v1.1 evaluations, as available.  
 
The relationship between cytogenetic abnormalities and safety parameters was to be evaluated per 
protocol, however this was not done since there is no cytogenetic abnormality assessment. 
 


  
 
  
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Protocol no: 3000-PN162-01-001 
Version Date: Final v2.0, 21-Mar-2019 
 
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 Study Objectives 
6.1 Phase 1 
6.1.1 Primary Objectives 
x 
To evaluate dose-limiting toxicities (DLTs) of combination treatment with niraparib and 
pembrolizumab during the first cycle of treatment. 
x 
To establish a recommended Phase 2 dose (RP2D) and schedule.  
 
6.1.2 Secondary Objectives 
x 
To evaluate the safety and tolerability of combination treatment with  
niraparib and pembrolizumab using Common Terminology Criteria for Adverse Events (CTCAE, 
v.4.03)  
x 
To evaluate the pharmacokinetics (PK) of niraparib and associated major metabolite M1 during 
combination treatment. 
 
6.2 Phase 2 
6.2.1 Primary Objective:  
x 
To estimate the clinical activity of combination treatment with niraparib and pembrolizumab in 
terms of objective response rate (ORR) as assessed by the Investigators using Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 separately for the triple-negative breast 
cancer (TNBC) and ovarian cancer (OC) cohorts.  
6.2.2 Secondary Objective:  
x 
To evaluate the safety and tolerability of combination treatment with niraparib and 
pembrolizumab using Common Terminology Criteria for Adverse Events (CTCAE, v.4.03)  
x 
Phase 2: To evaluate additional measures of clinical benefit as assessed by the Investigators, 
including:  
− ORR by immune-related RECIST v1.1 (irRECIST);  
− Duration of response (DOR) by RECIST v1.1 and irRECIST;  
− Disease control rate (DCR) by RECIST v1.1 and irRECIST;  
− Progression-free survival (PFS) by RECIST v1.1 and by irRECIST;  
− Overall survival (OS).  
x 
To evaluate the PK of niraparib and associated major metabolite M1 during combination 
treatment. 
6.2.3 Exploratory Objectives 
x 
To identify the biomarker-based patient population that would derive benefit from the 
combination treatment based on the tumor tissue molecular profile, molecular profile of tumor-
infiltrating lymphocytes (TILs) and circulating biomarkers.  
x 
To correlate homologous recombination deficiency (HRD) score with other immune-related 
biomarkers and with efficacy outcomes.  


  
 
  
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 Study Design 
This is a multicenter, open-label, single-arm Phase 1/2 study evaluating the safety and efficacy of 
combination treatment with niraparib and pembrolizumab in patients with previously treated TNBC or 
OC.  
The study will be conducted in 2 parts. The Phase 1 portion of the study will be a dose-escalation 
evaluation to determine the recommended Phase 2 dose (RP2D) and schedule of niraparib to be 
administered in combination with the recommended dose of pembrolizumab to be used in the Phase 2 
portion. 
Dosing will initiate at Dose Level 1 with a cohort of 6 patients with either TNBC or OC enrolled and 
treated with a combination of niraparib 200 mg PO daily for Days 1-21 and pembrolizumab 200 mg IV 
on Day 1 every 21 days. Once Dose Level 1 is determined to be safe, a cohort of 6 patients with either 
TNBC or OC will be enrolled in Dose Level 2 and treated with a combination of niraparib 300 mg PO 
daily for Days 1-21 and pembrolizumab 200 mg IV on Day 1 every 21 days. No further dose escalation 
will be considered if Dose Level 2 is reached. The maximum tolerated dose (MTD) will be defined as the 
highest dose with DLTs observed in less than one-third of patients (ie, < 2 of 6 patients or < 4 of 12 
patients) during Cycle 1 of combination treatment. If one-third or more of the evaluable patients 
experiences a DLT, then this dose will be considered to exceed the MTD and a lower dose level may be 
opened for enrollment if not yet evaluated. 
The following are 4 dose levels/schedules planned for the Phase 1 of the study; each cohort will contain 6 
patients but may be expanded to 12 patients: 
x 
Dose Level 1: niraparib 200 mg/day orally (PO) on Days 1-21 and pembrolizumab 200 mg 
intravenously (IV) on Day 1 of each 21-day cycle.  
x 
Dose Level 2: niraparib 300 mg/day PO on Days 1-21 and pembrolizumab 200 mg IV on Day 1 
of each 21-day cycle.  
x 
Dose Level (-1): niraparib 200 or 300 mg/day PO on Days 1-14 of each 21-day cycle and 
pembrolizumab 200 mg IV on Day 1 of each 21-day cycle.  
x 
Dose Level (-2): niraparib 200 or 300 mg/day PO on Days 1 – 7 of each 21-day cycle and 
pembrolizumab 200 mg IV on Day 1 of each 21-day cycle.  
The Phase 2 portion of the study will commence after the RP2D is determined during the Phase 1 portion. 
Two cohorts of approximately 48 patients each with advanced TNBC or OC will be evaluated.  
Patients in this phase of the study will receive the RP2D of niraparib in combination with pembrolizumab 
200 mg IV on Day 1 of each 21-day cycle. 
In Phase 2, pembrolizumab will be administered once every 21 days (200 mg IV). Pembrolizumab may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle after Cycle 2 due to 
administrative reasons. Niraparib is administered as a daily dose.  On day 1 of each cycle, niraparib dose 
will be administered upon completion of pembrolizumab infusion. The RP2D of the combination will be 
based on the results in Phase 1.  
Combination pembrolizumab/niraparib treatment may continue for up to 2 years unless specific 
withdrawal criteria are met (Section 4.3 of the protocol). Continued treatment with niraparib beyond 2 
years may be considered following discussion between the Sponsor and Investigator. Figure 1 describes 
the study schema. The schedule of events is added in the appendix of section 19.0. 


  
 
  
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Figure 1: Study Schema 
 
Abbreviations: AE=adverse event; d=day(s); DL=dose level; DLT=dose-limiting toxicity; OC=ovarian cancer; 
PK=pharmacokinetics; N=niraparib; P=pembrolizumab; RP2D=recommended Phase 2 dose; q21d=every 21 days; TNBC=triple-
negative breast cancer.  
 
7.1 Sample Size Considerations 
A total sample size of approximately 18 patients is estimated for the Phase 1 portion of the study to 
provide initial comparison of the incidence of DLTs and safety profiles of the combination treatment 
between dose schedules in each patient population. More patients could be enrolled (e.g., if the Dose 
Level -2 is explored, or if expansion at any dose level is required to better understand safety and 
tolerability); up to a total of 36 patients may be enrolled.  
A total of approximately 96 evaluable patients (48 patients in each tumor type) will be enrolled in Phase 2 
to ensure understanding of the activity of the combination treatment and to obtain adequate representation 
of different molecular cancer subtypes and biomarkers.  For each cohort, with 48 evaluable patients, the 
study has approximately 82%/94% power for each cohort to rule out a ≤15% ORR (null hypothesis) when 
the true ORR is 30%/35% at the 10% type I error rate (two-sided). 
7.2 Randomization 
Not applicable, as this is a single-arm study and Phase 2 is conducted in two cohorts. 
 Study Variables and Covariates 
8.1 Primary Variables 
Phase 1 
x 
DLTs of combination treatment during the first treatment cycle 


  
 
  
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x 
MTD defined as the highest dose of niraparib with DLTs observed in less than one-third of 
patients (i.e., < 2 of 6 patients or < 4 of 12 patients) during Cycle 1 of combination treatment. 
x 
RP2D - defined as the greatest dose intensity and regimen of niraparib that can be safely 
combined with the recommended dose and regimen of pembrolizumab 
Phase 2 
x 
ORR for combination treatment with pembrolizumab and niraparib using RECIST v1.1 criteria 
based on the investigator assessment. 
 
8.2 Secondary Variables 
8.2.1 Efficacy 
x 
ORR for combination treatment with pembrolizumab and niraparib using irRECIST criteria. 
x 
Duration of Response (DOR) per RECIST v1.1 
x 
Duration of Response (DOR) per irRECIST  
x 
Disease Control Rate per RECIST v1.1 
x 
Disease Control Rate (DCR) per irRECIST 
x 
Progression Free Survival (PFS) per RECIST v1.1 
x 
Progression Free Survival (PFS) per irRECIST 
x 
Overall Survival (OS) 
 
Protocol specified irRECIST endpoints were not consistently collected across all patients and therefore 
cannot formally be evaluated using standard summaries.  irRECIST timepoint assessments will be listed, 
as available. 
8.2.2 Safety 
. 
All treatment emergent adverse events including serious and non-serious will be collected.  Severity will 
be assessed based on CTCAE (v 4.03) grades.  The reported events will be assessed for causal 
relationship to study drugs.  Events of clinical interest for pembrolizumab and niraparib will also be 
collected. 
The following additional safety information will be collected. 
x 
Changes in clinical laboratory values (hematology, chemistry, coagulation, thyroid function, 
urinalysis) 
x 
Vital signs 
x 
ECG’s 
x 
Physical examination findings 
x 
Concomitant medications 


  
 
  
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8.2.3 Exploratory Endpoints 
The relationship between cytogenetic abnormalities and safety parameters was to be evaluated per 
protocol, however this was not done since there is no cytogenetic abnormality assessment. 
8.3 Pharmacokinetic Variables 
The pharmacokinetic analysis set will consist of all patients with sufficient data to enable estimation of at 
least one PK parameter listed below. 
The following PK parameters will be calculated for niraparib and major metabolite M1 for Phase 1 using 
standard non-compartmental methods in Phoenix® WinNonlin® (WNL) (Pharsight Corporation, Version 6.3 
or higher): 
Table 1: PK parameters 
Parameter 
Description 
SAS Programming Notes 
Cmax 
Observed maximum concentration during the dosing 
interval. 
Cmax from WNL 
Cmin 
Observed minimum concentration during the dosing 
interval 
Cmin from WNL 
Tmax 
Time of the maximum observed concentration.   
Tmax from WNL 
AUC(0-24) 
Area under the plasma concentration-time curve from 
time 0 to 24 hours. 
This parameter will be calculated for Phase 1, Cycle 1 
and Cycle 2 
AUC(0-24) from WNL (partial 
area) 
AUC(0-last) 
Area under the concentration-time curve between time 
zero (predose) and time of last quantifiable concentration. 
AUClast from WNL 
AUC(0-tau); 
AUC(0-tau) ss 
Area under the plasma concentration-time curve during a 
dosing interval. 
This parameter will be calculated after a single dose and 
after multiple doses at steady state based on available data 
AUCtau from WNL where 
tau is equal to XX hr 
AR 
The accumulation ratio will be calculated as the 
exposure at steady state within tau divided by the first 
dose exposure within tau. 
AUC(0-tau) ss / AUC(0-tau) 
AUC(0-inf) 
Area under the concentration-time curve between time 
zero (predose) extrapolated to infinity.  
AUC_%Extrap_obs ≤ 20%  or R2 > 0.70 is required to 
retain AUCinf 
This parameter will be calculated for Phase 1, Cycle 1 
only 
AUCINF_obs from WNL 
If AUC_%Extrap_obs > 
20% or Rsqadj ≤ .70 then 
parameter will not be 
reported. 
CL/F 
Apparent clearance calculated as CL = Dose/AUCinf 
Percent extrapolation less than or equal to 20% and r2 
greater than 0.70 is required to retain CL/F. 
Cl_F_obs from WNL  
If AUC_%Extrap_obs 
>20% or Rsq ≤ .70 then 
parameter is deleted 
Vz/F 
Apparent volume of distribution as Vz/F = (CL/F)/λz 
Percent extrapolation less than or equal to 20% and r2 
greater than 0.70 is required to retain Vz/F. 
Vz_F_obs from WNL  
If AUC_%Extrap_obs 
>20% or Rsq ≤ .70 then 
parameter is deleted 


  
 
  
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General statistics will be summarized for both Phase 1 and sparse data in Phase 2. 
PK analysis will use actual times as recorded on the CRF. If actual times are missing, nominal times may 
be used with sponsor approval. 
Concentrations are used as supplied by the analytical laboratory for PK analysis. The units of concentration 
and resulting PK parameters, with amount or concentration in the unit, will be presented as they are received 
from the analytical laboratory. Concentration values that are below the level of quantification (BLQ) will 
be set to zero, with defined exceptions as follows: any embedded BLQ value (between 2 quantifiable 
concentrations) and BLQ values following the last quantifiable concentration in a profile will be set to 
missing for the purposes of PK analysis. 
If there are late quantifiable concentration values following 2 BLQ concentration values in the apparent 
terminal phase, these values will be evaluated. If these values are considered to be anomalous, they will be 
set to missing. If an entire concentration-time profile is BLQ, the profile will be excluded from the PK 
analysis. If concentration values at the beginning of the profile (i.e. pre-dose) are missing, these values may 
be set to zero with sponsor approval. 
8.3.1 Presentation of Pharmacokinetic Concentrations 
x 
The following rules will be applied if there are values that are below the lower limit of 
quantification (BLQ) or if there are missing values (e.g., no result [NR]) in a plasma concentration 
data series to be summarized. 
o For the calculation of summary statistics, BLQ values will be set to zero. 
o Where there is NR, these will be set to missing. 
x 
If all the values are BLQ, then the arithmetic mean, arithmetic SD, median, min and max will be 
presented as zero and the geometric mean and geometric CV% will be denoted as not calculated 
(NC). 
x 
If the value of any descriptive statistic calculation is BLQ, these will be presented as zero and the 
geometric mean and geometric CV% will be denoted as NC. 
 
 Definitions 
 
Age: 
The age collected at time of screening, presented in whole years. 
 
Age Group: 
There will be three age groups summarized in the demographics tables: <65 years old, ≥65-<75 years old 
and ≥ 75 years old. 
 
Baseline: 
Unless otherwise specified, baseline is the last measurement taken on or prior to first dose of 
pembrolizumab or niraparib, whichever is earlier (baseline can be the same date as first dose, given the 
measurement is expected prior to first dose, otherwise consider both time and date of dosing (if time is 
available for both). 
 
Best Overall Response (BOR) per RECIST v1.1 - Confirmed:  
The best overall response (BOR) according to RECIST v1.1 will be assessed based on reported overall 
timepoint responses at different evaluation time points from the first dose date until documented disease 
progression, according to the following rules: 


  
 
  
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x 
CR = at least two determinations of CR at least 4 weeks apart with no evidence of progression between 
the two determinations. 
x 
PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not 
qualifying for a CR). 
x 
SD= at least one SD assessment (or better) ≥ 28 days after the baseline scan and before progression 
(and not qualifying for a CR or PR). 
x 
PD= progression after baseline.  
Only tumor assessments performed before the start of any further anti-cancer treatment will be considered 
in the assessment of BOR. Clinical deterioration will not be considered as documented disease progression. 
 
Best Overall Response (BOR) per RECIST v1.1 Without Confirmation Requirements:  
The best overall response (BOR) according to RECIST v1.1 without confirmation requirements will be 
assessed based on reported overall timepoint responses at different evaluation time points from the first 
dose date until documented disease progression, according to the following rules: 
x 
Confirmed CR = at least two determinations of CR at least 4 weeks apart with no evidence of 
progression between the two determinations. 
 
x 
Unconfirmed CR = at least one determinations of CR and not followed by another CR meeting 
the requirement for confirmation. 
 
x 
Confirmed PR = at least two determinations of PR or better at least 4 weeks apart before 
progression (and not qualifying for a CR). 
 
x 
Unconfirmed PR = at least one determinations of PR before progression (and not qualifying for a 
CR), and not followed by another PR meeting the requirement for confirmation. 
 
x 
SD= at least one SD assessment after baseline and before progression [and not qualifying for any 
type of CR or PR above (confirmed or unconfirmed)]. 
 
x 
PD= progression after baseline. 
 
Only tumor assessments performed before the start of any further anti-cancer treatment will be considered 
in the assessment of BOR. Clinical deterioration will not be considered as documented disease 
progression. 
 
Body Mass Index (BMI): 
Calculated at each visit and is equal to the weight (in kg)/ [height at screening (in m)2]. 
 
Clinical Benefit Rate at 18 weeks (CBR18) 
The clinical benefit rate at 18 weeks is the proportion of patients in the analysis population who achieved 
confirmed CR or PR, or achieved SD ≥18 weeks without evidence of radiologic progression prior to this 
point.  A seven day window will be used to accommodate scan timing, thereby considering any SD, PR or 
CR beyond 17 weeks (ie, ≥119 days).  Patients who are ongoing treatment who have not reached the 
timepoint of interest will not be included in the denominator. 
 
Corrected QT Interval (QTcF): 


  
 
  
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QTcF is defined as corrected QT interval with Fridericia’s correction formula: QTcF=QT/(RR)1/3, where 
QT is the heart rate interval, measured in milliseconds and RR is the interval from the onset of one QRS 
complex to the onset of the next QRS complex, measured in seconds. 
 
Disease Control Rate (DCR) per RECIST v1.1:  
Disease control rate will be assessed as a secondary endpoint and is defined as the proportion of patients 
achieving CR, PR, or stable disease (SD) as assessed by the Investigator per RECIST v1.1.  DCR will be 
assessed requiring confirmation and without confirmation requirements. 
 
 
Duration of Response (DOR) per RECIST v1.1: 
DOR is applicable to patients that achieve either CR/PR per RECISTv1.1 and is defined as time from the 
first assessment of CR/PR until the date of the first occurrence of PD, or until the date of death. Follow 
Table 2 for censoring rules of DOR.  DOR will be assessed for both confirmed responses only and for 
responses without confirmation requirements. 
 
ܦܱܴ (݉݋݊ݐℎݏ) = Date of PD/Death/Censoring – Date of First recorded CR or PR + 1
30.4375
 
 
 
Last Known Contact Date: 
The date of last known contact date will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following:  
• 
Patient assessment dates (blood draws [laboratory, PK], vital signs, performance status, ECG, tumor 
assessments, ECOG, tumor measurement, or tumor biopsy dates)  
• 
Start and end dates of anti-cancer therapies administered after study treatment discontinuation.  
• 
AE start and end dates  
• 
Last date of contact collected on the ‘Survival information’ eCRF (do not use date of survival follow-
up assessment unless status is ‘alive’)  
• 
Study treatment start and end dates  
• 
Date of discontinuation on disposition eCRF pages (do not use if reason for discontinuation is lost to 
follow-up).  
Only dates associated with actual examinations of the patient will be used in the derivation. Dates associated 
with a technical operation unrelated to patient status such as the date a blood sample was processed will not 
be used. Assessment dates after the cut-off date will not be applied to derive the last contact date, if 
applicable. 
 
 
Objective Response Rate (ORR) per RECIST v1.1: 
ORR will be assessed using tumor data recorded by the Investigator, and the denominator will be based 
on all patients in the defined analysis population. 
The ORR is the proportion of patients who achieved best overall response of CR (complete response) or 
PR (partial response). ORR will be assessed requiring confirmation and without confirmation requirements. 
When confirmation is required, the objective responses should be confirmed by a repeat tumor imaging 
assessment, at least 4 weeks apart, per RECIST v1.1. Each patient will have an objective response status 
(0: OR=no; 1: OR=yes). 
 
 


  
 
  
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Overall Response:  
Overall tumor response assessment at each time point is a combination of target lesions, non-target lesions 
and new lesions assessed by the investigator following the guidelines presented specified in RECIST v1.1. 
The response evaluation criteria per RECIST v1.1 are presented in Appendix D of the protocol.  
 
Overall Survival (OS): 
Overall survival will be assessed as a secondary endpoint and is defined as the time from date of first dose 
of study treatment to the date of death by any cause. Patients last known to be alive will be censored at date 
of last known contact. 
 
ܱܵ(݉݋݊ݐℎݏ) = Date of Death/Censoring –  Date of First Dose + 1
30.4375
 
 
Progression-Free Survival Time (PFS) per RECIST v1.1: 
Progression-free survival will be assessed as a secondary endpoint and is defined as the time from first dose 
of study treatment to the earlier date of assessment of progression or death by any cause in the absence of 
progression based on the time of first documentation of disease progression per RECIST v1.1.  
Censoring rules for PFS events follow the guidelines presented in Table 2. 
 
ܲܨܵ(݉݋݊ݐℎݏ) = Date of PD/Death/Censoring – Date of First Dose + 1
30.4375
 
  
Table 2: Censoring Rules for PFS and DOR. 
Scenario 
Date of event/censoring 
Outcome 
No baseline assessment or no post-baseline 
assessment 
First dose date 
Censored a 
Progression or death ≤ 18 weeks after last 
tumor assessment or ≤ 18 weeks after first dose 
date 
Date of progression or death 
Event 
 
Progression or death > 18 weeks after the last 
tumor assessment  
Date 
of 
last 
adequate 
assessment  
Censored 
 
No progression 
Date 
of 
last 
adequate 
assessment  
Censored 
 
New anticancer therapy given (excluding 
radiation therapy) 
Date 
of 
last 
adequate 
assessment before anticancer 
therapy given 
Censored 
a However if the patient dies ≤18 weeks after first dose date the death is an event with date on death date 
 
Study Treatments:  
Study treatments are niraparib and pembrolizumab.  
 
Treatment Cycle:  
Cycles will be identified in the visit label in the clinical database associated with dosing records. 
 
Treatment Emergent Adverse Event (TEAE): 
All AEs were collected and recorded in the eCRF for each patient from the day of signed 
informed consent until 30 days after the last dose of study treatment; SAEs were monitored 
through 90 days after the last dose of study treatment (or to a minimum of 30 days post-treatment 
if the patient started alternate anticancer therapy). All AEs and SAEs experienced by a patient, 


  
 
  
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irrespective of the suspected causality, were to be monitored until the AE or SAE was resolved, any 
abnormal laboratory values had returned to baseline or normal levels, until there was a 
satisfactory explanation for the changes observed, until the patient was lost to follow-up, or until 
the patient died. Per protocol (Section 6.1.1), a treatment emergent adverse event was defined as any new 
AE that began, or any preexisting condition that worsens in severity after at least 1 dose of study 
treatment has been administered.  For analysis, TEAE’s are AE’s with the onset date beginning on or after 
the day of first administration of either study treatment. It is expected that data cleaning activities will 
ensure collection of all reportable events in the clinical database. An AE with completely missing onset 
and stop dates, or with the onset date missing and a stop date later than the first dose date of either study 
treatment, will be considered to be treatment emergent. 
 
 Biomarker Definitions 
HRR status: Mutational status of Homologous Recombination Repair (HRR) pathway genes: . In this 
document, HRR status is primarily determined using the Myriad research assay on tumor sample collected 
prior to enrollment. This test only reports HRR mutational status in the tumor and cannot distinguish 
germline mutation from somatic mutation.  In addition, local germline testing results for BRCA1, BRCA2 
were collected from sites when available.  Local testing results for other HRR genes, when available, are 
also included. 
x 
BRCA mutant (BRCA-mut):  gBRCA mutant OR tBRCA mutant 
x 
gBRCA mutant (gBRCA-mut):  At least one deleterious or suspected deleterious mutation 
found in BRCA1 or BRCA2 in local germline testing. 
x 
tBRCA mutant (tBRCA-mut): At least one deleterious or suspected deleterious mutation found 
in BRCA1 or BRCA2 in the tumor. 
x 
BRCA wild type (BRCA-wt):  tBRCA-wt AND not gBRCA-mut 
x 
tBRCA wild type (tBRCA-wt): No deleterious or suspected deleterious mutation found in 
BRCA1 or BRCA2. 
x 
Unknown BRCA status:  Not BRCA-mut AND not BRCA-wt 
x 
Other HRR mutant (oHRR-mut): At least one deleterious or suspected deleterious mutation found 
in one or more of the HRR pathway genes, excluding BRCA1 and BRCA2. 
x 
Other HRR wild type (oHRR-wt): No deleterious or suspected deleterious mutation found in any 
of the HRR pathway genes, excluding BRCA1 and BRCA2. 
x 
HRR mutant (HRR-mut): BRCA-mut or oHRR-mut. 
x 
HRR wild type (HRR-wt): BRCA-wt AND oHRR-wt. 
x 
Unknown HRR status:  No sample tested or failed sample AND not gBRCA mutant 
 
HRD status: Homologous recombination deficiency (HRD) – Dysregulation in the homologous 
recombination pathway (due to genetic mutations or alterations) leading to cellular genomic instability and 
an inability to efficiently repair damaged DNA. In this document, HRD status is determined using the 
Myriad research assay test on tumor sample collected prior to enrollment. 


  
 
  
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x 
HRD positive (HRD-pos): Any tumor with an HRD score ≥42, OR BRCA mutant, is considered 
HRD positive. 
x 
HRD negative (HRD-neg): Any tumor with an HRD score <42, AND not BRCA mutant, is 
considered HRD negative. 
x 
HRD unknown (HRD-unk):  No sample tested or failed sample AND not gBRCA mutant. 
 
PD-L1 status: PD-L1 is one of the ligands that bind to PD-1 on tumor infiltrating T cells and renders the T 
cells inactive. PD-L1 expression has been used as a biomarker for identifying patients who may benefit 
from anti-PD1/L1 therapies. In this document, PD-L1 status is determined using the Agilent/DAKO 22C3 
immunohistochemistry (IHC) clinical trial assay (CTA) on tumor sample collected prior to enrollment. 
x 
PD-L1 positive (PD-L1-pos): Any tumor with a combined proportion score (CPS) score ≥1. CPS 
is defined as: (the number of PD-L1 positive tumor and immune cells/the number total tumor 
cells)*100. 
x 
PD-L1 negative (PD-L1-neg): Any tumor with a combined proportion score (CPS) score <1. 
x 
PD-L1 unknown:  No sample tested or failed sample. 
  Analysis Sets 
11.1 Screening Analysis Set 
All patients that signed the informed consent form including screen failures. 
11.2  Full Analysis Set  
The full analysis set (FAS) will consist of all Phase 2 patients who receive any amount of study treatment. 
If a patient receives more than one dose level of study treatment, the patient will be classified according to 
the original dose level received. The primary analysis of efficacy endpoints will be performed on the FAS 
population.  
11.3 Pooled OC Full Analysis Set:  
Given the similarities of the Phase 1 and Phase 2 patient population for the ovarian cancer cohort, 
corresponding efficacy analyses will be provided using the pooled Phase 1 and Phase 2 data. This analysis 
set will include all OC patients that are treated with any amount of study treatment. 
11.4 Safety Analysis Set  
The safety analysis set will include all patients who receive any amount of study treatment in Phase 1 or 
Phase 2. In Phase 1, patients will be evaluated by dose level actually received and tumor type. In Phase 2, 
patients can be evaluated by tumor type. If a patient receives more than one dose level, the patient will be 
classified according to the first dose level received. In this non-randomized study, the FAS and the safety 
analysis set in Phase 2 are identical.  The safety analysis set will be used to summarize patient disposition. 
11.5 DLT Analysis Set 
The DLT analysis set will consist of all Phase 1 patients who complete the first cycle of therapy i.e. patients 
who started cycle 2 or discontinued at least 21 days after the first dose of either study medications in cycle 


  
 
  
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1, unless the patient discontinues due to a DLT, and is able to take more than 80% of the intended dose of 
both agents. The DLT analysis set will be used for the evaluation of the MTD in Phase 1. 
11.6 Efficacy Evaluable (EE) Analysis Set  
The EE analysis set will consist of all dosed (with either pembrolizumab or niraparib) FAS patients with at 
least one evaluable post-baseline tumor assessment.  Tumor response endpoints including ORR and DCR 
will be analyzed using the EE analysis set. 
11.7 Pooled OC EE Analysis Set  
Given the similarities of the Phase 1 and Phase 2 patient population for the ovarian cancer cohort, 
corresponding efficacy analyses will be provided using the pooled Phase 1 and Phase 2 data. This analysis 
set will include all OC patients that are treated with any amount of study treatment and least one evaluable 
post-baseline tumor assessment. 
11.8 Pharmacokinetic (PK) Analysis Set 
The pharmacokinetic analysis set will consist of all patients with sufficient data to enable estimation of at 
least one PK parameter. Patients who are enrolled without meeting inclusion/exclusion criteria may be 
excluded upon Sponsor’s review. 
 Interim Analyses 
To minimize the risk of exposing patients to an ineffective treatment, a series of response assessments will 
be performed when 6, 12, 18, 48 Phase 2 patients from each cancer type have at least 2 post-baseline tumor 
assessments. A formal decision regarding futility, which could result in stopping the study early, will be 
conducted separately for the TNBC and OC cohorts and will only be made from the analysis of 24 patients 
within each cohort. The earlier assessments, however, will inform the conduct of the formal interim analysis 
as follows: If no responder is observed in all three response assessments from 6, 12 and 18 patients, then 
enrollment will be suspended after 24 patients have been enrolled, and no further patients will be enrolled 
until the result of the formal interim analysis of 24 patients is known.  If ≥ 1 responder are observed in any 
single response assessment from 6, 12 or 18 patients, then enrollment will not be curtailed.  The decision 
rule regarding the formal interim analysis at N=24 is as follows:  If there are fewer than 3 responders of 24, 
enrollment may be closed, and the corresponding cohort may be stopped for futility.  Otherwise, the study 
will continue to the planned enrollment of 48 patients.   
 
 Data Review 
Final data for analysis will be cleaned prior to receipt by statistical programming. Ongoing data handling 
will take place by the study programmer, until the time at which the study team has full access to the data. 
13.1 Data Handling and Transfer 
All the data will come from the TESARO data management group and be extracted in SAS® dataset format 
(SAS v9.4 or later) and converted to SDTM v3.2. Please refer to the Data Management Plan for details. 


  
 
  
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13.2 Data Cleaning 
Beyond the data cleaning built into the DMP, PRA will be programming analysis datasets and TFLs and 
will provide additional data cleaning. Data issues identified during the process of programming analysis 
datasets and TFLs programming, will be sent to Data Management.  
All derived datasets will include patient-level variables, such as analysis set inclusion, sex, tumor cohort, 
and dose dates.  
Any methodologies used to address any issues identified in the data will be documented in the analysis 
data set specifications and finalized before database lock.  
Variables generated at the patient level will be stored in a consolidated data set for the study. Variables at 
the patient level or below (e.g., at the visit level) will be generated in analysis data set programs, not in 
the programs generating the TFLs. Exceptions may include simple concatenation or formatting that will 
only be used once.  
The content of the analysis data sets will be detailed in a separate document. For each derived data set, the 
label, sort order, and structure (expected number of records per patient/visit) will be specified. For each 
variable, the name, label, type, length, format, and source or derivation description will be specified. 
Detailed rules devised to handle specific data patterns found in data reviews will be included. The analysis 
dataset specifications will be finalized before database lock. 
Review of a pre-lock TFL run on the ready-to-lock database allows for further data screening prior to 
lock. The pre-lock TFLs may be discussed with TESARO in a data review meeting to identify any final 
data issues and seek corrections prior to database lock. The PRA and TESARO statistician must approve 
database lock ahead of locking the database. The TESARO statistician will sign off per TESARO process.  
13.3 Handling of Dropouts or Missing Data 
Missing observations will generally be treated as missing at random and will not be imputed, unless 
otherwise noted. 
Incomplete dates for disease history (e.g. initial diagnosis date, date of documented, locally 
advanced, metastatic disease diagnosis, date of response or progression in prior treatment) will be 
imputed as follows:  
1. If the day is missing, it will be imputed to the 1st day of the month.  
2. If both day and month are missing, the month and day will be imputed as January 1st.  
3. If the date is completely missing, no imputation will be performed.  
Incomplete days for the calculation of platinum-free interval (PFI) will be imputed as follows: 
x 
Platinum start/end dates: 
o If the day is missing, it will be imputed to the 1st day of the month.  
o If both day and month are missing, the month and day will be imputed as January 1st.  
o If the date is completely missing, no imputation will be performed.  
 
x 
Date of progression: 
o If the day is missing, it will be imputed to the 1st day of the month.  
o If day and month are missing or the date is completely missing, the start of the next 
chemotherapy regimen will be used.    


  
 
  
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Incomplete dates for adverse event and concomitant medication dates will be imputed as follows: 
Start Date:   
x 
If only ‘day’ is missing, and the month and year are not the same as the month and year of first 
dose, then impute day with ‘01’. Otherwise, if the month and year are the same as first dose date, 
use first dose date.  
x 
If ‘day’ and ‘month’ are missing, and ‘year’ is not missing, then impute month and day with month 
and day of first dose date (assuming same ‘year’).  
x 
If the year is not the same as the year of first dose, impute 01 for day and 01 for month.  
x 
If the start date is completely missing, it will be set to the first dose date. 
Stop Date: 
x 
If only ‘day’ is missing, impute day with last day of the month.  
x 
If ‘day’ and ‘month’ are missing, and ‘year’ is not missing, then impute month with '12' and day 
with '31' (or date of study discontinuation/completion if earlier than 12-31).  
x 
If the stop date is completely missing, it will be set to the date of study discontinuation/completion. 
A stop date will not be applied to ongoing AEs. 
x 
If the imputed stop date is greater than last contact date, then set to last contact date.  
Note, for all listings the actual value for date (not imputed) will be presented in all data listings and imputed 
dates will only be used for programming flags, etc. 
 Statistical Methods 
In general, categorical data will be summarized using number of patients (n), frequency and percentages, 
with the denominator for percentages being the number of patients in the analysis set for each cohort. 
Percentages will be rounded to 1 decimal place except for 100%, which will have no decimal place. 
Continuous data will be summarized using the number of patients, mean, standard deviation, median, 
quartiles (Q1, Q3), minimum, and maximum. The mean, median and quartiles (Q1, Q3) will be presented 
to 1 decimal place greater than the original data; the standard deviation will be presented to 2 decimal places 
greater than the original data; and the minimum and maximum will have the same number of decimal places 
as the original data.  
Results will be displayed for each of the TNBC and OC cohorts as well as the overall population. All 
statistical analyses and data listings will be performed using SAS.  
Two-sided exact 90% confidence intervals (CIs) based on the Clopper-Pearson method (3) will be provided 
to summarize the binomial proportion of the derived best overall response for RECISTv1.1 assessments 
where applicable: 
The Clopper-Pearson CI (3) can be carried out using the FREQ procedure in SAS v9.4 or higher.  
Time-to-event analyses will be performed using Kaplan-Meier (KM) methods. Comparisons in the Phase 
1 portion of the study will be made using descriptive statistics. Subgroup analyses will be performed using 
descriptive statistics and are considered exploratory.   
 
In addition: 
o Weeks will be calculated as number of days divided by 7 
o Months will be calculated as number of days divided by 30.4375 
o Study Day 1 will be considered the first day of study treatment 


  
 
  
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14.1 Patient Disposition 
Disposition of patients includes the number and percentage of patients for the following categories:  
x 
patients in each of the analysis sets,  
x 
patients discontinued from treatment,  
x 
primary reason for discontinuation from treatment,  
x 
patients discontinued from the study, and  
x 
primary reason for discontinuation from the study.  
Numbers and percentages of patients will be presented by dose level in the Phase 1 portion and for all 
patients by tumor cohort in the Phase 2 portion.   
A listing will present data for patient disposition. 
14.2 Protocol Deviations 
A protocol deviation (PD) is any failure to comply with the study protocol as approved by the relevant 
regulatory authority, ethics committee and/or institutional review board, whether planned or unplanned.  
 
PD will be assessed and classified as important or significant. A protocol deviation is classified as an 
important PD if there is the potential to:  
x 
Impact the completeness, accuracy, and/or reliability of the study data, or  
x 
Affect a subject's rights, safety, or well-being.  
A protocol deviation is classified as a significant PD if it has been confirmed to:  
x 
Adversely impact the completeness, accuracy, and/or reliability of the study data  
x 
Affect a subject’s rights, safety, or well-being.  
All PDs will be identified and finalized prior to database lock.   
 
The number of patients with each type of important protocol deviations and the number of deviations will 
be tabulated by deviation category and by deviation type for all patients in the safety analysis set per dose 
level in in Phase 1 and per tumor cohort in Phase 2. A listing of all deviations (including deviation date, 
deviation type, important or significant categorization, and deviation description) will be generated. 
 
14.3 Treatments 
14.3.1 Extent of Study Treatment Exposure 
The following study drug exposure parameters will be summarized: 
Any study drug 
 
x 
Duration of study drug exposure in months defined as: 
 
max(Date of last dose of niraparib, Date of last dose of pembrolizumab, End of treatment date per CFR) 
− min(Date of first dose of niraparib, Date of first dose of pembrolizumab) + 1
30.4375
 
 


  
 
  
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The number of study treatment cycles initiated as a categorical and continuous variable 
 
A listing of patients who discontinued one treatment but continued with the other will be provided along 
with number of cycles and last dosing date for each treatment. 
 
Niraparib 
x 
Duration of niraparib treatment in months 
Date of last dose of niraparib − Date of first dose of niraparib +  1
30.4375
 
x 
The number of niraparib treatment cycles initiated as a categorical and continuous variable  
x 
Cumulative niraparib dose (mg) defined as the sum of all niraparib doses received.  This will be 
derived using pill count data (dispensed - returned), when available.  If the returned pill count 
data is not available for a particular cycle, the dosing data along with dosing modifications will 
be used to compute cumulative dose for that cycle. 
x 
Actual dose intensity (mg/day) for niraparib defined as: 
Cumulative niraparib dosage (mg) received
(# of ݏݐݑ݀ݕ ݐݎ݁ܽݐ݉݁݊ݐ cycles initiated) ∗# planned dosing days per cycle 
The intended dose intensities (IDI) for the different dose levels are provided below: 
o Dose level 1:  IDI =200mg/day 
o Dose level 2:  IDI =300mg/day 
o Recommended phase 2 dose:  IDI=200mg/day 
x 
Relative dose intensity (%) for niraparib defined as: 
Actual dose intensity
Intended dose intensity × 100% 
x 
The number and percentage of patients with niraparib dose reductions, dose-escalations above 
starting dose, dose interruptions, and number of patients with at least one reported missed dose 
will also be presented. 
In addition, the starting dose of niraparib by cycle will be summarized. 
 
Pembrolizumab 
 
x 
Duration of pembrolizumab treatment in months 


  
 
  
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Date of last dose of pembrolizumab − Date of first dose of pembrolizumab +  21
30.4375
 
 
x 
The number of pembrolizumab cycles initiated as a categorical and continuous variable. 
x 
Cumulative pembrolizumab dose (mg) defined as the sum of all pembrolizumab doses received. 
x 
Actual dose intensity (mg/cycle) for pembrolizumab defined as 
Cumulative pembrolizumab dosage (mg) received
(# of ݏݐݑ݀ݕ ݐݎ݁ܽݐ݉݁݊ݐ cycles initiated)
 
x 
Intended dose intensity (mg/cycle) for pembrolizumab defined as 
200 (mg)
1 (cycle) = 200 (mg/cycle) 
x 
Relative dose intensity (%) for pembrolizumab defined as 
Actual dose intensity
Intended dose intensity × 100% 
x 
Number of patients with pembrolizumab infusion interruptions. 
 
A by-patient listing based on the safety population will also be produced per each study treatment, disease 
type and phase of the study. 
14.3.2 Prior and Concomitant Medications 
Medications collected at Screening and during the study will be coded using the current version of the 
World Health Organization (WHO) Drug dictionary. The medications will be categorized as prior or 
concomitant using the following definitions: 
x 
Prior medications: any medications, other than study treatments and pre-medications for study 
treatment, which started prior to the first dose date of study treatment. 
x 
Concomitant medications: any medications, other than study treatments, being taken on or after the 
initial study treatment dosing date through 30 days after the last dose or until the start of subsequent 
antitumor therapy 
Using the definition above, medications can be classified as both prior and concomitant.  Both prior 
medications and concomitant medications will be summarized by Anatomical Therapeutic Chemical 
(ATC) classification drug class level 3 and WHO preferred name using the number and percentage of 
patients for each cohort (WHO Drug Dictionary, September 2017). A patient reporting the same 
medication more than once will be counted only once when calculating the number and percentage of 
patients who received that medication in a given time category (prior or concomitant). The summary of 
concomitant medications will be ordered by descending frequency with respect to drug class and by 
descending frequency of preferred name in total within the drug class. For drugs with the same frequency, 
sorting will be done alphabetically. Summaries will be based on the safety population.  


  
 
  
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All prior and concomitant medications (other than per-protocol study treatments) will be provided in a by-
patient listing sorted by patient ID number and administration date in chronological order.  
14.4 Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized per dose level in Phase 1, per tumor cohort 
in Phase 2, and for all OC patients combined in Phase 1 and Phase 2. Descriptive statistics will be provided 
for age (<65, t65 to - <75, and t75), sex (male versus female), race (American Indian or Alaska Native, 
Asian, Black, Native Hawaiian or other Pacific Islander, White, or other), Ethnicity (Hispanic or Latino 
Not Hispanic or Latino), baselines for weight (kg), height (m), and BMI (kg/m2). Additionally, PD-L1, 
BRCA, 
HRD, 
and 
HRR 
status 
will 
be 
summarized 
as 
below:  
 
x 
PD-L1Status (Positive, Negative, Unknown) 
x 
BRCA Status (BRCA-mut [gBRCA-mut, s-BRCA (gBRCAwt/tBRCA-mut), 
gBRCAunk/tBRCA-mut], BRCA-wt, Unknown) 
x 
HRD Status (HRD-positive [BRCA-mut, BRCA-wt/HRD-positive], HRD-negative, Unknown) 
x 
HRR Status (HRR-mut [BRCA-mut, BRCAwt/oHRR-mut, BRCAunk/oHRR-mut], HRR-wt, 
Unknown) 
 
The concordance between gBRCA status and tBRCA status will also be evaluated. 
14.4.1 Primary Cancer History 
A summary of primary cancer history will be presented including: the tumor site, histology and grade of 
disease at diagnosis, the most recent cancer stage, and the most recent grade and histology. 
A by-patient listing for primary cancer history characteristics will also be provided. 
14.4.2 Medical History, Surgical History  
General medical history information (including past and ongoing) and prior medications and will be 
summarized for category and conditions ongoing or resolved at study entry based on the FAS (Phase 2) or 
safety set (Phase 1). Medical history conditions will be collected by CRF at time of screening. General 
medical history information will be coded by System Organ Class (SOC) and Preferred Term (PT) using 
the Medical Dictionary for Regulatory Activities (MedDRA), using version 20.0. The count and 
percentage of patients with each medical history event will be summarized by MedDRA SOC and PT for 
all patients and by dose cohort. SOCs will be presented by descending frequency with PTs in descending 
order of frequency for adverse events within the SOC (and further sorted alphabetically, for PTs with the 
same number of AEs reported within a SOC).   
 
A by-patient listing of general medical history will be provided by patient ID number in ascending order. 
A special table and listing will be added to summarize any prior blood disorders of thrombocytopenia, 
leukopenia, anemia or neutropenia. 
Prior anticancer treatment will be summarized per agent preferred name and grouping for all patients in 
the FAS.  Groupings are defined as platinum therapies (cisplatin and carboplatin); anthracycline therapies  
(doxorubicin, pegylated liposomal doxorubicin, doxorubicin hydrochloride, pegylated liposomal 
doxorubicin hydrochloride), taxanes (docetaxel, paclitaxel or nab-paclitaxel) and other. The following 
two summaries will be produced: 
x 
All therapies (regardless of what setting therapy was given in) 


  
 
  
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x 
Therapies in metastatic/recurrent setting (excluding the treatments given in adjuvant or 
neoadjuvant setting) 
 
Prior surgery, and prior anti-cancer regimens, along with prior response information will be listed. 
The number and percentage of patients in each of the following prior anti-cancer therapy categories will 
be tabulated: 
x 
Patients with at least one type of any prior anti-cancer treatment (drug, radiotherapy or surgery) 
x 
Patients with at least one prior anti-cancer drug therapy 
x 
Patients with at least one prior anti-cancer radiotherapy 
x 
Patients with at least one prior anti-cancer surgery 
Prior anti-cancer drug therapy will be summarized as follows based on the number and percentage of 
patients with the following: 
x 
Patients with at least one prior anti-cancer drug therapy 
o Number of any prior anti-cancer therapy regimens: 0, 1, 2, 3, 4, t5. Hormonal agents, 
monoclonal antibodies that inhibit angiogenesis, tyrosine kinase inhibitors and all 
investigational drugs are not considered for either cohort. Agents will be categorized as 
noted in Appendix 6. 
o Phase 1: Adjuvant and neo-adjuvant are not considered when counting lines.  
o Phase 2:  
 
OC cohort, neo-
adjuvant, adjuvant, and the combination of both will be considered as one line of 
therapy.   
 
TNBC cohort, adjuvant and neo-adjuvant are not considered when counting lines. 
o Pooled OC: Phase 2 rules will be followed for the pooled analysis.   
x 
Intent of Therapy: Neo-Adjuvant / Adjuvant / Chemotherapy/ Other.  
x 
Prior Bevacizumab Therapy (Yes [first-line, recurrent setting, both], No) 
In addition, the platinum-free interval (PFI) will be used to classify the response to last platinum therapy.   
Platinum-based therapeutics will consist of cisplatin and carboplatin regimens. PFI will be defined as the 
time between the end date of last platinum therapy to progression.  If PD date is not available, the onset of 
the next therapy will be used.  Using the PFI, the response to last platinum therapy will be determined 
using the following definitions for ovarian patients: 
o Platinum-refractory:  PFI <=28 days 
o Platinum-resistant:  28 days < PFI < 180 days 
o Platinum-sensitive:  PFI >=180 days 
For TNBC patients, the following categories will be used: 
o PFI < = 56 days (8 weeks) 
o PFI > 56 days (8 weeks) 
14.5 Efficacy Analyses 
All efficacy endpoints will be summarized on the Phase 2 FAS analysis set by disease type (OC, TNBC).   
In addition, response endpoints will be evaluated using the EE analysis set.  In addition, given the 
similarities of the Phase 1 and Phase 2 patient population for the ovarian cancer cohort, corresponding 
efficacy analyses will be provided using the pooled Phase 1 and Phase 2 data.  


  
 
  
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All analyses will include summary statistics, including number and percentage for categorical variables 
and number of patients, mean, standard deviation, median, minimum, and maximum for continuous 
variables. Two-sided exact 90% CIs based on the Clopper-Pearson method will be presented for the 
primary efficacy endpoint ORR per RECIST v1.1 as well as the following secondary endpoints: DCR per 
RECIST v1.1. Time-to-event data will be summarized by 25th, 50th (median), and 75th percentiles with 
associated 2-sided 90% CIs as well as percent of censored observations.   
Tumor size (sum of longest (non-nodal) dimension and shortest (nodal) axes of all target lesions) will be 
presented graphically using waterfall plots, to present each subject’s best percentage change in tumor size 
as a separate bar, with the bars ordered from the largest increase to the largest decrease. A reference line 
at the –30% change in tumor size levels will be added to the plots, which corresponds with the definition 
of ‘partial’ response. 
 
Swimmer plots will be produced. This depicts each patient’s nature and duration of response as a separate 
bar (horizontally) over time. 
 
14.5.1 Primary Endpoints 
Objective Response Rate (ORR): Evaluated separately for TNBC and OC cohorts in Phase 2 of the study. 
The ORR is defined as the proportion of patients achieving a confirmed best overall response of CR or PR 
as assessed by the Investigator per RECIST (v1.1). Tumor assessments after the initiation of further 
anticancer therapy are excluded. Point estimates and two-sided 90% exact confidence intervals will be 
provided for ORR.    
14.5.2 Methods for Handling Dropouts and Missing Data 
Missing observations will generally be treated as missing at random and will not be imputed, unless 
otherwise noted. Adverse event and concomitant medication dates will be imputed as mentioned in Section 
13.3. Note, for all listings the actual value for date (not imputed) will be presented in all data listings and 
imputed dates will only be used for programming flags, etc. 
14.5.3 Multiplicity 
Adjustments for multiplicity will not be made since this is an estimation study and separate inferences will 
be drawn for each tumor cohort.  
14.5.4 Pooling of Sites 
All data from all sites will be pooled. Study center or treatment-by-center interaction will not be included 
in any statistical analysis.  
14.5.5 Secondary Endpoints 
The following are the secondary endpoints to be evaluated in Phase 2 of the study per disease type: 
− Duration of response: DOR by RECIST v1.1;  
− Disease control rate: DCR by RECIST v1.1;  
− Progression-free survival: PFS by RECIST v1.1;  
− Overall survival (OS).  
 


  
 
  
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DOR, PFS, and OS will be presented through use of summary statistics using KM methods, to include 
25th, 50th (median), and 75th percentiles and associated 2-sided 95% CI’s using the method of 
Brookmeyer and Crowley (5), number of events and number of censored observations.  
Additionally, PFS will be summarized at months 3, 6, 9, 12 and 15 and OS rates will be summarized 
at months 3, 6, 9, 12, 15 and 18. The standard error of the KM estimates of event-free probability will 
be estimated using the Greenwood’s formula (6).  
DOR and PFS defined by RECIST v1.1 will be analyzed separately by both criteria. The time to event 
endpoints (PFS, DOR, and OS) will also be summarized graphically with KM estimates of the 
survivor function and the number of patients at risk for selected timepoints. Additionally, the figures 
will include the median of the survival distribution. 
All time to event analysis (i.e. PFS, OS and DOR) may be performed if more than 10 events are 
observed in each cohort. Additionally, duration of follow-up, defined as the time from first dose until 
date of death or date patients were censored for overall survival, will be summarized.  The KM 
estimate of the median potential follow-up, treating death as censors, and censored observations as 
events, will be presented. 
 
Tumor response endpoints (ORR, DOR, DCR) will also be analyzed without the confirmation 
requirements for CR and PR and without duration requirement for SD using the same methodology as 
described above. 
 
Protocol specified irRECIST secondary endpoints were not consistently collected across all patients 
and therefore cannot formally be evaluated using standard summaries.  These endpoints will be 
listed.  For patients who received treatment beyond radiological progression per RECIST v1.1 by ≥ 28 
days and who have post-progression tumor assessments, the irRECIST evaluations will be listed along-
side the RECIST v1.1 evaluations, as available. Date of study treatment discontinuation will also be 
included. 
 
Exploratory analyses of clinical benefit rate (CBR) at 18 weeks, per definition in Section 8, will be 
performed for the EE population.  
14.5.6 Examination of Subgroups 
  
Descriptive exploratory subgroup analyses of ORR, DCR (with and without confirmation requirements), 
PFS and OS will be performed.  The EE population will be used for ORR and DCR whereas the FAS will 
be used to analyze PFS and OS.  For the TNBC cohort, the respective Phase 2 populations will be of focus, 
whereas for the OC cohort, the respective pooled Phase 1 and Phase 2 populations will be used.  
o Prior Lines of Therapy:  OC cohort (1-2; 3+); TNBC cohort (0-1; 2+) 
o Response to Last Platinum-Based Therapy in OC cohort (refractory, resistant, sensitive and 
refractory/resistant pooled) 
o Prior Bevacizumab Use in OC cohort (yes [first line setting, recurrent setting, both first 
line/recurrent], no prior bevacizumab) 
o BRCA status (BRCA-mut, BRCA-wt, unknown) for OC and TNBC.   


  
 
  
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o HRD status (HRD-pos, HRD-neg, unknown); further breakdown of HRD-pos as BRCA-mut and 
BRCA-wt will be performed for OC and TNBC. 
o HRR status for TNBC cohort only (HRR-mut, HRR-wt, unknown); further breakdown of HRR-
mut as BRCA-mut and non-BRCA-mut/oHRR-mut will be performed.  Non-BRCA-mut includes 
BRCAwt and BRCAunk. 
o PD-L1 status (PDL1-pos, PDL1-neg, unknown) for OC and TNBC. 
A detailed listing for responders and patients with SD will be produced including the above-mentioned 
variables. A summary of all analyses to be conducted by population and subgroups is included in Table 4. 
 
Table 4: Efficacy analyses to be conducted by population and subgroup 
 
 
 
Analysis 
TNBC Phase 2 
OC Phase 2 
OC Pooled  
(Phase 1+Phase 2) 
 
FAS 
EE 
FAS 
EE 
FAS 
EE 
ORR/DCR 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
DOR 
Xa 
  
Xa 
  
Xa 
  
PFS 
X 
 
X 
 
X 
 
OS 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
ORR/DCR Subgroups 
 
Xa 
 
 
 
Xa 
PFS Subgroups 
X 
 
 
 
X 
 
OS Subgroups 
X 
 
 
 
X 
 
a)  Analyses will be performed using RECIST v1.1 and repeated for Best Observed Overall 
Response. 
 
Note: 
TNBC Subgroups: 
1. Prior Lines of Therapy;  
2. BRCA Status 
3. HRR Status 
4. HRD Status 
5. PD-L1 Status 
 
OC Subgroups: 
1. Prior Lines of Therapy 
2. Prior Bevacizumab Use 
3. Response to Last Platinum Therapy 
4. BRCA Status 
5. HRD Status 
6. PD-L1 Status 
 


  
 
  
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14.6 Safety Analyses 
Safety Tables and Listings will be presented to summarize TEAE’s, laboratory data and vital signs and in 
Phase 1 as well as Phase 2. Phase 1 patients with RP2D dose levels may be pooled with Phase 2 patients 
in the same tables/listings by tumor type if deemed necessary at the end of the study. In general, all 
summaries of by-cycle and day safety parameters will be summarized through all cycles where 
information is available, as well as at the treatment discontinuation visit. This includes laboratory values, 
vital signs and ECG parameters. Additional summaries will be derived as the minimum and maximum for 
all on-study assessments and presented similarly to the other time points at the end of the summary table.  
This will allow an assessment of either the best or worst value assessed throughout the conduct of the 
study.  The maximum and minimum calculations will use all post-baseline data, including any 
unscheduled assessments.  
  
14.6.1 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 
20.0. Only TEAE’s (refer to Section 8 for definition) will be analyzed but all AEs occurring on-study will 
be listed in patient data listings. By-patient listings will also be provided for the following: patient deaths, 
SAEs, and AEs leading to withdrawal. 
A high-level overview of AEs will be presented in a summary table.  This table will include the numbers 
and percentages of patients who had: 
x 
at least one TEAE,  
x 
any TEAE’s related to study treatment,  
x 
any grade 3 or higher TEAE,  
x 
any grade 3 or higher TEAE’s related to study treatment,  
x 
any SAE 
x 
any SAE related to study treatment, 
x 
any grade 3 or higher SAE related to study treatment, 
x 
any TEAE’s resulting in withdrawal of study medication,  
x 
any TEAE’s resulting in dose reduction of niraparib, 
x 
any TEAE’s resulting in dose interruption of either study treatment, 
x 
any TEAE’s of clinical interest, 
x 
any drug-related TEAE leading to withdrawal of study medication, 
x 
any TEAE with outcome of death. 
x 
any drug-related TEAE with outcome of death  
x 
DLT’s for the Phase 1 portion only.  
AEs will be tabulated by SOC and preferred term. Summary tabulations include the following subsets: 
x 
DLT’s during the period of Cycle 1/Day 1 through Cycle 1/Day 21 for Phase 1 will be 
summarized by dose level to which they were originally assigned, including those who receive 
subsequent treatment at a different dose. The AE’s will also be classified by their CTCAE 4.03 
grades.  
x 
Incidence of TEAEs. 


  
 
  
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x 
Incidence of related TEAEs defined as treatment-emergent AEs assessed by the Investigator as 
related to either study treatment (‘Related’, ‘Possibly Related’, or missing),  
x 
Incidence of treatment-emergent SAEs. In addition, a by-patient listing of SAEs will be 
presented (the patient listing will contain all SAEs regardless of treatment-emergent AE status). 
x 
Incidence of related treatment-emergent SAEs. 
x 
Incidence of TEAEs with outcome of death.  A by-patient listing of deaths (including days since 
last dose) will be presented.  All AEs with outcome of deaths occurring on-study and during 
follow-up will be displayed in the listing (regardless of treatment-emergent AE status).  
x 
Incidence of related TEAEs with outcome of death. 
x 
Incidence of TEAEs resulting in withdrawal of study treatment, and a by-patient listing of 
TEAEs resulting in withdrawal of study treatment will be presented.  
x 
Incidence of related TEAEs resulting in withdrawal of study treatment 
x 
Incidence of TEAEs resulting in dose reduction of niraparib.  
x 
Incidence of TEAEs resulting in dose interruption of either study drugs.  
x 
Incidence of TEAEs by maximum CTCAE grade 
x 
Incidence of related TEAEs by maximum CTCAE grade 
x 
Incidence of CTCAE Grade 3 or greater TEAEs.  
x 
Incidence of CTCAE Grade 3 or greater treatment related TEAE’s.  
x 
Most commonly reported (at least 5% of all patients) TEAEs. 
x 
Most commonly reported (at least 5% of all patients) treatment related TEAEs. 
x 
Incidence of AE’s of clinical interest as specified in the protocol: 
o Overdose of pembrolizumab (defined as a dose ≥ 1000 mg [5 times the dose]). 
o An elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value 
that is ≥ 3× upper limit of normal (ULN) concurrent with an elevated total bilirubin value 
that is ≥ 2× ULN and, at the same time, an alkaline phosphatase value that is < 2× ULN. 
o New malignancy 
o Overdose of niraparib 
o MDS/AML 
 
Myelodysplastic syndrome 
 
Myelodysplastic syndrome transformation 
 
Myelodysplastic syndrome unclassifiable 
 
Acute myeloid leukaemia 
 
Acute myeloid leukaemia recurrent 
 
Blast crisis in myelogenous leukaemia 
 
Myeloid leukaemia 
x 
A summary of hematologic events including thrombocytopenic (preferred 
terms='thrombocytopenia' or 'platelet count decreased'), anemic (preferred terms='anaemia' and 
'haemoglobin decreased') and neutropenic events (preferred terms = 'neutropenia', 'febrile 
neutropenia', 'neutrophil count decreased' and 'neutropenic sepsis').    
x 
A summary of immune related adverse events as defined in Appendix 7. 


  
 
  
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Overall, patients with the same AE more than once will have that event counted only once within each 
SOC, and once within each PT.  When summarized by severity, patients with the same AE more than 
once will have the maximum severity of that event counted within each SOC, and once within each PT. 
Adverse event summaries will be ordered by decreasing frequency for SOC and decreasing frequency for 
PT within SOC (and further sorted alphabetically, for PTs with the same number of AEs reported within a 
SOC). 
Additionally, by-patient listings of AE’s of clinical interest will be presented if appropriate. 
14.6.2 Laboratory Data 
All laboratory values, for which a normal range is available, will be classified into NCI CTCAE v 4.03 
grades. The categories are defined according to the criteria available on the following website: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
For the purposes of summarization in both the tables and listings, all laboratory values will be converted to 
standardized units and differentials of white blood cell (WBC) count should always be converted to absolute 
counts in SI units for summarization (e.g. % is not an SI unit).  If a laboratory value is reported using a non-
numeric qualifier it will not be taken into consideration in the derivation of CTCAE criteria (e.g., 
hypokalemia grade 1 and grade 2 are only distinguished by a non-numerical qualifier (symptomatic; 
intervention indicated) and therefore grade 2 will not be derived). In general, clinical assessments listed 
will not be considered, only numeric results will be assessed. Additional laboratory results that are not part 
of NCI-CTCAE will be presented according to the categories: below normal limit, within normal limits and 
above normal limit (according to the laboratory normal ranges).  Furthermore, only the numeric part in 
laboratory values that contain non-numeric qualifiers, such as less than (<) a certain value, or greater than 
(>) a certain value, will be used in the summary statistics.  
Multiple measurements taken during the visit for a patient will be represented by the most severe value for 
each hematology test. The most severe value will be determined first by the value closest to the upper or 
lower limit of the normal limits (dependent on which direction is considered severe) if the value is within 
the normal limits. If the value is outside the normal limits, the value furthest from the upper or lower limit 
will be selected (dependent on which direction is considered severe). If this algorithm does not allow for 
determining the most severe (i.e., a tie) the measurement closest to dosing date (either niraparib or 
pembrolizumab) will be selected.  Patients who develop ≥ Grade 3 toxicity will be listed.  
The following hematology tests will be summarized: 
x 
WBC count, lymphocytes, monocytes, absolute neutrophil count, eosinophils, basophils, 
hemoglobin, platelets, erythrocyte mean corpuscular volume. 
The following chemistry tests will be summarized: 
x 
Sodium, amylase, potassium, total bilirubin, calcium, alkaline phosphatase (ALP), magnesium, 
AST, chloride, ALT, glucose, total protein, creatinine, albumin, urea or blood urea nitrogen, 
lactate dehydrogenase.  Only non-fasting glucose will be included in summary tables as fasting 
glucose was only collected per-protocol at screening. 
The following coagulation factors will be listed: International normalized ratio (INR) and 
activated partial thromboplastin time (aPTT).  
The following urinalysis parameters will be summarized: 


  
 
  
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x 
Specific gravity, protein, leukocyte esterase, glucose, nitrite, ketones, blood, urobilinogen, 
bilirubin.  
Additionally, a by-patient listing will be presented for thyroid functions (thyroid-stimulating hormone, 
triiodothyronine (T3), or free T3 and free thyroxin), serum CA-125 (OC patients only) and serum 
pregnancy testing /urine pregnancy testing 
NCI CTCAE grades (given in Appendix 1) will be applied for the following lab parameters: 
x 
Hematology: hemoglobin (anemia), WBC (leukopenia), lymphocytes (lymphopenia), neutrophils 
(neutropenia), and platelets (thrombocytopenia). 
x 
Chemistry: albumin (hypoalbuminemia), alkaline phosphatase (alkaline phosphatase increased), 
ALT, AST, total bilirubin (blood bilirubin increased), corrected calcium (hypocalcemia, 
hypercalcemia), creatinine (creatinine increased), glucose (hyperglycemia, hypoglycemia), 
magnesium (hypermagnesemia, hypomagnesemia), potassium (hyperkalemia, hypokalemia), and 
sodium (hyponatremia, hypernatremia).  
x 
Coagulation: aPTT, INR. 
Where corrected calcium is derived with the following formula: 
Corrected calcium (mmol/L) = (0.02 * (40 (g/L) – normal albumin (g/L))) + serum calcium (mmol/L). 
For Hyperglycemia, CTCAE grades 1 and 2 will not be derived as they require fasting glucose. Fasting 
glucose was required by the protocol only at screening, and therefore, will not be utilized in any summaries. 
These will be displayed in Table as NA (not applicable). 
A summary of maximum severity observed on-study treatment for all parameters noted above will be 
generated for the coded hematology and chemistry parameters. Patients will only be included once, in the 
maximum severity, for each laboratory parameter. Additionally, a shift summary of baseline to maximum 
severity on-study treatment will also be produced.  All patients in safety population will be included, 
patients without an assessment present at baseline or on-study treatment will be included as a missing 
category. 
Laboratory measurements that are within their institutional limits of normal and are not graded as 1-4, per 
the CTCAE, will be summarized as “Grade 0,” which is defined as normal. Additionally, if a lab parameter 
is graded in both directions (e.g. glucose: hyperglycemia and hypoglycemia), then low direction toxicity 
grades at baseline and post baseline will be set to 0 when the variables are derived for summarizing high 
direction toxicity, and vice versa.  Hyperglycemia will only be coded to grades ≥ 3 using non-fasting 
glucose and therefore will not be included in shift tables. 
Liver function tests: ALT, AST, and total bilirubin are used to assess possible drug induced liver toxicity. 
The ratios of test result over ULN will be calculated and classified for these three parameters during the 
on-treatment period.    
Summary of liver function tests will include the following categories.  The number and percentage of 
patients with each of the following during the on-treatment period will be summarized by treatment group: 
x 
ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
x 
AST ≥ 3×ULN, AST ≥ 5xULN, AST ≥ 10×ULN, AST ≥ 20×ULN 
x 
(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or AST) ≥ 
20×ULN 
x 
Total bilirubin ≥ 2×ULN 
x 
Concurrent ALT ≥ 3×ULN and total bilirubin ≥ 2×ULN 


  
 
  
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x 
Concurrent AST ≥ 3×ULN and total bilirubin ≥ 2×ULN 
x 
Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN  
x 
Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN and ALP > 2×ULN 
x 
Potential Hy’s law: Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN and ALP < 
2×ULN or missing 
Concurrent measurements are those occurring on the same date. 
Categories will be cumulative, i.e., a patient with an elevation of AST ≥ 10×ULN will also appear in the 
categories ≥ 5×ULN and ≥ 3×ULN. Liver function elevation and possible Hy’s Law cases will be 
summarized using frequency and percentage.  
By-patient listings will be presented for hematology, coagulation factors, urinalysis and serum chemistry. 
Any laboratory values assessed as clinically significant should be recorded as an AE. 
14.6.3 Vital Signs 
Vital signs: diastolic and systolic blood pressure (mm Hg), body temperature, pulse rate (beats/min) at 
each visit, change from baseline to each post-baseline visit, post-baseline maximum/minimum, and 
change from baseline to post-baseline maximum/minimum will be summarized for the safety analysis set 
using descriptive statistics (n, mean, SD, median, Q1, Q3, minimum, and maximum) by dose level or 
tumor cohort. 
A by-patient listing of vital signs will be provided by patient ID number and visit in chronological order.  
14.6.4 Physical Examinations and Other Observations Related to Safety 
ECOG parameters will be presented by tumor cohort for each dose level and within each tumor cohort at 
baseline, at each post-treatment time point and at the end of treatment. The ECOG shift from baseline to 
highest score during the on-treatment period will be summarized by dose level or tumor cohort. 
Height, Weight, Pregnancy test results will be presented in a by-patient listing. Physical examination at 
screening will also be listed. 
14.6.5 ECG  
The following analyses will be performed for each applicable ECG parameters (RR, PR, QRS, QT, 
ventricular rate -denoted as HR in what follows, QTcB and QTcF) by treatment group, during the on-
treatment period. 
x 
For each of the ECG parameters (HR, and QT, QTcF, QTcB, QRS, PR intervals), descriptive statistics 
at baseline, at each post-baseline time point and changes from baseline at each post-baseline time point  
x 
Frequency (number and percentage) of patients with notable ECG values according to the following 
categories presented in  
x 
 
x 
Table 5. 
 
 
 
Table 5: Notable ECG Values for QTc Interval Prolongation 
TEST 
Notable ECG Values 
Heart Rate 
≤ 50 bpm and decrease from baseline ≥ 20 bpm 


  
 
  
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≥ 120 bpm and increase from baseline ≥ 20 bpm 
PR Interval 
≥ 220 ms and increase from baseline ≥ 20 ms 
QRS 
 ≥ 120 ms 
QTcF and QTcB Absolute 
interval >450 msec and interval ≤480 msec 
interval >480 msec and interval ≤ 500 msec  
interval >500 msec 
QTcF and QTcB change from baseline 
Increase from baseline > 30 ms and ≤ 60 ms 
Increase from baseline > 60 ms 
 
Frequency (number and percentage) of patients with post-baseline qualitative ECG abnormalities 
(morphology) will be summarized. 
Patients with notable ECG interval values and qualitative ECG abnormalities will be listed for each patient 
and time point and the corresponding notable values and abnormality findings will be included in the 
listings. 
Unscheduled ECG measurements will not be used in computing the descriptive statistics for change from 
baseline at each post-baseline time point. However, they will be used in the analysis of notable ECG 
changes. 
 Validation 
PRA's goal is to ensure that each table, listing and figure (TFL) delivery is submitted to the highest level 
of quality. Our quality control procedures will be documented separately in the study-specific quality 
control plan.  
x 
Derived datasets are independently reprogrammed by a second programmer. The separate 
datasets produced by the 2 programmers must match 100%. Detailed specifications for the 
derived datasets are documented in the study Data Mapping Tool provided to the client at study 
conclusion. 
x 
Tables are independently quality controlled by a second programmer for numeric results.  
x 
Figures are checked for consistency against corresponding tables and listings, or independently 
reprogrammed if there are no corresponding tables or listings. 
x 
Listings are double programmed and checked for consistency against corresponding tables, 
figures, and derived datasets. 
The complete set of TFLs are checked for completeness and consistency prior to its delivery to the client 
by the lead clinical programmer, the lead statistician, and a senior level or above statistician, who is not a 
member of the project team. 
The PRA Health Sciences validation process is repeated any time TFL are redelivered using different 
data. Execution of this validation process is documented through the study Table of Programs that is 
provided to the client at study conclusion. 
PRA's goal is to ensure that each TFL delivery is submitted to the highest level of quality. Our quality 
control procedures will be documented separately in the study specific quality control plan.  
 
 


  
 
  
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 References 
1. Data on file at TESARO. 
2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European journal 
of cancer. 2009;45(2):228-47. 
3. Clopper C, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika. 1934;26:404-13. 
4. 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. 
5. Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982:38: 29-41. 
6. Kalbfleisch, J.D. and Prentice, R.L. (1980).  The Statistical Analysis of Failure Time Data, New 
York: John Wiley & Sons. 


  
 
  
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 List of Abbreviations 
 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the concentration × time curve 
AUCss 
area under the concentration × time curve at steady state 
BP 
blood pressure 
CBC 
complete blood count 
CI 
confidence interval 
CL/F 
clearance after oral administration 
Cmax 
maximum concentration 
Cmax,ss 
maximum concentration at steady state 
Cmin 
minimum concentration 
Cmin,ss 
minimum concentration at steady state 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DCR 
disease control rate 
DKA 
diabetic ketoacidosis 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
ECG 
electrocardiogram 
ECI 
events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 


  
 
  
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EE 
efficacy-evaluable 
ELISA 
enzyme-linked immunosorbent assay 
EOT 
end of treatment 
ER- 
estrogen receptor 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
FAS 
full analysis set 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
HBsAg 
hepatitis B surface antigen 
HCV RNA 
hepatitis C virus ribonucleic acid 
HER2 
human epidermal growth factor receptor 
HIV 
human immunodeficiency virus 
HR 
homologous recombination 
HRD 
homologous recombination deficiency 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
Ig 
immunoglobulin 
IgG 
immunoglobulin G 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
irRECIST 
immune-related Response Evaluation Criteria in Solid Tumors 
IV 
intravenous(ly) 
KM 
Kaplan-Meier 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
OC 
primary peritoneal ovarian cancer 
ORR 
objective response rate 


  
 
  
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OS 
overall survival 
PARP 
poly(ADP-ribose) polymerase 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1 
programmed death ligand-1 
PET 
positron emission tomography 
PFI 
Platinum-free interval 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PO 
oral(ly) 
PR 
partial response 
PR- 
progesterone receptor 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QD 
once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
 


  
 
  
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 Appendix 1: Common Terminology Criteria for Adverse Events 
V4.03 (CTCAE) 
 
Lab Test 
Name 
Lab Test 
Code 
Standard 
Unit 
CTCAE v4.03 SOC 
CTCAE v4.03 
Term 
Grade 1 
Grade 2 
Grade 3 
Grade 
4 
Activated 
partial 
thrombopla
stin time  
APTT 
sec 
Investigations 
Activated 
partial 
thromboplasti
n time 
prolonged 
>ULN - 
1.5 x 
ULN 
>1.5 - 2.5 x 
ULN 
>2.5 x ULN 
 
Albumin 
ALB 
g/L 
Metabolism and 
nutrition disorders 
Hypoalbumine
mia 
<LLN - 3 
g/dL; 
<LLN - 
30 g/L 
<3 - 2 
g/dL; <30 - 
20 g/L 
<2 g/dL; 
<20 g/L 
 
Hemoglobi
n 
HGB 
g/L 
Blood and 
lymphatic system 
disorders 
Anemia 
<LLN - 
100 g/L 
 <100 - 
80g/L 
<80 g/L 
  
Leukocytes 
WBC 
10^9/L 
Investigations 
White blood 
cell decreased 
<LLN - 
3.0 u 
109/L 
<3.0 - 2.0 u 
109/L 
<2.0 - 1.0 u 
109 /L 
<1.0 u 
109/L 
Platelets 
PLAT 
10^9/L 
Investigations 
Platelet count 
decreased 
<LLN - 
75.0 u 
109/L 
<75.0 - 
50.0 u 
109/L 
<50.0 - 
25.0 u 
109/L 
<25.0 
u 
109/L 
Neutrophils 
NEUT 
10^9/L 
Investigations 
Neutrophil 
count 
decreased 
<LLN - 
1.5 u 
109/L 
<1.5 - 1.0 u 
109/L 
<1.0 - 0.5 u 
109/L 
<0.5 u 
109/L 
Lymphocyt
es 
LYM 
10^9/L 
Investigations 
Lymphocyte 
count 
decreased 
<LLN - 
0.8 x109 
/L 
<0.8 - 0.5 u 
109 /L 
<0.5 - 0.2 u 
109 /L 
<0.2 u 
109 /L 
Lymphocyt
es 
LYM 
10^9/L 
Investigations 
Lymphocyte 
count 
increased 
  
>4x109/L – 
20*109/L 
>20*109/L 
  
Sodium 
SODIUM 
mmol/L 
Metabolism and 
nutrition disorders 
Hyponatremia 
<LLN - 
130 
mmol/L 
  
<130 - 120 
mmol/L 
<120 
mmol/
L 
Sodium 
SODIUM 
mmol/L 
Metabolism and 
nutrition disorders 
Hypernatremi
a 
>ULN - 
150 
mmol/L 
>150 - 155 
mmol/L 
>155 - 160 
mmol/L 
>160 
mmol/
L 
Potassium 
K 
mmol/L 
Metabolism and 
nutrition disorders 
Hypokalemia 
<LLN - 
3.0 
mmol/L 
  
<3.0 - 2.5 
mmol/L 
<2.5 
mmol/
L 
Potassium 
K 
mmol/L 
Metabolism and 
nutrition disorders 
Hyperkalemia 
>ULN - 
5.5 
mmol/L 
>5.5 - 6.0 
mmol/L 
>6.0 - 7.0 
mmol/L 
>7.0 
mmol/
L 
Creatinine 
CREAT 
umol/L 
Investigations 
Creatinine 
increased 
>ULN - 
1.5 u 
ULN 
>1.5 - 3.0 u 
ULN 
>3.0 - 6.0 u 
ULN 
>6.0 u 
ULN 
Glucose 
GLUC 
mmol/L 
Metabolism and 
nutrition disorders 
Hypoglycemia 
<LLN - 
3.0 
mmol/L 
<3.0 - 2.2 
mmol/L 
<2.2 - 1.7 
mmol/L 
<1.7 
mmol/
L 
Glucose 
GLUC 
mmol/L 
Metabolism and 
nutrition disorders 
Hyperglycemia 
NA 
NA 
>13.9 - 
27.8 
mmol/L 
>27.8 
mmol/
L 
Bilirubin 
BILI 
umol/L 
Investigations 
Blood bilirubin 
increased 
>ULN - 
1.5 u 
ULN 
>1.5 - 3.0 u 
ULN 
>3.0 - 10.0 
u ULN 
>10.0 u 
ULN 
Alanine 
Aminotrans
ferase 
ALT 
U/L 
Investigations 
Alanine 
aminotransfer
ase increased 
>ULN - 
3.0 u 
ULN 
>3.0 - 5.0 x 
ULN 
>5.0 - 20.0 
x ULN 
>20.0 u 
ULN 
Aspartate 
Aminotrans
ferase 
AST 
U/L 
Investigations 
Aspartate 
aminotransfer
ase increased 
>ULN - 
3.0 u 
ULN 
>3.0 - 5.0 x 
ULN 
>5.0 - 20.0 
x ULN 
>20.0 u 
ULN 


  
 
  
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Alkaline 
phosphatas
e  
ALP 
U/L 
Investigations 
Alkaline 
phosphatase 
increased 
>ULN - 
2.5 x 
ULN 
>2.5 - 5.0 x 
ULN 
>5.0 - 20.0 
x ULN 
>20.0 x 
ULN 
Magnesium 
MG 
mmol/L 
Metabolism and 
nutrition disorders 
Hypomagnese
mia 
<LLN - 
1.2 
mg/dL; 
<LLN - 
0.5 
mmol/ 
<1.2 - 0.9 
mg/dL; 
<0.5 - 0.4 
mmol/L 
<0.9 - 0.7 
mg/dL; 
<0.4 - 0.3 
mmol/L 
<0.7 
mg/dL; 
<0.3 
mmol/
L 
Magnesium 
MG 
mmol/L 
Metabolism and 
nutrition disorders 
Hypermagnese
mia 
>ULN - 
3.0 
mg/dL; 
>ULN - 
1.23 
mmol/L 
 
>3.0 - 8.0 
mg/dL; 
>1.23 - 
3.30 
mmol/L 
>8.0 
mg/dL; 
>3.30 
mmol/
L 
Calcium 
(corrected) 
CA 
mmol/L 
Metabolism and 
nutrition disorders 
Hypocalcemia 
<LLN - 
2.0 
mmol/L 
<2.0 - 1.75 
mmol/L 
<1.75 - 1.5 
mmol/L 
<1.5 
mmol/
L 
Calcium 
(corrected) 
CA 
mmol/L 
Metabolism and 
nutrition disorders 
Hypercalcemia 
 >ULN - 
2.9 
mmol/L 
>2.9 - 3.1 
mmol/L 
>3.1 - 3.4 
mmol/L 
>3.4 
mmol/
L 
Prothrombi
n Intl. 
Normalized 
Ratio 
INR 
  
Investigations 
INR increased 
>1 - 1.5 
x ULN 
>1.5 - 2.5 x 
ULN 
>2.5 x ULN 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


  
 
  
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 Appendix 2: Schedule of events 
  
 
 
 
 


  
 
  
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Phase 2 Only 
  
 
 


  
 
  
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 Appendix 3 Response Evaluation Criteria in Solid Tumors 
(RECIST), v1.1 
Response Criteria by RECIST v1.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the 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 to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of one or more new lesions is also considered progressions). 
 
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 
 
Complete Response (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). 
 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 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. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a 
later time by the review panel (or Principal Investigator). 
 
Table 8: RECIST Response for Patients with Measurable Disease (ie, Target Disease) 
 
 


  
 
  
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Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease 
*            See RECIST v1.1 publication for further details on what is evidence of a new lesion. 
**          Only for non-randomized trials with response as primary endpoint. 
***        In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. 
Note:     Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic deterioration.” Every effort should be made to document the objective progression 
even after discontinuation of treatment. 
 
Table 9: RECIST Response For Patients with Non-Measurable Disease (ie, Non-Target Disease) 
 
Abbreviations: CR = complete response; PD = progressive disease 
*‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be measured is not 
Advised. 
 
 


  
 
  
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 Appendix 4: Immune-Related response evaluation criteria in 
solid tumors 
Table 10: Imaging and Treatment after First Radiologic Evidence of Progressive 
 
Abbreviations: CR = complete response; irRECIST = immune-related Response Criteria in Solid Tumors; N/A = not 
applicable; PD = progressive disease; PR = partial response; RECIST = Response Criteria in Solid Tumors; SD = 
stable disease 
 
 


  
 
  
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 Appendix 5: Laboratory Standard Units 
Laboratory Test 
SI Unit 
Albumin 
g/L 
Alkaline Phosphatase 
U/L 
Absolute neutrophil count  
109/L 
Basophils 
109/L 
Bicarbonate 
mmol/L 
Total Bilirubin 
Pmol/L 
Blood Urea Nitrogen 
mmol/L 
Calcium 
mmol/L 
Chloride 
mmol/L 
Creatinine 
Pmol/L 
Eosinophils 
109/L 
Glucose 
mmol/L 
Granulocytes 
109/L 
Hematocrit 
frac of 1 
Hemoglobin 
g/L 
INR 
1 
Lymphocytes 
109/L 
Magnesium 
mmol/L 
Mean Corpuscular Hemoglobin 
pg 
Mean Corpuscular Volume 
fL 
Monocytes 
109/L 
Platelets 
109/L 
Potassium 
mmol/L 
Total Protein 
g/L 
Prothrombin Time 
s 
Partial Thromboplastin Time 
s 
Red Blood Cells 
1012/L 
Aspartate Transaminase 
U/L 
Alanine Transaminase 
U/L 
Sodium 
mmol/L 
White Blood Cells 
109/L 
 
 
 


  
 
  
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 Appendix 6: Drugs Excluded from Prior Lines of Therapy 
The following table lists the drugs that are not included when counting the number of prior lines of therapy. 
Agent Name 
Agent If Other, specify 
Agent If Other, specify PT 
Group 
Bevacizumab 
  
  
monoclonal 
antibody 
Other 
ABEMACICLIB 
ABEMACICLIB 
CDK inhibitor 
Other 
ABT 888 
VELIPARIB 
investigational 
drug 
Other 
ADENOSINE A2A RECEPTOR 
ANTAGONIST CPI-444 
ANTINEOPLASTIC 
AGENTS 
investigational 
drug 
Other 
ANASTRAZOLE 
ANASTROZOLE 
Hormonal therapy 
Other 
ANASTROZOLE 
ANASTROZOLE 
Hormonal therapy 
Other 
ANTI-PTK7 
ANTIBODY-DRUG 
CONJUGATE 
PROTEIN KINASE 
INHIBITORS 
investigational 
drug 
Other 
ARIMIDEX 
ANASTROZOLE 
Hormonal therapy 
Other 
ARQ 092 
PROTEIN KINASE 
INHIBITORS 
investigational 
drug 
Other 
AVASTATIN (BEVACIZUMAB) 
BEVACIZUMAB 
monoclonal 
antibody 
Other 
AVASTATIN (BEVACIZUMAB) 
BEVACIZUMAB 
monoclonal 
antibody 
Other 
AVASTIN (BEVACIZUMAB) 
BEVACIZUMAB 
monoclonal 
antibody 
Other 
AVASTIN(BEVACIZUMAB) 
BEVACIZUMAB 
monoclonal 
antibody 
Other 
AVASTIN(NFI) 
BEVACIZUMAB 
monoclonal 
antibody 
Other 
AZD1775 
PROTEIN KINASE 
INHIBITORS 
investigational 
drug 
Other 
BEVACIZUMAB 
BEVACIZUMAB 
monoclonal 
antibody 
Other 
CRLX101 
OTHER ANTINEOPLASTIC 
AGENTS 
investigational 
drug 
Other 
ENZALUTAMIDE 
ENZALUTAMIDE 
nonsteroidal 
antiandrogen 
Other 
EVEROLIMUS 
EVEROLIMUS 
motor inhibitor 
investigational 
drug 
Other 
FEMARA 
LETROZOLE 
Hormonal therapy 
Other 
FULVESTRANT 
FULVESTRANT 
Hormonal therapy 


  
 
  
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Other 
GLUTAMINASE INHIBITOR CB-
839 
ANTINEOPLASTIC 
AGENTS 
investigational 
drug 
Other 
GOG 212 (PACLITAXEL) 
PACLITAXEL 
Chemo 
maintenance 
therapy 
Other 
GSK 2141795 
UPROSERTIB 
investigational 
drug 
Other 
HERCEPTIN 
TRASTUZUMAB 
monoclonal 
antibody 
Other 
INTRAPERITONEAL THERAPY- 
DRUG UNKNOWN 
ALL OTHER 
THERAPEUTIC 
PRODUCTS 
investigational 
drug 
Other 
INVESTIGATIONAL PRODUCT 
INVESTIGATIONAL DRUG 
investigational 
drug 
Other 
IPAFRICEPT 
IPAFRICEPT 
investigational 
drug 
Other 
KADYCLA 
TRASTUZUMAB 
EMTANSINE 
monoclonal 
antibody 
Other 
LDE225 600 MG DAILY 
SONIDEGIB 
investigational 
drug 
Other 
LETROZOLE 
LETROZOLE 
Hormonal therapy 
Other 
LUPRON 
LEUPRORELIN ACETATE 
Hormonal therapy 
Other 
MIFAPRISTONE 
MIFEPRISTONE 
RU 486, for the 
abortion 
Other 
PALBOCICLIB 
PALBOCICLIB 
CDK inhibitor 
Other 
PERJECTA 
PERTUZUMAB 
monoclonal 
antibody 
Other 
PERJETA 
PERTUZUMAB 
monoclonal 
antibody 
Other 
PERTUZUMAB 
PERTUZUMAB 
monoclonal 
antibody 
Other 
PEXIDARTINIB (PLX3397) 
PEXIDARTINIB 
investigational 
drug 
Other 
PFIZER B - B7661001- PF-
6657020 - CLINICAL TIRAL 
INVESTIGATIONAL DRUG 
investigational 
drug 
Other 
PLACEBO 
PLACEBO 
  
Other 
TAMOXIFEN 
TAMOXIFEN 
Hormonal therapy 
Other 
TARGETED T-CELL THERAPY 
ON A CLINICAL TRIAL 
INVESTIGATIONAL 
ANTINEOPLASTIC DRUGS 
investigational 
drug 
Other 
TRAMETINIB 
TRAMETINIB 
inhibitor tyrosine 
kinase 


  
 
  
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investigational 
drug 
Other 
TRASTUZUMAB 
TRASTUZUMAB 
monoclonal 
antibody 
Other 
VANTICTUMAB 
VANTICTUMAB 
monoclonal 
antibody 
Other 
VX-970 
PROTEIN KINASE 
INHIBITORS 
investigational 
drug 
 
 
 
 


  
 
  
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 Appendix 7: Immune-Related Adverse Events 
 
Below is a list of MedDRA preferred terms that will be used to identify immune-related adverse events. 
Pneumonitis 
Autoimmune colitis 
Autoimmune hepatitis 
Hypophysitis 
Hyperthyroidism 
Hypothyroidism 
Thyroiditis 
Diabetic ketoacidosis 
Hyperglycaemia 
Adrenal insufficiency 
Autoimmune dermatitis 
Autoimmune nephritis 
Dermatitis exfoliative 
Pemphigoid 
Toxic epidermal necrolysis  
Steven Johnson syndrome 
Encephalitis autoimmune 
Arthritis 
Uveitis 
Myositis 
Guillain-Barre syndrome 
Myasthenia gravis 
Vasculitis 
Pancreatitis 
Haemolytic anaemia 
Seizure 
Myelitis 
Myocarditis 
Infusion related reaction 
Rhabdomyolysis 
Iritis 
Facial paresis 
Demyelination 
Polymyalgia rheumatica 
Autoimmune neuropathy 
Hypopituitarism 


  
 
  
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Systemic inflammatory response syndrome 
Gastritis 
Duodenitis 
Sarcoidosis 
Histiocytic necrotising lymphadenitis 
Motor dysfunction 
Aplastic anaemia 
Pericarditis 
Myasthenic syndrome 
Vogt-Koyanagi-Harada syndrome 
 
 


  
 
  
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 Document History 
 
 
Version Date 
Version Number 
Modified/Reviewed 
By 
Brief Summary of Changes  
5-Feb-2016 
1.0 
 
Initial version 
22-Jun-2018 
1.1 
 
Incorporated addition of the OC Pooled 
analyses as well as other changes based on 
Amendment 2 of the protocol and the updated 
clinical study database at the time of approval. 
21-Mar-2019 
2.0 
 
 
Incorporated changes as a result of dry run 
review August 2018. 
 
PPD
PPD
PPD
PP
D