Conditions: Neoplasms
Keywords: Niraparib NSCLC Pembrolizumab Dostarlimab TSR-042
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: no

Brief summary:
This is a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of niraparib alone and in combination with PD-1 inhibitors in participants with locally advanced and metastatic non-small cell lung cancer (NSCLC). The study will consist of 2 stages. In stage 1, participants from Cohorts 1 and 2 will receive niraparib plus PD-1 inhibitor; pembrolizumab and participants from Cohort 3 will receive niraparib alone. In Stage 2, participants from Cohorts 1A and 2A will receive niraparib plus the PD-1 inhibitor, TSR-042 (Dostarlimab).

Detailed description:

Arms:
arm 1: Participants with locally advanced and metastatic NSCLC (all histologies) with no prior systemic chemotherapy or PD-1/programmed death-ligand 1 (PD-L1) inhibitor treatment and whose tumors have high PD-L1 expression (tumor proportion score \[TPS\]: \>= 50 percent \[%\]) will receive combination of niraparib and a PD-1 inhibitor; pembrolizumab. arm 2: Participants with locally advanced and metastatic NSCLC (all histologies) with no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment and whose tumors have PD-L1 expression (TPS: 1% to 49%) will receive combination of niraparib and a PD-1 inhibitor; pembrolizumab. arm 3: Participants with locally advanced and metastatic squamous NSCLC who have been previously treated with both platinum and either PD-1 or PD-L1 inhibitor will receive single agent niraparib. arm 4: Participants with locally advanced and metastatic NSCLC (all histologies) with no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment and whose tumors have high PD-L1 expression (TPS: \>= 50%) will receive combination of niraparib and a PD-1 inhibitor; TSR-042 (Dostarlimab). arm 5: Participants with locally advanced and metastatic NSCLC (all histologies) with no prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment and whose tumors have PD-L1 expression (TPS: 1% to 49%) will receive combination of niraparib and a PD-1 inhibitor; TSR-042 (Dostarlimab).

Interventions: intervention 1: Niraparib intervention 2: Pembrolizumab intervention 3: TSR-042 (Dostarlimab)
Intervention descriptions: intervention 1: Niraparib is an orally available, potent, highly selective poly adenosine diphosphate- ribose (poly ADP-ribose) polymerase-1 (PARP-1) and PARP-2 inhibitor. It will be available as 100 milligrams (mg) capsules and will be administered as 2 X 100 mg capsules (200 mg per day) orally once daily (QD). intervention 2: Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G-4 (IgG4)/kappa isotype designed to directly block the interaction between PD-1 and its ligands (PD-L1 and PD-L2). It will be available as 50 mg lyophilized powder single-use vials or 100 mg/4 milliliters (mL) (25 mg/mL) solution in a single-dose vial. It will be administered at a dose of 200 mg intravenous (IV) using a 30-minute IV infusion intervention 3: TSR-042 (Dostarlimab) is a humanized mAb of the IgG4/kappa isotype that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. It will be administered at a dose of 500 mg for every 3 weeks (Q3W) for first 4 cycles followed by 1000 mg for every 6 weeks (Q6W) for all subsequent cycles using a 30-minute IV infusion. TSR-042 (dostarlimab) will be supplied as a solution of 160 mg (20 mg/mL) or 500 mg (50 mg/mL) in a single-dose vial.

Protocol document:
Prot_002.pdf: 
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Niraparib  
 
 
Clinical Study Protocol 3000-02-001, Amendment 3, Version 4.0 
 
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INVESTIGATOR’S AGREEMENT 
 
Declaration of the Principal Investigator 
 
Title: A Phase 2, Multi-Arm Study of Niraparib Administered Alone and in Combination 
with a PD-1 Inhibitor in Patients with Non-Small Cell Lung 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/Institutional 
Review Board, in accordance with the study protocol, the current International Council for 
Harmonisation Guideline for Good Clinical Practice, and applicable regulatory requirements. I 
will ensure that all personnel involved in the study under my direction will be informed about the 
contents of this study protocol and will receive all necessary instructions for performing the 
study according to the study protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 
 
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Table 1: 
Summary of Changes for Amendment 3 (Version 4.0) 
Section(s) Affected 
Description of Change 
Brief Rationale 
Header, cover page, and 
Table 1: Summary of 
Changes for Amendment 3 
(Version 4.0) 
Cover page updated with new 
amendment and version number, 
and date of approval. Header 
updated with new amendment and 
version number, Table 1 created to 
include rationale for this version. 
Updated per best documentation 
practices 
Entire document 
Included dostarlimab to TSR-042 
nomenclature, ie, TSR-042 
(dostarlimab) 
Clarity 
Entire document 
Typographical corrections to 
address noted inconsistencies 
Clarity 
Entire document 
Removed OS as a secondary 
endpoint 
Sponsor decision based on 
portfolio prioritization following 
completion of the primary 
endpoint. 
Synopsis – Study Period 
completion date 
Revised from Q4 2019 to Q1 2021 
Clarity 
Synopsis – Duration of 
Treatment  and Section 
6.3.1.4 
Describes option for patient on 
study to continue to receive 
niraparib treatment in an 
alternative study 
Provisions for patients on study 
should study terminate 
Synopsis – Methodology / 
Duration of Treatment / 
Section 3.1.1 / Section 9.3 / 
Section 9.5 
Provided updated cohort status 
(completed/closed)  
Clarification 
Section 6.3.1.1, Table 5 
Updated niraparib dose 
reduction/discontinuation 
guidelines for nonhematologic 
toxicities 
Per Sponsor’s recommended 
safety practices as documented 
in Global Data Sheet 
Section 6.3.1.2, Table 6 
Updated niraparib dose 
reduction/discontinuation 
guidelines for hematologic 
toxicities 
Per Sponsor’s recommended 
safety practices as documented 
in Global Data Sheet 
Section 6.3.3. and Table 8 
Updated treatment guidelines for 
irAEs 
Per Sponsor’s recommended 
safety practices 
Section 6.7.4 
Added new treatment guidelines 
for AE of uveitis 
Per Sponsor’s recommended 
safety practices 
Section 7.1.2 
Added definition of a SUSAR 
Previously omitted in error 
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Table 1: 
Summary of Changes for Amendment 3 (Version 4.0) (Continued) 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 7.1.2.1 and Section 
7.1.7 
Explains no AESIs identified for 
TSR-042 (dostarlimab) 
Clarification 
Section 7.1.7.1 
Removed pneumonitis and 
embryo-fetal toxicity as AESIs for 
niraparib 
ADRs and pregnancy are 
tracked through other reporting 
mechanisms 
Section 7.1.8 
Added new monitoring 
requirements for hypertension  
Updated per niraparib IB, 
Version 11 
Section 7.1.9 
Added new monitoring 
requirements for PRES 
Updated per niraparib IB, 
Version 11 
Section 7.1.10 
Added new monitoring 
requirements for allergic reaction  
Updated per niraparib IB, 
Version 11 
Section 7.1.11 
New monitoring requirements for 
potential photosensitivity  
Updated per niraparib IB, 
Version 11 
Table 15, Schedule of Events, 
Cohort 3 
Added X (Cycle 1, Day 8 and 15) 
and footnote (14) to clarify 
monitoring requirement for vital 
signs 
Added footnote (15) to clarify 
monitoring requirement for CBC 
New monitoring requirements 
for hypertension and CBC 
Section 10.13 
Explains that Sponsor has 
discretion to terminate study and 
will notify Investigators under this 
outcome  
Clarification 
Abbreviations:  ADR=adverse drug reaction; AESI=adverse events of special interest; CBC=complete blood count; 
CSR=clinical study report; FDA=Food and Drug Administration; IB=Investigator’s Brochure; irAE = immune-
related adverse event; OS=overall survival; PRES=posterior reversible encephalopathy syndrome; 
SUSAR=suspected unexpected serious adverse reaction. 
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SYNOPSIS 
Name of Sponsor/Company: TESARO, a GSK company 
Name of Investigational Product: Niraparib, pembrolizumab, and TSR-042 (also known as 
dostarlimab) 
Name of Active Ingredient: Niraparib, pembrolizumab, and TSR-042 (dostarlimab) 
Title of Study: A Phase 2, Multi-Arm Study of Niraparib Administered Alone and in Combination 
with a PD-1 Inhibitor in Patients with Non-Small Cell Lung Cancer 
Study Center(s): North America 
Study Period (years):  
Estimated date first patient enrolled: Q4 2017 
Estimated date last patient completed: Q1 2021 
Phase of Development: 2 
Objectives:  
Primary Objectives: 
• 
To evaluate the efficacy of the combination of niraparib and a programmed cell death-1 
(PD-1) inhibitor in chemotherapy-naïve and PD-1 inhibitor-naïve patients with locally 
advanced and metastatic non-small cell lung cancer (NSCLC) whose tumors have high 
programmed death ligand-1 (PD-L1) expression (Tumor Proportion Score [TPS] ≥ 50%), 
as assessed by objective response rate (ORR)  
• 
To evaluate the efficacy of the combination of niraparib and a PD-1 inhibitor in 
chemotherapy-naïve and PD-1 inhibitor-naïve patients with locally advanced and 
metastatic NSCLC whose tumors express PD-L1 (TPS between 1 and 49%), as assessed 
by ORR 
• 
To evaluate the efficacy of single agent niraparib in patients with locally advanced and 
metastatic squamous NSCLC (sqNSCLC) who have been previously treated with both 
platinum-based chemotherapy and either PD-1 or PD-L1 inhibitor, as assessed by ORR 
Secondary Objectives: 
• 
To evaluate the safety and tolerability of single agent niraparib and of the combination of 
niraparib and a PD-1 inhibitor 
• 
To evaluate the following additional measures of clinical benefit of single agent niraparib 
and of the combination of niraparib and a PD-1 inhibitor:  
− 
Duration of response (DOR)  
− 
Disease control rate (DCR)  
− 
Progression-free survival (PFS)  
• 
To evaluate the pharmacokinetics (PK) of niraparib following administration of single 
agent niraparib or the combination of niraparib and a PD-1 inhibitor 
 
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Exploratory Objectives: 
• 
To explore blood and tumor-based biomarkers that predict sensitivity or resistance to 
single agent niraparib and to the combination of niraparib and a PD-1 inhibitor 
Methodology:  
This is a multicenter, open-label, multi-arm Phase 2 study to evaluate the efficacy and safety of single 
agent niraparib in patients with locally advanced and metastatic sqNSCLC and of the combination of 
niraparib and a PD-1 inhibitor in locally advanced and metastatic NSCLC (all histologies) patients. 
The study has 2 stages, each of which will evaluate separate cohorts of different cancer patients with a 
sample size that is deemed statistically significant to determine whether further examination may be 
warranted in the individual indications. In Stage 1, Cohorts 1 and 2 will receive niraparib plus the 
PD-1 inhibitor pembrolizumab, and Cohort 3 will receive niraparib alone. In Stage 2, Cohorts 1A and 
2A will receive niraparib plus the PD-1 inhibitor TSR-042 (dostarlimab). (As of Amendment 2, 
following a cross-program review and decision to move forward with other studies, the Sponsor 
decided that Cohort 3 would close to further enrollment. As of Amendment 3, Cohort 1 and Cohort 2 
had completed enrollment, Cohort 1A had closed after partial enrollment and Cohort 2A was not 
opened for enrollment.) 
Stage 1:  
 
Stage 2: 
 
*Completion of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant 
therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of 
metastatic disease 
Abbreviations: NSCLC = non-small cell lung cancer; PD-1 = programmed cell death-1; PD-L1 = programmed 
death ligand-1; TPS = Tumor Proportion Score 
Cohorts 1 and 1A: Locally advanced and metastatic NSCLC patients (all histologies) with no prior 
systemic chemotherapy or PD-1/PD-L1 inhibitor treatment, whose tumors have high PD-L1 
expression (TPS ≥ 50%), and no known epidermal growth factor receptor (EGFR) sensitizing 
mutation and/or ROS-1 or anaplastic lymphoma kinase (ALK) translocations will receive 
combination of niraparib and a PD-1 inhibitor (pembrolizumab or TSR-042 (dostarlimab)). 
Completion of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy 
is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic 
disease. 
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Cohorts 2 and 2A: Locally advanced and metastatic NSCLC patients (all histologies) with no prior 
systemic chemotherapy or PD-1/PD-L1 inhibitor treatment, whose tumors have PD-L1 expression 
(TPS between 1% and 49%) and no known EGFR sensitizing mutation and/or ROS-1 or ALK 
translocations, will receive combination of niraparib and a PD-1 inhibitor (pembrolizumab or TSR-
042 (dostarlimab)). Completion of treatment with chemotherapy and/or radiation as part of 
neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to 
the diagnosis of metastatic disease. 
Cohort 3: Locally advanced and metastatic sqNSCLC patients who have been previously treated with 
both platinum and either PD-1 or PD-L1 inhibitor will receive single agent niraparib. 
This study will consist of a Screening Period (Day -21 to Day -1), a Treatment Period, an End of 
Treatment (EOT) Period occurring within 7 days of the decision to discontinue treatment for any 
reason, a Safety Follow-up Visit occurring 30 + 7 days after the last dose of study drug, and a Follow-
up Assessment occurring every 90 ± 14 days, which will continue until death or the end of study data 
collection (a minimum of 6 months after the enrollment of the last patient, provided that this allows 
the opportunity for completion of all 90-day follow-up assessments). 
Patients must have a baseline tumor assessment by computed tomography (CT) or magnetic 
resonance imaging (MRI) scans of the chest, abdomen, and other sites as clinically indicated. If the 
patient has had appropriate imaging scans (eg, routine clinical management) performed within 
28 days prior to Cycle 1/Day 1, then the results of those scans may be used if they are of diagnostic 
quality. Subsequent postbaseline tumor assessments will be done in locations with tumor lesions 
identified at baseline only, unless clinically indicated. 
Clinic visits will occur in each cycle (every 3 weeks [Q3W] ± 3 days). For follow-up tumor 
assessments in Cohorts 1, 1A, 2, and 2A, CT/MRI scans will be performed every 9 weeks ± 7 days 
from first treatment dose until Week 72 and every 12 weeks ± 7 days thereafter. For sqNSCLC 
patients in Cohort 3, follow-up tumor assessment CT/MRI scans will be performed every 6 weeks 
(Q6W) ± 7 days from the first dose until Week 24, then every 9 weeks ± 7 days until Week 52 
(12 months) and every 12 weeks ± 7 days until disease progression. 
Per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, complete response (CR) or partial 
response (PR) should be confirmed; tumor imaging for confirmation of response must be performed 
at the earliest 28 days after the first indication of response but no later than 35 days after the response. 
The subsequent scan after the confirmatory scan should be obtained per original schedule (9 weeks ± 
7 days from confirmatory scan for Cohorts 1, 1A, 2 and 2A, and 6 weeks ± 7 days from confirmatory 
scan for Cohort 3). 
For Cohorts 1, 1A, 2, and 2A (a PD-1 inhibitor and niraparib), patients with radiologic evidence of 
progressive disease (PD) who are clinically stable may continue treatment at the Investigator’s 
discretion while awaiting confirmatory tumor imaging. Repeat imaging should be performed at 
≥ 4 weeks. If repeat imaging shows stable disease (SD), PR, or CR, patients can continue study 
treatment at the Investigator’s discretion. In the event that PD is confirmed, patients still may 
continue to receive study treatment even after confirmed radiologic progression if the patient is 
clinically stable and the Investigator deems that the patient is deriving clinical benefit. This allowance 
to continue treatment despite radiologic progression takes into account the observation that some 
patients may have a transient tumor flare in the first few months after the start of immunotherapy but 
with subsequent disease response. 
For Cohort 3 (single agent niraparib), patients with radiologic evidence of PD should be discontinued 
from treatment. 
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Tumor assessment should occur according to study schedule regardless of whether study treatment is 
interrupted. If a patient discontinues treatment for a reason other than progression, death, withdrawal 
of consent, or lost to follow-up, scans should continue at the specified intervals until progression is 
confirmed or until the start of subsequent anticancer treatment.  
Each patient will have an EOT visit within 7 days of the decision to discontinue treatment for any 
reason, a Safety Follow-up Visit occurring 30 + 7 days after the last dose of study drug, and a 
Follow-up Assessment every 90 ± 14 days, which will continue until death or the end of study data 
collection (a minimum of 6 months after the enrollment of the last patient, provided that this allows 
the opportunity for completion of all 90-day follow-up assessments).  
Treatment with niraparib will continue until progression. Treatment with pembrolizumab or TSR-042 
(dostarlimab) will continue for a maximum of 24 months in patients without disease progression or 
unacceptable toxicity. 
For Cohorts 1, 1A, 2 and 2A, local assessment of PD-L1 is acceptable on either archival or fresh 
tissue. PD-L1 status will be confirmed retrospectively in a central immunohistochemistry laboratory 
using a Food and Drug Administration (FDA)-approved in vitro companion diagnostic indicated as an 
aid in identifying NSCLC patients for treatment with a PD-1 inhibitor. 
An archival formalin fixed paraffin embedded (FFPE) tumor tissue is required for exploratory 
biomarker analysis. If archival tissue is not available, a fresh biopsy is needed. Archival FFPE sample 
should be submitted within 30 days of patient’s first dose. (For Cohort 3 only: if diagnosis was made 
by cytology and archival tissue is not available, patient will not need to provide tumor tissue.) 
Number of Patients (Planned):  
Stage 1: 59 (Cohort 1 = 16, Cohort 2 = 20, Cohort 3 = 23) 
Stage 2: 83 (Cohort 1A = 36, Cohort 2A = 47) 
(As of Amendment 2, following a cross-program review and decision to move forward with other 
studies, the Sponsor decided that Cohort 3 would close to further enrollment. As of Amendment 3, 
Cohort 1 and Cohort 2 had completed enrollment, Cohort 1A had closed after partial enrollment and 
Cohort 2A was not opened for enrollment). 
Criteria for Inclusion:  
General Inclusion Criteria: 
1. At least 18 years of age 
2. Histological or cytological proven advanced (unresectable) or metastatic NSCLC as defined 
as stage IIIB (positive supraclavicular lymph nodes) not amenable to definitive 
chemoradiotherapy or stage IV NSCLC  
3. Measurable disease by RECIST v1.1 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1  
5. Adequate organ function, defined as follows: 
Note: complete blood count (CBC) test should be obtained without transfusion or receipt of 
colony-stimulating factors within 4 weeks prior to the first dose of study treatment. 
a. Absolute neutrophil count (ANC) ≥1,500/µL 
b. Platelets ≥100,000/µL 
c. Hemoglobin ≥9 g/dL or ≥5.6 mmol/L 
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d. Serum creatinine ≤ 1.5× upper limit of normal (ULN) or creatinine clearance 
≥ 50 mL/min (as calculated using the Cockcroft Gault equation or measured using 
24-hour urine creatinine clearance) for patients with creatinine levels > 1.5 × institutional 
ULN 
e. Total bilirubin ≤ 1.5× ULN except in patients with Gilbert’s syndrome. Patients with 
Gilbert’s syndrome may enroll if direct bilirubin ≤ 1.5 × ULN of the direct bilirubin. 
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN 
unless liver metastases are present, in which case they must be ≤5 × ULN 
6. Patient must have recovered to Grade 1 toxicity from prior cancer therapy (a patient with 
Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may qualify for 
this study). 
7. Patient agrees to submit FFPE tumor tissue specimen, which may have been collected at any 
time prior to Screening. If no archival FFPE tumor tissue is available, patient agrees to 
undergo a tumor tissue biopsy before Cycle 1/Day 1. (For Cohort 3 only: if diagnosis was 
made by cytology and archival tissue is not available, patient will not need to provide tumor 
tissue).  
8. Patient is able to take oral medications 
9. Female patient meets the following criteria: 
a. Female patient (of childbearing potential) is not breastfeeding, has a negative serum 
pregnancy test within 72 hours prior to taking study drug, and agrees to abstain from 
activities that could result in pregnancy from enrollment through 180 days after the last 
dose of study treatment or is of nonchildbearing potential; or 
Note: A urine pregnancy test may be performed if the serum pregnancy result is not 
available before dosing. 
b. Female patient is of nonchildbearing potential, other than medical reasons, defined as 
follows: 
i. 
≥ 45 years of age and has not had menses for > 1 year 
ii. 
Amenorrheic for < 2 years without a hysterectomy and oophorectomy and 
a follicle-stimulating hormone (FSH) value in the postmenopausal range 
upon Screening evaluation 
iii. 
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 highly effective contraception methods 
throughout the study, starting with the screening visit through 180 days 
after the last dose of study therapy. Please see Section 6.7.3 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 method for the patient. 
10. Male patient agrees to use an adequate method of contraception and not donate sperm 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 method 
for the patient. 
11. Patient is able to understand the study procedures and agree to participate in the study by 
providing written informed consent 
Cohort-Specific Inclusion Criteria: 
1. Cohorts 1 and 1A (combination of niraparib and a PD-1 inhibitor): patients must have tumors 
with high PD-L1 expression (TPS ≥ 50%) per local assessment, with no known 
EGFR-sensitizing mutation and/or ROS-1 or ALK translocation, and no prior systemic 
chemotherapy or PD-1/PD-L1 inhibitor treatment for metastatic NSCLC 
2. Cohorts 2 and 2A (combination of niraparib and a PD-1 inhibitor): patients must have tumors 
with PD-L1 expression (TPS between 1% and 49%) per local assessment, with no known 
EGFR-sensitizing mutation and/or ROS-1 or ALK translocations, and no prior systemic 
chemotherapy or PD-1/PD-L1 inhibitor treatment for metastatic NSCLC (all histologies) 
3. Cohort 3 (single agent niraparib): patients must have metastatic sqNSCLC and have 
progressed after both prior platinum-based chemotherapy and prior PD-1 or PD-L1 inhibitor 
treatment 
Criteria for Exclusion:  
Exclusion Criteria for Cohorts 1, 1A, 2 and 2A: 
1. Has received systemic therapy for the treatment of advanced stage NSCLC. Completion of 
treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is 
allowed as long as therapy was completed at least 6 months prior to the diagnosis of 
metastatic disease 
2. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-programmed death-ligand 2 
(anti-PD-L2) agent 
3. Known hypersensitivity to the components of niraparib, pembrolizumab, TSR-042 
(dostarlimab), or their excipients  
4. Known EGFR (exon 19 and 21) mutations, ALK translocations, and/or ROS-1 translocations  
5. Patient has a history or current 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.  
6. Known diagnosis of immunodeficiency or receiving systemic steroid therapy (except as 
allowed in exclusion criterion #9 below) or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of study treatment 
7. Patient is immunocompromised, in the opinion of the Investigator (Note: patients with 
splenectomy are allowed)  
8. Current participation in a treatment study or past participation in a study of an investigational 
agent within 4 weeks before the first dose of study treatment 
9. Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered 
“controlled,” central nervous system [CNS] disease must have undergone treatment 
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[eg, radiation or chemotherapy] at least 1 month prior to study entry. The patient must not 
have any new or progressive signs or symptoms related to the CNS disease and must be 
taking < 10 mg of prednisone or equivalent per day or no steroids.) Patients who have 
untreated brain metastases and who are not symptomatic may enroll if the Investigator feels 
that treatment of these metastases is not indicated. A scan to confirm the absence of brain 
metastases is not required. Patients with spinal cord compression may be considered if they 
have received definitive treatment for this and evidence of clinically SD for 28 days  
10. Active autoimmune disease that 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) is not considered a form of systemic treatment 
11. Major surgery within 3 weeks of starting the study or patient has not recovered from any 
effects of any major surgery 
12. Other active concomitant malignancy that warrants systemic therapy  
13. Poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic 
disease, or active, uncontrolled infection. Examples include, but are not limited to, 
uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava 
syndrome, uncontrolled hypertension, active uncontrolled coagulopathy, or any psychiatric 
disorder that prohibits obtaining informed consent 
14. Known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis 
requiring steroid treatment 
15. Patient is pregnant, breastfeeding, or expecting to conceive children while receiving study 
treatment and for 180 days (for pregnancy or conception) or 30 days (for breastfeeding) after 
the last dose of study treatment  
16. Male patient is expecting to donate sperm or father children while receiving study drug or for 
120 days after the last dose of study treatment 
17. Known active hepatic disease (known hepatic cirrhosis, hepatitis B surface antigen-positive 
status, or suspected active hepatitis C infection) 
18. Prior treatment with a known poly-(adenosine diphosphate-ribose) polymerase (PARP) 
inhibitor 
19. Patient received a live vaccine within 30 days of planned start of study therapy 
20. Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) 
Exclusion Criteria for Cohort 3: 
1. Platinum-treated patient who progressed while on or within less than 8 weeks from the last 
day of platinum administration 
2. Known hypersensitivity to the components of niraparib or excipients 
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3. Patient has a history or current 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.  
4. Known diagnosis of immunodeficiency or receiving systemic steroid therapy (except as 
allowed in exclusion criterion #6 below) or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of study treatment  
5. Current participation in a treatment study or past participation in a study of an investigational 
agent within 4 weeks before the first dose of study treatment 
6. Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered 
“controlled,” CNS disease must have undergone treatment [eg, radiation or chemotherapy] at 
least 1 month prior to study entry. The patient must not have any new or progressive signs or 
symptoms related to the CNS disease and must be taking < 10 mg of prednisone or equivalent 
per day or no steroids.) Patients who have untreated brain metastases and who are not 
symptomatic may enroll if the Investigator feels that treatment of these metastases is not 
indicated. A scan to confirm the absence of brain metastases is not required. Patients with 
spinal cord compression may be considered if they have received definitive treatment for this 
and evidence of clinically SD for 28 days  
7. Major surgery within 3 weeks of starting the study or patient has not recovered from any 
effects of any major surgery.  
8. Other active concomitant malignancy that warrants systemic therapy 
9. Poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic 
disease, or active, uncontrolled infection. Examples include, but are not limited to, 
uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava 
syndrome, uncontrolled hypertension, active uncontrolled coagulopathy, or any psychiatric 
disorder that prohibits obtaining informed consent 
10. Known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis 
requiring steroid treatment 
11. Patient is pregnant, breastfeeding, or expecting to conceive children, while receiving study 
treatment and for 180 days (for pregnancy or conception) or 30 days (for breastfeeding) after 
the last dose of study treatment  
12. Male patient is expecting to donate sperm or father children while receiving study drug or for 
120 days after the last dose of study treatment 
13. Patient is immunocompromised, in the opinion of the Investigator (Note: patients with 
splenectomy are allowed)  
14. Known active hepatic disease (known hepatic cirrhosis, hepatitis B surface antigen-positive 
status, or suspected active hepatitis C infection) 
15. Prior treatment with a known PARP inhibitor 
16. Known history of MDS or AML 
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Investigational Product, Dosage, and Mode of Administration:  
Niraparib: 
Niraparib will be administered orally once a day, continuously throughout the 21-day cycle. 
Two capsules of 100 mg strength (200 mg/day) will be taken at each dose administration. Patients 
will be instructed to take their niraparib dose in the morning at approximately the same time each day. 
Niraparib may be taken with or without food or water. Patients must swallow and not chew the 
capsules.  
For those patients experiencing nausea and who are at Cycle 5 and beyond, bedtime administration 
may be a potential method for managing nausea. For those patients experiencing nausea who are not 
yet at Cycle 5, please seek approval from Medical Monitor to permit bedtime administration. 
For Cohorts 1, 1A, 2, and 2A, niraparib will be administered upon completion of pembrolizumab or 
TSR-042 (dostarlimab) infusion per respective cohorts. 
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 administration of niraparib. 
Niraparib dose may be escalated on or after Cycle 3/Day 1 from 200 mg daily (2 capsules) to 300 mg 
daily (3 capsules) if platelets ≥100,000/μL, hemoglobin ≥ 9 g/dL, and neutrophils ≥ 1,500/μL for all 
laboratory tests performed during the first 2 cycles after discussion with Medical Monitor or designee. 
Dose interruption will be allowed for no longer than 28 days. In addition, dose reduction will be 
allowed based on treatment side effects. Dose reductions to 100 mg daily (1 capsule) will be allowed. 
No further dose reductions will be allowed. The timing of efficacy or safety evaluations should not be 
affected by dose interruptions or reductions. 
Pembrolizumab: 
Pembrolizumab infusion will be administered before niraparib dose at the study site on Day 1 of each 
21-day treatment cycle after all procedures and assessments have been completed. Pembrolizumab 
may be administered up to 3 days before or after the scheduled Day 1 of each cycle after Cycle 1 due 
to administrative reasons.  
Pembrolizumab will be administered at a dose of 200 mg IV using a 30-minute 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. Dose interruption will be allowed for no longer than 28 days. 
Refer to United States Prescribing Information for specific instructions for the preparation of the 
pembrolizumab infusion and administration of the infusion solution. 
TSR-042 (dostarlimab): 
TSR-042 (dostarlimab) infusion will be administered before niraparib dose at the study site on Day 1 
of each 21-day treatment cycle (Q3W) in Cycles 1 through 4 and on Day 1 of every other cycle 
(Q6W) thereafter, beginning on Cycle 5 Day 1 (ie, Cycle 5, Cycle 7, Cycle 9, etc.). 
TSR-042 (dostarlimab) will be administered after all procedures and assessments have been 
completed, unless otherwise indicated. TSR-042 (dostarlimab) may be administered up to 3 days 
before or after the scheduled Day 1 of each cycle after Cycle 1 due to administrative reasons.  
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TSR-042 (dostarlimab) will be administered at a dose of 500 mg IV Q3W in Cycles 1 through 4 and 
at a dose of 1,000 mg IV Q6W thereafter, beginning on Cycle 5 Day 1, for the rest of the treatment 
using a 30-minute 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 + 15 minutes is permitted. Dose interruption to manage adverse reactions 
will be allowed for no longer than 28 days. 
The Pharmacy Manual contains information for specific instructions for the preparation of the TSR-
042 (dostarlimab) infusion and administration of the infusion solution. 
Duration of Treatment: 
Patients may continue treatment until disease progression, unacceptable toxicity, patient withdrawal, 
Investigator’s decision, or death. Treatment with niraparib will continue until disease progression. 
Treatment with pembrolizumab or TSR-042 (dostarlimab) will continue for a maximum of 24 months 
in patients without disease progression or unacceptable toxicity. 
Those patients deemed to derive clinical benefit from niraparib monotherapy treatment at the time of 
final analysis and who are no longer receiving a PD-1 inhibitor will have the option to continue 
treatment with niraparib through the extension “rollover” protocol, if available, and at the discretion 
of the Investigator and Sponsor. 
Long-Term Follow-Up Assessment: Every 90 days, via telephone. 
Planned study conduct duration:  
• 
Stage 1: It may take 8 to 12 months to complete enrollment in each cohort. For each 
cohort, analysis will be done after the last patient enrolled in that cohort has discontinued 
treatment or completed 2 postbaseline tumor assessments (approximately 3 to 5 months 
from baseline), whichever occurs earlier.  
(As of Amendment 2, following a cross-program review and decision to move forward 
with other studies, the Sponsor decided that Cohort 3 would close to further enrollment. 
As of Amendment 3, Cohort 1 and Cohort 2 had completed enrollment, Cohort 1A had 
closed after partial enrollment and Cohort 2A was not opened for enrollment.) 
• 
Stage 2: It may take 12 to 14 months to complete enrollment in each cohort. For each 
cohort, analysis will be done after the last patient enrolled in that cohort has discontinued 
treatment or completed 2 postbaseline tumor assessments (approximately 3 to 5 months 
from baseline), whichever occurs earlier. 
Criteria for Evaluation: 
Efficacy: 
The primary endpoint is the ORR, which is defined as the proportion of patients with a confirmed best 
overall response of CR or PR in the analysis population. Tumor assessment will be done by the 
Investigator per RECIST v1.1. 
Secondary efficacy endpoints include: 
• 
DOR, defined as the time from first documented CR or PR until the subsequently 
documented disease progression or death, whichever occurs earlier. 
• 
DCR defined as the proportion of patients with a best overall response of CR, PR, or SD.  
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• 
PFS is defined as the time from the date of first dose to the date of disease progression or 
death due to any cause, whichever occurs earlier. 
Safety: 
Safety and tolerability of single agent niraparib and of the combination of niraparib and a PD-1 
inhibitor will be evaluated throughout the study, including assessment of treatment-emergent adverse 
events (AEs), discontinuations due to AEs, clinical laboratory assessments (CBC, serum chemistry, 
and urinalysis), vital signs, electrocardiograms, physical examination, and use of concomitant 
medications. 
Pharmacokinetics: 
The PK of niraparib when given alone and in combination with pembrolizumab or TSR-042 
(dostarlimab) will be evaluated. Samples for PK determination will be collected from patients in 
plasma for single agent niraparib (Cohort 3) and serum and plasma for the combination of niraparib 
and pembrolizumab or TSR-042 (dostarlimab) (Cohorts 1, 1A, 2, and 2A).  
Biomarkers: 
Biomarker analysis will be carried out on tumor tissue and blood to include but not be limited to 
circulating tumor DNA (ctDNA) or circulating tumor cells (CTC) to identify prognostic or predictive 
biomarkers and to explore potential mechanisms of either de novo or treatment-emergent resistance.  
Biomarkers will be evaluated in archival or fresh tumor samples obtained during screening to confirm 
histology morphology, presence of tumor, and to conduct biomarker analysis. Archival FFPE sample 
should be submitted within 30 days of patient’s first dose. (For Cohort 3 only: if diagnosis was made 
by cytology and archival tissue is not available, patient will not need to provide tumor tissue.) 
Blood samples for the analysis of tumor-related circulating biomarkers such as CTC will be collected 
at Cycle 1/Day 1 predose. Blood samples for the analysis of ctDNA will be obtained at Screening, 
Cycle 2/Day 1 predose, as well as EOT.  
Statistical Methods: 
Data from Stage 1 will be used to determine whether further enrollment of Stage 2 patients is 
warranted. The criteria for continuing Stage 2 enrollment are provided in Section 9. For each cohort, 
if the number of responders by the end of Stage 1 is the same or less as defined by the criterion, the 
cohort will be terminated. Only cohorts with number of responders larger than that defined by the 
criteria will continue Stage 2 enrollment. (As of Amendment 2, following a cross-program review and 
decision to move forward with other studies, the Sponsor decided that Cohort 3 would close to further 
enrollment. As of Amendment 3, Cohort 1 and Cohort 2 had completed enrollment, Cohort 1A had 
closed after partial enrollment and Cohort 2A was not opened for enrollment.) 
Number of responders, ORR, and its 80% and 95% binomial exact confidence interval will be 
reported by cohort and stage. 
Results for DCR and PFS will be summarized in a descriptive manner. DCR will be analyzed using 
the same methods for ORR. Kaplan-Meier estimates including median and its 95% confidence 
interval will be tabulated for time-to-event variables. In addition, Kaplan-Meier curves will also be 
presented for time-to-event variables. 
Pharmacokinetics: 
PK parameters will be summarized by cohort and dose schedule using descriptive statistics. The 
concentration-time data for niraparib will be used to perform a population PK analysis. The 
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relationship between measures of niraparib exposure and measures of efficacy, including, but not 
limited to, ORR, PFS, DOR, and DCR, will be explored. The relationship between niraparib exposure 
and key safety variables, including, but not limited to, AEs of special interest in the population will be 
explored. 
 
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TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 
TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
SYNOPSIS ......................................................................................................................................6 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ..................................18 
LIST OF FIGURES .......................................................................................................................26 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................27 
1. 
INTRODUCTION ......................................................................................................31 
1.1. 
Background .................................................................................................................31 
1.1.1. 
Lung Cancer ................................................................................................................31 
1.1.2. 
Overview of PARP and Homologous Recombination Deficiency .............................32 
1.1.2.1. 
Nonclinical Experience with PARP Inhibitors in NSCLC .........................................32 
1.1.2.2. 
Clinical Experience with PARP inhibitors .................................................................33 
1.1.3. 
Overview of PD-1 Inhibitors ......................................................................................34 
1.1.3.1. 
Clinical Experience with PD-1/PD-L1 Inhibitors in NSCLC .....................................34 
1.1.3.2. 
Clinical Experience with TSR-042 (Dostarlimab) .....................................................35 
1.1.4. 
Combination of PARP Inhibitors and PD-1 Inhibitors ...............................................36 
1.1.4.1. 
Nonclinical Experience Combining PARP inhibitors and PD-1 Inhibitors ................36 
1.1.4.2. 
Clinical Experience Combining Niraparib and Pembrolizumab ................................37 
1.1.4.3. 
Clinical Experience Combining Niraparib and TSR-042 (Dostarlimab) ...................38 
1.2. 
Study Treatments ........................................................................................................38 
1.2.1. 
Niraparib .....................................................................................................................38 
1.2.2. 
Pembrolizumab ...........................................................................................................41 
1.2.3. 
TSR-042 (Dostarlimab) ..............................................................................................41 
1.3. 
Rationale for Current Study ........................................................................................41 
2. 
STUDY OBJECTIVES AND PURPOSE ..................................................................43 
2.1. 
Primary Objectives .....................................................................................................43 
2.2. 
Secondary Objectives .................................................................................................43 
2.3. 
Exploratory Objectives ...............................................................................................43 
3. 
INVESTIGATIONAL PLAN .....................................................................................44 
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3.1. 
Overall Study Design and Plan ...................................................................................44 
3.1.1. 
Overview .....................................................................................................................44 
3.1.2. 
General Study Conduct ...............................................................................................45 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................49 
4.1. 
Subject Inclusion Criteria ...........................................................................................49 
4.1.1. 
General Inclusion Criteria ...........................................................................................49 
4.1.2. 
Cohort-Specific Inclusion Criteria ..............................................................................50 
4.2. 
Subject Exclusion Criteria ..........................................................................................51 
4.2.1. 
Exclusion Criteria for Cohorts 1, 1A, 2, and 2A ........................................................51 
4.2.2. 
Exclusion Criteria for Cohort 3 ..................................................................................52 
4.3. 
Subject Withdrawal Criteria .......................................................................................53 
4.3.1. 
Discontinuation from Treatment .................................................................................53 
4.3.2. 
Discontinuation from the Study ..................................................................................54 
4.3.3. 
Replacement of Patients .............................................................................................55 
4.4. 
Patient Identification and Randomization ..................................................................55 
4.4.1. 
Patient Identification ...................................................................................................55 
4.4.2. 
Randomization Scheme ..............................................................................................55 
5. 
TREATMENT OF SUBJECTS ..................................................................................56 
5.1. 
Description of Study Drug ..........................................................................................56 
6. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................57 
6.1. 
Study Drug ..................................................................................................................57 
6.1.1. 
Niraparib .....................................................................................................................57 
6.1.2. 
Pembrolizumab ...........................................................................................................57 
6.1.3. 
TSR-042 (Dostarlimab) ..............................................................................................57 
6.2. 
Administration ............................................................................................................57 
6.2.1. 
Niraparib .....................................................................................................................57 
6.2.2. 
Pembrolizumab ...........................................................................................................58 
6.2.3. 
TSR-042 (Dostarlimab) ..............................................................................................58 
6.3. 
Dose Modification ......................................................................................................58 
6.3.1. 
Niraparib .....................................................................................................................58 
6.3.1.1. 
Niraparib Dose Modifications for Nonhematologic Toxicity ....................................59 
6.3.1.2. 
Niraparib Dose Modifications for Hematologic Toxicity ..........................................59 
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6.3.1.3. 
Niraparib Dose Escalation ..........................................................................................61 
6.3.1.4. 
Niraparib Extended Treatment ...................................................................................62 
6.3.2. 
Pembrolizumab ...........................................................................................................62 
6.3.3. 
TSR-042 (Dostarlimab) ..............................................................................................65 
6.4. 
Study Drug Packaging, Labeling, and Storage ...........................................................67 
6.5. 
Study Drug Accountability .........................................................................................68 
6.6. 
Study Drug Handling and Disposal ............................................................................68 
6.7. 
Previous and Concomitant Medications .....................................................................68 
6.7.1. 
Prohibited Medications ...............................................................................................69 
6.7.2. 
Radiation Therapy ......................................................................................................69 
6.7.3. 
Contraception ..............................................................................................................69 
6.7.4. 
Rescue Medications and Supportive Care Guidelines During Treatment with 
Pembrolizumab ...........................................................................................................70 
6.7.5. 
Rescue Medications and Supportive Care Guidelines During Treatment with 
TSR-042 (Dostarlimab) ..............................................................................................74 
6.7.5.1. 
Management of Infusion-related Reactions ................................................................75 
6.7.6. 
Other Study Restrictions .............................................................................................77 
7. 
ENDPOINTS AND METHODS OF ASSESSMENT ...............................................78 
7.1. 
Safety Endpoints .........................................................................................................78 
7.1.1. 
Definitions ..................................................................................................................78 
7.1.1.1. 
Adverse event (AE) ....................................................................................................78 
7.1.1.2. 
Serious adverse event (SAE) ......................................................................................78 
7.1.1.3. 
Treatment-emergent adverse event .............................................................................79 
7.1.2. 
Suspected Unexpected Serious Adverse Reaction .....................................................79 
7.1.2.1. 
Adverse event of special interest ................................................................................79 
7.1.2.2. 
Special Situations: Abuse, Misuse, Medication Errors, Overdose, and 
Accidental or Occupational Exposure: .......................................................................79 
7.1.3. 
Assessment of Adverse Events ...................................................................................80 
7.1.3.1. 
Expectedness ...............................................................................................................80 
7.1.3.2. 
Intensity ......................................................................................................................80 
7.1.3.3. 
Causality .....................................................................................................................81 
7.1.4. 
Collecting and Recording Adverse Events .................................................................81 
7.1.5. 
Reporting Disease Progression ...................................................................................82 
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7.1.6. 
Serious Adverse Events ..............................................................................................83 
7.1.6.1. 
Reporting Serious Adverse Events .............................................................................83 
7.1.6.2. 
Submission and Distribution of Serious Adverse Events ...........................................83 
7.1.7. 
Adverse Events of Special Interest .............................................................................83 
7.1.7.1. 
Niraparib .....................................................................................................................83 
7.1.7.2. 
Pembrolizumab ...........................................................................................................84 
7.1.8. 
Hypertension, Including Hypertensive Crisis .............................................................84 
7.1.9. 
Posterior Reversible Encephalopathy Syndrome ........................................................84 
7.1.10. 
Allergic Reaction ........................................................................................................84 
7.1.11. 
Lifestyle Considerations .............................................................................................84 
7.1.12. 
Protocol-defined Overdose .........................................................................................85 
7.1.12.1. 
Reporting of Overdoses and Special Situations ..........................................................85 
7.1.13. 
Pregnancy Reporting and Follow-up ..........................................................................85 
7.1.14. 
Clinical Laboratory Assessments ...............................................................................86 
7.1.15. 
Physical Examination and Vital Signs ........................................................................87 
7.1.16. 
Eastern Cooperative Oncology Group Performance Status ........................................88 
7.1.17. 
Additional Safety Assessments...................................................................................88 
7.2. 
Demographics and Baseline Characteristics ...............................................................88 
7.2.1. 
Patient Eligibility ........................................................................................................88 
7.2.2. 
Patient Demography ...................................................................................................88 
7.2.3. 
Disease History ...........................................................................................................88 
7.2.4. 
Medical and Surgical History .....................................................................................89 
7.2.5. 
Previous and Concomitant Medications and Procedures ............................................89 
7.3. 
Clinical Activity Endpoints ........................................................................................89 
7.3.1. 
Evaluation of Tumor Response ..................................................................................89 
7.3.1.1. 
Overview .....................................................................................................................89 
7.3.1.2. 
Timing of Radiographic Evaluations ..........................................................................90 
7.3.1.3. 
Assessment of Response by RECIST .........................................................................91 
7.3.2. 
Efficacy Endpoints ......................................................................................................91 
7.3.2.1. 
Objective Response Rate ............................................................................................91 
7.3.2.2. 
Duration of Response .................................................................................................91 
7.3.2.3. 
Disease Control Rate ..................................................................................................91 
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7.3.2.4. 
Progression-Free Survival ..........................................................................................92 
7.4. 
Pharmacokinetic Assessment ......................................................................................92 
7.4.1. 
Niraparib Concentrations ............................................................................................92 
7.4.2. 
Pembrolizumab Concentrations ..................................................................................92 
7.4.3. 
TSR-042 (Dostarlimab) Concentrations .....................................................................93 
7.4.4. 
Determination of Pharmacokinetic Parameters ..........................................................93 
7.4.4.1. 
Niraparib .....................................................................................................................93 
7.4.4.2. 
Pembrolizumab ...........................................................................................................93 
7.4.4.3. 
TSR-042 (Dostarlimab) ..............................................................................................93 
7.5. 
Biomarkers ..................................................................................................................93 
7.5.1. 
Biomarker Sample Collection .....................................................................................93 
7.5.2. 
Biomarker Testing on Tumor Samples .......................................................................94 
7.5.3. 
Biomarker Testing on Circulating Biomarkers in Blood ............................................94 
8. 
STUDY CONDUCT ...................................................................................................96 
8.1. 
Schedule of Procedures ...............................................................................................96 
8.2. 
Procedures by Visit ...................................................................................................105 
8.2.1. 
Screening (Day -21 to Day -1) ..................................................................................105 
8.2.1.1. 
Screening: Cohorts 1, 1A, 2, and 2A (Table 14) ......................................................105 
8.2.1.2. 
Screening: Cohort 3 (Table 15) ................................................................................106 
8.2.2. 
Cycle 1 ......................................................................................................................107 
8.2.2.1. 
Cycle 1/Day 1: Cohorts 1, 1A, 2, and 2A (Table 14) ...............................................107 
8.2.2.2. 
Cycle 1/Day 1: Cohort 3 (Table 15) .........................................................................108 
8.2.2.3. 
Cycle 1/Day 8: All Cohorts (Table 14 and Table 15) ...............................................109 
8.2.2.4. 
Cycle 1/Day 15: Cohorts 1, 1A, 2, and 2A (Table 14) .............................................109 
8.2.2.5. 
Cycle 1/Day 15: Cohort 3 (Table 15) .......................................................................109 
8.2.3. 
Subsequent Cycles ....................................................................................................109 
8.2.3.1. 
Cohorts 1, 1A, 2, and 2A (Table 14) ........................................................................109 
8.2.3.2. 
Cohort 3 (Table 15) ..................................................................................................111 
8.2.4. 
End of Treatment (Within 7 Days of Last Dose) ......................................................112 
8.2.4.1. 
End of Treatment: Cohorts 1, 1A, 2, and 2A (Table 14) ..........................................112 
8.2.4.2. 
End of Treatment: Cohort 3 (Table 15) ....................................................................113 
8.2.5. 
Safety Follow-Up Visit (30 + 7 days Post-treatment): .............................................114 
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8.2.5.1. 
Cohorts 1, 1A, 2, and 2A (Table 14) ........................................................................114 
8.2.5.2. 
Cohort 3 (Table 15) ..................................................................................................114 
8.2.6. 
Follow-Up Assessments (Every 90 ± 14 Days): .......................................................115 
8.2.6.1. 
Cohorts 1, 1A, 2, and 2A (Table 14) ........................................................................115 
8.2.6.2. 
Cohort 3 (Table 15) ..................................................................................................115 
8.2.7. 
Unscheduled Assessments ........................................................................................116 
8.3. 
Intensive Niraparib PK evaluation: All Cohorts .......................................................116 
9. 
STATISTICS ............................................................................................................117 
9.1. 
Analysis Populations ................................................................................................117 
9.2. 
Demographics, Medical History, Baseline Characteristics ......................................117 
9.3. 
Sample Size Determination ......................................................................................117 
9.4. 
Statistical Analysis ....................................................................................................118 
9.4.1. 
Efficacy Analyses .....................................................................................................118 
9.4.1.1. 
Analysis for Primary Efficacy Endpoint ...................................................................118 
9.4.1.2. 
Analysis for Secondary Efficacy Endpoints .............................................................118 
9.4.2. 
Safety Analyses ........................................................................................................119 
9.5. 
Interim Analyses .......................................................................................................119 
9.6. 
Pharmacokinetic Analyses ........................................................................................120 
9.7. 
Biomarker Analyses ..................................................................................................120 
10. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ..................................121 
10.1. 
Data Quality Assurance ............................................................................................121 
10.2. 
Access to Source Data/Documents ...........................................................................121 
10.3. 
Archiving Study Documents .....................................................................................122 
10.4. 
Good Clinical Practice ..............................................................................................122 
10.5. 
Informed Consent .....................................................................................................122 
10.6. 
Protocol Approval and Amendment .........................................................................122 
10.7. 
Patient Confidentiality and Data Protection .............................................................123 
10.8. 
Study Monitoring ......................................................................................................123 
10.9. 
Audits and Inspections ..............................................................................................123 
10.10. 
Ethical Considerations ..............................................................................................124 
10.11. 
Publication Policy .....................................................................................................124 
10.12. 
Study Committee ......................................................................................................124 
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10.13. 
Criteria for Study Termination .................................................................................124 
11. 
LIST OF REFERENCES ..........................................................................................125 
APPENDIX A. COCKCROFT-GAULT EQUATION .............................................................128 
APPENDIX B. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS .....................................................................................129 
APPENDIX C. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS, V1.1 .........130 
APPENDIX D. ACCEPTABLE METHODS OF CONTRACEPTION ...................................132 
 
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LIST OF TABLES 
Table 1: 
Summary of Changes for Amendment 3 (Version 4.0) ................................................4 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................27 
Table 3: 
Progression-Free Survival in Ovarian Cancer Patients in NOVA ..............................39 
Table 4: 
Investigational Product ...............................................................................................56 
Table 5: 
Niraparib Dose Reductions for Nonhematologic Toxicity .........................................59 
Table 6: 
Management of Hematologic Toxicities ....................................................................60 
Table 7: 
Pembrolizumab Dose Modifications for Nonhematologic Toxicities ........................63 
Table 8: 
Guidelines for Treatment of Immune-related Adverse Events of Interest .................65 
Table 9: 
Timing of Contraception and Sperm Donation ..........................................................70 
Table 10: Pembrolizumab Infusion Reaction Treatment Guidelines ..........................................73 
Table 11: TSR-042 (Dostarlimab) Infusion Reaction Treatment Guidelines .............................76 
Table 12: Collecting and Reporting Adverse Events, Pregnancy, and Survival ........................82 
Table 13: Schedule of Events for Cohorts 1, 1A, 2, and 2A .......................................................97 
Table 14: Schedule of Events for Cohort 3 ...............................................................................100 
Table 15: Pharmacokinetic Sampling: All Cohorts ..................................................................103 
Table 16: Intensive Niraparib Pharmacokinetic Sampling: Subset of Patients in All 
Cohorts ......................................................................................................................104 
Table 17: Sample Size by Cohort .............................................................................................118 
Table 18: Criteria for Considering Treatment Efficacious by Cohort and Stage .....................118 
Table 19: RECIST Response for Patients with Measurable Disease (ie, Target Disease) .......131 
 
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LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................44 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation  
Explanation 
ADL 
activity of daily living 
ADP 
adenosine diphosphate 
AE 
adverse event 
AESI 
adverse event of special interest  
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATM 
ataxia telangiectasia mutated 
AUC 
area under the concentration × time curve 
AUCss 
area under the concentration × time curve at steady state 
BIW 
biweekly  
BP 
blood pressure  
BRCA 
breast cancer (gene) 
CBC 
complete blood count 
CI 
confidence interval 
CL 
clearance 
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 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
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Abbreviation  
Explanation 
CYP 
cytochrome P450 
DCR 
disease control rate 
DDR 
DNA damage repair  
DKA 
diabetic ketoacidosis 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSB 
double-stranded breaks 
EC 
endometrial cancer 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
ELISA 
enzyme-linked immunosorbent assay 
EOT 
end of treatment 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FFPE 
formalin fixed paraffin embedded 
FSH 
follicle-stimulating hormone 
FT3 
free triiodothyronine 
FT4 
free thyroxine 
gBRCAmut 
germline breast cancer gene mutation 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
H0 
null hypothesis 
Ha 
alternative hypothesis 
HR 
hazard ratio 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair  
IB 
Investigator Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
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Abbreviation  
Explanation 
Ig 
immunoglobulin 
IHC 
immunohistochemistry 
irAEI 
immune related adverse event of interest 
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  
ITT 
intent-to-treat 
IV 
intravenous 
mAb 
monoclonal antibody 
MDS 
myelodysplastic syndrome 
MRI 
magnetic resonance imaging 
MSI-H 
microsatellite instability-high 
NSCLC 
non-small cell lung cancer 
OAE 
other significant adverse event 
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly (ADP-ribose) polymerases 
PD 
progressive disease 
PD-1 
programmed cell death-1 
PD-L1 
programmed death-ligand 1 
PD-L2 
programmed death-ligand 2 
PDX 
patient-derived xenograft 
PET 
positron emission tomography  
PFS 
progression-free survival 
PK 
pharmacokinetics 
PO 
oral(ly) 
PR 
partial response 
PTEN 
phosphatase and tensin homolog  
Q3W 
every 3 weeks 
Q6W 
every 6 weeks 
QD 
once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
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Abbreviation  
Explanation 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
RRs 
standard of care response rate 
RRt 
target response rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCLC 
small cell lung cancer 
SD 
stable disease 
sqNSCLC 
squamous non-small cell lung cancer 
SUSAR 
suspected unexpected serious adverse reaction 
T1DM 
type 1 diabetes mellitus 
T3 
triiodothyronine 
TCGA 
The Cancer Genome Atlas 
TEAE 
treatment-emergent adverse event 
TIL 
tumor-infiltrating lymphocytes 
TMB 
tumor mutation burden 
TPS 
Tumor Proportion Score 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
USPI 
United States Prescribing Information 
vs. 
versus 
WHO 
World Health Organization 
Trademark Information 
Trademarks of the TESARO-
GlaxoSmithKline group of companies 
 
Trademarks not owned by the TESARO- 
GlaxoSmithKline group of companies 
Zejula 
 
None 
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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
Lung Cancer 
Lung cancer is the most common cause of cancer mortality globally and the second most 
common cancer in both men and women. About 14% of all new cancers are lung cancers. In the 
United States (US), there are projected to be 222,500 new cases of lung cancer (116,990 in men 
and 105,510 in women) and 155,870 deaths from lung cancer (84,590 in men and 71,280 in 
women) in 2017.1  
The 2 major forms of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung 
cancer. NSCLC is a heterogeneous disease that consists of adenocarcinoma, large-cell 
carcinoma, and squamous cell carcinoma (sqNSCLC), and comprises approximately 80% to 85% 
of all lung cancers.2 Despite advances in early detection and standard treatment, NSCLC is often 
diagnosed at an advanced stage, has poor prognosis, and is the leading cause of cancer deaths 
worldwide.  
Platinum-based doublet therapy, maintenance chemotherapy, and anti-angiogenic agents in 
combination with chemotherapy have contributed to improved patient outcomes in advanced 
NSCLC.3 The identification of point mutations (epidermal growth factor receptor [EGFR], 
BRAF), gene fusions due to chromosomal translocations (anaplastic lymphoma kinase [ALK], 
ROS-1), and gene amplifications (mesenchymal epithelial transition factor [MET]) as oncogenic 
drivers in a small subset of patients has led to the new era of personalized medicine, taking 
targeted therapy to the frontline setting for these patients.4 
For most NSCLC patients without targetable oncogene drivers, first-line platinum-based 
chemotherapy was until recently the only standard treatment approach.3 However, the recent 
understanding of the interactions between immune system and tumor growth has led to the 
development of a new class of immunotherapies. Approval of pembrolizumab in the US and 
European Union in 2016 and 2017, respectively, as the first-line treatment approach for NSCLC 
patients whose tumors express high programmed death ligand-1 (PD-L1) [Tumor Proportion 
Score, (TPS) ≥50%] led to a change in the lung cancer management paradigm.5-7 Pembrolizumab 
was also approved for patients with PD-L1 TPS ≥ 1% as second-line treatment.7 Other 
immunotherapies such as the programmed cell death-1 (PD-1) inhibitor nivolumab and the 
PD-L1 inhibitor atezolizumab were similarly approved for NSCLC patients following 
platinum-based chemotherapy.8-10  
Squamous cell carcinoma of the lung accounts for 20% to 30% of NSCLC. Despite the 
differences in disease characteristics between squamous and nonsquamous, both have 
historically been treated similarly. However, clinical studies have shown poorer tolerability and 
efficacy of new therapeutic drugs in patients with squamous histology.11,12  
Patients with sqNSCLC rarely have EGFR, BRAF, ALK, or ROS-1 alterations in their tumors, 
and molecular testing is not routine.  
Until the recent approval of pembrolizumab, the standard first-line therapy for sqNSCLC 
consisted of 4 to 6 cycles of platinum-based doublet chemotherapy not containing 
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pemetrexed.11,13,14 In the second-line setting, gemcitabine, docetaxel with or without 
ramucirumab, afatinib as well as the recently approved immunotherapies pembrolizumab, 
nivolumab, and atezolizumab5-10 are considered the standard treatment options for patients.15 
1.1.2. 
Overview of PARP and Homologous Recombination Deficiency 
Normal cells repair up to 10,000 deoxyribonucleic acid (DNA) defects daily; single-strand 
breaks being the most common form of DNA damage. Cells unable to repair their DNA are 
susceptible to the accumulation of mutations that ultimately lead to cancer development.  
Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP)1 and PARP2 are zinc-finger 
DNA-binding-enzymes that play a crucial role in single-strand DNA repair.16 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 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 activating the base excision repair and single-strand break repair pathways.16-18  
Niraparib is a potent, orally active PARP 1/2 inhibitor being developed as an agent for tumors 
with defects in the homologous recombination DNA repair pathway. PARP inhibitors prevent 
single-strand break repair leading to double-stranded breaks (DSB) and γH2AX foci formation. 
DSB repair occurs preferentially through the homologous recombination pathway.17 This 
pathway is disrupted in several conditions, including ataxia telangiectasia mutated (ATM) 
deficiency (10%–15% prevalence in NSCLC), phosphatase and tensin homologue (PTEN) 
deficiency, Fanconi deficiency, and breast cancer gene 1 or 2 (BRCA1/2) deficiency.19,20 BRCA 
deficient cells are highly sensitive to single-agent PARP inhibition.17  
Treatment with PARP inhibitors represents a novel opportunity to selectively kill a subset of 
cancer cells by exploiting their deficiencies in DNA repair. 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 the other DNA 
repair pathways for maintenance of genomic integrity. 
1.1.2.1. 
Nonclinical Experience with PARP Inhibitors in NSCLC 
Homologous recombination deficiencies, which render tumor sensitivity to PARP inhibitors, 
were evaluated across 15 different cancer types in The Cancer Genome Atlas (TCGA), showing 
that squamous cell carcinoma and adenocarcinoma of the lung were among the highest ranking 
cancer types with homologous recombination deficiencies.21 Moreover, deficiency in the Fanconi 
anemia pathway, a major mechanism of homologous recombination DNA repair, was found in 
22% of NSCLC cases studied.22  
TESARO in-house analysis of TCGA data also showed that more than 10% of NSCLC patients 
harbor aberrations in BRCA1/2, ATM, or other genes in homologous recombination repair 
(HRR) while a study of BRCA1 protein levels using immunohistochemistry (IHC) showed that 
11-19% of NSCLC patients are BRCA1 deficient.23  
Synthetic lethality between PARP inhibitor and HRR deficiency was observed in several NSCLC 
in vitro models. One study showed that BRCA1-deficient NSCLC cells, generated by ribonucleic 
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acid (RNA) interference, were more sensitive to PARP-1 inhibition. This study also showed that 
BRCA-deficient, platinum-resistant cells were still sensitive to PARP inhibition.23 Another study 
reported that lung cancer cells deficient in ERCC1, an endonuclease essential for HRR, were 
highly sensitive to PARP inhibitors.24  
In an effort to evaluate the in vivo activity of niraparib in NSCLC models, a large panel of 
patient-derived xenograft models, comprising 35 adenocarcinomas and 28 squamous cell 
carcinomas, was treated with niraparib (50 mg/kg PO once daily [QD] for adenocarcinoma and 
75 mg/kg PO 5-on/2-off for squamous cell carcinoma) or vehicle control (0.5% Methyl 
Cellulose, PO QD). The results showed that more than 50% tumor growth inhibition was 
achieved in 7 adenocarcinoma models (20%) and 7 squamous cell carcinoma models (25%) 
[Study E0322-U1502, Study E0322-U1505 (US), Study E0322-U1505 (China), Study P381B 
and Study 16079-64] (Study references on file).  
1.1.2.2. 
Clinical Experience with PARP inhibitors 
Clinical studies have shown that PARP inhibitors are active in recurrent ovarian cancer.16,25-30 
PARP inhibition appears to be most active in patients with gBRCAmut and in patients who are 
sensitive to platinum-containing therapy. However, clinical benefit has also been observed in 
gBRCA wild type.26-29 Maintenance treatment of high-grade serous ovarian cancer patients with 
recurrent platinum sensitivity showed that the PARP1/2 inhibitor niraparib significantly 
improved progression-free survival (PFS) in gBRCAmut patients (21 months for niraparib vs. 
5.5 months for control). Furthermore, in the gBRCA wild-type population, significantly 
improvement in PFS was observed for both HRD (homologous recombination deficient patients 
identified by myChoice HRD assay developed by Myriad) positive (12.9 months for niraparib 
versus (vs.) 3.8 months for placebo, hazard ratio [HR]=0.38, p=0.0001) and HRD negative 
(HRDneg) patients (9.3 months for niraparib vs. 3.9 months for placebo, HR=0.45, 
p<0.0001).30,31 Niraparib has been recently approved in the US for the treatment of platinum-
sensitive patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.32  
The use of PARP inhibitors in lung cancer may not be limited to alterations in the BRCA genes 
as in tumors carrying intrinsically high genomic instability, targeting PARP might induce a 
saturation of the systems controlling DNA damage, leading to uncontrolled accumulation of 
mutations and subsequent cell death.33 Data from niraparib Phase 1 development program 
showed that clinical benefit was observed in 2 of 2 patients with NSCLC.30 One patient with 
gBRCAmut was treated with 110 mg niraparib QD and had stable disease (SD) for 6 months, 
and another patient was treated with 40 mg niraparib QD and had SD for 11 months. 
Additionally, preliminary data from a randomized Phase 2 study in advanced NSCLC patients 
treated with carboplatin/paclitaxel or the combination of the PARP inhibitor veliparib plus 
chemotherapy demonstrated that addition of veliparib was associated with improvements in 
outcomes: 5.8 months vs. 4.2 months (PFS), 11.7 months vs. 9.1 months overall survival (OS) 
[HR= 0.56; 95% confidence interval (CI)=0.54-1.18; P=0.27]. Improvements in PFS and OS 
were more pronounced in squamous histology: 6.5 months vs. 4.1 months (PFS) [HR=0.54; 
95% CI=0.26-1.12; P=0.098], 10.3 months vs. 8.4 months (OS) [HR= 0.73; 95% CI=0.43-1.24; 
P=0.24].34 The reasons behind the efficacy in squamous histology may be related to the higher 
genomic instability observed in this patient population, which is more vulnerable to agents that 
enhanced DNA damage.34-36 A Phase 3 trial in squamous and nonsquamous NSCLC have 
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completed enrollment. These findings indicate that PARP inhibitors may have a potential role in 
the treatment of NSCLC. 
1.1.3. 
Overview of PD-1 Inhibitors  
The recognition of tumors by the immune system has been appreciated for multiple decades and 
provides an impetus to utilize the immune system to control tumor growth. Studies have reported 
the presence of tumor-infiltrating lymphocytes (TILs) as a positive prognostic feature in multiple 
tumors supporting a role for the immune system in limiting tumor growth. Despite evidence of 
immune reactivity, tumors are able to grow in the presence of an immune system suggesting a 
suboptimal immune response.37-39  
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.40 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 responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin superfamily 
member related to CD28 and CTLA-4, which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands. PD-1 is expressed on activated lymphocytes, 
including peripheral CD4+ and CD8+, T cells, B cells, Tregs, and natural killer cells.41 
Expression has also been shown during thymic development on CD4-/CD8- (double-negative), 
T cells, as well as subsets of macrophages and dendritic cells.42-44  
The ligands for PD-1 (PD-L1 and programmed death-ligand 2 [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 nonhematopoietic 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 The binding of PD-1 ligands 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. While healthy organs express little (if any) PD-L1, a variety of cancers were shown to 
express abundant levels,46,47 which, via its interaction with the receptor 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  
1.1.3.1. 
Clinical Experience with PD-1/PD-L1 Inhibitors in NSCLC 
Lung cancer had been considered a poorly immunogenic malignancy, however, in recent years, 
immune checkpoint inhibitors have emerged as promising therapeutic agents in NSCLC. There 
are currently three PD-1/PD-L1 inhibitors available for the treatment of lung cancer: nivolumab, 
pembrolizumab and atezolizumab.5-10,50 Keynote-024 Study showed that treatment with PD-1 
inhibitor pembrolizumab achieved statistically significant clinical benefits in terms of 
progression free survival, OS and objective responses in advanced NSCLC patients whose 
tumors express high PD-L1 (TPS ≥ 50%), which led to the approval of pembrolizumab as the 
first-line treatment for that patient population. Pembrolizumab was approved as second-line 
treatment in advanced NSCLC PD-L1 positive patients [TPS ≥ 1%] who progressed during or 
after platinum-based therapy. The PD-1 inhibitor nivolumab and the PD-L1 inhibitor 
atezolizumab were also approved as second-line treatment for advanced NSCLC after showing 
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significant improvement in OS compared to docetaxel during or after first-line platinum 
treatment.  
1.1.3.2. 
Clinical Experience with TSR-042 (Dostarlimab)  
As of April 2018, there were 4 ongoing Phase 1 studies with TSR-042: Study 4010-01-001 
(TSR-042 monotherapy), Study 4020-01-001 (TSR-042 combination therapy), Study 
3000-01-002 (TSR-042 combination therapy), and Study 4040-01-001 (TSR-042 combination 
therapy). 
1.1.3.2.1. TSR-042 (Dostarlimab) Monotherapy  
GARNET (Study 4010-01-001) is an ongoing, first-in-human Phase 1 study of TSR-042 
(dostarlimab) that aims to evaluate the safety and tolerability, PK, pharmacodynamics (PDy), 
and clinical activity of TSR-042 (dostarlimab) in patients with recurrent or advanced solid 
tumors. A total of 21 subjects were dosed in the dose escalation phase of the study (Part 1). Dose 
escalation continued to a maximally administered dose of 10 mg/kg every 2 weeks (Q2W) and a 
maximum tolerated dose (MTD) was not identified. No dose-limiting toxicities (DLTs) were 
observed. In Part 2A of the study, the safety and tolerability of TSR-042 (dostarlimab) was 
evaluated at 2 fixed dosing schedules: 500 mg every 3 weeks (Q3W) and 1,000 mg every 
6 weeks (Q6W). For both doses, the mean last measurable concentration (Clast) was 
approximately 40 μg/mL, which is approximately 16-fold higher than the lowest TSR-042 
(dostarlimab) serum concentration at which maximal receptor occupancy has been observed. 
These results led to a proposed TSR-042 (dostarlimab) recommended Phase 2 dose (RP2D) 
regimen of 500 mg Q3W for 4 cycles, followed by 1,000 mg Q6W for all subsequent cycles, 
which is being evaluated in expansion cohorts for microsatellite instability-high (MSI-H) and 
microsatellite stable (MSS) endometrial cancer (EC), non-small cell lung cancer (NSCLC), and 
non-endometrial MSI-H or polymerase ε-mutated cancer in Part 2B of study.  
As of 21 January 2018, 135 subjects with heavily pretreated advanced solid tumors have been 
treated with TSR-042 (dostarlimab) in GARNET. Preliminary data indicate that the majority of 
these subjects (92.6%) reported at least 1 treatment-emergent adverse event (TEAE), with events 
of fatigue, nausea, and decreased appetite being the most frequently reported. Study drug-related 
TEAEs of Grade ≥ 3 were reported in 13 subjects (9.6%). The majority of these events occurred 
in only 1 subject each, with the exception of aspartate aminotransferase increased (3 subjects), 
alanine aminotransferase increased (2 subjects), and fatigue (2 subjects). Serious adverse events 
(SAEs) occurred in 38 subjects (28.1%), for 5 of these subjects the event was considered study 
drug-related. Eight subjects had an adverse event (AE) leading to study drug discontinuation. 
Six subjects had an AE leading to study drug discontinuation which was considered study 
drug-related. Three subjects had an AE leading to death. None of the AEs leading to death were 
considered to be related to the study drug. 
Preliminary efficacy data from 15 subjects with MSI-H EC and 24 subjects with NSCLC who 
had at least 1 tumor assessment were presented at AACR (April 2018). Responses were assessed 
by Investigators using immune-related Response Evaluation Criteria in Solid Tumors 
(irRECIST). Among the 15 subjects with MSI-H EC, the objective response rate (ORR) was 
47% and consisted of all partial responses (PRs), 20% with SD and 33% had disease progression 
(PD). Among the 24 subjects with NSCLC, the ORR was 29% and consisted of all PRs, 42% had 
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SD and 17% had PD. Although preliminary, efficacy data from subjects with NSCLC treated 
with TSR-042 (dostarlimab) appears to be comparable to the reported efficacy of other PD-(L)1 
inhibitors in the advanced and recurrent population, including nivolumab (ORR 19-20%),8,51 
pembrolizumab (ORR 19%)50 and atezolizumab (ORR 14%).52  
1.1.3.2.2. Investigational Therapeutic Combinations with TSR-042 (Dostarlimab) 
In addition to the GARNET TSR-042 (dostarlimab) monotherapy, three additional studies 
involving TSR-042 (dostarlimab) and other therapeutic agents are being conducted.  
Study 4020-01-001 is an open-label, first-in-human Phase 1 study of another mAb, TSR-022 - 
anti-TIM3, that is being conducted in 2 parts in patients with advanced solid tumors. In Part 1C 
of this study, TSR-042 (dostarlimab) will be administered in combination with TSR-022. 
Study 3000-01-002 is an open-label, Phase 1b study of TSR-042 (dostarlimab) that is being 
conducted in 4 parts in patients with advanced or metastatic cancer. The study will evaluate 
DLTs, safety, and tolerability of TSR-042 (dostarlimab) in combination with niraparib with or 
without bevacizumab or carboplatin and paclitaxel with or without bevacizumab.  
Study 4040-01-001 is an open-label, first-in-human Phase 1 study of another mAb, TSR-033 - 
anti-LAG3, that is being conducted in 2 parts in patients with advanced solid tumors. In Part 1C, 
TSR-042 (dostarlimab) will be administered in combination with TSR-033 to establish the RP2D 
regimen for this study drug combination. In Part 2 of the study, the efficacy of TSR-033 plus 
TSR-022 with or without TSR-042 (dostarlimab) will be evaluated in patients with advanced 
solid tumors. 
As of 21 January 2018, a total of 51 subjects with heavily pretreated advanced solid tumors have 
received TSR-042 (dostarlimab) in combination with other therapeutic agents. The majority 
(80.4%) of subjects receiving TSR-042 (dostarlimab) combination therapy reported at least 
1 TEAE, with events of fatigue and dyspnoea being the most frequently reported. One DLT 
(Grade 3 aspartate aminotransferase increased) was reported in a subject in Part B of 
Study 3000-01-002. Serious AEs occurred in 14 subjects, none of these events were considered 
study drug-related. One subject had at least 1 AE leading to study drug discontinuation (alanine 
aminotransferase increased and aspartate aminotransferase increased). Both events were 
considered study drug-related. No subject had an AE leading to death. 
Given the encouraging clinical activity in patients with diverse tumor types and the manageable 
safety profile of TSR-042 (dostarlimab), the benefit-risk profile for TSR-042 (dostarlimab) as a 
treatment for patients with advanced cancers appears positive.  
1.1.4. 
Combination of PARP Inhibitors and PD-1 Inhibitors 
1.1.4.1. 
Nonclinical Experience Combining PARP inhibitors and PD-1 Inhibitors 
Multiple lines of evidence suggest that the combination of PARP inhibitors with anti-PD-1 
agents may provide additional benefits. PARP inhibitors have been shown to elevate PD-L1 
expression, in a cell-autonomous fashion, and to enhance the antitumor activity of an anti-PD-1 
antibody in preclinical syngeneic breast cancer models.53 Additionally, there is reason to believe 
that PARP inhibition could potentially synergize with anti-PD-1/anti-PD-L1 therapy by 
enhancing local immune surveillance in the tumor microenvironment via induction of DNA 
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damage. The intracellular accumulation of self DNA fragments resulting from inefficient DNA 
repair and/or genomic instability has been linked to activation of innate immunity pathway. 
Multiple molecular mechanisms have been elucidated by which both tumor and immune cells 
could be leveraged to sense the accumulated cytosolic DNA fragments and subsequently enable 
innate immune responses via production of type I interferons.54-58 Elevated type I interferon level 
within tumor immune microenvironment promotes immune surveillance by engaging and 
enhancing immune cell functions to exert antitumor activities.59 The resulting immune-
stimulating tumor microenvironment will adaptively induce PD-L1 expression to counteract 
antitumor immune responses which can be blocked by targeting PD-1/PD-L1 signaling. By 
suppressing the enzymatic activity of PARP1/2, PARP inhibitor impairs the base excision repair 
process, resulting in accumulation of DNA damages within the cells, which in turn may promote 
immune surveillance through elevation of interferon-α production. 
The efficacy and tolerability of the combination of niraparib and anti-PD-1 inhibitor was 
evaluated in several preclinical models. The combination was well-tolerated in all of these 
studies. Given the lack of syngeneic model in homologous recombination deficient NSCLCs, the 
combination was first tested in a homologous recombination deficient ovarian cancer model 
derived from BRCA-null genetic background, where PARP inhibition has been shown to 
increase immune cell infiltration.60,61 In this study, niraparib (50 mg/kg PO QD) and an 
anti-PD-1 antibody (5 mg/kg intravenously [IV] biweekly [BIW]) were administered either alone 
or in combination. The combination was well tolerated, with no treatment-related death. Almost 
all the tumors achieved complete regression upon niraparib, anti-PD-1 antibody, and the 
combination treatment in the study. Complete regression was first observed on treatment day 16, 
in 2 of 6, 1 of 6 and 4 of 6 mice from niraparib, anti-PD-1, or the combination group, 
respectively, suggesting that the therapeutic approach of combining niraparib with an anti-PD-1 
agent may provide additional benefit for patients with homologous recombination deficient 
tumors (CrownBio BRKRAS, Study reference on file). 
The combination of niraparib and PD-1 inhibitor was also evaluated in several syngeneic models 
representing BRCA1/2-wild type tumors, one of which was the breast cancer model LPA1-T22. 
In this study niraparib and an anti-PD-1 antibody were administered either alone or in 
combination for 15 days. While the tumors were slightly responsive to niraparib or anti-PD-1 
antibody alone, with average tumor growth inhibition around 50% for niraparib and 30% for 
PD-1 antibody, synergistic antitumor activity with near complete tumor growth inhibition 
(> 95%) was achieved with the combination (G. Mills report, Study reference on file). In a 
similar study using the lung squamous syngeneic model KLN205, stronger tumor growth 
inhibition was observed for the combination (52.3%) than for niraparib alone (36.7%) or 
anti-PD-1antibody alone (30.5%) (Pharmaron KLN205, Study reference on file). Together, these 
data support the therapeutic approach of combining niraparib with an anti-PD-1 agent in either 
BRCA1/2-mutant or wild type tumors. 
1.1.4.2. 
Clinical Experience Combining Niraparib and Pembrolizumab 
TOPACIO (Study 3000-PN162-01-001) is an open-label, single-arm Phase 1/2 study evaluating 
the safety and efficacy of the combination of niraparib and pembrolizumab in patients with 
advanced triple-negative breast cancer or ovarian cancer. TOPACIO was initiated in April 2016 
and is currently ongoing. In the Phase 1 portion of the study, 14 patients were enrolled in Dose 
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Level 1 (200 mg) or Dose Level 2 (300 mg). Based on Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1, 4 of 8 patients with ovarian cancer responded, 3 of whom were gBRCA 
wild type; 4 patients with ovarian cancer had SD (range 3-6 cycles), and 1 patient with breast 
cancer had SD for 10 cycles. Dose limiting toxicity was myelosuppression (neutropenia, anemia 
and predominantly thrombocytopenia) consistent with the known adverse events (AEs) 
associated with single agent niraparib (Section 1.2.1). The recommended Phase 2 dose was 
determined as niraparib 200 mg PO daily and pembrolizumab 200 mg IV on day 1 of each 
21-day cycle. This dose was implemented in the ongoing Phase 2 portion of the study.  
As of January 2018, 60 of 62 patients in the recurrent ovarian cancer cohort were evaluable for 
response assessment with ≥ 1 on-study scan; the ORR was 25%, and the disease control rate 
(DCR) was 68%. Among the 11 tumor BRCA mutation evaluable patients, the ORR and DCR 
were 45% and 73%, respectively. The most common Grade ≥ 3 TEAEs were anemia (19%) and 
thrombocytopenia (9%). In the metastatic triple-negative breast cancer cohort, 45 patients were 
evaluable with ≥ 1 on-study scan; the ORR was 29%, and the DCR was 49%, including 
3 (7%) patients with complete response (CR), 10 (22%) patients with PR, 9 (20%) patients with 
SD, and 23 (51%) patients with progressive disease (PD). Ten of 13 responders have ongoing 
responses. Results from the 12 patients with BRCA mutations included 1 CR, 7 PRs, 1 SD, and 
3 PDs. Median PFS in the BRCA mutation group is 8.1 months. ORR in any BRCA status was 
33% in PD-L1-postive patients (combined proportion score ≥ 1%) versus 15% in PD-L1-negative 
patients. Treatment-related Grade ≥ 3 AEs occurred in 27 patients (50%), most common were 
thrombocytopenia (13%) and anemia (11%). No new safety signals were identified with this 
combination in either of the 2 cohorts. 
1.1.4.3. 
Clinical Experience Combining Niraparib and TSR-042 (Dostarlimab) 
Study 3000-01-002 is a Phase 1b dose-finding study of niraparib, niraparib/bevacizumab, 
carboplatin/paclitaxel, or carboplatin-paclitaxel/bevacizumab in combination with TSR-042 
(dostarlimab) in patients with advanced or metastatic cancer. The study was initiated on 12 
October 2017 and is the first to assess TSR-042 (dostarlimab) and niraparib combination 
treatment. In Part A of this study, the objectives are to evaluate the DLTs of TSR-042 
(dostarlimab) and niraparib combination treatment during the first cycle of treatment, to establish 
an RP2D of niraparib in combination with TSR-042 (dostarlimab), and to evaluate the safety and 
tolerability of TSR-042 (dostarlimab) and niraparib combination treatment. An initial cohort of 
12 patients was enrolled at niraparib dose level 1 (200 mg), which has been determined to be 
safe. Niraparib dose level 2 (300 mg) is currently open for enrollment of an additional cohort of 
6 to 12 patients. Study 3000-01-002 is currently ongoing, and no results have been made 
available yet. 
1.2. 
Study Treatments  
1.2.1. 
Niraparib 
Niraparib is an orally available, potent, and highly selective PARP 1/2 inhibitor. The crystalline 
tosylate monohydrate salt of niraparib is being developed as a monotherapy agent for tumors 
with defects in the homologous recombination DNA repair pathway, as a sensitizing agent in 
combination with cytotoxic agents and radiotherapy, and in combination with immune-oncology 
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biologics. Zejula™ (niraparib) has been recently approved for the maintenance treatment of adult 
patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in 
a complete or PR to platinum-based chemotherapy. For more details, refer to Zejula United 
States Prescribing Information (USPI).32  
Nonclinical data, including cell-derived and patient-derived xenograph studies demonstrating 
response to niraparib in both BRCA mutated and BRCA wild-type tumors, are discussed in detail 
in Section 1.1.2.1 and in the Investigator Brochure (IB). 
There are 3 ongoing Phase 3 niraparib studies: Study PR-30-5010-C (BRAVO), 
Study PR-30-5017-C (PRIMA), and Study PR-30-5011-C (NOVA). There is also 1 ongoing 
Phase 1/2 study (Study 3000-PN162-01-001 [TOPACIO]) and 1 ongoing Phase 2 study (Study 
PR-30-5020-C [QUADRA]). 
NOVA is a double-blind, placebo-controlled study in patients with platinum-sensitive ovarian 
cancer who have received at least 2 platinum-based regimens.31 A total of 553 patients were 
categorized according to the presence or absence of a gBRCAmut (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 QD. The primary end point was PFS. The 
study enrolled 203 patients in the gBRCAmut cohort and 350 patients in the non-BRCAmut 
cohort. Among the 350 patients in the non-gBRCAmut cohort, 162 had tumors that were defined 
as HRD-positive (HRDpos) and 134 had tumors that were HRDneg. HRD status was not 
determined for 54 patients.  
Demographic and baseline characteristics were well balanced. Table 3 shows the results for the 
PFS primary endpoint for each of the 3 primary efficacy populations (ie, gBRCAmut cohort, 
HRDpos cohort, and overall non-gBRCAmut cohort). In addition, median PFS in patients with 
HRDneg tumors was 6.9 months (95% CI: 5.6, 9.6) in the niraparib arm, vs. 3.8 months 
(95% CI: 3.7, 5.6) in the placebo arm, with an HR of 0.58 (95% CI: 0.361, 0.922) (p=0.0226). 
Table 3: 
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) 
21.0 
(12.9, NR) 
5.5 
(3.8, 7.2) 
9.3 
(7.2, 11.2) 
3.9 
(3.7, 5.5) 
12.9 
(8.1, 15.9) 
3.8 
(3.5, 5.7) 
p-value 
<0.0001 
<0.0001 
<0.0001 
Hazard ratio 
(Nir:Plac) 
(95% CI) 
0.27 
(0.173, 0.410) 
0.45 
(0.338, 0.607) 
0.38 
(0.243, 0.586) 
Abbreviations: CI = confidence interval; gBRCAmut = germline breast cancer gene mutation; HRD = homologous 
recombination deficiency; HRDpos = homologous recombination deficiency-positive; Nir = niraparib; NR = not 
reported; PFS = progression-free survival; Plac = placebo 
PFS is defined as the time in months from the date of first dose to progression or death 
Source: Zejula USPI.32 
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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 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 vs. 
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 nonhematologic 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 nonhematological 
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 anticancer 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. Approximately 36% patients were kept on 300 mg and approximately 
64% patients had dose adjustment after 3 cycles in NOVA. However, in the Phase 1 portion of 
the TOPACIO study (combination of niraparib and pembrolizumab), no patients were able to 
tolerate the 300 mg dose of niraparib. 
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are potential adverse 
class effects associated with PARP inhibitors.62 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; 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 7.1.14 and Section 8.2.7. 
Study PR-30-5011-C1 (NOVA corrected QT interval [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). 
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1.2.2. 
Pembrolizumab 
Pembrolizumab is a potent humanized IgG4 monoclonal antibody (mAb) with high specificity of 
binding to PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2 ligands. Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity 
for PD-1.  
Pembrolizumab (KEYTRUDA) is in clinical development as an IV immunotherapy for 
numerous advanced malignancies. In NSCLC, pembrolizumab demonstrated a statistically 
significant improvement in PFS when compared to chemotherapy and has been approved as 
first-line treatment for metastatic NSCLC patients with no EGFR or ALK genomic tumor 
aberrations and whose tumors express high PD-L1 (TPS ≥ 50%).6 Pembrolizumab is also 
indicated for patients with metastatic NSCLC with no EGFR or ALK genomic tumor aberrations, 
whose tumors express PD-L1 (TPS ≥ 1%) with disease progression on or after 
platinum-containing chemotherapy.5,7 
The safety of pembrolizumab was determined in patients with advanced NSCLC who had 
documented disease progression following treatment with platinum-based chemotherapy. A total 
of 991 patients received pembrolizumab 2 mg/kg (n=339) or 10 mg/kg (n=343) every 3 weeks or 
docetaxel (n=309) at 75 mg/m2 every 3 weeks. Adverse reactions leading to interruption of 
pembrolizumab occurred in 23% of patients; and the profile was similar for the 2 mg/kg and 
10 mg/kg dose. The most common AEs were (≥1%) were diarrhea (1%), fatigue (1.3%), 
pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis 
(1%). Other clinically important adverse reactions were fatigue (25%), diarrhea (14%), asthenia 
(11%), and pyrexia (11%). For more details refer to KEYTRUDA USPI.  
1.2.3. 
TSR-042 (Dostarlimab) 
TSR-042 (dostarlimab) is an IgG4 humanized mAb that binds with high affinity to PD-1, 
resulting in inhibition of binding to PD-L1 and PD-L2. This antibody was generated based on a 
proprietary platform that utilizes affinity maturation to select highly specific antibodies with 
desired functional characteristics. The functional antagonist activity of TSR-042 (dostarlimab) 
was confirmed in a mixed lymphocyte reaction assay, demonstrating enhanced interleukin-2 (IL 
2) production upon addition of TSR-042 (dostarlimab).  
TSR-042 (dostarlimab) has shown an acceptable clinical and nonclinical safety profile. No 
signals have been identified in the clinical and nonclinical studies. A 1-month toxicity and TK 
study in cynomolgus monkeys showed no TSR-042 (dostarlimab)-related effects on any 
parameters evaluated, including neurological examinations, electrocardiography, blood pressure, 
and respiration. 
As of 21 January 2018, a total of 186 patients have received at least 1 dose of TSR-042 
(dostarlimab). Additional safety data are presented in the current TSR-042 (dostarlimab) IB. 
1.3. 
Rationale for Current Study 
Given that preclinical data suggest a 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 a PD-1 
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inhibitor in a treatment-naïve NSCLC population with PD-L1 tumor expression (Cohorts 1, 1A, 
2, and 2A).  
Although substantial advances have been made in the management of nonsquamous NSCLC, an 
unmet need exists for effective treatment of sqNSCLC. Niraparib is being explored in this study 
as a potential treatment option for patients with sqNSCLC who previously achieved clinical 
benefit from platinum chemotherapy (Cohort 3). 
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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1. 
Primary Objectives 
The primary objectives of this study are: 
• To evaluate the efficacy of the combination of niraparib and a PD-1 inhibitor in 
chemotherapy-naïve and PD-1 inhibitor-naïve patients with locally advanced and 
metastatic NSCLC whose tumors have high PD-L1 expression (TPS ≥ 50%), as 
assessed by ORR  
• To evaluate the efficacy of the combination of niraparib and a PD-1 inhibitor in 
chemotherapy-naïve and PD-1inhibitor-naïve patients with locally advanced and 
metastatic NSCLC whose tumors express PD-L1 (TPS between 1 and 49%) as 
assessed by ORR  
• To evaluate the efficacy of single agent niraparib in patients with metastatic 
sqNSCLC who have been previously treated with both platinum-based chemotherapy 
and either PD-1 or PD-L1 inhibitor, as assessed by ORR  
2.2. 
Secondary Objectives 
The secondary objectives of the study are as follows: 
• To evaluate the safety and tolerability of single agent niraparib and of the 
combination of niraparib and a PD-1 inhibitor  
• To evaluate the following additional measures of clinical benefit of single agent 
niraparib and of the combination of niraparib and a PD-1 inhibitor:  
− Duration of response (DOR)  
− DCR  
− PFS  
• To evaluate the pharmacokinetics (PK) of niraparib following administration of single 
agent niraparib or the combination of niraparib and a PD-1 inhibitor 
2.3. 
Exploratory Objectives 
• To explore blood and tumor-based biomarkers that predict sensitivity or resistance to 
single agent niraparib and to the combination of niraparib and a PD-1 inhibitor 
 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
3.1.1. 
Overview 
This is a multicenter, open-label, multi-arm Phase 2 study to evaluate the efficacy and safety of 
single agent niraparib in patients with locally advanced and metastatic sqNSCLC and of the 
combination of niraparib and a PD-1 inhibitor in locally advanced and metastatic NSCLC (all 
histologies) patients. 
The multi-arm design will evaluate separate cohorts of different cancer patients with enough 
statistical power to determine whether further examination may be warranted in the individual 
indications. A 2-stage design will be used for all cohorts. In Stage 1, Cohorts 1 and 2 will receive 
niraparib plus the PD-1 inhibitor pembrolizumab, and Cohort 3 will receive niraparib alone. In 
Stage 2, Cohorts 1A and 2A will receive niraparib plus the PD-1 inhibitor TSR-042 
(dostarlimab). (As of Amendment 2, following a cross-program review and decision to move 
forward with other studies, the Sponsor decided that Cohort 3 would close to further enrollment. 
As of Amendment 3, Cohort 1 and Cohort 2 had completed enrollment, Cohort 1A had closed 
after partial enrollment and Cohort 2A was not opened for enrollment. In Amendment 3, OS was 
removed as a secondary endpoint, following completion of the primary endpoint and Sponsor 
review of portfolio prioritization.) Enrollment in Stage 2 must not begin until the clinical study 
site has received the necessary approval of this amendment from the ethics committee of record 
for that site. Enrollment in Stage 2 will not be allowed under previous versions of the protocol. 
Figure 1 presents an overview of the study design. The schedule of events for the study is 
provided in Table 13 and Table 14. 
Figure 1: 
Study Design 
Stage 1: 
 
Stage 2: 
 
*Completion of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as 
long as therapy was completed at least 6 months prior to the diagnosis of metastatic disease 
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Abbreviations: NSCLC = non-small cell lung cancer; PD-1 = programmed cell death-1; PD-L1 = programmed death 
ligand-1; TPS = tumor progression score. 
 
 
Cohorts 1 and 1A: Locally advanced and metastatic NSCLC patients (all histologies) with no 
prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment, whose tumors have high PD-L1 
expression (TPS ≥ 50 %), and no known EGFR sensitizing mutation and/or ROS-1 or ALK 
translocations will receive combination of niraparib and a PD-1 inhibitor (pembrolizumab or 
TSR-042 (dostarlimab)). Completion of treatment with chemotherapy and/or radiation as part of 
neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months 
prior to the diagnosis of metastatic disease. 
Cohorts 2 and 2A: Locally advanced and metastatic NSCLC patients (all histologies) with no 
prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment, whose tumors have PD-L1 
expression (TPS between 1 % and 49 %), and no known EGFR sensitizing mutation and/or 
ROS-1 or ALK translocation, will receive combination of niraparib and a PD-1 inhibitor 
(pembrolizumab or TSR-042 (dostarlimab)). Completion of treatment with chemotherapy and/or 
radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed 
at least 6 months prior to the diagnosis of metastatic disease. 
Cohort 3: Locally advanced and metastatic sqNSCLC patients who have been previously treated 
with both platinum and either PD-1 or PD-L1 inhibitor will receive single agent niraparib. 
Data from Stage 1 will be used to determine whether further enrollment of Stage 2 patients is 
necessary. The criteria for continuing Stage 2 enrollment are provided in Statistical Analysis 
Section 9. 
3.1.2. 
General Study Conduct 
This study will consist of a Screening Period (Day -21 to Day -1), a Treatment Period, an End of 
Treatment (EOT) Period occurring within 7 days of the decision to discontinue treatment for any 
reason, a Safety Follow-up Visit occurring 30 + 7 days after the last dose of study medication, 
and a Follow-up Assessment Period occurring every 90 ± 14 days, which will continue until 
death or the end of study data collection (a minimum of 6 months after the enrollment of the last 
patient, provided that this allows the opportunity for completion of all 90-day follow-up 
assessments).  
Following informed consent, all patients 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, smoking, and medication history; complete physical 
examination, including vital signs, height, and weight; Eastern Cooperative Oncology Group 
(ECOG) performance status; clinical laboratory assessments (complete blood count [CBC], 
serum chemistry, and urinalysis); pregnancy test for women of childbearing potential (a urine 
pregnancy test may be performed if the serum pregnancy result is not available before dosing); 
and electrocardiogram (ECG). 
Patients must have a baseline tumor assessment by computed tomography (CT, preferred 
method) or magnetic resonance imaging (MRI, if clinically indicated) of the chest, abdomen, and 
other sites as clinically indicated, to determine extent of disease and confirm presence of 
measurable disease. If the patient has had appropriate imaging scans (eg, routine clinical 
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management) performed within 28 days prior to Cycle 1/Day 1, then the results of those scans 
may be used if they are of diagnostic quality. Subsequent postbaseline tumor assessments will be 
done in locations with tumor lesions identified at baseline only, unless clinically indicated. 
Response will be assessed as per RECIST v1.1 by the Investigator.  
In Stage 1, patients will begin treatment with niraparib and pembrolizumab (Cohorts 1 and 2) or 
niraparib monotherapy (Cohort 3) on Cycle 1/Day 1. In Stage 2, patients will begin treatment 
with niraparib and TSR-042 (dostarlimab) (Cohorts 1A and 2A) on Cycle 1/Day 1. Patients 
enrolled during Stage 1 will continue with their original study treatment until discontinuation 
from treatment. Clinic visits will occur in each cycle (every 3 weeks ± 3 days). 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, ECOG performance status, clinical 
laboratory assessments (CBC, serum chemistry, and urinalysis) (Table 13 and Table 14). 
For follow-up tumor assessments, CT/MRI scans will be performed every 9 weeks ± 7 days from 
the date of first dose until Week 72, and every 12 weeks ± 7 days thereafter for Cohorts 1, 1A, 2, 
and 2A. For sqNSCLC patients in Cohort 3, follow- up tumor assessment CT/MRI scans will be 
performed every 6 weeks ± 7 days from the date of first dose until Week 24, then every 
9 weeks ± 7 days until Week 52 (12 months), and every 12 weeks ± 7 days until progression. 
The same modality (CT or MRI) should be used throughout the study for a given patient.  
Per RECIST v1.1, CR or PR should be confirmed; tumor imaging for confirmation of response 
must be performed at the earliest 28 days after the first indication of response but no later than 
35 days after the response. The subsequent scan after the confirmatory scan should be obtained 
per original schedule (9 weeks ± 7 days from confirmatory scan for Cohorts 1, 1A, 2 and 2A, and 
6 weeks ± 7 days from confirmatory scan for Cohort 3). 
For Cohorts 1, 1A, 2, and 2A (a PD-1 inhibitor and niraparib), patients with radiologic evidence 
of PD who are clinically stable may continue treatment at the Investigator’s discretion while 
awaiting confirmatory tumor imaging. Repeat imaging should be performed at ≥ 4 weeks. If 
repeat imaging shows SD, PR, or CR, patients can continue study treatment at the Investigator’s 
discretion. In the event that PD is confirmed, patients still may continue to receive study 
treatment even after confirmed radiologic progression if the patient is clinically stable 
(Section 7.3.1.2) and the Investigator deems that the patient is deriving clinical benefit. This 
allowance to continue treatment despite radiologic progression takes into account the observation 
that some patients may have a transient tumor flare in the first few months after the start of 
immunotherapy but with subsequent disease response. Before making a decision to continue 
treatment after radiological progression, the Investigator will discuss with the patient that this is 
not considered standard in the treatment of cancer and will discuss alternative treatment options 
including available approved therapies and other clinical trials. The Investigator will document 
this discussion in the source documents. 
For Cohort 3 (single agent niraparib), patients with radiologic evidence of PD should be 
discontinued from treatment. 
Tumor assessment should occur according to study schedule regardless of whether study 
treatment is interrupted.  
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If a patient discontinues treatment for a reason other than progression, death, withdrawal of 
consent, or lost to follow-up, scans should continue at the specified intervals (ie, every 9 weeks 
for the first 72 weeks and every 12 weeks thereafter for Cohorts 1, 1A, 2, and 2A; every 6 weeks 
for the first 24 weeks, every 9 weeks until Week 52 [12 months], and then every 12 weeks until 
progression for Cohort 3) until radiological progression is confirmed or until the start of 
subsequent anticancer treatment. 
Each patient will have an EOT assessment within 7 days of the decision to discontinue treatment 
for any reason, a Safety Follow-up Visit occurring 30 + 7 days after the last dose of study drug, 
and a Follow-up Assessment every 90 ± 14 days, which will continue until death or the end of 
study data collection (a minimum of 6 months after the enrollment of the last patient, provided 
that this allows the opportunity for completion of all 90-day follow-up assessments). 
Blood samples will be collected prior to, during, and after treatment to evaluate PK of niraparib 
when given alone and in combination with a PD-1 inhibitor in accordance with Section 7.4 and 
Section 8.1. Plasma samples will be collected from patients receiving single agent niraparib 
(Cohort 3), and serum and plasma will be collected from patients treated with the combination of 
niraparib and pembrolizumab (Cohorts 1 and 2) or niraparib and TSR-042 (dostarlimab) 
(Cohorts 1A and 2A).  
Blood samples for the analysis of tumor-related circulating biomarkers such as circulating tumor 
cells (CTC) will be collected at Cycle 1/Day 1 predose. Blood samples for the analysis of 
circulating tumor DNA (ctDNA) will be obtained at Screening, Cycle 2/Day 1 predose, as well 
as EOT. 
PD-L1 status must be available for patients in Cohorts 1, 1A, 2, and 2A. Local assessment of 
PD-L1 is acceptable on either archival or fresh tissue (see Laboratory Manual for details on 
sample collection and management). PD-L1 status will be confirmed retrospectively in a central 
IHC laboratory using a Food and Drug Administration (FDA)-approved in vitro companion 
diagnostic indicated as an aid in identifying NSCLC patients for treatment with a PD-1 inhibitor. 
An archival formalin fixed paraffin embedded (FFPE) tumor tissue is required for exploratory 
biomarker analysis and will be obtained during screening to confirm histology morphology, 
presence of tumor, and to conduct biomarker analysis. If archival tumor tissue is not available, a 
fresh biopsy is needed. Archival FFPE sample should be submitted within 30 days of patient’s 
first dose. (For Cohort 3 only: if diagnosis was made by cytology and archival tissue is not 
available, patient will not need to provide tumor tissue). 
All patients will undergo an EOT assessment within 7 days of the decision to discontinue 
treatment for any reason and a Safety Follow-up Visit occurring 30 + 7 days post-treatment. 
Thereafter, all patients will enter the post-Treatment Period for telephone assessment of survival 
status every 90 ± 14 days.  
Treatment with niraparib will continue until disease progression. Treatment with a PD-1 
inhibitor (pembrolizumab or TSR-042 (dostarlimab)) will continue for a maximum of 24 months 
in patients without disease progression or unacceptable toxicity. 
All AEs will be collected and recorded for each patient from the day of signing the informed 
consent form (ICF) until 30 days after last study drug administration (Section 7.1.4); SAEs are 
required to be captured at least through 90 days after cessation of study treatment (or to a 
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minimum of 30 days post-treatment if the patient starts alternate anticancer therapy), and any 
pregnancies are to be captured through 180 days post-treatment (Section 7.1.6). Adverse events 
of special interest (AESIs), as well as study-drug-related SAEs, will be collected until study 
closeout or as otherwise indicated in Section 7.1.7 . AESIs must be reported as soon as the 
Investigator becomes aware of them. 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 stabilized and 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. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1. 
Subject Inclusion Criteria 
4.1.1. 
General Inclusion Criteria 
To be considered eligible to participate in this study, all of the following requirements must be 
met: 
1. At least 18 years of age 
2. Histological or cytological proven advanced (unresectable) or metastatic NSCLC as 
defined as stage IIIB (positive supraclavicular lymph nodes) not amenable to definitive 
chemoradiotherapy or stage IV NSCLC  
3. Measurable disease by RECIST v1.1 
4. ECOG performance status of 0 to 1  
5. Adequate organ function, defined as follows: 
Note: CBC test should be obtained without transfusion or receipt of colony-stimulating 
factors within 4 weeks prior to the first dose of study treatment. 
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 creatinine clearance 
≥50 mL/min (as calculated using the Cockcroft Gault equation or measured using 
24-hour urine creatinine clearance) for patients with creatinine levels 
> 1.5 × institutional ULN (Appendix A) 
e. Total bilirubin ≤1.5 × ULN except in patients with Gilbert’s syndrome. Patients with 
Gilbert’s syndrome may enroll if direct bilirubin ≤1.5 × ULN of the direct bilirubin. 
f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN 
unless liver metastases are present, in which case they must be ≤5 × ULN 
6. Patient must have recovered to Grade 1 toxicity from prior cancer therapy (a patient with 
Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may qualify 
for this study). 
7. Patient agrees to submit FFPE tumor tissue specimen, which may have been collected at 
any time prior to Screening. If no archival FFPE tumor tissue is available, patient agrees 
to undergo a tumor tissue biopsy before Cycle 1/Day 1. (For Cohort 3 only: if diagnosis 
was made by cytology and archival tissue is not available, patient will not need to provide 
tumor tissue).  
8. Patient is able to take oral medications 
9. Female patient meets the following criteria: 
a. Female patient (of childbearing potential) is not breastfeeding, has a negative serum 
pregnancy test within 72 hours prior to taking study drug, and agrees to abstain from 
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activities that could result in pregnancy from enrollment through 180 days after the 
last dose of study treatment or is of nonchildbearing potential; or  
Note: A urine pregnancy test may be performed if the serum pregnancy result is not 
available before dosing. 
b. Female patient is of nonchildbearing potential, other than medical reasons, defined as 
follows: 
i. 
≥45 years of age and has not had menses for >1 year 
ii. 
Amenorrheic for < 2 years without a hysterectomy and oophorectomy 
and a follicle-stimulating hormone (FSH) value in the postmenopausal 
range upon screening evaluation 
iii. 
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 highly 
effective contraception methods throughout the study, starting with the 
screening visit through 180 days after the last dose of study therapy. 
Please see Section 6.7.3 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 method for the patient. 
10. Male patient agrees to use an adequate method of contraception and not donate sperm 
starting with the first dose of study therapy through 120 days after the last dose of study 
therapy (please see Section 6.7.3 for a list of acceptable birth control methods). Note: 
Abstinence is acceptable if this is the established and preferred contraception method for 
the patient. 
11. Patient is able to understand the study procedures and agree to participate in the study by 
providing written informed consent 
4.1.2. 
Cohort-Specific Inclusion Criteria 
1. Cohorts 1 and 1A (combination of niraparib and a PD-1 inhibitor): patients must have 
tumors with high PD-L1 expression (TPS ≥ 50%) per local assessment; with no known 
EGFR sensitizing mutation and/or ROS-1 or ALK translocations, and no prior systemic 
chemotherapy or PD-1/PD-L1 inhibitor treatment for metastatic NSCLC 
2. Cohorts 2 and 2A (combination of niraparib and a PD-1 inhibitor): patients must have 
tumors with PD-L1 expression (TPS between 1% and 49%) per local assessment, with no 
known EGFR-sensitizing mutation and/or ROS-1 or ALK translocation, and no prior 
systemic chemotherapy or PD-1/PD-L1 inhibitor treatment for metastatic NSCLC 
3. Cohort 3 (single agent niraparib): patients must have metastatic sqNSCLC and have 
progressed after both prior platinum-based chemotherapy and prior PD-1 or PD-L1 
inhibitor treatment 
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4.2. 
Subject Exclusion Criteria 
4.2.1. 
Exclusion Criteria for Cohorts 1, 1A, 2, and 2A 
Patients will not be eligible for study entry if any of the following criteria are met: 
1. Has received systemic therapy for the treatment of advanced stage NSCLC. Completion 
of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy 
is allowed as long as therapy was completed at least 6 months prior to the diagnosis of 
metastatic disease 
2. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent 
3. Known hypersensitivity to the components of niraparib, pembrolizumab, TSR-042 
(dostarlimab), or their excipients  
4. Known EGFR (exon 19 and 21) mutations, ALK translocations, and/or ROS-1 
translocations  
5. Patient has a history or current 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.  
6. Known diagnosis of immunodeficiency or receiving systemic steroid therapy (except as 
allowed in exclusion criterion #9 below) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of study treatment 
7. Patient is immunocompromised, in the opinion of the Investigator (Note: patients with 
splenectomy are allowed)  
8. Current participation in a treatment study or past participation in a study of an 
investigational agent within 4 weeks before the first dose of study treatment 
9. Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered 
“controlled,” central nervous system [CNS] disease must have undergone treatment [eg, 
radiation or chemotherapy] at least 1 month prior to study entry. The patient must not 
have any new or progressive signs or symptoms related to the CNS disease and must be 
taking < 10 mg of prednisone or equivalent per day or no steroids.) Patients who have 
untreated brain metastases and who are not symptomatic may enroll if the Investigator 
feels that treatment of these metastases is not indicated. A scan to confirm the absence of 
brain metastases is not required. Patients with spinal cord compression may be 
considered if they have received definitive treatment for this and evidence of clinically 
SD for 28 days  
10. Active autoimmune disease that 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) is not considered a form of systemic 
treatment 
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11. Major surgery within 3 weeks of starting the study or patient has not recovered from any 
effects of any major surgery 
12. Other active concomitant malignancy that warrants systemic therapy  
13. Poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic 
disease, or active, uncontrolled infection. Examples include, but are not limited to, 
uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena 
cava syndrome, uncontrolled hypertension, active uncontrolled coagulopathy, or any 
psychiatric disorder that prohibits obtaining informed consent 
14. Known history of interstitial lung disease, drug-related pneumonitis, or radiation 
pneumonitis requiring steroid treatment 
15. Patient is pregnant, breastfeeding, or expecting to conceive children while receiving 
study treatment and for 180 days (for pregnancy or conception) or 30 days (for 
breastfeeding) after the last dose of study treatment  
16. Male patient is expecting to donate sperm or father children while receiving study drug or 
for 120 days after the last dose of study treatment 
17. Known active hepatic disease (known hepatic cirrhosis, hepatitis B surface 
antigen-positive status, or suspected active hepatitis C infection) 
18. Prior treatment with a known PARP inhibitor 
19. Patient received a live vaccine within 30 days of planned start of study therapy 
20. Known history of MDS or AML 
4.2.2. 
Exclusion Criteria for Cohort 3 
Patients will not be eligible for study entry if any of the following criteria are met: 
1. Platinum-treated patient who progressed while on or within less than 8 weeks from the 
last day of platinum administration 
2. Known hypersensitivity to the components of niraparib or excipients 
3. Patient has a history or current 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.  
4. Known diagnosis of immunodeficiency or receiving systemic steroid therapy (except as 
allowed in exclusion criterion #6 below) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of study treatment  
5. Current participation in a treatment study or past participation in a study of an 
investigational agent within 4 weeks before the first dose of study treatment 
6. Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered 
“controlled,” CNS disease must have undergone treatment [eg, radiation or 
chemotherapy] at least 1 month prior to study entry. The patient must not have any new 
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or progressive signs or symptoms related to the CNS disease and must be taking < 10 mg 
of prednisone or equivalent per day or no steroids.) Patients who have untreated brain 
metastases and who are not symptomatic may enroll if the Investigator feels that 
treatment of these metastases is not indicated. A scan to confirm the absence of brain 
metastases is not required. Patients with spinal cord compression may be considered if 
they have received definitive treatment for this and evidence of clinically SD for 28 days  
7. Major surgery within 3 weeks of starting the study or patient has not recovered from any 
effects of any major surgery  
8. Other active concomitant malignancy that warrants systemic therapy 
9. Poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic 
disease, or active, uncontrolled infection. Examples include, but are not limited to, 
uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, 
uncontrolled major seizure disorder, unstable spinal cord compression, superior vena 
cava syndrome, uncontrolled hypertension, active uncontrolled coagulopathy, or any 
psychiatric disorder that prohibits obtaining informed consent 
10. Known history of interstitial lung disease, drug-related pneumonitis, or radiation 
pneumonitis requiring steroid treatment 
11. Patient is pregnant, breastfeeding, or expecting to conceive children, while receiving 
study treatment and for 180 days (for pregnancy or conception) or 30 days (for 
breastfeeding) the last dose of study treatment  
12. Male patient is expecting to donate sperm or father children while receiving study drug or 
for 120 days after the last dose of study treatment 
13. Patient is immunocompromised, in the opinion of the Investigator (Note: patients with 
splenectomy are allowed)  
14. Known active hepatic disease (known hepatic cirrhosis, hepatitis B surface 
antigen-positive status, or suspected active hepatitis C infection) 
15. Prior treatment with a known PARP inhibitor 
16. Known history of MDS or AML 
4.3. 
Subject Withdrawal Criteria 
4.3.1. 
Discontinuation from Treatment 
Patients may be discontinued from study treatment at any time. Specific reasons for 
discontinuing all study treatments include the following: 
• Unacceptable toxicity that cannot be managed by dose modification 
• Disease progression per RECIST v1.1 (see Section 7.3.1) 
• It is in the best interest of the patient as judged by the Investigator and/or Sponsor 
• Severe noncompliance with the protocol as judged by the Investigator and/or Sponsor  
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• Withdrawal of consent 
Note: All reasonable efforts should be made to encourage patients to remain on study 
even if they withdraw from treatment. 
• Patient becomes pregnant 
• Sponsor decision to terminate study 
• Death 
• Confirmed CR in a patient who was treated for at least 24 weeks with study treatment 
and had at least 2 cycles of treatment beyond the date when the initial CR was 
declared 
Details of required niraparib dose modifications, including interruptions, dose reductions, and 
permanent discontinuations, related to toxicity, are provided in Section 6.3.1. 
Details of required pembrolizumab dose interruptions and permanent discontinuation related to 
toxicity are provided in Section 6.3.2. 
Details of required TSR-042 (dostarlimab) dose modifications, including interruptions, dose 
reductions, and permanent discontinuations, related to toxicity, are provided in Section 6.3.3. 
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. 
Patients who discontinue from all study treatments will continue to receive follow-up 
assessments (Table 13 and Table 14) as part of the study unless they are discontinued from the 
study (Section 4.3.2). 
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 
• Death from any cause 
• Loss to follow-up 
• Sponsor decision to terminate study 
Patients who withdraw from study drug will be asked to continue the study visits and 
assessments as outlined in the schedule of procedures (Section 8, Table 13 and Table 14). If a 
patient is lost to follow-up, attempts should be made to contact the patient to determine the 
reason for discontinuation. For patients who are lost to follow-up, at least 3 documented 
attempts, including one via certified mail, should be made to contact the patient before 
considering the patient lost to follow-up. 
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4.3.3. 
Replacement of Patients 
If a patient discontinues study treatment due to withdrawal of consent prior to the first 
assessment of disease (either scheduled radiological assessment at 9 [Cohorts 1, 1A, 2, and 2A] 
or 6 weeks [Cohort 3] post-treatment initiation), the patient may be replaced for the purposes of 
efficacy analysis after consultation between the Sponsor and Investigator. The analysis 
population will include all patients who received any study medication and did not withdraw 
consent prior to having at least 1 postbaseline tumor assessment. 
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. 
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5. 
TREATMENT OF SUBJECTS 
5.1. 
Description of Study Drug 
Table 4: 
Investigational Product 
 
Investigational Product 
Product Name: 
Niraparib 
Pembrolizumab 
TSR-042 (dostarlimab) 
Dosage Form: 
100 mg capsule 
infusion 
infusion 
Unit Dose 
2 capsules of 100 mg each 
(200 mg/day) 
Administered once daily 
21-day cycle 
200 mg infusion 
Administered over 
30 minutes 
Day 1 of each 21-day 
cycle 
500 mg or 1,000 mg 
infusion 
Administered over 
30 minutes 
500 mg: Day 1 of each 
21-day cycle (Q3W) for 
the first 4 cycles 
1,000 mg: Day 1 of every 
other 21-day cycle 
(Q6W) for the rest of 
treatment, beginning on 
Cycle 5 
Route of Administration 
PO 
IV 
IV 
Physical Description 
capsule 
powder or solution 
solution for intravenous 
infusion in single-use vial 
Abbreviations: IV = intravenous; PO = oral; Q3W = every 3 weeks; Q6W = every 6 weeks 
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6. 
STUDY DRUG MATERIALS AND MANAGEMENT 
6.1. 
Study Drug 
6.1.1. 
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. 
6.1.2. 
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 for injection may be supplied as 50-mg lyophilized powder single-use vials or 
100 mg/4 mL (25 mg/mL) solution in a single-dose vial.  
6.1.3. 
TSR-042 (Dostarlimab) 
TSR-042 (dostarlimab) is a humanized mAb of the IgG4/kappa isotype that binds with high 
affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. TSR-042 (dostarlimab) 
for IV infusion is supplied as a solution of 160 mg (20 mg/mL) or 500 mg (50 mg/mL) in a 
single-dose vial. 
6.2. 
Administration 
6.2.1. 
Niraparib 
Niraparib will be supplied as 100-mg capsules and will be administered PO QD continuously 
starting on Cycle 1/Day 1. The starting dose of 2 capsules of 100-mg strength (200 mg/day) will 
be taken at each dose administration. Patients will be instructed to take their niraparib dose in the 
morning at approximately the same time each day, except for days when PK sampling will be 
performed. On these days, patients will be instructed to hold their niraparib dose until the 
pre-dose PK sample has been taken. Niraparib may be taken with or without food or water. 
Patients must swallow and not chew the capsules.  
For those patients experiencing nausea and who are at Cycle 5 and beyond, bedtime 
administration may be a potential method for managing nausea. For those patients experiencing 
nausea who are not yet at Cycle 5, please seek approval from Medical Monitor to permit bedtime 
administration. 
On days where a PD-1 inhibitor is administered (Cohorts 1, 1A, 2, and 2A), niraparib will be 
administered upon completion of PD-1 inhibitor infusion on Day 1 of each cycle. 
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 administration of niraparib. 
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6.2.2. 
Pembrolizumab 
Pembrolizumab infusion will be administered before niraparib dose 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 13 and Table 14. Pembrolizumab may be administered up to 3 days before or 
after the scheduled Day 1 of each cycle after Cycle 1 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. 
Refer to USPI for specific instructions for the preparation of the pembrolizumab infusion and 
administration of the infusion solution. 
6.2.3. 
TSR-042 (Dostarlimab) 
TSR-042 (dostarlimab) infusion will be administered before the niraparib dose at the study site 
on Day 1 of each 21-day treatment cycle (Q3W) in Cycles 1 through 4 and on Day 1 of every 
other cycle (Q6W) thereafter, beginning on Cycle 5 Day 1 (ie, Cycle 5, Cycle 7, Cycle 9, etc.). 
TSR-042 (dostarlimab) will be administered after all procedures and assessments have been 
completed, unless otherwise indicated. TSR-042 (dostarlimab) may be administered up to 3 days 
before or after the scheduled Day 1 of each cycle after Cycle 1 due to administrative reasons. 
TSR-042 (dostarlimab) will be administered at a dose of 500 mg IV Q3W in Cycles 1 through 4 
and at a dose of 1,000 mg IV Q6W, starting in Cycle 5, for the rest of the treatment using a 30-
minute 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 + 15 minutes is permitted. 
The Pharmacy Manual contains information for specific instructions for the preparation of the 
TSR-042 (dostarlimab) infusion and administration of the infusion solution. 
6.3. 
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 
vacation, 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 eCRF.  
6.3.1. 
Niraparib 
Dose interruption of niraparib may be implemented at any time per the Investigator’s judgment. 
See the following sections for permitted duration of interruption prior to required discontinuation 
from treatment. 
Niraparib dose reduction will be allowed based on treatment side effects. Dose reductions to 
1 capsule daily (100 mg) will be allowed (Table 5). No further dose reductions will be allowed. 
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The timing of efficacy or safety evaluations should not be affected by dose interruptions or 
reductions.  
6.3.1.1. 
Niraparib Dose Modifications for Nonhematologic Toxicity 
Treatment with niraparib must be interrupted for any treatment-related nonhematologic Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 3 or 4 event unless it is deemed by the 
Investigator to be pembrolizumab-related Table 7), in which case treatment with niraparib may 
continue without interruption. If toxicity is appropriately resolved to Grade 1 or less within 
28 days of interruption, the patient may restart treatment with niraparib with a dose level 
reduction according to Table 5 unless prophylaxis is considered feasible. If the event recurs at a 
similar or worse grade, treatment should be interrupted.  
If the toxicity requiring dose interruption has not resolved to CTCAE Grade 1 or less during a 
maximum 4-week (28-day) dose interruption period, or the patient has already undergone a dose 
reduction (to a minimum dose of 100 mg QD), or both, the patient must permanently discontinue 
treatment with niraparib. Once the dose of niraparib has been reduced, any re-escalation must be 
discussed with the Sponsor. Note that treatment with pembrolizumab may continue if 
discontinuation criteria as outlined in Section 6.3.2 have not been met. 
Table 5: 
Niraparib Dose Reductions for Nonhematologic Toxicity 
Event 
Dose 
Nonhematalogic NCI CTCAE Grade ≥3 TEAE or SAE where 
treatment or prophylaxis is not considered feasible or TEAE 
persists despite treatment or prophylaxis. 
Withhold niraparib for a maximum 
of 28 days or until resolution of 
TEAE. 
Resume niraparib at 100 mg QD 
NCI CTCAE Grade ≥3 TEAE or SAE ≥ lasting more than 28 
days while the patient is administered niraparib 100 mg QD 
Discontinue niraparib 
NCI CTCAE Grade ≥2 Posterior Reversible Encephalopathy 
Syndrome (PRES) (see Section 7.1.9) 
Discontinue niraparib 
Abbreviations:, NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; QD = 
once daily; PRES=Posterior Reversible Encephalopathy Syndrome; SAE = serious adverse event; TEAE = treatment 
emergent adverse event 
6.3.1.2. 
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 6. 
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Table 6: 
Management of Hematologic Toxicities 
Laboratory Abnormality 
Intervention 
Weekly CBC is to be obtained for the first 4 weeks from the start of niraparib treatment, followed by 
assessment at least every 4 weeks for the first year. If niraparib requires a dosing hold or dose 
reduction, weekly CBC is to be performed for the 4 weeks following restart of niraparib. If patients 
have not recovered within 28 days or have persistent cytopenia following dose modification, further 
investigations including bone marrow analysis and blood sample for cytogenetics must be done in 
addition to monthly monitoring, and consideration given as to whether to discontinue niraparib 
treatment. 
Platelet count < 100,000/μL   
Niraparib must be interrupted until platelet count is 
≥ 100,000/μL with twice-weekly CBC monitored until recovery. 
After recovery, niraparib may then be resumed at same or 
reduced dose (Table 5); with monitoring of blood counts once 
weekly for 4 weeks. 
If nadir platelet count was <75,000/µL, resume niraparib at a 
reduced dose after recovery. 
Second occurrence of platelet 
count < 100,000/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 
(Table 5); after recovery, blood counts are monitored once 
weekly for 4 weeks to ensure the safety of the new dose level. 
(Dose not to be decreased below 100 mg daily). Discontinue 
niraparib if the platelet count has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the 
patient has already undergone dose reduction to 100 mg once 
daily. 
Platelet count < 25,000/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 
(Table 5); after recovery, blood counts are monitored once 
weekly for 4 weeks to ensure the safety of the new dose level. 
Discontinue niraparib if the platelet count has not returned to 
acceptable levels within 28 days of the dose interruption period, 
or if the patient has already undergone dose reduction to 100 mg 
once daily. 
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 dose (Table 5); after 
recovery, blood counts once weekly for 4 weeks to ensure the 
safety of the new dose level. (Dose not to be decreased below 
100 mg daily) 
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 dose (Table 5); after recovery, 
blood counts once weekly for 4 weeks to ensure the safety of the 
new dose level 
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Laboratory Abnormality 
Intervention 
Hematologic adverse reaction 
requiring transfusion  
For patients with platelet count ≤ 10,000/μL, prophylactic 
platelet transfusion per guidelines should be considered. 60,61 If 
there are other risk factors such as coadministration of 
anticoagulation or antiplatelet drugs, consider interrupting these 
drugs and/or prophylactic transfusion at a higher platelet count. 
RBC transfusion is at the discretion of the Investigator 
Resume niraparib at a reduced dose (dose not to be decreased 
below 100 mg daily). 
Confirmed diagnosis of 
MDS/AML 
Permanently discontinue niraparib. 
Abbreviations: AML=acute myeloid leukemia; CBC = complete blood count; MDS=myelodysplastic syndrome; 
RBC=red blood cell. Note: If blood counts do not recover within 28 days to normal values (ie, platelets 
≥ 100,000/μL, hemoglobin ≥ 9g/dL, neutrophils ≥ 1,500/μL) niraparib should be discontinued. 
If clinically indicated, use of granulocyte colony-stimulating factor (G-CSF) is allowed 
according to current American Society of Clinical Oncology (ASCO) guidelines.63 If clinically 
indicated, red blood cell transfusions are allowed according to institutional guidelines. 
If the hematologic toxicity does not recover to the specified level within 4 weeks (28 days) of 
dose interruption and/or the patient has already undergone 1 dose reduction (to a minimum dose 
of 100 mg QD), then niraparib should be discontinued.  
Any patient requiring transfusion of platelets or red blood cells (1 or more units) or 
hematopoietic growth factor support may undergo a niraparib dose reduction upon recovery if 
study treatment is resumed. 
Once the dose of study treatment has been reduced, any re-escalation must be discussed with the 
Sponsor’s Medical Monitor or designee. 
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’s 
Medical Monitor or designee if discontinuation criteria as outlined in Section 6.3.2 have not been 
met. 
The reason for interruption, reduction, or discontinuation of niraparib should be recorded in the 
eCRF. 
6.3.1.3. 
Niraparib Dose Escalation 
Niraparib dose may be escalated on or after Cycle 3/Day 1 from 200 mg daily (2 capsules) to 
300 mg daily (3 capsules) if platelets ≥100,000/μL, hemoglobin ≥9 g/dL, and neutrophils 
≥1,500/μL for all laboratory tests performed during the first 2 cycles after discussion with 
Medical Monitor or designee. 
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6.3.1.4. 
Niraparib Extended Treatment 
Those patients deemed to derive clinical benefit from niraparib monotherapy treatment at the 
time of final analysis and who are no longer receiving their study-assigned PD-1 inhibitor will 
have the option to continue treatment with niraparib through the extension “rollover” protocol, if 
available, and at the discretion of the Investigator and Sponsor . 
Eligibility to receive continued niraparib treatment through the extension “rollover” protocol will 
be at the discretion of the Investigator and Sponsor and will follow review of the enrolling 
study’s inclusion criteria and completion of the required screening assessments. Continued 
treatment in the study will be based on documented evidence of clinical benefit determined by 
local standard of care disease assessment frequency.  
6.3.2. 
Pembrolizumab 
AEs (both nonserious 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 7. See also Section 7.1.7.  
Table 7 provides detailed information for dose interruptions and discontinuations related to 
toxicity for pembrolizumab. No dose reductions of pembrolizumab are permitted. Note that 
treatment with niraparib may continue following discussion with the Sponsor’s Medical Monitor 
or designee if discontinuation criteria as outlined in Section 6.3.1 have not been met. 
The reason for interruption or discontinuation of pembrolizumab should be recorded in the 
eCRF. 
 
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Table 7: 
Pembrolizumab Dose Modifications for Nonhematologic 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. Patients with Grade 3 
hyperthyroidism may restart if they are treated with 
thyroid suppression therapy, and the hyperthyroidism 
resolves to Grade 2 or less. 
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 
2b 
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 7: 
Pembrolizumab Dose Modifications for Nonhematologic 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 
toxicityc 
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/h to 
50 mL/h). Otherwise dosing will be held until symptoms resolve, and the subject should be premedicated for the next scheduled dose; refer to Section 6.7.4 
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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6.3.3. 
TSR-042 (Dostarlimab) 
AEs (both nonserious and serious) associated with TSR-042 (dostarlimab) exposure may 
represent an immunologic etiology. These AEs may occur shortly after the first dose or several 
months after the last dose of treatment. 
In general, TSR-042 (dostarlimab) must be withheld for drug-related Grade 3 toxicities, as well 
as for certain immune related adverse events of interest (irAEIs), but may be resumed upon 
recovery to Grade ≤1; TSR-042 (dostarlimab) will be permanently discontinued for any drug-
related Grade 4 AE. TSR-042 (dostarlimab) must be permanently discontinued for certain irAEIs 
as described in Table 8. This guideline does not include a complete list of all irAEs associated 
with immune checkpoint inhibitor therapy. The recent joint ASCO and NCCN guideline for 
diagnosis and management of immune related adverse events treated with immune checkpoint 
inhibitor therapy may be used as a supplement to Table 8 and may be applied in association with 
local guidelines.64 
The specific immune-related AEs typically observed with anti-PD-1 antibodies will be managed 
according to the guidelines summarized below. 
The reason for interruption or discontinuation of TSR-042 (dostarlimab) should be recorded in 
the eCRF. 
Table 8: 
Guidelines for Treatment of Immune-related Adverse Events of Interest 
Toxicity 
Withhold Treatment for 
AE Grade 
Restarting Treatment/Discontinuation 
Diarrhea/colitis 
2 or 3 
Withhold dose. Restart dosing when toxicity resolves to 
Grade 0 or 1. 
4 
Permanently discontinue. 
AST, ALT, or increased 
bilirubin 
2  
(AST or ALT >3 and ≤5× 
ULN or total bilirubin 
>1.5 and ≤3× ULN) 
Withhold dose Restart dosing when toxicity resolves to 
Grade 0 or 1. 
 
3 or 4  
(AST or ALT >5× ULN 
or total bilirubin 
>3× ULN) 
Withhold dose. Permanently discontinue (see exception 
below).a 
T1DM or hyperglycemia 
3 or 4 hyperglycemia or 
T1DM (associated with 
metabolic acidosis or 
ketonuria) 
Withhold dose. Restart dosing in appropriately 
managed, clinically and metabolically stable patients; 
insulin replacement therapy is required. 
Immune-related 
encephalitis 
Any grade 
Permanently discontinue. 
Uveitis 
Symptomatic any grade 
Withhold dose. Restart the treatment when toxicity 
resolves to normal. For any recurrent uveitis or uveitis 
resistant to topical steroids, permanently discontinue 
treatment. 
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Toxicity 
Withhold Treatment for 
AE Grade 
Restarting Treatment/Discontinuation 
Myositis 
2 or 3 
Withhold dose. Restart the treatment when toxicity 
resolves to Grade 1 or normal. 
Hypophysitis 
2 to 4 
For Grade 2 to 3 AEs, withhold until hormonal therapy 
results in return to adequate levels by laboratory values 
and restart dosing when toxicity resolves to 
Grade 0 to 1. For recurrence or worsening of Grade ≥2 
hypophysitis after corticosteroid taper has been 
completed and patient is on adequate hormone 
replacement therapy, permanently discontinue. For 
Grade 4 AEs, permanently discontinue. 
Adrenal insufficiency 
2 or 3 
Withhold dose. Hold until hormonal therapy results in 
return to adequate levels by laboratory values and 
restart dosing when toxicity resolves to Grade 0 or 1. 
For recurrent or worsening ≥Grade 2 adrenal 
insufficiency while adequate hormonal replacement is 
continuing, permanently discontinue study drug. 
4 
Permanently discontinue. 
Hypo- and 
hyperthyroidism 
3 
Withhold dose until hormonal therapy results in return 
to adequate levels by laboratory values and restart 
dosing when toxicity resolves to Grade 0 or 1. 
4 
Permanently discontinue. 
Infusion-related reaction 
2b 
Withhold dose. Restart dosing when toxicity resolves to 
Grade 0 or 1. 
3 or 4 
Permanently discontinue. 
Pneumonitis 
2 
Withhold dose. Restart dosing when toxicity resolves to 
Grade 0 or 1. If Grade 2 recurs, permanently 
discontinue. 
3 or 4 
Permanently discontinue. 
Immune-related rash 
3 
Withhold dose. Restart dosing when toxicity resolves to 
Grade 0 or 1. 
4 
Permanently discontinue. 
Renal failure or nephritis 
2 
Withhold dose. Restart dosing when toxicity resolves to 
Grade 0 or 1. 
3 or 4 
Permanently discontinue. 
Recurrence of AEs after 
resolution to Grade ≤1 
3 or 4 
Permanently discontinue. 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
T1DM = type 1 diabetes mellitus; PO = orally; ULN = upper limit of normal. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
≥50% relative to baseline and lasts for at least 1 week, then study treatment should be discontinued. 
b Upon resolution within 1 hour of stopping drug infusion, the infusion may be restarted at 50% of the original 
infusion rate (eg, from 100 to 50 mL/h). Otherwise, study treatment will be withheld until symptoms resolve, and 
the patient should be premedicated for the next scheduled dose with diphenhydramine 50 mg PO (or equivalent 
dose of antihistamine) and acetaminophen 500 to 1,000 mg PO (or equivalent dose of antipyretic) for the next 
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scheduled dose. Patients who develop Grade 2 toxicity despite adequate premedication should be permanently 
discontinued from further study treatment administration. 
In addition to the irAEs listed in Table 8, treatment with dostarlimab may be associated with 
other irAEs, including events that may be less commonly associated with PD-1 or PD-L1 
inhibitors but can similarly result from activation of cellular immune response (eg, pancreatitis). 
For these events, the general guidance from ASCO/NCCN should be considered. Patients should 
receive appropriate supportive care measures as deemed necessary by the treating Investigator, 
including but not limited to the items outlined below: 
• In general, treatment can continue with close monitoring for Grade 1 toxicities. 
• Withhold treatment for most Grade 2 toxicities and consider resuming when 
symptoms and/or laboratory values revert to Grade 1 or less. Corticosteroids (initial 
dose 0.5 to 1 mg/kg/day of prednisone or equivalent) must be administered. 
• Withhold treatment for Grade 3 toxicities and initiate high-dose corticosteroids 
(prednisone 1 to 2 mg/kg/day or methylprednisolone IV 1 to 2 mg/kg/day). 
Corticosteroids should be tapered over the course of at least 4 to 6 weeks. If 
symptoms do not improve within 48 to 72 hours of high-dose corticosteroids, 
infliximab may be offered for some toxicities. It is highly recommended that 
Investigators discuss any AEs with the Sponsor prior to using infliximab. 
• When symptoms and/or laboratory values revert to Grade 1 or less, rechallenging 
with immunotherapy may be offered, however caution is advised, especially in 
patients with early-onset immune-mediated events. Dose adjustments are not 
recommended. 
6.4. 
Study Drug Packaging, Labeling, and Storage 
Niraparib 100-mg capsules may be packed in high-density polyethylene bottles with child-
resistant closures or in blister cards.  
Pembrolizumab is obtained from commercial sources according to local practice standards, and it 
is provided as a commercially available dosage formulation. Pembrolizumab is an approved 
treatment for Cohort 1; it is expected that pembrolizumab will be supplied as standard of care for 
this cohort. Please refer to pembrolizumab USPI for instructions and precautions regarding 
preparation. 
TSR-042 (dostarlimab) for injection is supplied in vials containing either 160 mg at a 
concentration of 20 mg/mL or 500 mg at a concentration of 50 mg/mL. 
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 nonpatient-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. 
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6.5. 
Study Drug Accountability 
The Investigator or designee is responsible for maintaining accurate dispensing records of the 
study treatments throughout the clinical study. Study drug accountability should be maintained 
by each site based on capsules dispensed vs. returned to the clinic at each visit and the number 
days since last visit. 
Details of maintaining drug accountability, including information on the accountability log, will 
be provided in the Pharmacy Manual. 
All dispensation and accountability records will be available for Sponsor review. The Study 
Monitor will assume the responsibility to reconcile the study treatment accountability log. The 
pharmacist will dispense study treatment for each patient according to the protocol and 
Pharmacy Manual, if applicable. 
6.6. 
Study Drug Handling and Disposal 
At the end of study, when all patients have stopped protocol treatment, complete drug 
reconciliation per batch should be available at the site for verification in order to allow drug 
destruction or return procedure. After receiving Sponsor approval in writing, the investigational 
site is responsible for destruction of study drug according to local regulations. If a site does not 
have the capability for on-site destruction, the Sponsor will provide a return for destruction 
service to a third party. Both the unused and expired study medication must be destroyed, upon 
authorization of the Sponsor, according to local regulations and procedures, and a copy of the 
destruction form must be filed in the study binder. 
The drug provided for this study is to be used only as indicated in this protocol and only for the 
patients entered in this study. 
6.7. 
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 weakly induces cytochrome P450 (CYP) 1A2 in vitro and is an insensitive substrate 
for P-glycoprotein; therefore, investigators should be advised to use caution with drugs that are 
sensitive substrates for CYP1A2 with a narrow therapeutic range, ie, theophylline and tizanidine. 
The niraparib safety profile includes risk for thrombocytopenia; therefore, the Investigators 
should be advised to use caution with anticoagulation and antiplatelet drugs (Table 6). 
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6.7.1. 
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 
• Chemotherapy or immunotherapy not specified in this protocol 
• Investigational agents other than niraparib, pembrolizumab, or TSR-042 
(dostarlimab) 
• Cohorts 1, 1A, 2, and 2A only: 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, and typhoid (oral) vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed. 
However, intranasal influenza vaccines (eg, Flu-Mist) are live attenuated vaccines 
and therefore 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.63  
• Systemic glucocorticoids for any purpose other than to manage symptoms of 
suspected irAEIs. (Note: Use of inhaled steroids, local injection of steroids, topical 
steroids, and steroid eye drops are allowed.) If medically deemed necessary (eg, acute 
asthma or chronic obstructive pulmonary disease exacerbation, prophylaxis for IV 
contrast if indicated), Investigators are allowed to use their judgment to treat patients 
with systemic steroids. In such cases, systemic steroids should be stopped at least 
24 hours prior to the next dose of TSR-042 (dostarlimab). 
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. 
6.7.2. 
Radiation Therapy 
Radiation therapy to pre-existing small areas of painful metastases that cannot be managed with 
local or systemic analgesics is allowed as long as no evidence of disease progression is present. 
The patient must have clear measurable disease outside the radiated field.  
6.7.3. 
Contraception 
Pembrolizumab, TSR-042 (dostarlimab), and niraparib are known to have properties that require 
the patient to use contraception. For details on niraparib and TSR-042 (dostarlimab), please refer 
to the respective IBs.  
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The study drugs may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab and niraparib have transient adverse effects on the composition of sperm. 
Therefore, nonpregnant, nonbreastfeeding women may only be enrolled if they are willing to use 
2 highly effective contraception methods or are considered highly unlikely to conceive. Highly 
unlikely to conceive is defined as (1) surgically sterilized; (2) postmenopausal (a woman who is 
≥ 45 years of age and has not had menses for > 1 year will be considered postmenopausal); 
(3) amenorrheic for < 2 years without a hysterectomy and oophorectomy and a follicle 
stimulating hormone (FSH) value in the postmenopausal range upon screening evaluation; or 
(4) not heterosexually active for the duration of the study. Female patients should start using 
birth control from screening throughout the study period up to 180 days after the last dose of 
study treatment (Table 9). See Appendix D for a list of acceptable contraceptive methods.   
Abstinence is acceptable if this is the established and preferred contraception for the patient.  
Male patients must use an adequate method of contraception and not donate sperm starting with 
the first dose of study treatment through 120 days after the last dose of study treatment (Table 9). 
Abstinence is acceptable if this is the established and preferred contraception for the patient. 
Table 9: 
Timing of Contraception and Sperm Donation 
Parameter 
Timeframe 
Contraception use, 
female patients 
Starting with the screening visit through 180 days after the last dose of study 
treatment 
Contraception use, 
male patients 
Starting with the first dose of study treatment through 120 days after the last 
dose of study treatment 
Sperm donation 
Starting with the first dose of study treatment through 120 days after the last 
dose of study treatment 
6.7.4. 
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. 
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− For Grade 3 to 4 events, immediately treat with IV steroids. Administer additional 
anti-inflammatory measures, as needed. 
− 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, and 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) or 
≥ Grade 3 hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis: 
− For Type 1 diabetes mellitus or Grade 3 to 4 hyperglycemia 
• Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3 to 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 to 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 to 4 hypothyroidism): 
− In hyperthyroidism, nonselective 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 to 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 to 4 events, treat with IV 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 to 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.  
• Uveitis: 
− Symptomatic (any grade):  Hold treatment and consult ophthalmologist for 
treatment with corticosteroid eye drops. Restart dosing after resolution of 
symptoms. 
− Recurrent symptomatic uveitis or symptomatic uveitis unresponsive to topical 
corticosteroids:  Permanently discontinue. 
• 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 10 
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shows treatment guidelines for patients who experience an infusion reaction 
associated with administration of pembrolizumab. 
Table 10: 
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 h 
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/h to 50 mL/h). 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 be included 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 
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Abbreviations: IV=intravenous; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National 
Cancer Institute; 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. 
6.7.5. 
Rescue Medications and Supportive Care Guidelines During Treatment with 
TSR-042 (Dostarlimab) 
During treatment with TSR-042 (dostarlimab), patients should receive appropriate supportive 
care measures for AEs as deemed necessary by the treating Investigator, including but not 
limited to the items outlined below. Prophylactic cytokines (eg, 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.65 Note: It may be necessary to perform additional 
procedures such as bronchoscopy, endoscopy, or skin photography as part of the evaluation of 
the AE. The following sections detail specific guidance by type of AE. 
• Pneumonitis 
− Treat with systemic corticosteroids, oral for Grade 2 (eg, 0.5 to 1 mg/kg/day of 
prednisone or equivalent) and IV for Grade 3 or 4 (eg, 1 to 2 mg/kg/day of 
prednisone or equivalent). 
− Administer additional anti-inflammatory measures, as needed. 
− Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
− If Grade 2 and no improvement or worsening over 2 weeks, treat as Grade 3 or 4. 
− Consider prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
• Diarrhea/Colitis 
− Monitor carefully 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 diarrhea/colitis that persists >3 days, administer oral corticosteroids 
(eg, 0.5 to 1.0 mg/kg/day of prednisone or equivalent). If symptoms persist or 
worsen with steroids, treat as Grade 3 or 4. 
− For Grade 3 or 4 diarrhea/colitis that persists >3 days, treat with IV steroids 
(eg, 1 to 2 mg/kg/day of prednisone or equivalent) followed by high-dose oral 
steroids. 
− Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
• Type 1 Diabetes Mellitus or Grade 3 or 4 Hyperglycemia 
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− For type 1 diabetes mellitus and for Grade 3 or 4 hyperglycemia associated with 
metabolic acidosis or ketonuria, insulin replacement therapy is required. 
• Hypophysitis 
− Treat with systemic corticosteroids, oral for Grade 2 (eg, 0.5 to 1 mg/kg/day of 
prednisone or equivalent) and IV for Grade 3 or 4 (eg, 1 to 2 mg/kg/day of 
prednisone or equivalent). 
− Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
− Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
• Hyperthyroidism or Hypothyroidism 
− Thyroid disorders have been reported with other PD-1 inhibitors occurring 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: Consider nonselective beta-blockers 
(eg, propranolol) as initial therapy. 
− Grade 3 or 4 HYPERthyroidism: Treat with an initial dose of IV corticosteroids 
followed by oral corticosteroids (eg, 0.5 to 1 mg/kg/day of prednisone or equivalent). 
Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
− Grade 2 to 4 HYPOthyroidism: Thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care. 
• Hepatitis 
− Treat with systemic corticosteroids, oral for Grade 2 (initial dose of 1 to 
2 mg/kg/day of prednisone or equivalent) and IV for Grade 3 or 4 (1 to 
2 mg/kg/day of prednisone or equivalent).  
− Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
• Renal Failure or Nephritis 
− Treat with systemic corticosteroids, oral for Grade 2 (initial dose of 0.5 to 
1 mg/kg/day of prednisone or equivalent) and IV for Grade 3 or 4 (1 to 
2 mg/kg/day of prednisone or equivalent). 
− Taper corticosteroids when symptoms improve to Grade ≤1 over ≥4 weeks. 
6.7.5.1. 
Management of Infusion-related Reactions  
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Table 11 shows treatment guidelines for 
patients who experience infusion-related reactions associated with administration of TSR-042 
(dostarlimab). 
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Table 11: 
TSR-042 (Dostarlimab) Infusion Reaction Treatment Guidelines 
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, or 
IV fluids); prophylactic 
medications indicated 
for ≤24 hours 
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/h to 50 mL/h). 
Otherwise, dosing will be withheld 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 hours 
(± 30 min) prior to infusion of TSR-042 
(dostarlimab) with the following:  
• 
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine) 
• 
Acetaminophen 500 to 
1000 mg PO (or 
equivalent dose of 
antipyretic) 
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CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
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 the 
following:  
• 
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: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; 
NSAID = nonsteroidal anti-inflammatory drug; PO = orally. 
Note: Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of study treatment administration. 
6.7.6. 
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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7. 
ENDPOINTS AND METHODS OF ASSESSMENT 
7.1. 
Safety Endpoints 
Safety parameters evaluated during this study will include AEs, discontinuations due to AEs, 
clinical laboratory values (CBC, serum chemistry, thyroid function [Cohorts 1, 1A, 2, and 2A 
only], and urinalysis), vital signs, ECGs, physical examination findings, and use of concomitant 
medications. 
All safety parameters will be performed in accordance with the schedules of events presented in 
each cohort-specific supplement. 
7.1.1. 
Definitions 
7.1.1.1. 
Adverse event (AE) 
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. 
AEs may include the onset of new illness and the exacerbation of pre-existing medical 
conditions. An AE can include an undesirable medical condition occurring at any time, including 
baseline or washout periods, even if no study treatment has been administered. 
Disease progression will not be recorded as an AE. 
7.1.1.2. 
Serious adverse event (SAE) 
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: Preplanned hospitalization (eg, for observation, protocol compliance, 
elective procedures, social reasons) will not be considered an SAE; however, the 
reason for the planned hospitalization should be captured in medical history 
section in the eCRF. Complications experienced during these hospitalizations 
must be reported as AEs.  
• Results in persistent or significant disability or incapacity 
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• Is a congenital anomaly or birth defect 
• Is an important medical event(s) 
− Medical and scientific judgment should be exercised in determining whether 
situations or events should be considered SAEs. An important medical event may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or require intervention to prevent one of the above 
outcomes. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not 
result in hospitalization, or development of drug dependency or drug abuse. See 
Section 7.1.6.1 for information about SAE reporting. 
7.1.1.3. 
Treatment-emergent adverse event  
A TEAE is any event that was not present prior to the initiation of study treatment or any event 
already present that worsens in either intensity or frequency following exposure to study 
treatment.  
7.1.2. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction is a serious adverse reaction, the nature and 
severity of which are not consistent with the information about the medicinal product set out in 
the Investigator’s Brochure, Reference Safety Information section. 
7.1.2.1. 
Adverse event of special interest  
Any AE (serious or non-serious) that is of scientific and medical concern specific to the study 
treatment, for which ongoing monitoring and rapid communication by the Investigator to the 
Sponsor is appropriate. The AESIs for niraparib are MDS, AML, and second primary cancers 
(new malignancies other than MDS/AML).  
To date, no AESIs have been identified for TSR-042 (dostarlimab). 
7.1.2.2. 
Special Situations: Abuse, Misuse, Medication Errors, Overdose, and Accidental 
or Occupational Exposure:  
• Abuse: is the persistent or sporadic, intentional excessive use of the study treatment, 
which is accompanied by harmful physical or psychological effects. 
• Misuse: medicinal product is intentionally and inappropriately used not in accordance 
with the authorized/approved product information. 
• Medication error: is any preventable incident that may cause or lead to inappropriate 
study treatment use or patient harm while the study treatment is in the control of the 
health care professionals or patients. Such incident may be due to health care 
professional practice, product labeling, packaging and preparation, procedures for 
administration, and systems, including the following: prescribing, order 
communication, nomenclature, compounding, dispensing, distribution, 
administration, education, monitoring, and use. 
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• Overdose: is a deliberate or accidental administration of study treatment to a study 
patient at a dose greater than that which was assigned to that patient per the study 
protocol and under the direction of the Investigator.  
• Accidental/Occupational exposure: is the unintentional exposure to a study 
treatment as a result of one’s professional or nonprofessional occupation, or 
accidental exposure to a nonprofessional to whom exposure was not intended (ie, 
study product given to wrong patient). 
See Section 7.1.12.1 for information about special situations reporting. 
7.1.3. 
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. 
7.1.3.1. 
Expectedness 
Expectedness (whether an AE is “expected” or “unexpected”) will be determined by the Sponsor. 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information provided in the Reference Safety Information for niraparib 
and TSR-042 (dostarlimab) in the respective IBs and for pembrolizumab in the USPI. 
7.1.3.2. 
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; easily tolerated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADLs). (Instrumental ADL 
refer to preparing meals, shopping for groceries or clothes, using the telephone, or 
managing money.) 
• 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 7.1.1. 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. 
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7.1.3.3. 
Causality 
The Investigator will assess the causality/relationship between the study drug and the AE. One of 
the following categories should be selected based on medical judgment, considering the 
definitions and all contributing factors: 
• Definitely related: A clinical event, including laboratory test abnormality, that occurs 
in a plausible time relationship to treatment administration and that concurrent 
disease or other drugs or chemicals cannot explain. The response to withdrawal of the 
treatment should be clinically plausible. 
• Possibly related: A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the treatment, unlikely to be attributed 
to concurrent disease or other drugs or chemicals. 
• Unlikely related: A clinical event, including laboratory test abnormality, with a 
temporal relationship to treatment administration that 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). 
7.1.4. 
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, SAEs, and drug-related SAEs will be collected and recorded in the eCRF for each 
patient from the day of signed informed consent until the time points outlined in Table 12. 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 the event has stabilized and 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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Table 12: 
Collecting and Reporting Adverse Events, Pregnancy, and Survival 
Parameter 
Timepoint 
AEs 
Through 30 days after cessation of study treatment 
SAEs 
Through 90 days after cessation of study treatment (or to a minimum of 
30 days post-treatment if the patient starts alternate anticancer therapy) 
Pregnancy 
180 days following the last dose of study treatment (applies to female patients 
and female partners of male patients) 
Drug-related SAEs 
Until study closeout 
AESIs 
Until study closeout 
Survival 
Until study closeout 
Abbreviations: AE = adverse event; SAE = serious adverse event; AESI = adverse event of special interest. 
Note: Collection and reporting will begin on the day of informed consent. 
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. 
AEs may be volunteered spontaneously by the study patient, or discovered by the study staff 
during physical examinations or by asking an open, nonleading 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. 
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. 
7.1.5. 
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 7.1.4 and Section 7.1.6. 
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7.1.6. 
Serious Adverse Events 
7.1.6.1. 
Reporting Serious Adverse Events 
The Investigator must report all SAEs and all follow-up information to the Sponsor on an SAE 
Report Form within 24 hours of becoming aware of the initial event or follow-up information. 
The Investigator must provide a causality assessment and must sign and date all SAE Report 
Forms. 
It is the responsibility of the Investigator to review source document and describe pertinent 
information on the SAE Report Form. If supporting documentation is requested (eg, hospital 
reports, consultant reports, death certificates, and autopsy reports), the Investigator should 
highlight all relevant and pertinent information within such documents, ensure that any patient’s 
personal identifiers (including medical record number) are removed, and submit the documents 
with the SAE Report Form to the Sponsor. The Sponsor (or designee) will return a confirmation 
of receipt of all email reports (if received from other than a “no reply” domain) within 1 business 
day.  
After receipt of the initial report, the Sponsor (or designee) will review the information and, if 
necessary, contact the Investigator to obtain further information. The Investigator must promptly 
respond to queries from the Sponsor. 
7.1.6.2. 
Submission and Distribution of Serious Adverse Events 
Per regulatory requirements, if an event is assessed by the Sponsor as a suspected unexpected 
serious adverse reaction (SUSAR), it is the responsibility of the Sponsor to submit the SUSAR to 
regulatory authorities according to applicable regulations. In addition, the SUSAR will be 
distributed to the Investigators/sites, utilizing a Council for International Organizations of 
Medical Sciences report form or the MedWatch 3500A form. The Investigator/site will submit a 
copy of the report to their respective Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) as per the governing institutional requirements and in compliance with local 
laws and guidelines. 
7.1.7. 
Adverse Events of Special Interest 
Selected nonserious AEs and SAEs are also known as AESI and must be recorded as such on the 
eCRF and reported within 24 hours to the Sponsor as soon as the Investigator becomes aware of 
them, as noted for SAEs in Section 7.1.6.1. 
In conjunction with the survival assessment, AESI (regardless of causality) and study-drug 
related SAEs will be collected until study closeout (Table 12, Section 7.1.4 and Section 8.2.6). 
AESIs for niraparib and pembrolizumab, are outlined in Section 7.1.7.1 and Section 7.1.7.2, 
respectively. 
To date, no AESIs have been identified for TSR-042 (dostarlimab). 
7.1.7.1. 
Niraparib 
Patients are to be monitored from the day of informed consent as noted below:  
• MDS and AML (through study closeout) 
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• Secondary primary cancers (new malignancies other than MDS/AML).  
7.1.7.2. 
Pembrolizumab 
Patients are to be monitored from the day of informed consent through study closeout for 
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 Hy’s law and available regulatory guidance documents.66 
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). 
7.1.8. 
Hypertension, Including Hypertensive Crisis 
Hypertension, including hypertensive crisis, has been reported with the use of niraparib. 
Preexisting hypertension should be adequately controlled before starting niraparib treatment. 
While receiving treatment, hypertension should be medically managed with antihypertensive 
medicinal products with or without niraparib dose adjustment.  
BP and heart rate should be monitored at least weekly for the first 2 months of niraparib 
treatment in the maintenance setting, then monthly for the first year and periodically thereafter 
during treatment with niraparib. Niraparib should be discontinued in case of hypertensive crisis 
or if medically significant hypertension cannot be adequately controlled with antihypertensive 
therapy. 
7.1.9. 
Posterior Reversible Encephalopathy Syndrome 
There have been rare reports of niraparib-treated patients developing signs and symptoms that 
are consistent with posterior reversible encephalopathy syndrome (PRES). PRES is a rare 
neurologic disorder that can present with the following signs and symptoms including seizures, 
headache, altered mental status, visual disturbance, or cortical blindness, with or without 
associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, 
preferably MRI. In patients developing PRES, treatment of specific symptoms including control 
of hypertension is recommended, along with discontinuation of niraparib. The safety of 
reinitiating niraparib therapy in patients previously experiencing PRES is not known. 
7.1.10. 
Allergic Reaction 
Niraparib capsules contain tartrazine, which may cause allergic-type reactions. 
7.1.11. 
Lifestyle Considerations  
Cases of photosensitivity have been reported for patients on niraparib treatment. Participants 
must be informed on measures to decrease exposure to ultraviolet light, such as minimizing time 
in direct sunlight unless wearing hats and long-sleeves and application of sun protection creams. 
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7.1.12. 
Protocol-defined Overdose 
A niraparib overdose is defined as a deliberate or accidental administration of study treatment to 
a study patient, at a dose greater than that which was assigned to that patient per the study 
protocol and under the direction of the Investigator.   
An overdose of pembrolizumab is defined, for this study, as a dose ≥ 1,000 mg (5 times the 
dose). 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. 
For fixed doses, an overdose of TSR-042 (dostarlimab) is defined as any dose that is ≥ 20% than 
1000 mg Q6W.  
7.1.12.1. Reporting of Overdoses and Special Situations 
All occurrences of abuse, misuse, medication error, overdose, and accidental or occupational 
exposure with any study treatment must be reported on a Special Situations Report Form to the 
Sponsor within 5 calendar days of becoming aware of the occurrence, regardless of whether it is 
categorized as an AE. If the occurrence is associated with an SAE, an SAE Report Form, along 
with the Special Situations Report Form, must be submitted to the Sponsor within 24 hours of 
awareness.  
7.1.13. 
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 of 
female study patients and partners of male study patient that occur within 180 days following the 
last dose of study treatment must be captured in the eCRF (Table 12). 
The Investigator should complete the Initial Pregnancy Notification report form and forward it to 
the Sponsor (or designee) within 24 hours of knowledge of the pregnancy. If there is an 
associated serious outcome, then both the Initial Pregnancy Notification report form and SAE 
Report Form should be completed. 
The site will follow-up with the patient at least monthly and document the patient’s status until 
the pregnancy has been completed or terminated. The Investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the fetus or 
newborn to the Sponsor. The Pregnancy Outcome report form should be completed and 
submitted to the Sponsor within 24 hours after the Investigator becomes aware of the pregnancy 
outcome. If an SAE occurred, then the SAE Report Form must be completed and submitted as 
well. 
In the event the pregnancy outcome occurs following the end of the study and database lock, the 
Investigator will report the pregnancy outcome to the Sponsor (or designee) within 24 hours after 
the outcome of the pregnancy is known to the Investigator in accordance with the procedure for 
reporting SAEs (Section 7.1.6.1). 
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 
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complications should not be considered AEs unless they were therapeutic abortions, but should 
be reported to the Sponsor. Hospitalization for normal delivery of a healthy newborn should not 
be considered an SAE. Pregnancy is not considered an SAE unless there is an associated serious 
outcome. Spontaneous abortions should always be reported as SAEs. 
Any SAE that occurs during pregnancy must be recorded on the SAE Report Form (eg, maternal 
serious complications, therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, 
congenital anomaly, and birth defect) and reported within 24 hours in accordance with the 
procedure for reporting SAEs. 
The Pregnancy Notification form, the Pregnancy Outcome form, and any related SAE Report 
Forms must be reported to the Sponsor as outlined for SAEs in Section 7.1.6. 
7.1.14. 
Clinical Laboratory Assessments 
The following laboratory variables will be determined in accordance with the schedule of events 
(Table 13 and Table 14). These tests will be performed by the local laboratory at the clinical site. 
• CBC: 
− Hemoglobin 
− Platelets 
− Mean corpuscular volume 
− Differential white cell count 
− White blood cell count 
 
• Serum chemistry: 
− Sodium 
− Total bilirubin 
− Potassium 
− Alkaline phosphatase 
− Chloride 
− Aspartate aminotransferase 
− Creatinine 
− Alanine aminotransferase 
− Urea or blood urea nitrogen 
− Glucose  
− Total protein  
− Albumin 
− Calcium  
− Amylase 
− Phosphate 
− Magnesium 
− Lactate dehydrogenase  
• Urinalysis: 
− Specific gravity 
− Protein 
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− Leukocyte esterase 
− Glucose 
− Nitrite 
− Ketones 
− Blood 
− Bilirubin 
• Thyroid-stimulating hormone (TSH), triiodothyronine (T3), or free 
triiodothyronine (FT3), and free thyroxine (FT4) (Applies only to Cohorts 1, 1A, 2, 
and 2A) 
• Serum pregnancy testing (a urine pregnancy test may be performed if the serum 
pregnancy result is not available before dosing) 
Any laboratory values assessed as clinically significant should be recorded as an AE. If SAE 
criteria are met or the laboratory abnormality is an AESI (Section 7.1.7), the event should be 
recorded and reported according to the SAE reporting process (Section 7.1.6). 
Hematological testing may occur more frequently than is specified in Table 13 and Table 14 
when additional testing is medically indicated per Investigator judgment or if the event meets the 
criteria for niraparib dose modification (Section 6.3.1). 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 or designee. 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)67 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. The hematologist’s report should also be reported 
with the MDS/AML SAE Report Form and specialized questionnaire within 24 hours of 
becoming aware per Section 7.1.6. 
Further details on sample collection and analysis can be found in the Laboratory Manual. 
7.1.15. 
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 13 and Table 14). 
Any physical examination or vital signs assessed as clinically significant should be recorded as 
an AE or SAE. If SAE criteria are met or the abnormality is an AESI (Section 7.1.7), the event 
should be recorded and reported according to the SAE reporting process (Section 7.1.6). 
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7.1.16. 
Eastern Cooperative Oncology Group Performance Status 
Performance status will be assessed using the ECOG scale (see Appendix B) in accordance with 
the schedule of events (Table 13 and Table 14). The same observer should assess performance 
status each time. 
7.1.17. 
Additional Safety Assessments 
All patients will undergo ECGs in accordance with the schedule of events (Table 13 and 
Table 14). 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 the event should be recorded and reported according to the SAE reporting process 
(Section 7.1.6). 
7.2. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics consist of those variables that are assessed at 
screening/baseline. 
7.2.1. 
Patient Eligibility 
Compliance with inclusion and exclusion criteria will be assessed as outlined in Section 4.1 and 
Section 4.2. 
7.2.2. 
Patient Demography 
Patient demography consists of age at screening, race, ethnicity, smoking status (nonsmoker, 
former smoker, and current smoker), and sex. 
7.2.3. 
Disease History 
For disease history the following will be documented: 
• Date of first diagnosis of lung cancer 
• Histology at diagnosis and most recent biopsy if additional biopsy performed 
• Date of first diagnosis of advanced (unresectable) or recurrent or metastatic disease 
• Stage at enrollment 
• EGFR mutation, BRAF mutation, KRAS mutation, ALK translocation, and ROS-1 
translocation, if known 
• Information on prior neoadjuvant/adjuvant treatment, if applicable: 
− Date of start of treatment 
− Agents used in treatment 
− Date of last dose of treatment 
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• Information on first anticancer treatment, if applicable: 
− 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, if applicable: 
− 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 
7.2.4. 
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. 
7.2.5. 
Previous and Concomitant Medications and Procedures 
Previous and concomitant medication will be documented as described in Section 6.7. 
Medications will be coded using the most up-to-date version of the WHO Anatomical 
Therapeutic Chemical classification.  
All concomitant procedures (including transfusions) will be recorded from the time of the first 
dose of any study drug through the Safety Follow-up Visit (30 + 7 days after the last dose of 
study drug).  
7.3. 
Clinical Activity Endpoints 
7.3.1. 
Evaluation of Tumor Response 
7.3.1.1. 
Overview 
The efficacy of single agent niraparib as well as the combination treatment of niraparib and a 
PD-1 inhibitor will be evaluated by assessment of tumor response to treatment according to 
RECIST v1.168 per Investigator assessment (Appendix C).  
Response to treatment will be based on Investigator evaluation of radiographic images. All 
radiographic images/scans at the time points specified in Table 13 and Table 14 as well as any 
unscheduled images/scans should be archived by the study sites for potential future evaluation. 
Tumor imaging (chest, abdomen, and other sites as clinically indicated) should be performed by 
CT (preferred). MRI should only be used when CT is contraindicated and preferably for imaging 
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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 (PET)/CT may be 
used according to RECIST guidelines (Appendix C) and as clinically indicated. 
7.3.1.2. 
Timing of Radiographic Evaluations 
All patients will undergo serial radiographic evaluation 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 28 days prior to first dose date. 
For patients in Cohorts 1, 1A, 2, and 2A, the first on-study imaging tumor assessment should be 
performed 9 weeks (63 ± 7 days) after the first dose of study treatment. Subsequent tumor 
imaging will be performed every 9 weeks (63 ± 7 days) until Week 72, or more frequently if 
clinically indicated. After Week 72, patients should have imaging performed every 12 weeks 
(84 ± 7 days) until progression (Section 8). 
For sqNSCLC patients in Cohort 3, the first on-study imaging tumor assessment should be 
performed 6 weeks (42 ± 7 days) after the first dose of study treatment. Subsequent tumor 
imaging will be performed every 6 weeks (42 ± 7 days) until Week 24 (6 months), or more 
frequently if clinically indicated. After Week 24, patients should have imaging performed every 
9 weeks (63 ± 7 days) until Week 52 (12 months) and then every 12 weeks (84 ± 7 days) until 
progression (Section 8).  
Imaging should not be delayed for delays in cycle starts or extension of combination treatment 
cycle intervals. 
Per RECIST v1.1 (see Appendix C), CR or PR should be confirmed by a repeat tumor imaging 
assessment. The tumor imaging for confirmation of response must be performed at the earliest 
28 days after the first indication of response but no later than 35 days after the response. The 
subsequent scan after the confirmatory scan should be obtained per original schedule (9 weeks 
± 7 days from confirmatory scan for Cohorts 1, 1A, 2, and 2A, and 6 weeks ± 7 days from 
confirmatory scan for Cohort 3). 
Continue to perform imaging until whichever of the following occurs: 
• Withdrawal of consent 
• Death 
• End of the study (when responder or discontinuation status for all patients is known) 
For Cohorts 1, 1A, 2, and 2A: 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. 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 study treatment 
if they are clinically stable as defined by the following criteria: 
• Absence of symptoms and signs indicating clinically significant progression of 
disease (including worsening of laboratory values) 
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• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• 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 by repeat 
imaging. In addition, patients may continue to receive study treatment even after confirmed 
radiologic progression if all the above conditions continue to be met and the Investigator deems 
that the patient is deriving clinical benefit. This allowance to continue treatment despite 
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 PD. 
For Cohort 3 (single agent niraparib), patients with radiologic evidence of PD should be 
discontinued from treatment. 
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 
6, 9 or 12 weeks ± 7 days depending on the length of treatment with the study combination 
drugs, until disease progression, start of a nonstudy anticancer treatment, withdrawal of consent 
to study participation, becoming lost to follow-up, death, or end of the study. 
All radiographic images/scans should be archived for potential future evaluation. 
7.3.1.3. 
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. Details on RECIST v1.1, including evaluation of target and nontarget lesions and 
definitions of response are provided in Appendix C. 
7.3.2. 
Efficacy Endpoints 
7.3.2.1. 
Objective Response Rate 
The primary efficacy endpoint is ORR, defined as the proportion of patients with a confirmed 
best overall response of CR or PR in the analysis population. Tumor assessments after the 
initiation of further anticancer therapy are excluded for the assessment of best overall response. 
7.3.2.2. 
Duration of Response 
DOR will be evaluated as a secondary endpoint and is defined as the time from first documented 
CR or PR until the subsequently documented disease progression or death, whichever occurs 
earlier.  
7.3.2.3. 
Disease Control Rate 
DCR will be evaluated as a secondary endpoint and is defined as the proportion of patients with 
a best overall response of CR, PR or SD. 
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7.3.2.4. 
Progression-Free Survival 
PFS will be assessed as a secondary endpoint and is defined as the time from the date of first 
dose to the date of disease progression or death due to any cause, whichever occurs earlier.  
7.4. 
Pharmacokinetic Assessment 
Pharmacokinetic samples will be collected from patients in all cohorts. An overview of blood 
sampling times for PK analysis is presented in Table 15 and Table 16.  
7.4.1. 
Niraparib Concentrations 
Blood samples for PK assessment of niraparib will be collected in Cycle 1/Day 1, Cycle 2/Day 1, 
Cycle 4/Day 1, and Cycle 8/Day 1 (or EOT if patient discontinues before Cycle 8) in all patients 
in Cohorts 1, 2, and 3. Blood samples for PK assessment of niraparib will be collected in 
Cycle 1/Day 1, Cycle 2/Day 1, Cycle 4/Day 1, and Cycle 9/Day 1 (or EOT if patient discontinues 
before Cycle 9) in all patients in Cohorts 1A and 2A. 
The samples will be collected at predose (within 30 minutes prior to dosing of niraparib) and 
4 hours ± 15 minutes post dosing of niraparib in all cohorts (Table 15).  
In a subset of patients, who consent to additional PK blood draws, (N = 8) in each cohort, blood 
samples for PK assessment of niraparib will be collected on Cycle 1/Day 1 and Cycle 4/Day 1 at 
predose (within 30 minutes prior to dosing of niraparib) at 0.5 hour ± 5 minutes, 1 hour ± 
10 minutes, 2 hours ± 15 minutes, 4 hours ± 15 minutes, 8 hours ± 1 hour, and 24 hours ± 
3 hours postdosing of niraparib. For all these time points the exact collection time needs to be 
recorded (Table 16). Niraparib will be analyzed in plasma using liquid chromatography with 
mass spectroscopic detection. The timing of each required sample collection for niraparib for PK 
blood draws will be recorded.  
Complete instructions for collection, processing, shipping, storage and handling of samples are 
detailed in the Laboratory Manual. 
7.4.2. 
Pembrolizumab Concentrations 
Blood samples for PK assessment of pembrolizumab will be collected on Cycle 1/Day 1, 
Cycle 2/Day 1, Cycle 4/Day 1, and Cycle 8/Day 1 (or EOT if patient discontinues before 
Cycle 8) in all patients in Cohorts 1 and 2. The samples will be collected at predose (within 
30 minutes prior to dosing of pembrolizumab) and 30 minutes (- 5, + 20 minutes) from the 
beginning of infusion (immediately following the end of infusion) (Table 15).  
Blood samples for pembrolizumab will only be analyzed to understand an AE in an individual 
patient. The samples will be collected according to the specified schedule, stored, and analyzed 
as needed.  
For pembrolizumab, serum PK 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 for pembrolizumab for PK blood draws will be recorded.  
Complete instructions for collection, processing, shipping, storage and handling of samples are 
detailed in the Laboratory Manual. 
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7.4.3. 
TSR-042 (Dostarlimab) Concentrations 
Blood samples for PK assessment of TSR-042 (dostarlimab) will be collected on Cycle 1/Day 1, 
Cycle 2/Day 1, Cycle 4/Day 1, and Cycle 9/Day 1 (or EOT if patient discontinues before 
Cycle 9) in all patients in Cohorts 1A and 2A. The samples will be collected at predose (within 
30 minutes prior to dosing of TSR-042 (dostarlimab)) and 30 minutes (- 5, + 20 minutes) from 
the beginning of infusion (immediately following the end of infusion) (Table 15).  
For TSR-042 (dostarlimab), serum PK samples in an individual patient will be analyzed using 
ELISA. The timing of each required sample collection for TSR-042 (dostarlimab) for PK blood 
draws will be recorded.  
Complete instructions for collection, processing, shipping, storage, and handling of samples are 
detailed in the Laboratory Manual. 
7.4.4. 
Determination of Pharmacokinetic Parameters 
7.4.4.1. 
Niraparib 
In the subset of patients with intense PK sampling (N=8 per cohort), noncompartmental methods 
will be used to evaluate the PK characteristics of niraparib and, as appropriate. Pharmacokinetic 
parameters to be determined may include area under the concentration × time curve (AUC), 
AUC at steady state (AUCss), minimum concentration (Cmin), maximum concentration (Cmax), 
clearance after oral administration (CL/F), volume of distribution after oral administration 
(Vz/F), Cmin at steady state (Cmin,ss), and Cmax at steady state (Cmax,ss). Additional PK parameters 
may be estimated if deemed appropriate.  
In patients where no intense sampling was performed, model predicted AUCs will be derived. 
Parameters of interest may include AUC, Cmin, Cmax, CL/F, Vz/F, AUCss, Cmin,ss, and Cmax,ss. 
Plasma concentrations and PK parameter estimates will be presented using descriptive statistics 
by cohort. 
7.4.4.2. 
Pembrolizumab 
If samples are analyzed for pembrolizumab concentrations to understand an AE, the plasma 
concentrations will be summarized by cohort.  
Model predicted AUCs may be derived. Parameters of interest may include AUC, Cmin, Cmax, 
CL, Vss AUCss, Cmin,ss, and Cmax,ss. 
7.4.4.3. 
TSR-042 (Dostarlimab) 
The plasma concentrations for TSR-042 (dostarlimab) will be summarized by cohort. Model 
predicted AUCs may be derived. Parameters of interest may include AUC, Cmin, Cmax, CL, Vss, 
AUCss, Cmin,ss, and Cmax,ss. 
7.5. 
Biomarkers 
7.5.1. 
Biomarker Sample Collection 
The following patient samples are required for biomarker assessment: 
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1. Archival FFPE tumor tissue block, which may have been collected at any time prior to 
Screening, should be submitted to confirm histological morphology, presence of tumor, 
and to conduct biomarker analysis. A fresh biopsy is required if archival tumor tissue is 
not available. Open biopsies, punch biopsies, and core biopsies (3) are acceptable.  Fine 
needle aspirate, frozen sample, plastic embedded sample, cell block, clot, and cytological 
specimen (with the exception of Cohort 3) are not acceptable for analysis. (For Cohort 3 
only: if diagnosis was made by cytology and archival tissue is not available, patient will 
not need to provide tumor tissue.) The archival tumor tissue sample should be submitted 
within 30 days of the patient's first dose. If a replacement biopsy is required in lieu of an 
archival FFPE sample, then the biopsy should be performed prior to dosing (before 
Cycle 1 Day 1).  
2. Blood samples for the analysis of tumor-related circulating biomarkers such as CTC will 
be collected at Cycle 1/Day 1 predose. Blood samples for the analysis of ctDNA will be 
obtained at Screening, Cycle 2/Day 1 predose, as well as EOT.  
All samples will be collected and managed centrally when possible, and distributed either 
directly or subsequently to designated translational research laboratories for biomarker testing. 
Details on blood and tissue sample collection, processing, storage, shipping, and handling 
instructions can be found in the Laboratory Manual. 
7.5.2. 
Biomarker Testing on Tumor Samples 
PD-L1 status will be confirmed retrospectively in a central IHC laboratory using an FDA-
approved in vitro companion diagnostic indicated as an aid in identifying NSCLC patients for 
treatment with a PD-1 inhibitor to confirm results from local testing. Additional markers for 
infiltrating immune cells may also be performed. 
DNA may be extracted from tumor and analyzed for specific genomic aberrations (eg, 
BRCA1/2, ATM) that impair homologous recombination repair, other mechanisms of DNA 
damage repair (DDR), as well as other oncogenic lesions (eg, KRAS mutation). Homologous 
recombination deficiency (HRD) status may also be evaluated using algorithms based on overall 
genomic instability. Tumor mutation burden (TMB) may also be assessed. 
RNA may be extracted and analyzed for gene expression signatures associated with sensitivity/ 
resistance to niraparib, PD-1 inhibitors (pembrolizumab or TSR-042 (dostarlimab)), or the 
combination. 
Results from biomarker analyses will be correlated with efficacy outcomes. 
Remaining tumor tissue samples and tumor derived samples such as DNA and RNA may be 
stored for potential future biomarker testing, including potential bridging to candidate companion 
diagnostic assays. 
7.5.3. 
Biomarker Testing on Circulating Biomarkers in Blood 
ctDNA may be extracted from plasma and analyzed for specific genomic aberrations 
(eg, BRCA1/2, ATM) that impair HRR, other mechanisms of DNA damage repair, as well as 
other oncogenic lesions. 
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CTCs may be stained by immunofluorescence and evaluated for HRD using algorithms based on 
cell morphology. Alternatively, they may be stained for other protein biomarkers or used for 
DNA extraction and sequencing. 
Results from blood based biomarker analyses will be compared with corresponding analyses on 
tumor samples for concordance, whenever applicable. They may also be correlated with efficacy 
outcomes. 
Remaining blood and/or blood derived samples such as plasma, ctDNA and CTC will be stored 
for potential future biomarker testing, including potential bridging to candidate companion 
diagnostic assays. 
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8. 
STUDY CONDUCT 
8.1. 
Schedule of Procedures 
A schedule of study procedures is provided in Table 13 and Table 14. 
 
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Table 13: 
Schedule of Events for Cohorts 1, 1A, 2, and 2A 
Cycle/Visit 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety 
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n,  
Day 1 
 
30 + 7 days 
post-treatment 
(every 90 ± 
14 days) 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical, surgical, cancer, smoking, and 
medication history 
X 
 
 
 
 
 
 
 
Archival FFPE tumor tissue 
X1 
 
 
 
 
 
 
 
Blood sample for ctDNA  
X 
 
 
 
X2 
X 
 
 
Blood sample for CTC 
 
X 
 
 
 
 
 
 
Blood sample for PK 
 
X3, 4 
 
 
X3, 4 
 
 
 
Tumor assessment 
X5 
First on-study imaging assessment should be 
performed 9 weeks (63 ± 7 days) after first dose. 
Subsequent tumor imaging will be performed 
every 9 weeks (63 ± 7 days) until Week 72 and 
every 12 weeks (84 ± 7 days) thereafter6 
If patient discontinues treatment for a reason 
other than progression, death, withdrawal of 
consent, or loss to follow-up, imaging 
should continue every 9 weeks (63 ± 7 days) 
until Week 72 and every 12 weeks (84 
± 7 days) thereafter6 
Clinical laboratory assessments 
CBC 
X 
X7 
X 
X 
X 
X 
X 
X8 
Serum chemistry 
X 
X7 
 
X 
X 
X 
X 
X8 
Pregnancy test9 
X 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
TSH, T3 or FT3, and FT4 
X10 
 
 
 
X10 
X10  
X10 
 
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Table 13: 
Schedule of Events for Cohorts 1, 1A, 2, and Cohort 2A (Continued) 
Abbreviations: AE = adverse event; AESI = Adverse Event of Special Interest, CBC = complete blood count; CTC = circulating tumor cell; ctDNA = circulating 
tumor DNA; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; 
FFPE = formalin fixed paraffin embedded; FT3 = free triiodothyronine; FT4 = free thyroxine; ICF = informed consent form; PK = pharmacokinetics; 
RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; T3 = triiodothyronine; TSH = thyroid-stimulating hormone. 
1 An archival FFPE tumor tissue specimen, which may have been collected at any time prior to Screening, should be submitted for exploratory biomarker 
analysis within 30 days of the patient's first dose. If no archival FFPE tumor tissue is available, a tumor tissue biopsy should be obtained before Cycle 1/Day 1. 
2 Required for Cycle 2/Day 1 only. 
3 Blood sample for niraparib and pembrolizumab PK will be collected on Cycle 1/Day 1, Cycle 2/Day 1, Cycle 4/Day1, and Cycle 8/ Day 1 (or EOT if patient 
discontinues before Cycle 8) in all patients in Cohorts 1 and 2. Blood samples for PK assessment of niraparib will be collected in Cycle 1/Day 1, Cycle 2/Day 
Cycle/Visit 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety 
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n,  
Day 1 
 
30 + 7 days 
post-treatment 
(every 90 ± 
14 days) 
ECG 
X 
 
 
 
 
X 
 
 
Physical examination 
X 
 
 
 
 
X 
 
 
Symptom-directed physical examination 
 
X 
 
X 
X 
 
X 
 
Vital signs and weight 
X 
X 
 
 
X   
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
ECOG performance status 
X 
X 
 
 
X 
X 
 
 
Concomitant medications/procedures11 
 
Recorded from first dose of study drug through Safety Follow-up 
 
AE monitoring12 
X 
X 
X 
X 
X 
X 
X13 
X13 
Pembrolizumab treatment administered14 
(Stage 1 only) 
 
X 
 
 
X 
 
 
 
TSR-042 (dostarlimab) treatment 
administered (Stage 2 only) 
 
X 
 
 
X15 
 
 
 
Niraparib treatment dispensed/collected 
 
X 
 
 
X 
X 
 
 
Survival/AESI (regardless of causality) 
and study-drug related SAEs 
(Telephone assessment allowed) 
 
 
 
 
 
 
 
X16 
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1, Cycle 4/Day 1, and Cycle 9/Day 1 (or EOT if patient discontinues before Cycle 9) in all patients in Cohorts 1A and 2A. Blood sample for TSR-042 
(dostarlimab) will be collected on Cycle 1/Day 1, Cycle 2/Day 1, Cycle 4/Day1, and Cycle 9/ Day 1 (or EOT if patient discontinues before Cycle 9). See 
Table 15 for detailed schedule.  
4 Intensive niraparib PK sampling will be collected only for a subset of patients (N = 8/cohort) in Cycle 1 and Cycle 4. See Section 8.3 and Table 16 for detailed 
schedule. Patients in this subset will be instructed to hold their niraparib dose, which will be taken in clinic on specified days for PK sampling. 
5 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 are performed within 28 days prior to first dose date 
6 For details on tumor assessment per RECIST v1.1 see Section 7.3.1, Section 8.2, and Appendix C. All radiographic images/scans at the specified time points as 
well as any unscheduled images/scans should be archived by the study sites for potential future evaluation. 
7 If screening assessments were performed within 72 hours of Day 1, repeat testing is not required. 
8 CBC and serum chemistry at the Follow-up Assessment should be conducted only on Day 90 post-treatment to assess for possible AESI (Section 7.1.7). 
9 Serum pregnancy test for women of childbearing potential within 72 hours of first dose of study treatment. If the serum pregnancy result is not available before 
dosing, a urine pregnancy test may be performed. 
10 Blood samples for TSH, T3 or FT3, and FT4 are to be collected at screening, every 6 weeks from Cycle 1/Day 1, and at EOT. Blood samples for TSH, T3 or 
FT3, and FT4 should be collected at 30-day post-treatment Safety Follow-up only if assessment is clinically indicated. 
11 Any new anticancer treatment started during the study should also be collected. 
12 Collection of AEs begins when the ICF is signed. 
13 AEs are required to be captured through 30 days after cessation of study treatment (Section 7.1.4). However, SAEs are required to be captured through 90 days 
after cessation of study treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy) (Section 7.1.6), and any 
pregnancies that occur within 180 days post-treatment are to be captured. AESIs should be collected until study closeout, regardless of causality (Section 7.1.7).    
14 Pembrolizumab should be administered once every 21 days (200 mg intravenous) on Day 1 of each cycle. Pembrolizumab may be administered up to 3 days 
before or after the scheduled Day 1 of each cycle after Cycle 1 due to administrative reasons. On days where pembrolizumab is administered, it should be 
administered before niraparib. 
15 TSR-042 (dostarlimab) will be administered at a dose of 500 mg on Day 1 every 3 weeks in Cycles 1 through 4, followed by 1,000 mg every other cycle (every 
6 weeks) thereafter, beginning on Cycle 5 Day 1. On days where TSR-042 (dostarlimab) is administered, it should be administered before niraparib. 
16Patients will be followed until study closeout for survival status, AESI (regardless of causality), and study-drug related SAEs (Section 7.1.7). 
  
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Table 14: Schedule of Events for Cohort 3 
Cycle/Visit: 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety  
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n,  
Day 1 
 
30 + 7 days 
post-treatment 
(every 90 ± 14 
days) 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical, surgical, cancer, smoking, and 
medication history 
X 
 
 
 
 
 
 
 
Archival tumor tissue 
X1 
 
 
 
 
 
 
 
Blood sample for ctDNA  
X 
 
 
 
X2 
X 
 
 
Blood sample for CTC 
 
X 
 
 
 
 
 
 
Blood sample for PK 
 
X3, 4 
 
 
X3, 4 
 
 
 
Tumor assessment 
X5 
First on-study imaging assessment should be 
performed 6 weeks (42 ± 7 days) after first 
dose. Subsequent tumor imaging will be 
performed every 6 weeks (42 ± 7 days) until 
Week 24 (6 months). After Week 24, tumor 
imaging will be performed every 9 weeks 
(63 ± 7 days) until Week 52 (12 months) and 
every 12 weeks (84 ± 7 days) thereafter6 
If patient discontinues treatment for a reason 
other than progression, death, withdrawal of 
consent, or loss to follow-up, imaging 
should continue every 6 weeks (42 ± 7 days) 
until Week 24 (6 months), then every 
9 weeks (63 ± 7 days) until Week 52 
(12 months) and every 12 weeks (84 ± 
7 days) thereafter6 
Clinical laboratory assessments 
 
 
 
 
 
 
 
 
CBC15 
X 
X7 
X 
X 
X 
X 
X 
X8 
Serum chemistry 
X 
X7 
 
X 
X 
X 
X 
X8 
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Table 14: 
Schedule of Events for Cohort 3 (Continued) 
Abbreviations: AE = adverse event; AESI = Adverse Event of Special Interest; CBC = complete blood count; CTC = circulating tumor cell; 
DNA = deoxyribonucleic acid; ctDNA = circulating tumor DNA; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of 
treatment; FFPE = formalin fixed paraffin embedded; ICF = informed consent form; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event 
1 An archival FFPE tumor tissue specimen, which may have been collected at any time prior to Screening, should be submitted for exploratory biomarker 
analysis within 30 days of the patient's first dose. If diagnosis was made by cytology and archival FFPE tissue is not available, patient will not need to provide 
tumor tissue. 
2 Required for Cycle 2/Day 1 only. 
3 Blood sample for niraparib PK will be collected on Cycle 1/Day 1, Cycle 2/Day 1, Cycle 4/Day 1, and Cycle 8/Day 1 (or EOT if patient discontinues before 
Cycle 8). See Table 15 for detailed schedule. 
Cycle/Visit: 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety  
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n,  
Day 1 
 
30 + 7 days 
post-treatment 
(every 90 ± 14 
days) 
Pregnancy test9 
X 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
X 
 
 
Physical examination 
X 
 
 
 
 
X 
 
 
Symptom-directed physical examination 
 
X 
 
X 
X 
 
X 
 
Vital signs and weight14 
X 
X 
X 
X 
X (weekly for 
5 weeks) 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
ECOG performance status 
X 
X 
 
 
X 
X 
 
 
Concomitant medications/procedures10 
 
Recorded from first dose of study drug through Safety Follow-up 
 
AE monitoring11 
X 
X 
X 
X 
X 
X 
X12 
X12 
Niraparib treatment dispensed/collected 
 
X 
 
 
X 
X 
 
 
Survival/AESI (regardless of causality) and 
study-drug related SAEs 
(telephone assessment allowed) 
 
 
 
 
 
 
 
X13 
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4 Intensive niraparib PK sampling will be collected only for a subset of patients (N = 8/cohort) on Cycle 1 and Cycle 4. See Section 8.3 and Table 16 for detailed 
schedule. Patients in this subset will be instructed to hold their niraparib dose, which will be taken in clinic on specified days for PK sampling. 
5 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 are performed within 28 days prior to first dose date. 
6 For details on tumor assessment per RECIST v1.1 see Section 7.3.1, Section 8.2 and Appendix C. All radiographic images/scans at the specified time point as 
well as any unscheduled images/scans should be archived by the study sites for potential future evaluation. 
7 If screening assessments were performed within 72 hours of Day 1, repeat testing is not required. 
8 CBC and serum chemistry at the Follow-up Assessment should be conducted only on Day 90 post-treatment to assess for possible AESI (Section 7.1.7) 
9 Serum pregnancy test for women of childbearing potential within 72 hours of first dose of study treatment. If the serum pregnancy result is not available before 
dosing, a urine pregnancy test may be performed. 
10 Any new anticancer treatment started during the study should also be collected. 
11 Collection of AEs begins when the ICF is signed. 
12 AEs are required to be captured through 30 days after cessation of study treatment (Section 7.1.4). However, SAEs are required to be captured through 90 days 
after cessation of study treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy) (Section 7.1.6), and any 
pregnancies that occur within 180 days post-treatment are to be captured. AESIs should be collected until study closeout, regardless of causality (Section 7.1.6). 
13 Patients will be followed until study closeout for survival status, AESI (regardless of causality), and study-drug related SAEs (Section 7.1.7). 
14 Vital signs include blood pressure (BP), pulse, heart rate, and temperature. BP and heart rate should be monitored at least weekly for the first 2 months of 
niraparib treatment, then monthly for the first year, and periodically thereafter.  
15  Weekly CBC is to be obtained for the first 4 weeks from the start of niraparib treatment, followed by assessment at least every 4 weeks for the first year. If 
niraparib requires a dosing hold or dose reduction, weekly CBC is to be performed for the 4 weeks following restart of niraparib. If patients have not recovered 
within 28 days or have persistent cytopenia following dose modification, further investigations including bone marrow analysis and blood sample for 
cytogenetics must be done in addition to monthly monitoring, and consideration given as to whether to discontinue niraparib treatment. 
 
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Table 15: 
Pharmacokinetic Sampling: All Cohorts 
Day 1 in Cycles 1, 2, 4, and 8 or 91 
Time Point 
Cohort 1/1A 
Cohort 2/2A 
Cohort 3 
Pre-pembrolizumab dose (within 30 min) 
X 
X 
 
Post-pembrolizumab dose (30 min [- 5, + 20 min])2 
X3 
X3 
 
Pre-TSR-042 (dostarlimab) dose (within 30 min) 
X 
X 
 
Post-TSR-042 (dostarlimab) dose (30 min [- 5, + 20 
min])2 
X3 
X3 
 
Pre-niraparib dose (within 30 min) 
X3, 4 
X3,  4 
X 
Post-niraparib dose (4 h ± 15 min)  
X 
X 
X 
Abbreviations: h = hours; min = minutes. 
1 Cycle 8 for niraparib and pembrolizumab (Cycle 9 for niraparib and TSR-042 (dostarlimab)) or EOT if patient 
discontinues before Cycle 8 (Cycle 9 for niraparib and TSR-042 (dostarlimab)) 
2 From beginning of infusion 
3 Post-pembrolizumab/TSR-042 (dostarlimab) dose and pre-niraparib dose can be the same blood draw. 
4 Niraparib will be administered upon completion of pembrolizumab or TSR-042 (dostarlimab) infusion (only 
Cohorts 1, 1A, 2, and 2A). 
 
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Table 16: 
Intensive Niraparib Pharmacokinetic Sampling: Subset of Patients in All Cohorts 
Day of Procedure 
Cycle 1 
Cycle 4 
1 
2 
1 
2 
Pre-niraparib dose1 
 
 
 
 
within 30 min 
X 
 
X 
 
Post-niraparib dose  
 
 
 
 
0.5 h (± 5 min) 
X 
 
X 
 
1 h (± 10 min) 
X 
 
X 
 
2 h (± 15 min) 
X 
 
X 
 
4 h (± 15 min) 
X 
 
X 
 
8 h (± 1h) 
X 
 
X 
 
24 h (± 3 h) 
 
X 
 
X 
Abbreviations: h = hours; min = minutes; PD-1 = programmed cell death-1. 
1 Niraparib should be administered upon completion of PD-1 inhibitor infusion (applies only for Cohorts 1, 1A, 2, and 2A). 
 
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8.2. 
Procedures by Visit 
Treatment cycles are 21 days long, with visits on Day 1, Day 8 and Day 15 of Cycle 1. Visits are 
on Day 1 of each subsequent cycle and continue every 21 ± 3 days until study treatment 
discontinuation. 
8.2.1. 
Screening (Day -21 to Day -1) 
Standard of care tests/procedures, including clinical laboratory assessments, ECG, physical 
examination, vital signs, height, and weight performed prior to the patient signing the ICF 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 with the exception of the pregnancy 
test, which must be conducted within 72 hours of first dose and the scans, which can be 
performed within 28 days prior to Cycle 1/Day 1) and any relevant guidelines (eg, diagnostic 
quality for scans).  
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. 
8.2.1.1. 
Screening: Cohorts 1, 1A, 2, and 2A (Table 13) 
At screening, the following procedures/tests will be performed: 
• Obtain written informed consent 
− The study ICF will be signed before any study procedures are performed. 
• Inclusion/exclusion criteria review 
• Demographics 
• Medical, surgical, cancer, smoking, and medication history 
• Archival FFPE tumor tissue for confirmation of PD-L1 status and biomarker testing 
− For patients who do not have archival tissue, or adequate sample amount, tissue 
from a fresh biopsy must be obtained prior to study treatment initiation (first 
dose). Refer to the Laboratory Manual for details on sample collection, 
processing, shipping, storage, and handling.  
• Blood sample collection for ctDNA 
• Tumor assessment (CT/MRI) for determination of measurable disease (RECIST v1.1)  
− Chest, abdomen, and other sites as clinically indicated CT (preferred method) or 
MRI (if clinically indicated). PET/CT may be used according to RECIST v1.1 
guidelines and as clinically indicated. 
− 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 are performed within 28 days prior to first dose date. 
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• Clinical laboratory assessments: 
− CBC  
− Serum chemistry 
− Serum pregnancy test for women of childbearing potential within 72 hours of first 
dose of study treatment 
Note: If the serum pregnancy result is not available before dosing, a urine 
pregnancy test may be performed. 
− Urinalysis 
− TSH, T3 or FT3, and FT4 
• ECG 
• Physical examination 
• Vital signs (BP, pulse, and temperature) and weight 
• Height 
• ECOG performance status 
• AE monitoring 
8.2.1.2. 
Screening: Cohort 3 (Table 14) 
At screening, the following procedures/tests will be performed: 
• Obtain written informed consent 
− The study ICF will be signed before any study procedures are performed.  
• Inclusion/exclusion criteria review 
• Demographics 
• Medical, surgical, cancer, smoking, and medication history 
• Archival FFPE tumor tissue for biomarker testing 
− Tissue specimen may have been collected at any time prior to Screening 
− If diagnosis was made by cytology and archival tissue is not available, patient will 
not need to provide tumor tissue 
• Blood sample collection for ctDNA.  
• Tumor assessment (CT/MRI) for determination of measurable disease (RECIST v1.1)  
− Chest, abdomen, and other sites as clinically indicated CT (preferred method) or 
MRI (if clinically indicated). PET/CT may be used according to RECIST v1.1 
guidelines and as clinically indicated. 
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− 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 are performed within 28 days prior to first dose date. 
• Clinical laboratory assessments: 
− CBC  
− Serum chemistry 
− Serum pregnancy test for women of childbearing potential within 72 hours of first 
dose of study treatment 
Note: If the serum pregnancy result is not available before dosing, a urine 
pregnancy test may be performed. 
− Urinalysis 
• ECG 
• Physical examination 
• Vital signs (BP, pulse, and temperature) and weight 
• Height 
• ECOG performance status 
• AE monitoring 
8.2.2. 
Cycle 1  
8.2.2.1. 
Cycle 1/Day 1: Cohorts 1, 1A, 2, and 2A (Table 13) 
At Cycle 1/Day 1 the following procedures/tests will be performed: 
• Inclusion/exclusion criteria review 
• Blood samples for pembrolizumab or TSR-042 (dostarlimab) PK assessment  
− Blood samples will be obtained predose (within 30 minutes) and 30 minutes (- 5, 
+ 20 minutes) from the beginning of infusion (immediately following the end of 
infusion) (Table 15). 
• Blood samples for niraparib PK assessment after completion of pembrolizumab or 
TSR-042 (dostarlimab) infusion  
− Blood samples will be obtained pre-niraparib dose (within 30 minutes) and 
4 hours (±15 minutes) postdose (Table 15) 
• Blood sample collection for CTC 
• Clinical laboratory assessments (if screening assessments were performed within 
72 hours of Day 1, repeat testing is not required): 
− CBC 
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− Serum chemistry  
• Symptom-directed physical examination 
• Vital signs (BP, pulse, and temperature) and weight 
• ECOG performance status 
• Concomitant medications and procedures will be recorded from first dose of the study 
drug through the Safety Follow-up Visit 
− Any new anticancer treatment started during the study should also be collected 
• AE monitoring 
• PD-1 inhibitor (pembrolizumab for Cohorts 1 and 2 and TSR-042 (dostarlimab) for 
Cohorts 1A and 2A) study treatment administered after other visit procedures are 
completed 
• Niraparib first dose administered in clinic after completion of PD-1 inhibitor infusion 
8.2.2.2. 
Cycle 1/Day 1: Cohort 3 (Table 14) 
At Cycle 1 1/Day the following procedures/tests will be performed: 
• Inclusion/exclusion criteria review 
• Blood samples for niraparib PK assessment  
− Blood samples will be obtained predose (within 30 minutes) and 4 hours 
(±15 minutes) postdose  
• Blood sample collection for CTC 
• Clinical laboratory assessments (if screening assessments were performed within 
72 hours of Day 1, repeat testing is not required): 
− CBC 
− Serum chemistry 
• Symptom-directed physical examination 
• Vital signs (BP, pulse, and temperature) and weight 
• ECOG performance status 
• Concomitant medications and procedures will be recorded from first dose of the study 
drug through Safety Follow-up  
− Any new anticancer treatment started during the study should also be collected 
• AE monitoring 
• Niraparib first dose administered in clinic 
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8.2.2.3. 
Cycle 1/Day 8: All Cohorts (Table 13 and Table 14) 
At Cycle 1/Day 8 the following procedures/tests will be performed: 
• Laboratory assessment: 
− CBC 
• Concomitant medications and procedures 
− Any new anticancer treatment started during the study should also be collected 
• AE monitoring 
8.2.2.4. 
Cycle 1/Day 15: Cohorts 1, 1A, 2, and 2A (Table 13) 
At Cycle 1/Day 15 the following procedures/tests will be performed: 
• Clinical laboratory assessments: 
− CBC 
− Serum chemistry  
• Symptom-directed physical examination 
• Concomitant medications and procedures 
− Any new anticancer treatment started during the study should also be collected 
• AE monitoring 
8.2.2.5. 
Cycle 1/Day 15: Cohort 3 (Table 14) 
At Cycle 1/Day 15 the following procedures/tests will be performed: 
• Clinical laboratory assessments: 
− CBC 
− Serum chemistry  
• Symptom-directed physical examination 
• Concomitant medications and procedures 
− Any new anticancer treatment started during the study should also be collected 
• AE monitoring 
8.2.3. 
Subsequent Cycles 
8.2.3.1. 
Cohorts 1, 1A, 2, and 2A (Table 13) 
8.2.3.1.1. Day 1 (Table 13) 
• Blood sample collection predose for ctDNA only on Cycle 2/Day 1 
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• Blood samples for pembrolizumab PK assessment on Cycles 2, 4, and 8 only and for 
TSR-042 (dostarlimab) on Cycles 2, 4, and 9 only 
− Blood samples will be obtained predose (within 30 minutes) and 30 minutes (- 5, 
+ 20 minutes) from the beginning of the pembrolizumab/TSR-042 (dostarlimab) 
infusion (immediately following the end of the infusion) (Table 15). 
• Blood samples for niraparib PK assessment after completion of PD-1 inhibitor 
infusion on Cycles 2, 4 and 8 only in all patients in Cohorts 1 and 2, and on 
Cycles 2, 4, and 9 only in all patients in Cohorts 1A and 2A 
− Blood samples will be obtained pre-niraparib dose (within 30 minutes) and 
4 hours (±15 minutes) postdose (Table 15). 
• Clinical laboratory assessments: may be done within 24 hours prior to the visit 
− CBC 
− Serum chemistry  
− TSH, T3 or FT3, and FT4 (should be done every 6 weeks from Cycle 1/Day 1) 
• Symptom-directed physical examination 
• Vital signs (BP, pulse, and temperature) and weight 
• ECOG performance status 
• Concomitant medications and procedures 
− Any new anticancer treatment started during the study should also be collected 
• AE monitoring 
• For Cohorts 1 and 2: Pembrolizumab study treatment administered after other visit 
procedures are completed. (Pembrolizumab may be administered up to 3 days before 
or after the scheduled Day 1 of each cycle after Cycle 1 due to administrative 
reasons). 
• For Cohorts 1A and 2A: TSR-042 (dostarlimab) study treatment administered after 
other visit procedures are completed. (TSR-042 (dostarlimab) will be administered at 
a dose of 500 mg on Day 1 Q3W for 4 cycles, followed by 1,000 mg on Day 1 of 
every other cycle (Q6W) beginning on Cycle 5 Day 1.) 
• Niraparib dose administered in clinic after completion of PD-1 inhibitor infusion 
8.2.3.1.2. Tumor Assessment (RECIST v1.1) (Table 13) 
• Conduct radiographic evaluations of chest, abdomen, and other sites as clinically 
indicated  
• The first on-study imaging assessment should be performed at 9 weeks (63 ± 7 days) 
from the date of first dose of study treatment. 
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• In the case of PD, a confirmatory image will be required 4 weeks later (eg, 13 weeks 
[91 ±7 days]) (Section 7.3.1.2).  
• Patients with CR or PR must have the response confirmed by a repeat tumor imaging 
assessment performed at the earliest 28 days after the first indication of response but 
no later than 35 days after the response. The subsequent scan after the confirmatory 
scan should be obtained per original schedule (9 weeks ± 7 days from confirmatory 
scan). 
• Subsequent tumor imaging will be performed every 9 weeks (63 ± 7 days) until 
Week 72, or more frequently if clinically indicated.  
• After Week 72 (18 months of radiographic assessments), patients should have 
imaging performed every 12 weeks (84 ± 7 days) until progression. 
• Delays in cycle starts or extension of combination treatment cycle intervals should 
not modify imaging schedule.  
• 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 and as clinically 
indicated. 
8.2.3.2. 
Cohort 3 (Table 14) 
8.2.3.2.1. Day 1 (Table 14) 
• Blood sample collection predose for ctDNA only on Cycle 2/Day 1 
• Blood samples for niraparib PK assessment on Cycles 2, 4, and 8 only  
− Blood samples will be obtained pre-niraparib dose (within 30 minutes) and 
4 hours (±15 minutes) postdose (Table 15) 
• Clinical laboratory assessments: may be done within 24 hours prior to the visit 
− CBC 
− Serum chemistry 
• Symptom-directed physical examination 
• Vital signs (BP, pulse, and temperature) and weight 
• ECOG performance status 
• Concomitant medications and procedures 
− Any new anticancer treatment started during the study should also be collected 
• AE monitoring 
• Niraparib dose administered in clinic  
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8.2.3.2.2. Tumor Assessment (RECIST v1.1) (Table 14) 
• Conduct radiographic evaluations of chest, abdomen, and other sites as clinically 
indicated  
• The first on-study imaging assessment should be performed at 6 weeks (42 ± 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, 10 weeks 
[70 ±7 days]) (Section 7.3.1.2).  
• Patients with CR or PR must have the response confirmed by a repeat tumor imaging 
assessment performed at the earliest 28 days after the first indication of response but 
no later than 35 days after the response. The subsequent scan after the confirmatory 
scan should be obtained per original schedule (6 weeks ± 7 days from confirmatory 
scan). 
• Subsequent tumor imaging will be performed every 6 weeks (42 ± 7 days) until 
Week 24, or more frequently if clinically indicated.  
• After Week 24 (6 months of radiographic assessments), patients should have imaging 
performed every 9 weeks (63 ± 7 days) until Week 52 (12 months). 
• After the first year, tumor imaging will be performed every 12 weeks (84 ± 7 days) 
until progression. 
• Delays in cycle starts or extension of combination treatment cycle intervals should 
not modify imaging schedule.  
• 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 and as clinically 
indicated. 
8.2.4. 
End of Treatment (Within 7 Days of Last Dose) 
8.2.4.1. 
End of Treatment: Cohorts 1, 1A, 2, and 2A (Table 13) 
• Blood sample collection for ctDNA  
• Tumor assessment (RECIST v1.1) 
− 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, death, 
withdrawal of consent, or loss to follow-up, radiographic scans/images should 
continue every 9 weeks (63 ± 7 days) until Week 72 (18 months) and every 
12 weeks (84 ±7 days) thereafter. 
• Clinical laboratory assessments: 
− CBC 
− Serum chemistry  
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− TSH, T3 or FT3, and FT4 
• ECG 
• Physical examination 
• Vital signs (BP, pulse, and temperature) and weight 
• ECOG performance status 
• Concomitant medications and procedures 
− Any new anticancer treatment started during the study should also be collected 
• AE monitoring 
• Niraparib study treatment collected 
8.2.4.2. 
End of Treatment: Cohort 3 (Table 14) 
• Blood sample collection for ctDNA  
• Tumor assessment (RECIST v1.1) 
− 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 should 
continue every 6 weeks (42 ±7 days) until Week 24 (6 months), then every 
9 weeks (63 ± 7 days) until Week 52 (12 months), and every 12 weeks 
(84 ±7 days) thereafter. 
• Clinical laboratory assessments: 
− CBC 
− Serum chemistry 
• ECG 
• Physical examination 
• Vital signs (BP, pulse, and temperature) and weight 
• ECOG performance status 
• Concomitant medications and procedures 
− Any new anticancer treatment started during the study should also be collected 
• AE monitoring 
• Niraparib study treatment collected 
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8.2.5. 
Safety Follow-Up Visit (30 + 7 days Post-treatment):  
8.2.5.1. 
Cohorts 1, 1A, 2, and 2A (Table 13)  
• Tumor assessment (RECIST v1.1)  
− If a patient discontinues treatment for a reason other than progression or death, 
withdrawal of consent, or loss to follow-up, radiographic scans/images should 
continue every 9 weeks (63 ± 7 days) until Week 72 (18 months) and every 
12 weeks (84 ± 7 days) thereafter. 
• Clinical laboratory assessments:  
− CBC 
− Serum chemistry 
− TSH, T3 or FT3, and FT4 only if clinically indicated  
• Symptom-directed physical examination 
• Vital signs (BP, pulse, and temperature) and weight 
• Concomitant medications and procedures 
− Any new anticancer treatment started during the study should also be collected. 
• AE monitoring  
− AEs are required to be captured through 30 days after cessation of study treatment 
(Section 7.1.4) 
− SAEs are required to be captured through 90 days after cessation of study 
treatment (or to a minimum of 30 days post-treatment if the patient starts alternate 
anticancer therapy), and any pregnancies that occur within 180 days 
post-treatment are to be captured (Section 7.1.6) 
8.2.5.2. 
Cohort 3 (Table 14) 
• Tumor assessment (RECIST v1.1)  
− If a patient discontinues treatment for a reason other than progression or death, 
withdrawal of consent, or loss to follow-up, radiographic scans/images should 
continue every 6 weeks (42 ± 7 days) until Week 24 (6 months), then every 
9 weeks (63 ± 7 days) until Week 52 (12 months), and every 12 weeks 
(84 ±7 days) thereafter. 
• Clinical laboratory assessments:  
− CBC 
− Serum chemistry 
• Symptom-directed physical examination 
• Vital signs (BP, pulse, and temperature) and weight 
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• Concomitant medications and procedures 
− Any new anticancer treatment started during the study should also be collected. 
• AE monitoring  
− AEs are required to be captured through 30 days after cessation of study treatment 
(Section 7.1.4) 
− SAEs are required to be captured through 90 days after cessation of study 
treatment (or to a minimum of 30 days post-treatment if the patient starts alternate 
anticancer therapy), and any pregnancies that occur within 180 days 
post-treatment are to be captured (Section 7.1.6) 
8.2.6. 
Follow-Up Assessments (Every 90 ± 14 Days): 
8.2.6.1. 
Cohorts 1, 1A, 2, and 2A (Table 13)  
• Tumor assessment (RECIST v1.1)  
− If a patient discontinues treatment for a reason other than progression or death, 
withdrawal of consent, or loss to follow-up, radiographic scans/images should 
continue every 9 weeks (63 ± 7 days) until Week 72 (18 months) and every 
12 weeks (84 ± 7 days) thereafter. 
• CBC and serum chemistry are to be conducted only on Day 90 post-treatment to 
assess for possible AESI (Section 7.1.7) 
• AE monitoring  
− AEs are required to be captured through 30 days after cessation of study treatment 
(Section 7.1.4) 
− SAEs are required to be captured through 90 days after cessation of study 
treatment (or to a minimum of 30 days post-treatment if the patient starts alternate 
anticancer therapy), and any pregnancies that occur within 180 days 
post-treatment are to be captured (Section 7.1.6) 
• Survival/AESI (regardless of causality) and study-drug related SAEs 
− Patients will be followed until study closeout for survival status, AESI (regardless 
of causality), and study-drug related SAEs (Section 7.1.7). Telephone assessment 
is allowed.  
8.2.6.2. 
Cohort 3 (Table 14) 
• Tumor assessment (RECIST v1.1)  
− If patient discontinues treatment for a reason other than progression, death, 
withdrawal of consent, or loss to follow-up, imaging should continue every 
6 weeks (42 ± 7 days) until Week 24 (6 months), then every 9 weeks 
(63 ± 7 days) until Week 52 (12 months) and every 12 weeks (84 ± 7 days) 
thereafter. 
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• CBC and serum chemistry to be conducted only on Day 90 post-treatment to assess 
for possible AESI (Section 7.1.7).  
• AE monitoring  
− AEs are required to be captured through 30 days after cessation of study treatment 
(Section 7.1.4) 
− SAEs are required to be captured through 90 days after cessation of study 
treatment (or to a minimum of 30 days post-treatment if the patient starts alternate 
anticancer therapy), and any pregnancies that occur within 180 days 
post-treatment are to be captured (Section 7.1.6) 
• Survival/AESI (regardless of causality) and study-drug related SAEs 
− Patients will be followed until study closeout for survival status AESI (regardless 
of causality), and study-drug related SAEs (Section 7.1.7). Telephone assessment 
is allowed.  
8.2.7. 
Unscheduled Assessments 
For any patient diagnosed with MDS/AML while on study, the patient will be referred to a local 
hematologist, who must perform a bone marrow aspirate and biopsy and sample collection 
(whole blood) for cytogenetic analysis will be obtained. See Section 7.1.14 for details. 
8.3. 
Intensive Niraparib PK evaluation: All Cohorts 
Blood samples for intensive niraparib PK assessment will be obtained from 8 patients, who 
consent to additional PK blood draws, in each cohort in Cycle 1 and Cycle 4 following the 
schedule described in Section 7.4.1 and Table 16. 
 
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9. 
STATISTICS 
Details of the statistical analyses presented below will be provided in the 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.  
9.1. 
Analysis Populations 
The modified intent-to-treat (ITT) population includes all patients who received any study drug 
and did not withdraw consent prior to having at least 1 postbaseline tumor assessment. The 
modified ITT population will be the primary analysis population for the efficacy analyses. 
The safety population includes all patients who received at least 1 dose of study medication. The 
safety population will be the primary analysis population for the safety analyses. 
9.2. 
Demographics, Medical History, Baseline Characteristics 
Patient disposition will be summarized, including the number of patients treated with single 
agent niraparib and combination of niraparib and a PD-1 inhibitor, the number of patients who 
discontinue and reason for discontinuation, and the number of patients included for analysis. 
Patient demographics will be summarized descriptively for the overall modified ITT population 
and by subgroup. 
9.3. 
Sample Size Determination 
 The null hypothesis for this study is H0: ORR ≤ Standard of Care Response Rate (RRs) vs. the 
alternative hypothesis: ORR ≥ Target Response Rate (RRt) for all cohorts. RRs and RRt for each 
cohort are specified in Table 17 below. 
As different study drugs will be used in Stage 1 and Stage 2, the sample size for each stage was 
calculated separately for Cohort 1 and Cohort 2. Sample size calculation was based on the 
primary efficacy endpoint ORR for each cohort assuming a 1-sided alpha level of 0.10 and 80% 
power. 
For Cohorts 1, 2, and 3, the number of patients in Stage 1 was determined based on Simon’s 
2-stage design. The sample size for Stage 2 (Cohorts 1A and 2A) was calculated based on a 
1-stage design. Once enrollment for Stage 1 is completed, Stage 2 enrollment will start. Stage 1 
data will be used to determine if further enrollment for Stage 2 is warranted. (As of Amendment 
2, following a cross-program review and decision to move forward with other studies, the 
Sponsor decided that Cohort 3 would close to further enrollment. As of Amendment 3, Cohort 1 
and Cohort 2 had completed enrollment, Cohort 1A had closed after partial enrollment and 
Cohort 2A was not opened for enrollment.) The total sample size for this study will range from 
59 to 142. 
The criteria for rejecting the alternative hypothesis and declaring the experiment treatment as not 
efficacious at the end of Stage 1 and Stage 2 are listed in Table 18 below. For each cohort, if the 
number of responders by the end of Stage 1 is the same or less as defined by the criterion, the 
cohort will be terminated. For a cohort that proceeds to Stage 2, if the number of responders by 
the end of Stage 2 is the same or less than the criterion, the alternative hypothesis will be rejected 
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and the experimental treatment will be considered not efficacious for the indication in the cohort, 
unless the clinical judgment suggests otherwise. For example, if greater than 8 patients in Cohort 
1/Stage 1 respond, then enrollment in Cohort 1A/Stage 2 will continue until completion.  
Table 17: 
Sample Size by Cohort 
Cohort 
No. 
Cohort Description 
Target 
RR 
SoC RR 
Sample Size 
1st 
Stage 
2nd 
Stage 
Total 
1/1A 
NSCLC (chemotherapy-naïve, PD-L1 
TPS ≥ 50%) 
65% 
45% 
16 
36 
52 
2/2A 
NSCLC (chemotherapy-naïve, PD-L1 
TPS 1-49%) 
50% 
33.5% 
20 
47 
67 
3 
SqNSCLC: Platinum and PD-1/PD-L1-
treated 
20% 
9% 
23 
0 
23 
Abbreviations: NSCLC = non-small cell lung cancer; PD-1 = programmed cell death-1; PD-L1 = programmed death 
ligand-1; RR = response rate; SoC = standard of care; SqNSCLC = squamous non-small cell lung cancer; 
TPS = tumor proportion score. 
Table 18: 
Criteria for Considering Treatment Efficacious by Cohort and Stage 
Cohort 
No. 
Cohort Description 
Stage 1 
Criteria* 
Stage 2 Criteria 
1/1A 
NSCLC (chemotherapy-naïve, PD-L1 TPS ≥ 50%) 
8 
20‡ 
2/2A 
NSCLC (chemotherapy-naïve, PD-L1 TPS 1-49%) 
7 
20‡ 
3 
SqNSCLC: Platinum and PD-1 or PD-L1-treated 
2 
NA 
Abbreviations: NA = not applicable; NSCLC = non-small cell lung cancer; PD-1 = programmed cell death-1; PD-L1 
= programmed death ligand-1; SqNSCLC = squamous non-small cell lung cancer; TPS = tumor proportion score. 
* Number of patients with responses (CR/PR)‡ Not including stage 1 responders. 
9.4. 
Statistical Analysis 
All cohorts in this study are independently designed based on different patient populations. 
Efficacy and safety analysis for each cohort will be done separately. There will be no multiplicity 
adjustment. 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Analysis for Primary Efficacy Endpoint 
The primary efficacy endpoint is ORR as assessed by Investigator using RECIST (v1.1). Number 
of responders, ORR, and its 80% and 95% binomial exact CI will be reported by cohort and 
stage. 
9.4.1.2. 
Analysis for Secondary Efficacy Endpoints 
Results for DOR, DCR, and PFS as assessed by Investigators per RECIST 1.1, will be 
summarized for each cohort separately. DCR will be analyzed using the same methods for ORR. 
Kaplan-Meier estimates including median and its 95% confidence interval will be tabulated for 
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time to event variables. In addition, Kaplan-Meier curves will also be presented for time to event 
variables. 
9.4.2. 
Safety Analyses 
All analysis for safety endpoints will be done in a descriptive nature. Summary statistics will be 
provided for safety endpoint TEAEs, clinical laboratory assessments (CBC, serum chemistry, 
and urinalysis), vital signs, ECGs, physical examinations, and use of concomitant medications. 
Medical history and AEs will be coded using the most up-to-date version of the Medical 
Dictionary for Regulatory Activities. CTCAE v4.03 will be used to grade the severity of AEs 
and laboratory abnormalities. Prior/concomitant medication and anticancer treatment will be 
coded using the most up-to-date version of the WHO Anatomical Therapeutic Chemical 
classification. 
AEs will include the following categories: 
• TEAEs 
• Drug-related TEAEs 
• Treatment-emergent drug-related Grade 3, 4, and 5 AEs (presented by grade and 
overall) 
• Treatment-emergent Grade 3, 4, and 5 AEs (presented by grade and overall) 
• TEAEs resulting in study drug discontinuation 
• Most commonly reported TEAEs (ie, those events reported by ≥10% of all patients) 
• Treatment-emergent SAEs 
Details for the safety analysis will be specified in the SAP. 
9.5. 
Interim Analyses 
No formal interim analysis will be done for this study. After the last patient in Stage 1 of each 
cohort is enrolled and has discontinued treatment or completed 2 postbaseline tumor assessments 
(approximately 3 to 5 months), whichever occurs earlier, the number of responders will be 
counted and compared to the criteria as specified in Table 18 in the sample size determination 
section. If the number of responders is equal or less than the number of responders specified in 
the criteria, enrollment will be discontinued and the cohort will be terminated for futility. Only 
cohorts with a number of responders larger than that defined by the criteria will be continued to 
finish the Stage 2 enrollment. In the case of responder criteria met before Stage 1 enrollment is 
finished, Stage 1 enrollment may be stopped and Stage 2 enrollment may begin. (As of 
Amendment 2, following a cross-program review and decision to move forward with other 
studies, the Sponsor decided that Cohort 3 would close to further enrollment. As of Amendment 
3, Cohort 1 and Cohort 2 had completed enrollment, Cohort 1A had closed after partial 
enrollment and Cohort 2A was not opened for enrollment.) 
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9.6. 
Pharmacokinetic Analyses 
Noncompartmental or modeling methods will be used to evaluate the PK characteristics of 
niraparib and pembrolizumab or TSR-042 (dostarlimab) as appropriate. Pharmacokinetic 
parameters to be determined may include AUC, AUCss, Cmin, Cmax, CL/F, Vz/F, Cmin,ss, and 
Cmax,ss as described in Section 7.4.4. 
Population PK modeling will be performed on the niraparib concentration-time data collected 
from this study to quantitatively describe the PK profile of niraparib in lung cancer patients, 
explore the PK variability, and identify any covariate effects such as demographic and 
pathophysiologic variables as well as co-medication on the PK of niraparib. In addition, the 
exposure-response relationship between measures of niraparib exposure and measures of 
efficacy, including, but not limited to, ORR, PFS, DOR, and DCR, will be explored. The 
relationship between niraparib exposure and key safety variables, including (but not limited to) 
AESI identified based on data, will be explored. In addition, tumor biomarkers (such as 
BRCA1/2 status, other HRR pathway mutations, HRD status, etc.) may be explored in the 
exposure-response analyses.  
The population PK and exposure-response analyses will be developed and reported separately 
from the clinical study report. 
9.7. 
Biomarker Analyses 
For each patient in the study, blood and tumor tissue samples will be collected, evaluated and 
archived to support exploratory biomarker analysis. BRCA1/2 and other HRR pathway 
mutations, HRD score, TMB, immune cell infiltrates, KRAS mutation status, and other 
exploratory biomarkers will be correlated with response. 
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10. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
10.1. 
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 or designee may review safety information as it 
becomes available throughout the study.  
All aspects of the study will be carefully monitored with respect to Good Clinical Practice (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 Investigator. 
10.2. 
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, AEs, concomitant medication reporting, and raw data collection forms) 
designed to record all observations and other pertinent data for each patient receiving study 
treatment.  
The Investigator will allow Sponsor representatives, contract designees, authorized regulatory 
authority inspectors, and the IRB/IEC to have direct access to all documents pertaining to the 
study. 
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10.3. 
Archiving Study Documents 
Essential clinical documents will be maintained to demonstrate the validity of the study and the 
integrity of the data collected. Master files should be established at the beginning of the study, 
maintained for the duration of the study, and retained according to the appropriate regulations. 
According to International Council for 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.  
10.4. 
Good Clinical Practice 
This study will be conducted in accordance with the ICH for 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).  
10.5. 
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, 
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; 1 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. 
10.6. 
Protocol Approval and Amendment 
Before the start of the study, the study protocol or other relevant documents, or both, 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 US, following approval, the protocol 
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amendment(s) will be submitted to the investigational new drug application under which the 
study is being conducted. 
Specifically, enrollment in Stage 2 of this study (added under Amendment 2) must not begin 
before the clinical study site has received approval for Amendment 2 from the ethics committee 
of record for that site. 
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. 
10.7. 
Patient Confidentiality and Data Protection 
All clinical study findings and documents will be regarded as confidential. Study documents 
(protocols, IBs, and other materials) will be stored appropriately to ensure their confidentiality. 
The Investigator and members of his or 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. 
10.8. 
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 (Study 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. 
10.9. 
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. 
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10.10. 
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, IB, 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. 
10.11. 
Publication Policy 
Information regarding publication of study results is contained in the Clinical Trial Agreement 
for this study. 
10.12. 
Study Committee 
A Study Committee comprised of Investigator 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.  
10.13. 
Criteria for Study Termination 
The Sponsor may terminate this study at any time. The Sponsor will notify the Investigators 
when the study is to be placed on hold, completed, or terminated. 
 
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11. 
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Paul I, Savage KI, Blayney JK, et al. PARP inhibition induces BAX/BAK-independent synthetic lethality 
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Postel-Vinay S, Bajrami I, Friboulet L, et al. A high-throughput screen identifies PARP1/2 inhibitors as a 
potential therapy for ERCC1-deficient non-small cell lung cancer. Oncogene. 2013;32(47):5377-5387. 
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25. 
Audeh MW, Carmichael J, Penson RT, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in 
patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 
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26. 
Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade serous or 
poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, 
non-randomised study. Lancet Oncol. 2011;12(9):852-861. 
27. 
Kummar S, Ji J, Morgan R, et al. A phase I study of veliparib in combination with metronomic 
cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin Cancer Res. 
2012;18(6):1726-1734. 
28. 
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed 
ovarian cancer. N Engl J Med. 2012;366(15):1382-1392. 
29. 
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive 
relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a 
randomised phase 2 trial. Lancet Oncol. 2014;15(8):852-861. 
30. 
Sandhu SK, Schelman WR, Wilding G, et al. The poly(ADP-ribose) polymerase inhibitor niraparib 
(MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. 
Lancet Oncol. 2013;14(9):882-892. 
31. 
Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent 
Ovarian Cancer. N Engl J Med. 2016;375(22):2154-2164. 
32. 
ZEJULATM (niraparib) capsules, for oral use [prescribing information]. Waltham, MA: TESARO, Inc.; 
2017. 
33. 
Olaussen KA, Adam J, Vanhecke E, et al. PARP1 impact on DNA repair of platinum adducts: preclinical 
and clinical read-outs. Lung Cancer. 2013;80(2):216-222. 
34. 
Ramalingam SS, Blais N, Mazieres J, et al. Randomized, Placebo-Controlled, Phase II Study of Veliparib 
in Combination with Carboplatin and Paclitaxel for Advanced/Metastatic Non-Small Cell Lung Cancer. 
Clin Cancer Res. 2016. 
35. 
Cancer Genome Atlas Research N. Comprehensive genomic characterization of squamous cell lung 
cancers. Nature. 2012;489(7417):519-525. 
36. 
Vincent MD. Promising targets and current clinical trials in metastatic squamous cell lung cancer. Front 
Oncol. 2014;4:320. 
37. 
Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial 
ovarian cancer. N Engl J Med. 2003;348(3):203-213. 
38. 
Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on 
clinical outcome. Nat Rev Cancer. 2012;12(4):298-306. 
39. 
Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal 
cancer. N Engl J Med. 2005;353(25):2654-2666. 
40. 
Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A. Programmed death-1 pathway in 
cancer and autoimmunity. Clin Immunol. 2014;153(1):145-152. 
41. 
Yao S, Chen L. PD-1 as an immune modulatory receptor. Cancer Journal. 2014;20(4):26. 
42. 
Nishimura H, Agata Y, Kawasaki A, et al. Developmentally regulated expression of the PD-1 protein on 
the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol. 1996;8(5):773-780. 
43. 
Huang X, Venet F, Wang YL, et al. PD-1 expression by macrophages plays a pathologic role in altering 
microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A. 
2009;106(15):6303-6308. 
44. 
Pena-Cruz V, McDonough SM, Diaz-Griffero F, Crum CP, Carrasco RD, Freeman GJ. PD-1 on immature 
and PD-1 ligands on migratory human Langerhans cells regulate antigen-presenting cell activity. J Invest 
Dermatol. 2010;130(9):2222-2230. 
45. 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev 
Immunol. 2008;26:677-704. 
46. 
Karim R, Jordanova ES, Piersma SJ, et al. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell 
infiltration and survival of patients with cervical carcinoma. Clin Cancer Res. 2009;15(20):6341-6347. 
47. 
Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression 
in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl 
Med. 2012;4(127):127ra137. 
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48. 
Sanmamed MF, Chen L. Inducible expression of B7-H1 (PD-L1) and its selective role in tumor site 
immune modulation. Cancer J. 2014;20(4):256-261. 
49. 
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor 
immunity. Curr Opin Immunol. 2012;24(2):207-212. 
50. 
Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-
positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 
2016;387(10027):1540-1550. 
51. 
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-
Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123-135. 
52. 
Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously 
treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. 
Lancet. 2017;389(10066):255-265. 
53. 
Jiao S, Xia W, Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and enhances cancer-
associated immunosuppression. Clin Cancer Res. 2017. 
54. 
Byrd AK, Zybailov BL, Maddukuri L, et al. Evidence that G-quadruplex DNA accumulates in the 
cytoplasm and participates in stress granule assembly in response to oxidative stress. J Biol Chem. 
2016;291(34):18041-18057. 
55. 
Chen Q, Sun L, Chen ZJ. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. 
Nat Immunol. 2016;17(10):1142-1149. 
56. 
Hartlova A, Erttmann SF, Raffi FA, et al. DNA damage primes the type I interferon system via the 
cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity. 2015;42(2):332-343. 
57. 
Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates 
the type I interferon pathway. Science. 2013;339(6121):786-791. 
58. 
Yu Q, Katlinskaya YV, Carbone CJ, et al. DNA-damage-induced type I interferon promotes senescence 
and inhibits stem cell function. Cell Rep. 2015;11(5):785-797. 
59. 
Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat 
Rev Cancer. 2016;16(3):131-144. 
60. 
Xing D, Orsulic S. A mouse model for the molecular characterization of BRCA1-associated ovarian 
carcinoma. Cancer Res. 2006;66(18):8949-8953. 
61. 
Huang J, Wang L, Cong Z, et al. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a 
BRCA1(-/-) murine model of ovarian cancer. Biochem Biophys Res Commun. 2015;463(4):551-556. 
62. 
Ricks TK, Chiu HJ, Ison G, et al. Successes and challenges of PARP inhibitors in cancer therapy. Front 
Oncol. 2015;5:222. 
63. 
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood 
cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006;24(19):3187-3205. 
64. 
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients 
Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical 
Practice Guideline. J Clin Oncol. 2018:JCO2017776385. 
65. 
ZEJULA (niraparib) capsules, for oral use [prescribing information]. Waltham, MA: TESARO; 2017. 
66. 
HHS. Drug-induced liver injury: Premarketing clinical evaluation. In: Administration UDoHaHSFaD, 
ed2009 (July). 
67. 
Vardiman JW, Thiele J, Arber DA, 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):937-951. 
68. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
69. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
 
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APPENDIX A. COCKCROFT-GAULT EQUATION 
 
For males:  
 
Creatinine Clearance= {
140 - age [years] × weight [kg]
72 × (serum creatine [mg
dL]) } OR {
140 - age [years] × weight [kg]
0.81 × (serum creatine [μmol
L ])}  
 
For females:  
 
Creatinine Clearance= {
0.85 (140 - age [years] × weight [kg])
72 × (serum creatine [mg
dL])
}  OR {
0.85 (140 - age [years] × weight [kg])
0.81  × (serum creatine [μmol
L ])
}  
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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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APPENDIX C. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS, V1.1 
Response Criteria by Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) 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 nontarget lesions and normalization of tumor 
marker level. All lymph nodes must be nonpathological 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 1 or more nontarget lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): 
Appearance of 1 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 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 PD 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 19: 
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 weeks Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
> 4 weeks 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 weeks 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; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease 
* See RECIST v1.1 publication for further details on what is evidence of a new lesion.68  
** Only for nonrandomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in nontarget 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. 
 
 
 
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APPENDIX D. ACCEPTABLE METHODS OF CONTRACEPTION 
Patients of childbearing potential, who are sexually active, and their partners must agree to the 
use of 2 highly effective forms of contraception throughout their participation during the study 
treatment and for 180 days after the last dose of study treatment(s). Acceptable birth control 
methods include the following: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral route 
− Intravaginal route 
− Transdermal route 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence, if it is the preferred and usual lifestyle of the subject 
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SAP_003.pdf: 
 
 
Statistical Analysis Plan 
 
Study ID:  213352 
 
Official Title of Study: Phase 2, Multi-Arm Study of Niraparib Administered Alone 
and in Combination with a PD1 inhibitor in Patients with Non-Small Cell Lung 
Cancer 
 
 
Other Identifiers: 3000-02-001 
 
Date of Document: 27-AUG-2019 
 
 


TESARO Inc.  
 
 
Protocol No. 3000-02-001 
 
 
Statistical Analysis Plan  
 
Confidential 
Page 1 of 45 
 
           
STATISTICAL ANALYSIS PLAN: Study 3000-02-001 
 
 
 
Protocol Title: 
Phase 2, Multi-Arm Study of Niraparib Administered 
Alone and in Combination with a PD1 inhibitor in Patients 
with Non-Small Cell Lung Cancer 
 
 
Protocol Number: 
3000-02-001 
 
 
Protocol Version and Date: 
Version 3.0, 31 May 31 2018 (amendment 2) 
Version 2.0, 05 September 2017 (Amendment 1) 
Version 1.0, 17 May 2017 (Original) 
 
 
Study Phase: 
Phase 2 
 
 
Product Name: 
Niraparib, Pembrolizumab, and TSR-042 
 
 
Sponsor: 
TESARO, Inc. 
 
 
Analysis Plan Version and Date: 
Version 0.8, 27 August 2019 
 
 
 
 
 
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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TESARO Inc.  
 
 
Protocol No. 3000-02-001 
 
 
Statistical Analysis Plan  
 
Confidential 
Page 3 of 45 
 
TABLE OF CONTENTS 
SPONSOR SIGNATURES ......................................................................................................2 
TABLE OF CONTENTS ........................................................................................................3 
LIST OF ABBREVIATIONS .................................................................................................6 
1 
INTRODUCTION ............................................................................................................8 
2 
STUDY DESIGN OVERVIEW ......................................................................................8 
2.1 
Overall Study Design .............................................................................................8 
2.2 
Sample Size ...........................................................................................................18 
2.3 
Randomization and Blinding ..............................................................................19 
3 
STUDY OBJECTIVES ..................................................................................................19 
3.1 
Primary Objectives ..............................................................................................19 
3.2 
Secondary Objectives...........................................................................................19 
4 
STUDY ENDPOINTS AND EVALUATIONS ............................................................20 
4.1 
Efficacy Endpoints ...............................................................................................20 
4.1.1 
Primary Efficacy Endpoint ..........................................................................20 
4.1.2 
Secondary Efficacy Endpoints .....................................................................20 
4.2 
Safety Evaluations ................................................................................................23 
4.3 
Other Evaluations ................................................................................................23 
5 
PLANNED ANALYSES ................................................................................................24 
5.1 
Changes from planned Analyses in the Protocol ..............................................24 
5.2 
Interim Analyses ..................................................................................................24 
5.3 
Final Analyses and Reporting .............................................................................24 
6 
ANALYSIS POPULATIONS AND APPLICATIONS ...............................................24 
6.1 
Modified Intent-to-Treat Population .................................................................24 
6.2 
Pharmacokinetic Population ...............................................................................24 
6.3 
Safety Population .................................................................................................24 
6.4 
Application of Analysis Populations ..................................................................25 
7 
STATISTICAL CONSIDERATIONS .........................................................................26 
7.1 
General Statistical Procedures ............................................................................26 
7.2 
Patient Enrolment and Disposition ....................................................................27 
7.2.1 
Patient Enrollment .......................................................................................27 
7.2.2 
Patient Disposition .......................................................................................27 
7.2.3 
Protocol Deviations ......................................................................................27 
7.3 
Demographic and Other Pre-treatment Variables ...........................................28 
7.3.1 
Demographics/Baseline Characteristics and Non-small Cell Lung Cancer 
History .........................................................................................................28 
7.3.2 
Medical History ...........................................................................................30 
7.3.3 
Medication Use/Procedures .........................................................................30 


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7.4 
Analysis of Efficacy Data.....................................................................................31 
7.4.1 
Primary Efficacy Data..................................................................................31 
7.4.2 
Secondary Efficacy Data..............................................................................32 
7.5 
Analysis of Safety Data ........................................................................................32 
7.5.1 
Adverse Events ............................................................................................32 
7.5.2 
Study Drug Exposure and Compliance ........................................................34 
7.5.3 
Clinical Laboratory Evaluations ..................................................................36 
7.5.4 
Vital Signs ....................................................................................................37 
7.5.5 
Electrocardiogram ........................................................................................37 
7.5.6 
Physical Examinations .................................................................................38 
7.5.7 
ECOG Performance Status ..........................................................................38 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ..........................38 
8.1 
Definition of Baseline ...........................................................................................39 
8.2 
Analysis Visit Window .........................................................................................39 
8.3 
Efficacy Data Handling .......................................................................................39 
8.4 
Safety Data Handling ...........................................................................................39 
8.4.1 
Handling of Repeated Clinical Laboratory Tests.........................................39 
8.4.2 
Handling of Partial Dates for AEs ...............................................................39 
8.4.3 
Handling of Partial Dates for Medications ..................................................40 
9 
REFERENCE .................................................................................................................41 
10 APPENDICES ................................................................................................................42 


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TABLES 
Table 1: Schedule of Events for Cohort 1, 1A, 2, 2A ........................................................11 
Table 2: Schedule of Events for Cohort 3 ..........................................................................15 
Table 3: Sample Size by Cohort ........................................................................................18 
Table 4: Criteria for Considering Treatment Efficacious by Cohort and Stage ................19 
Table 5: Censoring Rules for DOR ....................................................................................21 
Table 6: Censoring Rules for PFS .....................................................................................22 
Table 7: Application of Analysis Populations for Tables and Graphs...............................26 
Table 8: RECIST Response for Patients with Measurable Disease ...................................43 
Table 9: Common Terminology Criteria for Adverse Events v4.03 (CTCAE) .................44 
 


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LIST OF ABBREVIATIONS 
Abbreviation  Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
anaplastic lymphoma kinase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BOR 
best overall response 
CI 
confidence interval 
CBC 
complete blood count 
CR 
complete response 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
ECOG 
Easter Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EOS 
end of study 
EOT 
end of treatment 
FDA 
US Food and Drug Administration 
LLN 
lower limit of normal 
MedDRA 
medical dictionary for regulatory activities 
NSCLC  
non-small cell lung cancer  
ORR  
objective response rate  
OS  
overall survival  
PD  
progressive disease  
PD-1  
programmed cell death-1  
PD-L1  
programmed death-ligand 1  
PFS  
progression-free survival  
PK 
pharmacokinetics 
PO  
oral(ly)  


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Abbreviation  Definition 
PR  
partial response  
PT 
preferred term 
Q1 
first quartile 
Q3 
third quartile 
QD 
once daily 
RECIST 
response evaluation criteria in solid tumors 
RRs  
standard of care response rate  
RRt  
target response rate  
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SD 
stable disease or standard deviation 
sqNSCLC  
squamous non-small cell lung cancer  
TEAE 
treatment-emergent adverse event 
TPS  
tumor proportion score  
TSH  
thyroid-stimulating hormone  
ULN 
upper limit of normal 
WHO 
World Health Organization 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) provide the detailed statistical methods to be used for 
analyses and data presentation for reporting efficacy, safety, non-compartmental 
Pharmacokinetics of investigational drug niraparib for TESARO study protocol 3000-02-01.  
The pharmacokinetics and exposure-response analyses will be provided in a separate document. 
The exploration of blood and tumor-based biomarkers that predict sensitivity or resistance to 
niraparib will also be detailed in a separate document. This document has been prepared 
according to Study Protocol Amendment 2 dated 31 May 2018.  
 
2 
STUDY DESIGN OVERVIEW 
2.1 
Overall Study Design 
This is a multicenter, open-label, multi-arm Phase 2 study to evaluate the efficacy and safety of 
single agent niraparib in patients with locally advanced and metastatic squamous non-small cell 
lung cancer (sqNSCLC) and of the combination of niraparib and a PD-1 inhibitor in locally 
advanced and metastatic non-small cell lung cancer (NSCLC) all histologies patients.  
The study has 2 stages, each of which will evaluate separate cohorts of different cancer patients 
with a sample size that is deemed statistically significant to determine whether further 
examination may be warranted in the individual indications. In Stage 1, Cohorts 1 and 2 will 
receive niraparib plus the PD-1 inhibitor pembrolizumab, and Cohort 3 will receive niraparib 
alone. In Stage 2, Cohorts 1A and 2A will receive niraparib plus the PD-1 inhibitor TSR-042. 
The study design is presented graphically in Figure 1. 
 


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Figure 1 Study Design 
Stage 1: 
 
 
 
 
 
 
Stage 2: 
 
 
 
 
*Completion of treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as 
therapy was completed at least 6 months prior to the diagnosis of metastatic disease 
Abbreviations: NSCLC = non-small cell lung cancer; PD-1 = programmed cell death-1;  
PD-L1 = programmed death ligand-1; TPS = Tumor Proportion Score 
 
Cohorts 1 and 1A: Locally advanced and metastatic NSCLC patients (all histologies) with no 
prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment, whose tumors have high PD-L1 
expression (TPS ≥ 50%), and no known epidermal growth factor receptor (EGFR) sensitizing 
mutation and/or ROS-1 or anaplastic lymphoma kinase (ALK) translocations will receive 
combination of niraparib and a PD-1 inhibitor (pembrolizumab or TSR-042). Completion of 
treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is 
allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic 
disease. 
Cohorts 2 and 2A: Locally advanced and metastatic NSCLC patients (all histologies) with no 
prior systemic chemotherapy or PD-1/PD-L1 inhibitor treatment, whose tumors have PD-L1 
expression (TPS between 1% and 49%) and no known EGFR sensitizing mutation and/or ROS-1 
or ALK translocations, will receive combination of niraparib and a PD-1 inhibitor 
(pembrolizumab or TSR-042). Completion of treatment with chemotherapy and/or radiation as 
part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 
months prior to the diagnosis of metastatic disease.  
Cohort 3: Locally advanced and metastatic sqNSCLC patients who have been previously treated 
with both platinum and either PD-1 or PD-L1 inhibitor will receive single agent niraparib.  


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Table 1: Schedule of Events for Cohort 1, 1A, 2, 2A 
Cycle/Visit 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety 
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n, 
Day 1 
30 + 7 days 
post-treatment 
(every 90 ± 
14 days) 
Informed consent 
X 
Inclusion/exclusion criteria review 
X 
X 
Demographics 
X 
Medical, surgical, cancer, smoking, and 
medication history 
X 
Archival FFPE tumor tissue 
X1 
Blood sample for ctDNA 
X 
X2 
X 
Blood sample for CTC 
X 
Blood sample for PK 
X3, 4 
X3, 4 
Tumor assessment 
X5 
First on-study imaging assessment should be 
performed 9 weeks (63 ± 7 days) after first 
dose. Subsequent tumor imaging will be 
performed every 9 weeks (63 ± 7 days) until 
Week 72 and every 12 weeks (84 ± 7 days) 
thereafter6 
If patient discontinues treatment for a reason 
other than progression, death, withdrawal of 
consent, or loss to follow-up, imaging should 
continue every 9 weeks (63 ± 7 days) until 
Week 72 and every 12 weeks (84 ± 7 days) 
thereafter6 
Clinical laboratory assessments 
CBC 
X 
X7 
X 
X 
X 
X 
X 
X8 


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Statistical Analysis Plan  
 
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Cycle/Visit 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety 
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n, 
Day 1 
30 + 7 days 
post-treatment 
(every 90 ± 
14 days) 
Serum chemistry 
X 
X7 
X 
X 
X 
X 
X8 
Pregnancy test9 
X 
Urinalysis 
X 
TSH, T3 or FT3, and FT4 
X10 
X10 
X10 
X10 
ECG 
X 
X 
Physical examination 
X 
X 
Symptom-directed physical examination 
X 
X 
X 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
Height 
X 
ECOG performance status 
X 
X 
X 
X 
Concomitant medications/procedures11 
Recorded from first dose of study drug through Safety Follow-up 
AE monitoring12 
X 
X 
X 
X 
X 
X 
X13 
X13 
Pembrolizumab treatment administered14 
(Stage 1 only) 
X 
X 
TSR-042 treatment administered (Stage 2 
only) 
X 
X15 
Niraparib treatment dispensed/collected 
X 
X 
X 
Survival/AESI (regardless of causality) 
and study-drug related SAEs 


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Cycle/Visit 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety 
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n, 
Day 1 
30 + 7 days 
post-treatment 
(every 90 ± 
14 days) 
(Telephone assessment allowed) 
X16 
Abbreviations: AE = adverse event; AESI = Adverse Event of Special Interest, CBC = complete blood count; CTC = circulating tumor cell; ctDNA = 
circulating tumor DNA; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; 
FFPE = formalin fixed paraffin embedded; FT3 = free triiodothyronine; FT4 = free thyroxine; ICF = informed consent form; PK = pharmacokinetics; 
RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; T3 = triiodothyronine; TSH = thyroid-stimulating hormone. 
1 An archival FFPE tumor tissue specimen, which may have been collected at any time prior to Screening, should be submitted for exploratory biomarker 
analysis within 30 days of the patient's first dose. If no archival FFPE tumor tissue is available, a tumor tissue biopsy should be obtained before 
Cycle 1/Day 1. 
2 Required for Cycle 2/Day 1 only. 
3 Blood sample for niraparib and pembrolizumab PK will be collected on Cycle 1/Day 1, Cycle 2/Day 1, Cycle 4/Day1, and Cycle 8/ Day 1 (or EOT if patient 
discontinues before Cycle 8) in all patients in Cohorts 1 and 2. Blood samples for PK assessment of niraparib will be collected in Cycle 1/Day 1, Cycle 2/Day 
1, Cycle 4/Day 1, and Cycle 9/Day 1 (or EOT if patient discontinues before Cycle 9) in all patients in Cohorts 1A and 2A. Blood sample for TSR-042 will be 
collected on Cycle 1/Day 1, Cycle 2/Day 1, Cycle 4/Day1, and Cycle 9/ Day 1 (or EOT if patient discontinues before Cycle 9). See Table 15 of protocol for 
detailed schedule. 
4 Intensive niraparib PK sampling will be collected only for a subset of patients (N = 8/cohort) in Cycle 1 and Cycle 4. See Section 8.3 and Table 16 of 
protocol for detailed schedule. Patients in this subset will be instructed to hold their niraparib dose, which will be taken in clinic on specified days for PK 
sampling. 
5 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 are performed within 28 days prior to first dose date 
6 For details on tumor assessment per RECIST v1.1 see Section 7.3.1, Section 8.2, and Appendix C of protocol. All radiographic images/scans at the specified 
time points as well as any unscheduled images/scans should be archived by the study sites for potential future evaluation. 
7 If screening assessments were performed within 72 hours of Day 1, repeat testing is not required. 
8 CBC and serum chemistry at the Follow-up Assessment should be conducted only on Day 90 post-treatment to assess for possible AESI (Section 7.1.6 of 
protocol). 
9 Serum pregnancy test for women of childbearing potential within 72 hours of first dose of study treatment. If the serum pregnancy result is not available 
before dosing, a urine pregnancy test may be performed. 
10Blood samples for TSH, T3 or FT3, and FT4 are to be collected at screening, every 6 weeks from Cycle 1/Day 1, and at EOT. Blood samples for TSH, T3 or 
FT3, and FT4 should be collected at 30-day post-treatment Safety Follow-up only if assessment is clinically indicated. 
11Any new anticancer treatment started during the study should also be collected. 


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Cycle/Visit 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety 
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n, 
Day 1 
30 + 7 days 
post-treatment 
(every 90 ± 
14 days) 
12Collection of AEs begins when the ICF is signed. 
13AEs are required to be captured through 30 days after cessation of study treatment (Section 7.1.3 of protocol). However, SAEs are required to be captured 
through 90 days after cessation of study treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy) (Section 7.1.5 
of protocol), and any pregnancies that occur within 180 days post-treatment are to be captured. AESIs should be collected until study closeout, regardless of 
causality (Section 7.1.6 of protocol). 
14Pembrolizumab should be administered once every 21 days (200 mg intravenous) on Day 1 of each cycle. Pembrolizumab may be administered up to 3 days 
before or after the scheduled Day 1 of each cycle after Cycle 1 due to administrative reasons. On days where pembrolizumab is administered, it should be 
administered before niraparib. 
15 TSR-042 will be administered at a dose of 500 mg on Day 1 every 3 weeks in Cycles 1 through 4, followed by 1,000 mg every other cycle (every 6 weeks) 
thereafter, beginning on Cycle 5 Day 1. On days where TSR-042 is administered, it should be administered before niraparib. 
16Patients will be followed until study closeout for survival status, AESI (regardless of causality), and study-drug related SAEs (Section 7.1.6 of protocol). 
 


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Table 2: Schedule of Events for Cohort 3 
Cycle/Visit: 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety 
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n, 
Day 1 
30 + 7 days 
post-treatment 
(every 90 ± 14 
days) 
Informed consent 
X 
Inclusion/exclusion criteria review 
X 
X 
Demographics 
X 
Medical, surgical, cancer, smoking, and 
medication history 
X 
Archival tumor tissue 
X1 
Blood sample for ctDNA 
X 
X2 
X 
Blood sample for CTC 
X 
Blood sample for PK 
X3, 4 
X3, 4 
Tumor assessment 
X5 
First on-study imaging assessment should be 
performed 6 weeks (42 ± 7 days) after first 
dose. Subsequent tumor imaging will be 
performed every 6 weeks (42 ± 7 days) until 
Week 24 (6 months). After Week 24, tumor 
imaging will be performed every 9 weeks 
(63 ± 7 days) until Week 52 (12 months) and 
every 12 weeks (84 ± 7 days) thereafter6 
If patient discontinues treatment for a reason 
other than progression, death, withdrawal of 
consent, or loss to follow-up, imaging should 
continue every 6 weeks (42 ± 7 days) until 
Week 24 (6 months), then every 9 weeks (63 
± 7 days) until Week 52 (12 months) and 
every 12 weeks (84 ± 7 days) thereafter6 
Clinical laboratory assessments 
CBC 
X 
X7 
X 
X 
X 
X 
X 
X8 
Serum chemistry 
X 
X7 
X 
X 
X 
X 
X8 
Pregnancy test9 
X 
Urinalysis 
X 
ECG 
X 
X 
Physical examination 
X 
X 


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Cycle/Visit: 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety 
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n, 
Day 1 
30 + 7 days 
post-treatment 
(every 90 ± 14 
days) 
Symptom-directed physical examination 
X 
X 
X 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
Height 
X 
ECOG performance status 
X 
X 
X 
X 
Concomitant medications/procedure10 
Recorded from first dose of study drug through Safety Follow-up 
AE monitoring11 
X 
X 
X 
X 
X 
X 
X12 
X12 
Niraparib treatment dispensed/collected 
X 
X 
X 
Survival/AESI (regardless of causality) and 
study-drug related SAEs (telephone 
assessment allowed) 
X13 
Abbreviations: AE = adverse event; AESI = Adverse Event of Special Interest; CBC = complete blood count; CTC = circulating tumor cell; 
DNA = deoxyribonucleic acid; ctDNA = circulating tumor DNA; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of 
treatment; FFPE = formalin fixed paraffin embedded; ICF = informed consent form; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event 
1 An archival FFPE tumor tissue specimen, which may have been collected at any time prior to Screening, should be submitted for exploratory biomarker analysis 
within 30 days of the patient's first dose. If diagnosis was made by cytology and archival FFPE tissue is not available, patient will not need to provide tumor 
tissue. 
2 Required for Cycle 2/Day 1 only. 
3 Blood sample for niraparib PK will be collected on Cycle 1/Day 1, Cycle 2/Day 1, Cycle 4/Day 1, and Cycle 8/Day 1 (or EOT if patient discontinues before 
Cycle 8). See Table 15 of protocol for detailed schedule. 
4 Intensive niraparib PK sampling will be collected only for a subset of patients (N = 8/cohort) on Cycle 1 and Cycle 4. See Section 8.3 and Table 16 of protocol 
for detailed schedule. Patients in this subset will be instructed to hold their niraparib dose, which will be taken in clinic on specified days for PK sampling. 
5 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 are performed within 28 days prior to first dose date. 
6 For details on tumor assessment per RECIST v1.1 see Section 7.3.1, Section 8.2 and Appendix C of protocol. All radiographic images/scans at the specified 
time point as well as any unscheduled images/scans should be archived by the study sites for potential future evaluation. 
7 If screening assessments were performed within 72 hours of Day 1, repeat testing is not required. 


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Cycle/Visit: 
Screening 
Cycle 1 
Subsequent 
Cycles 
EOT 
Safety 
Follow-Up 
Follow-Up 
Assessment 
Day of Procedure 
-21 to -1 
1 
8 
15 
Cycle n, 
Day 1 
30 + 7 days 
post-treatment 
(every 90 ± 14 
days) 
8 CBC and serum chemistry at the Follow-up Assessment should be conducted only on Day 90 post-treatment to assess for possible AESI (Section 7.1.6 of 
protocol) 
9 Serum pregnancy test for women of childbearing potential within 72 hours of first dose of study treatment. If the serum pregnancy result is not available 
before dosing, a urine pregnancy test may be performed. 
10 Any new anticancer treatment started during the study should also be collected. 
11 Collection of AEs begins when the ICF is signed. 
12 AEs are required to be captured through 30 days after cessation of study treatment (Section 7.1.3 of protocol). However, SAEs are required to be captured 
through 90 days after cessation of study treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy) (Section 7.1.5 
of protocol), and any pregnancies that occur within 180 days post-treatment are to be captured. AESIs should be collected until study closeout, regardless of 
causality (Section 7.1.6 of protocol). 
13 Patients will be followed until study closeout for survival status, AESI (regardless of causality), and study-drug related SAEs (Section 7.1.6 of protocol). 
 
 


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2.2 
Sample Size 
The null hypothesis for this study is H0: ORR ≤ Standard of Care Response Rate (RRs) vs. 
the alternative hypothesis: ORR ≥ Target Response Rate (RRt) for all cohorts. RRs and RRt 
for each cohort are specified in Table 3 below. 
As different study drugs will be used in Stage 1 and Stage 2, the sample size for each stage 
was calculated separately for Cohort 1 and Cohort 2. Sample size calculation was based on 
the primary efficacy endpoint ORR for each cohort assuming a 1-sided alpha level of 0.10 
and 80% power. 
For Cohorts 1, 2, and 3, the number of patients in Stage 1 was determined based on Simon’
s 2-stage design. The sample size for Stage 2 (Cohorts 1A and 2A) was calculated based on a 
1-stage design. Once enrollment for Stage 1 is completed, Stage 2 enrollment will start. Stage 
1 data will be used to determine if further enrollment for Stage 2 is warranted. (Following a 
cross-program review and decision to move forward with other studies, the Sponsor has 
decided that Cohort 3 will close to any further enrollment as of Protocol Amendment 2.) The 
total sample size for this study will range from 59 to 142. 
The criteria for rejecting the alternative hypothesis and declaring the experiment treatment as 
not efficacious at the end of Stage 1 and Stage 2 are listed in Table 4 below. For each cohort, 
if the number of responders by the end of Stage 1 is the same or less as defined by the 
criterion, the cohort will be terminated. For a cohort that proceeds to Stage 2, if the total 
number of responders by the end of Stage 2 is the same or less than the criterion, the 
alternative hypothesis will be rejected and the experimental treatment will be considered not 
efficacious for the indication in the cohort, unless the clinical judgment suggests otherwise.  
Table 3: Sample Size by Cohort 
Cohort 
No. 
Cohort Description 
Target 
RR 
SoC  
RR 
Sample Size 
1st 
Stage 
2nd 
Stage 
Total 
1/1A 
NSCLC (chemotherapy-naïve, PD-L1 TPS ≥ 
50%) 
65% 
45% 
16 
36 
52 
2/2A 
NSCLC (chemotherapy-naïve, PD-L1 TPS 1-
49%) 
50% 
33.5% 
20 
47 
67 
3 
SqNSCLC: Platinum and PD-1/PD-L1- treated 
20% 
9% 
23 
0 
23 
Abbreviations: NSCLC = non-small cell lung cancer; PD-1 = programmed cell death-1; PD-L1 = programmed death 
ligand-1; RR = response rate; SoC = standard of care; SqNSCLC = squamous non-small cell lung cancer; TPS = tumor 
proportion score. 
 
 


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Table 4: Criteria for Considering Treatment Efficacious by Cohort and Stage 
Cohort 
No. 
 Cohort Description 
Stage 1 
Criteria* 
Stage 2 Criteria*  
1/1A 
NSCLC (chemotherapy-naïve, PD-L1 TPS ≥ 50%) 
8 
20‡ 
2/2A 
NSCLC (chemotherapy-naïve, PD-L1 TPS 1-49%) 
7 
20‡ 
3 
SqNSCLC: Platinum and PD-1 or PD-L1-treated 
2 
NA 
Abbreviations: NA = not applicable; NSCLC = non-small cell lung cancer; PD-1 = 
programmed cell death-1; PD-L1 = programmed death ligand-1; SqNSCLC = squamous non-
small cell lung cancer; TPS = tumor proportion score. * Number of patients with responses 
(CR/PR) ‡ Not including stage 1 responders. 
 
2.3 
Randomization and Blinding 
This is an open-label study and patients will not be randomized.   
3 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
The primary objectives of this study are:  
• To evaluate the efficacy of the combination of niraparib and a PD-1 inhibitor in 
chemotherapy-naïve and PD-1 inhibitor-naïve patients with locally advanced and 
metastatic NSCLC whose tumors have high PD-L1 expression (TPS ≥ 50%), as 
assessed by objective response rate (ORR)  
• To evaluate the efficacy of the combination of niraparib and a PD-1 inhibitor in 
chemotherapy-naïve and PD-1inhibitor-naïve patients with locally advanced and 
metastatic NSCLC whose tumors express PD-L1 (TPS between 1 and 49%) as 
assessed by ORR  
• To evaluate the efficacy of single agent niraparib in patients with metastatic sqNSCLC 
who have been previously treated with both platinum-based chemotherapy and either 
PD-1 or PD-L1 inhibitor, as assessed by ORR 
 
3.2 
Secondary Objectives 
The secondary objectives of the study are as follows:  
• To evaluate the safety and tolerability of single agent niraparib and of the combination 
of niraparib and a PD-1 inhibitor  


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• To evaluate the following additional measures of clinical benefit of single agent 
niraparib and of the combination of niraparib and a PD-1 inhibitor:  
o Disease control rate (DCR)  
o Duration of response (DOR)  
o Progression-Free Survival (PFS)  
o Overall Survival (OS)  
 
4 
STUDY ENDPOINTS AND EVALUATIONS 
4.1 
Efficacy Endpoints 
4.1.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is objective response rate (ORR), defined as the proportion of 
patients with a confirmed best overall response (BOR) of complete response (CR) or partial 
response (PR) in the analysis population (See Section 6). Tumor assessments after the 
initiation of further anticancer therapy are excluded for the assessment of BOR. 
Response to treatment will be determined based on investigator evaluation of radiographic 
images according to RECIST v1.1. If CR or PR is observed, tumor imaging for confirmation 
of response needs to be performed at the earliest 28 days after the first indication of response, 
but no later than 35 days after the response.  
Confirmed BOR will be determined based on the RECIST v1.1. For a confirmed response, 
the tumor assessment date for the first recorded CR or PR will be considered as the date 
CR/PR achieved. 
All final efficacy analyses for response rate will be based on the confirmed response. 
Confirmation of response is not required for the purpose of determining if the study should 
continue enrolling stage 2 patients.  
4.1.2 Secondary Efficacy Endpoints 
4.1.2.1 Disease Control Rate 
Disease control rate (DCR) is defined as the proportion of patients with a best overall 
response of CR, PR or SD. 
4.1.2.2 Duration of Response 
Duration of Response (DOR) is defined as the time from first documented CR or PR until the 
subsequently documented disease progression or death, whichever occurs earlier. 


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DOR will be calculated as shown below for responders only using the censoring rules 
specified in Table 5.  
𝐷𝐷𝐷𝐷𝐷𝐷 (𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ𝑠𝑠) =
Date of PD/Death/Censoring –  Date of First recorded CR or PR + 1
30.4375
 
 
Table 5: Censoring Rules for DOR 
Situation  
Date of Event Censoring 
Outcome  
Start of subsequent anti-cancer therapy prior to a 
documented radiologic progression or death 
Date of last radiologic tumor assessment 
prior to or on the date of initiation of the 
subsequent anti-cancer therapy 
Censored 
No documented radiologic progression, no 
subsequent anti-cancer therapy started, and no 
death 
Date of last radiologic tumor assessment  
 
 
Censored  
Documented radiologic progression or death after 
two or more consecutive missing radiologic 
assessments* 
 
Date of last radiologic tumor assessment 
before the missed tumor assessments 
Censored  
Documented radiologic progression or death 
without two or more consecutive missing 
radiologic assessments* 
Earliest date of documented radiologic 
progression or death 
Event  
* Cohort 1, 1A, 2, and 2A: On-study tumor imaging requires an assessment every 9 weeks (63 ± 7 days) until Week 72, every 12 weeks 
(84 ± 7 days) after Week 72 from start of protocol treatment until progression or start of subsequent anticancer treatment. 
.  
Cohort 3: On-study tumor imaging requires assessment every 6 weeks (42 ± 7 days) until Week 24; every 9 weeks (63 ± 7 days) after 
Week 24 until Week 52, and then every 12 weeks ((84 ± 7 days) from start of protocol treatment until progression or start of subsequent 
anticancer treatment. 
 
 
4.1.2.3 Progression Free Survival (PFS) 
PFS defined as the time from the date of first dose to the date of disease progression or death 
due to any cause, whichever occurs earlier. 
PFS will be calculated as shown below using the censoring rules specified in Table 6. 
 
𝑃𝑃𝑃𝑃𝑃𝑃(𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ𝑠𝑠) =
Date of PD/Death/Censoring –  Date of First Dose + 1
30.4375


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Table 6: Censoring Rules for PFS 
Situation  
Date of Event Censoring 
Outcome  
No baseline tumor assessments 
First dose date 
Censored 
No post-baseline tumor assessments and no death  
First dose date 
Censored 
Start of subsequent anti-cancer therapy prior to a 
documented radiologic progression or death 
Date of last radiologic tumor assessment 
prior to or on the date of initiation of the 
subsequent anti-cancer therapy 
Censored 
No documented radiologic progression, no 
subsequent anti-cancer therapy started, and no 
death 
Date of last radiologic tumor assessment 
Censored  
Documented radiologic progression or death after 
two or more consecutive missing radiologic 
assessments* 
Date of last radiologic tumor assessment 
before the missed tumor assessments 
Censored  
Documented radiologic progression or death 
without two or more consecutive missing 
radiologic assessments* 
Earliest date of documented radiologic 
progression or death 
Event  
* Cohort 1, 1A, 2, and 2A: On-study tumor imaging requires an assessment every 9 weeks (63 ± 7 days) until Week 72, every 12 weeks 
(84 ± 7 days) after Week 72 from start of protocol treatment until progression or start of subsequent anticancer treatment. 
.  
Cohort 3: On-study tumor imaging requires assessment every 6 weeks (42 ± 7 days) until Week 24; every 9 weeks (63 ± 7 days) after 
Week 24 until Week 52, and then every 12 weeks ((84 ± 7 days) from start of protocol treatment until progression or start of subsequent 
anticancer treatment. 
 
4.1.2.4 Overall Survival 
Overall survival (OS) is defined as the time from date of first dose to the date of death due to 
any cause. Patients without documented death at the time of the final analysis will be 
censored at the last known alive date. 
The date of last known alive date will be derived for patients not known to have died at the 
analysis cut-off date using the latest complete date among the following:  
• Patient assessment dates (blood sampling [laboratory], vital signs, ECGs, tumor 
assessment) 
• Start and end date of AEs 
• Start and end date of study treatment 
• Start and end date of subsequent anti-cancer therapies administered after study 
treatment discontinuation 
• Date of study discontinuation for reasons other than lost-to-follow-up 
• Last date of contact recorded on the survival follow-up 
• Any assessment date after the analysis cut-off date will not be applicable. 
OS will be calculated as:  


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𝑂𝑂𝑂𝑂(𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ𝑠𝑠) = Date of Death/Censoring –  Date of First Dose + 1
30.4375
 
4.2 
Safety Evaluations 
The safety evaluations include:  
• Treatment emergent adverse events (TEAEs) 
• Extent of exposure 
• Clinical laboratory assessments  
- Hematology (including CBC and coagulation) 
- Chemistry (including thyroid function tests) 
- Urinalysis 
• Serum or urine pregnancy testing 
• Vital signs 
• Physical examination findings 
• ECG 
 
4.3 
Other Evaluations 
Other evaluations include: 
 
• Demographics and baseline characteristics (including NSCLC History) 
• Medical history 
- General medical history 
- Other cancer History 
- Surgical history  
- Prior blood disorders  
- Smoking history  
• Medication use/procedures 
- Prior medications and concomitant medications 
- Prior anticancer treatment for primary cancer 
- Subsequent anticancer treatment for primary cancer  
- Growth factors 
- Transfusions 
- Concomitant Procedures 
- Concomitant radiotherapy 
• ECOG Performance status  
• Drug accountability (Niraparib)  
• Pembrolizumab Administration 


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• TSR-042 Administration 
• Niraparib dose modification 
 
  
5 
PLANNED ANALYSES 
5.1 
Changes from planned Analyses in the Protocol 
5.2 
Interim Analyses 
Confirmation of response is not required for the purpose of determining if the study should 
continue enrolling stage 2 patients. Therefore, there will be no formally interim conducted 
for the study 
5.3 
Final Analyses and Reporting 
All final planned analyses per protocol and this SAP will be performed after database lock. All 
final efficacy analyses for response rate will be based on the confirmed response. 
 
6 
ANALYSIS POPULATIONS AND APPLICATIONS 
Statistical analysis and data tabulation will be performed using the following analysis 
populations unless specified otherwise: 
6.1 
Modified Intent-to-Treat Population 
Modified intent-to-treat (mITT) population includes all patients who received any study drug 
and did not withdraw consent prior to having at least one post-baseline tumor assessment. 
The modified ITT population will be the primary analysis population for the efficacy 
analyses. 
6.2 
Pharmacokinetic Population 
Pharmacokinetic (PK) population includes patients who have at least one of measurable 
niraparib concentration.  
6.3 
Safety Population 
Safety population includes patients who receive at least one dose of either study medications.  
The safety population will be the primary analysis population for the safety analyses. 


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6.4 
Application of Analysis Populations 
The analysis population(s) that will be used for creating the summary table(s) of each type is 
provided in Table 7.  All data will be presented in listings for the Enrolled population. 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). 
 
 


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Table 7: Application of Analysis Populations for Tables and Graphs 
Type 
Safety 
mITT 
PK* 
Disposition 
X 
X 
Demographics and baseline 
characteristics 
X 
X 
 
Protocol deviations 
X 
Medical and disease history 
X 
 
 
Prior and concomitant medications 
X 
 
 
Summary and analyses on efficacy 
endpoints 
 
X 
 
Summary statistics on PK 
 
 
Safety evaluations 
X 
 
 
Extent of Exposure 
X 
 
 
* The PK analyses will be provided in a separate document. 
7 
STATISTICAL CONSIDERATIONS 
All analyses described in this plan are considered priori analyses in that they have been 
defined prior to locking the database.  All other analyses, if any, designed subsequently to 
locking the database, will be considered post hoc analyses and will be described as 
exploratory analyses in the Clinical Study Report.  
All summaries and analyses for demographics, baseline characteristics, and safety data will 
be done by cohort and overall separately for  
• Stage 1 Receiving Combination of Niraparib and Pembrolizumab 
• Stage 1 Receiving Niraparib only Treatment 
• Stage 2 Receiving Combination of Niraparib and TSR-042  
The summaries and analyses of efficacy data will be provided by stage and cohort.  
All summaries and statistical analyses will be performed by SAS v9.3 or later.  
7.1 
General Statistical Procedures 
The descriptive statistics for continuous variables will be the mean, median, standard 


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deviation (SD), quartiles (Q1, Q3), minimum, maximum, and number of patients.  
Frequency distributions for all categorical variables will be presented using counts and 
percentages. 
7.2 
Patient Enrolment and Disposition 
7.2.1 Patient Enrollment  
Number of patients will be provided for each analysis population.  The denominators for 
percentages are number of enrolled. A patient is considered as enrolled when the patient has 
been consented, screened, and all eligibility criteria have been confirmed in the electronic 
case report form (eCRF).   
Enrollment information will be provided in a data listing. 
7.2.2 Patient Disposition 
Patient disposition will be summarized for the Safety population.  The summary will present 
frequency distribution for patients completing the study and discontinuing from the study 
overall and by reason for discontinuation.   
Additionally, the frequency distribution will be provided by reason for discontinuation as 
applicable for each cohort  
• for patients discontinuing treatment niraparib  
• for patients discontinuing treatment pembrolizumb 
• for patients discontinuing treatment TSR-042  
The denominators for calculating the percentages will be based on number of patients for 
each cohort and overall in the Safety population.  
Patient disposition will be provided in a data listing. 
7.2.3 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:  
• Impact the completeness, accuracy, and/or reliability of the study data, or  


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• Affect a subject's rights, safety, or well-being.  
 
Important protocol deviations require review to confirm whether they are significant. The 
following are PDs that will always be considered important according to TESARO SOP 
1000-00021-CLN:  
• Failure to obtain informed consent for participation in the clinical trial  
• Enrollment of ineligible subject  
• Subject developed withdrawal criteria during the study but was not withdrawn  
• Subject received incorrect treatment  
• Incorrect or non-compliant dosing of a subject, i.e. dosing that is inconsistent with the 
protocol  
• Administration of an excluded concomitant treatment to a trial subject  
• Incorrect cohort assignment  
 
A protocol deviation is classified as a significant PD if it has been confirmed to:  
• Adversely impact the completeness, accuracy, and/or reliability of the study data  
• Affect a subject’s rights, safety, or well-being.  
 
The TESARO medical monitor in conjunction with other study team members as appropriate 
may determine any PD not listed above to be important or significant based on his/her 
assessment of (potential) impact. Additionally, a PD could be “downgraded.” In this case, the 
rationale for the change should be documented by the TESARO medical monitor.  
 
Criteria for important and/or significant PDs may be updated as needed throughout the 
course of the clinical trial. 
All PDs will be identified and finalized prior to database lock.   
Number and percentage of patients with important or significant protocol deviations will be 
summarized, further by type of deviation. The denominators for calculating the percentages 
will be based on number of patients.  
All protocol deviations will be listed. 
7.3 
Demographic and Other Pre-treatment Variables 
7.3.1 
Demographics/Baseline Characteristics and Non-small Cell Lung Cancer 
History 
7.3.1.1 Demographics/Baseline Characteristics 
Patient demographics and baseline characteristics include:  


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• Age (years) calculated as (date of screening - date of birth) / 365.25 if date of birth is 
reported, or age as reported on the eCRF will be used 
• Age categories (18 to <65, 65 to <75, ≥75; and ≥65) 
• Race (American Indian/Alaska Native, Asian, Black or African American, Native 
Hawaiian or other Pacific Islander, White, and Other) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, and Unknown) 
• Baseline weight (in kilograms; if weight is reported in pounds, convert to kilograms 
by dividing by 2.2) 
• Baseline height (in centimeters; if height is reported in inches, convert to centimeters 
by multiplying by 2.54) 
• Baseline body mass index (BMI) (kg/m2), calculated using the patient’s height and 
weight [BMI (kg/m2) = weight (kg) / height (m)2] 
• ECOG performance status at baseline 
• Smoking status (Current Smoker, Former Smoker, Never Smoked, Unknown) 
• If female, childbearing status (Childbearing potential, Non-childbearing potential)  
Continuous data will be summarized for both Safety and mITT populations, using descriptive 
statistics.  
Categorical data will be summarized with frequency distributions using counts and 
percentages of patients in each category.  The denominators for calculating the percentages 
will be based on the number of patients in both Safety and mITT populations. 
Demographics and baseline characteristics will be provided in a listing. 
7.3.1.2 Non-small Cell Lung Cancer Disease History 
The following NSCLC disease history will be collected. 
• date of original diagnosis 
• overall cancer stage of original diagnosis 
• date of first diagnosis of advanced or recurrent or metastatic disease 
• stage of first advanced or recurrent or metastatic disease 
• histology at diagnosis 
• EGFR mutation, KRAS mutation, BRAF mutation, BRCA1/BRCA2 mutation, ALK 
translocation, and ROS1 translocation. 


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Time from original diagnosis and time from first diagnosis of advanced or recurrent or 
metastatic disease to the date of first dose, stages of cancer, histology, mutations and 
translocations will be summarized using descriptive statistics for continuous variables and 
frequency distribution for categorical variables.  
 
 A data listing will be provided for NSCLC history. 
7.3.1.3 PD-L1 Test Results  
The PD-L1 test results will be summarized for location of testing, PD-L1 IHC assay, and 
PD-L1 status as collected on CRF, and percent of TPS. 
The PD-L1 test results will be provided data listings. 
7.3.2 
Medical History 
7.3.2.1 General Medical History 
The medical history will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA). The frequency count and percentage of patients 
experiencing any medical conditions will be tabulated by MedDRA SOC and PT for each 
analysis population.  The denominators for calculating the percentages will be based on 
number of patients in the Safety population.  
A data listing of medical history will be provided. 
7.3.2.2 Other Cancer History, Surgery History, and Prior Blood Disorders 
Prior blood disorders will be coded using current version of MedDRA and summarized by 
MedDRA SOC, PT and CTCAE grade. Additionally, they will also be summarized by event 
collected on CRF and CTCAE grade.  
Other cancer history will be summarized by the types listed on the CRF as well. 
Data listings will be provided separately for other cancer history, surgery, and prior blood 
disorders. 
7.3.3 
Medication Use/Procedures 
All medications will be coded using the current version of World Health Organization 
(WHO) Drug Dictionary (WHO-DD). The count and percentage of patients who took 
prior/concomitant medications will be provided using therapeutic class and WHO Drug 
preferred name.  The denominators for calculating percentages will be based on the number 
of patients in each cohort of the Safety population. For the summary tables, if a patient has 
taken a prior or concomitant medication/subsequent treatment more than once, the patient 


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will be counted only once for the medication/treatment. 
Prior medications are defined as medications received prior to the first dose of either study 
drugs. Concomitant medications are defined as medications received during the treatment 
period. 
Prior and subsequent anticancer treatments for primary cancer will be summarized for the 
following information: 
• agent name listed on CRF 
• reason for administration 
• number of anticancer treatments (categorical)  
• number of anticancer treatments (categorical) in neoadjuvant, adjuvant, metastatic 
and other settings 
• time since the end of last anticancer treatment (months) 
• best response of last anticancer treatment 
• reason for discontinuation 
• treatment ongoing (only for subsequent) 
The denominators for calculating the percentages will be based on number of patients in each 
cohort of safety population. 
Number of patients receiving transfusions will be summarized by the type of transfusions. 
For each type of transfusion, number of units transfused will be presented in the table.   
All medications, prior and subsequent anticancer treatments, and transfusions will be 
provided in data listings. In addition, separate listings will be provided for: 
• Growth factors 
• Concomitant Procedures 
• Concomitant radiotherapy 
7.4 
Analysis of Efficacy Data 
7.4.1 
Primary Efficacy Data 
The primary efficacy variable is objective response rate (ORR), defined as the proportion of 
patients with a confirmed best overall response of complete response (CR) or partial response 


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(PR) in the analysis population. Tumor assessments after the initiation of further anticancer 
therapy are excluded for the assessment of best overall response. 
Number of responders, ORR, and its two-sided 80% and 95% binomial exact 
(Clopper-Pearson) confidence interval will be reported for each cohort.  
7.4.2 
Secondary Efficacy Data 
DCR will be analyzed using the same methods for ORR for each cohort.  
For each cohort, time-to-event variables (DOR, PFS, and OS) will be summarized in a 
descriptive manner using Kaplan-Meier method including median and its 95% confidence 
interval (CI), progression rates and their 95% CI at 3 months, 6 month, 9 months, 12 months, 
and 15 months. In addition, Kaplan-Meier curves will also be presented for time-to-event 
variables.  
The above efficacy data will be provided in listings. 
 
7.5 
Analysis of Safety Data 
7.5.1 
Adverse Events 
Adverse events will be classified into a standardized terminology MedDRA system organ 
classifications (SOC) and preferred terms (PT). Severity of AEs will be assessed by 
investigators according to CTCAE (v4.03).  
A treatment-emergent AE (TEAE) will be defined as any new AE that begins, or any 
preexisting condition that worsens in severity during the treatment period, which is after the 
earlier date of first dose of niraparib, pembrolizumab or TSR-042 as applicable.    
AEs that were possibly or definitely related to study drug niraparib or pembrolizumab or 
TSR-042 will be defined to be related to the study drugs while unrelated and unlikely related 
AEs will be defined as “not related”. AEs with the closest relationship to study drugs will be 
used for summary.   
Adverse events of special interest (AESI) will be collected and summarized.  
• Patients who received pembrolizumab will be monitored for AESI caused by 
abnormal hepatic tests with 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 
• Patients who received niraparib will be monitored for 
o MDS and AML 


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o New malignancy information, i.e., any malignancy identified after the start of 
study medication 
o Pneumonitis 
o Embryo-fetal toxicity   
• Regarding AESIs for TSR-042, no AESIs have been reported to date, therefore all 
serious AEs will be reasonably considered as AESI for patients who received TSR-
042. 
The number and percentage of patients who experienced an AE will be summarized. The 
denominator for calculating the percentages will be based on the number of patients in each 
cohort of the safety population.  
The following types of summaries will be provided: 
• Overview of TEAEs 
• TEAEs by SOC and PT 
• by SOC, PT, and Maximum CTCAE toxicity grade 
o TEAE 
o CTCAE Grade 3 or Greater TEAEs  
• TEAEs by PT in descending frequency 
• Drug-related TEAEs by SOC, PT, and Relationship to study drug 
• by SOC, PT, Relationship to study drug, and Maximum CTCAE toxicity grade  
o Drug-related TEAEs   
o Drug-related CTCAE Grade 3 or Greater TEAEs  
• by PT in descending frequency 
o Drug-related TEAEs by PT in descending frequency 
o Niraparib-related TEAEs by PT in descending frequency 
o Pembrolizumab-related TEAEs by PT in descending frequency  
o TSR-042-related TEAEs by PT in descending frequency 
• Treatment emergent SAE by SOC and PT 
• Drug-related treatment emergent SAE by SOC, PT, and Relationship to study 
drug 
• TEAEs leading to study drug interruption, reduction, and discontinuation 
o TEAEs leading to study drug interruption by SOC, PT, and Interrupted 
Drug 
o TEAEs leading to study drug reduction by SOC, PT, and Reduced Drug  
o TEAEs leading to study discontinuation by SOC, PT, and Discontinued 
Drug 
• Drug-Related TEAEs leading to study drug discontinuation SOC, PT, 


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Relationship to Drug, and Discontinued Drug 
• TEAEs leading to death by SOC and PT 
• Most commonly reported TEAEs (i.e., those events reported by ≥5% of all 
patients  
If a preferred term or system organ class was reported more than once for a patient, the 
patient would only be counted once in the incidence for that preferred term or system organ 
class.  
In tabulation by severity (i.e., CTCAE toxicity grade),  
• For a given preferred term, only the most severe preferred term for each patient will be 
included.   
• For a given system organ class, only the most severe system organ class for each patient 
will be included.   
All AEs will be provided in a data listing.  
7.5.2 
Study Drug Exposure and Compliance  
The following study drug exposure and compliance parameters will be summarized: 
• Duration of study drug exposure in months is defined as 
max(Date of last dose of niraparib + 1, Date of last dose of pembrolizumab + 21) 
− min(Date of first dose of niraparib, Date of first dose of pembrolizumab)
30.4375
 
• niraparib exposure parameters 
o Duration of niraparib exposure in months defined as 
Date of last dose of niraparib − Date of first dose of niraparib +  1
30.4375
 
o Number of cycles initiated as continuous variable 
o Number of cycles initiated as a categorical variable (1 cycle, 2 cycles, etc.) 
o Number of patients with at least one dose escalation 
o Number of patients with at least one dose interruption 
o Number of patients with at least one dose reduction 


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o Number of patients with at least one missed dose 
o Starting dose for niraparib 
o Cumulative niraparib dosage (mg) received defined as sum of all niraparib 
dose received. This will be derived using pill count data (dispensed - 
returned), whenever 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. 
o Actual dose intensity (mg/day) for niraparib defined as 
Cumulative niraparib dosage (mg) received
# of cycle initated ×  # planned dosing days per cycle 
o Intended dose intensity (mg/day) for niraparib defined as 
Intended dose (mg) at first cycle × # of planned niraparib dosing days per cycle
# planned dosing days per cycle
 
• pembrolizumab exposure parameters 
o Duration of pembrolizumab exposure in months defined as  
Date of last dose of pembrolizumab − Date of first dose of pembrolizumab +  21
30.4375
 
o Cumulative pembrolizumab dosage (mg) received defined as sum of all 
pembrolizumab dose received 
o Actual dose intensity (mg/wk) for pembrolizumab defined as 
Cumulative pembrolizumab dosage (mg) received
Duration of pembrolizumab exposure (wk)
 
o Intended dose intensity (mg/wk) for pembrolizumab defined as 
200 (mg)
3 (wk)
= 66.7 (mg/wk) 
o Relative dose intensity (%) for pembrolizumab defined as 
Actual dose intensity
Intended dose intensity × 100% 


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• TSR-042 exposure parameters 
o Duration of TSR-042 exposure in months defined as  
(Date of last dose of TSR042 − Date of first dose of TSR042 +  21) for the first cycles +
(Date of last dose of TSR042 −Date of first dose of TSR042 + 42 ) for applicable Cycle 5 or later
30.4375
 
o Cumulative TSR-042 dosage (mg) received defined as sum of all TSR-042 
dose received 
o Actual dose intensity (mg/wk) for TSR-042 defined as 
Cumulative TSR042 dosage (mg) received
Duration of TSR042 exposure (wk)
 
o Intended dose intensity (mg/wk) for TSR042 defined as 
500 (mg)
3 (wk)  (𝑜𝑜𝑜𝑜 1000 (mg)
6 (wk)
 ) = 166.7 (mg/wk) 
o Relative dose intensity (%) for TSR-042 defined as 
Actual dose intensity
Intended dose intensity × 100% 
Study drug exposure parameters will be summarized using descriptive statistics. Details of 
study drug administration, dose modifications and duration of exposure will be listed. 
7.5.3 
Clinical Laboratory Evaluations 
Clinical laboratory assessments (CBC, serum chemistry, TSH, T3 or FT3, and FT4) will be 
summarized by visit in descriptive nature. Descriptive statistics will be provided for 
continuous laboratory data and associated change from baseline. Frequency distribution will 
be provided for categorical laboratory.  
Baseline and post-baseline results will be converted to SI units and categorized as low, 
normal, or high relative to the normal range. Shift tables will be done by visit for each cohort. 
In addition, the worst toxicity grades for selected laboratory tests as listed in Appendix B will 
be determined for each patient based on worst abnormal high and abnormal low lab values.  
The shift table from baseline CTCAE grade to the worst NCI CTC grade will be provided.  
Corrected calcium will be derived using the following formula:  


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(mmol/L)
 
calcium
 
serum
 + 
(g/L))
albumin 
 
normal
 - 
(40
 * 
0.02
 
(mmol/L)
 
calcium
 
Corrected
=
 
Unless otherwise specified, for frequency laboratory tables, the denominators for calculating 
the percentages will be based on the number of patients with non-missing values at each visit 
in the Safety population of each cohort. 
For shift table from baseline to post-baseline visit, the denominators for calculating the 
percentages will be based on the number of patients with non-missing values at both baseline 
and each post-baseline analysis visit in the Safety population of each cohort.  
Liver function tests post baseline will be summarized at any post baseline by the following 
categories. 
• ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
• AST ≥ 3×ULN, AST ≥ 5xULN, AST ≥ 10×ULN, AST ≥ 20×ULN 
• (ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, 
(ALT or AST) ≥ 20×ULN 
• Total bilirubin ≥ 2×ULN 
• Concurrent ALT ≥ 3×ULN and total bilirubin ≥ 2×ULN 
• Concurrent AST ≥ 3×ULN and total bilirubin ≥ 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and total bilirubin ≥ 2×ULN and ALP > 
2×ULN 
• 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 
Urinalysis is only collected at screening. The data will be provided in a listing. Other 
laboratory data will also be provided in data listings. 
7.5.4 
 Vital Signs  
Vital signs (systolic and diastolic blood pressure, pulse, temperature, and weight) will be 
summarized by visit. Actual values and changes from baseline will be summarized at each 
visit. Baseline is defined as the last observation prior to start of the first dose of study 
drug(s).  
7.5.5 
Electrocardiogram 


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ECG summaries will present frequency table analysis of ECG interpretation (normal vs 
abnormal - NCS, abnormal - CS) by stage and overall for baseline and end of treatment.  The 
shift table from Baseline to end of treatment will also be provided. 
A separate summary will be provided for ECG measurements including heart rate, PR 
interval, QT interval, RR interval, and QRS complex. 
 
QTc will be used for the data analysis and interpretation. Commonly used techniques 
including Bazett’s (QTcB) and Fridericia’s (QTcF) methods are applied. QTcF will be used 
for the primary QT evaluation. A summary of the number and percentage of patients with 
QTc interval exceeding some predefined upper limit (e.g., >450 ms, >480 ms, >500 ms) will 
be provided. A summary of the number and percentage of patients with change from baseline 
in QTc interval exceeding some predefined upper limit (e.g., >30 ms, >60 ms) will be 
provided.  
Furthermore, a summary will also provide the number and percentage of patients for 
1. maximum post-baseline QRS interval ≥ 120 ms,  
2. heart rate ≤ 50 bpm and decrease from baseline ≥ 20 bpm or ≥ 120 bpm and increase 
from baseline ≥ 20 bpm 
3. PR interval >=220 ms and increase from baseline ≥ 20 ms. 
Detailed ECG results will be provided in a data listing. 
7.5.6 
Physical Examinations 
Physical examinations will be provided in a data listing only. 
7.5.7 
ECOG Performance Status 
Summary of ECOG performance status will present frequency distribution for each category. 
The denominators for calculating the percentages will be based on the number of patients 
without missing values. 
Details on ECOG status will be provided in a data listing. 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING  
As a general rule, missing data values are not imputed unless otherwise specified below and, 
in presentation of categorical variables, unknown and missing data may be presented as a 
separate category in some case and the denominator will include unknown or missing values 
as appropriate. 


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8.1 
Definition of Baseline 
For all evaluations unless otherwise noted, baseline is defined as the most recent 
measurement prior to the first administration of study drug. Baseline can be the same date as 
first dose, given the measurement is expected prior to first dose when only date information 
is available. 
8.2 
Analysis Visit Window 
For safety parameters including clinical laboratory data, measurements collected from 
unscheduled visits will not be included in the by-visit summary tables but will be included in 
the listings.  
8.3 
Efficacy Data Handling 
See Section 4.1. 
8.4 
Safety Data Handling 
For all safety data, only observed data will be used for analyses, and missing data will not be 
imputed. 
8.4.1 
Handling of Repeated Clinical Laboratory Tests 
The last repeat of laboratory results will be used in the summary tables for that visit. All the 
laboratory test results (original test results and repeated results) will be included in the data 
listings. 
8.4.2 
Handling of Partial Dates for AEs   
When determining the treatment emergent AE, partial dates will be handled as follows.  
• If the day of the month is missing, the onset day will be set to the first day of the month 
unless it is the same month and year as study treatment. In this case, the onset date will be 
assumed to be the date of treatment. 
• If the onset day and month are both missing, the month and day will be assumed to be 
January 1 unless the event occurred in the same year as the study treatment. In this case, 
the event onset will be set to the day of treatment to conservatively report the event as 
treatment-emergent.  
• A completely missing onset date will be set as the day of treatment. If the resulting onset 
date is after a reported date of resolution, the onset date will be set equal to the date of 
resolution.   
• Imputation of partial dates is used only to determine whether an event is treatment-
emergent; data listings will present the partial date as recorded in the eCRF. 


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8.4.3 
Handling of Partial Dates for Medications  
A medication with a completely missing start date will be considered a prior medication. A 
medication with a completely missing stop date will be considered a concomitant medication.   
When determining prior or concomitant medications, partial start dates of prior and 
concomitant medications will be assumed to be the earliest possible date consistent with the 
partial date. Partial stop dates of prior and concomitant medications will be assumed to be the 
latest possible date consistent with the partial date. In the case of completely missing stop 
date, medication will be assumed to be ongoing. In the case of complete missing start date, 
medication will be assumed to be prior medication. 
 


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9 
REFERENCE 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 
1989;10(1):1-10. 


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10 APPENDICES 
Appendix A. Response Criteria by Response Evaluation Criteria in Solid 
Tumors (RECIST), v1.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or nontarget) 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 nontarget lesions and normalization of 
tumor marker level. All lymph nodes must be nonpathological 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 1 or more nontarget lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): 
Appearance of 1 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 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 8: RECIST Response for Patients with Measurable Disease  
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
> 4 weeks Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
> 4 weeks 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 weeks 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; RECIST = Response 
Evaluation Criteria in Solid Tumors; SD = stable disease 
* See RECIST v1.1 publication for further details on what is evidence of a new lesion.  
** Only for nonrandomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in nontarget 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. 
 
 


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