Cohort A: PARP Inhibitor-Naïve Platinum-Resistant Ovarian Cancer Treatment Cohort With TSR-042, Bevacizumab, and Niraparib
Phase: PHASE2
Conditions: Ovarian Neoplasm
Sponsor: Tesaro, Inc.

Protocol 
Study ID:  213357 
Official Title of Study: COHORT A: PARP INHIBITOR-NAÏVE PLATINUM-
RESISTANT OVARIAN CANCER TREATMENT COHORT WITH TSR-042, 
BEVACIZUMAB, AND NIRAPARIB 
Approval Date of Document: 20-MAR-2018 

 
S U P P L E M E N T A   
3 0 0 0 -0 2 -0 0 5  
C O H O R T A: P A R P I N HI B I T O R-N AÏ V E P L A TI N U M -
R E SI S T A N T O V A RI A N C A N C E R T R E A T M E N T 
C O H O R T WI T H T S R -0 4 2,  B E V A CI Z U M A B, A N D 
NI R A P A RI B  
 
S p o ns or:  
T E S A R O  
1 0 0 0 Wi nter Street, S uite 3 3 0 0  
Walt ha m, M A 0 2 4 5 1  
+ 1 3 3 9 9 7 0 0 9 0 0  
Me dic al M o nit or:  
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Or g a niz ati o n:  
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I N D N o.: 
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E u dr a C T N o.:  
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2  
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2 0  Marc h 2 0 1 8  
 
C o nfi de nti alit y St ate me nt  
All i nf or m ati o n c o nt ai ne d i n t his d oc u me nt is pri vile ge d a n d c o nfi de nti al t o T E S A R O. A n y 
distri b uti o n, c o p yi n g, or discl os ure is strictl y pr o hi bite d wit h o ut pri or writte n a p pr o v al b y 
T E S A R O.  
 
 
1.  
TI T L E P A G E  
P P D

P P D
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INVESTIGATOR’S AGREEMENT 
 
I have read this cohort-specific protocol supplement, including all appendices. By signing this 
supplement, I agree to conduct the clinical study, following approval by an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), in accordance with the study protocol 
(comprising the master protocol and this cohort-specific supplement), the current International 
Conference on Harmonisation (ICH) Guideline for Good Clinical Practice (GCP), the 
Declaration of Helsinki (2013), 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 
cohort-specific protocol supplement and will receive all necessary instructions for performing 
the study according to the study protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 

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PROCEDURES IN CASE OF EMERGENCY 
Procedures in case of emergency are outlined in the master protocol. 
 

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2. 
SYNOPSIS 
Name of Sponsor/Company: TESARO 
Name of Investigational Product: TSR-042, bevacizumab, and niraparib 
Name of Active Ingredient: TSR-042, bevacizumab, and niraparib 
Title of Study: Phase 2 Multicohort Study to Evaluate the Safety and Efficacy of Novel Treatment 
Combinations in Patients with Recurrent Ovarian Cancer 
Cohort A: PARP Inhibitor-Naïve Platinum-Resistant Ovarian Cancer Treatment Cohort with 
TSR-042, Bevacizumab, and Niraparib 
Study center(s): To be determined 
Principal Investigator: To be determined 
Investigators: To be determined 
Studied period (years):  
Estimated date first patient enrolled: Q3 2018 
Estimated date last patient completed: Q2 2020 
Phase of development: 2 
 
Objectives:  
Primary: 
• 
To evaluate the efficacy of the combination of TSR-042, bevacizumab, and niraparib, as 
assessed by confirmed objective response rate (ORR), in patients with advanced, relapsed, 
high-grade ovarian, fallopian tube, or primary peritoneal cancer who have received 1 to 2 prior 
lines of anticancer therapy, are poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 
inhibitor-naïve, and have platinum-resistant but not refractory disease. 
Secondary: 
• 
To evaluate the following measures of clinical benefit for TSR-042, bevacizumab, and 
niraparib in patients with advanced, relapsed, high-grade ovarian, fallopian tube, or primary 
peritoneal cancer who have received 1 to 2 prior lines of anticancer therapy, are PARP 
inhibitor-naïve, and have platinum-resistant but not refractory disease: 
o Progression-free survival (PFS) 
o Overall survival (OS) 
o Duration of response (DOR) 
o Disease control rate (DCR) 
• 
To evaluate safety and tolerability in patients treated with TSR-042, bevacizumab, and 
niraparib. 
Exploratory: 
• 
To identify potential biomarkers including breast cancer susceptibility gene (BRCA) status, 
homologous recombination repair (HRR) gene status, homologous recombination deficiency 
(HRD) score, programmed death-ligand 1 (PD-L1) expression, and other disease-related or 
treatment-related biomarkers that would associate with tumor responses to the combination of 
niraparib, TSR-042, and bevacizumab based on the molecular profile of tumor tissue, blood, 
and optional ascitic fluid samples. 
• 
To evaluate the evolution of the molecular profile of the tumor and tumor microenvironment in 
response to treatment. 

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Methodology:  
The overall study design is described in the master protocol. 
In this cohort, all patients will receive treatment with TSR-042, bevacizumab, and niraparib 
(collectively referred to as “study treatment”) beginning on Cycle 1 Day 1 using the regimen detailed 
in the figure below. 
The safety, tolerability, and maximum tolerated dose of combination treatment with TSR-042, 
bevacizumab, and niraparib is currently being assessed in ongoing Study 3000-01-002 
(NCT03307785). If results from that study are not available at the initiation of treatment for this 
cohort, an interim safety analysis, which will be detailed in the statistical analysis plan, will be 
performed after a total of 12 patients are enrolled between Cohorts A and B and have completed 
2 cycles of therapy. If results from Study 3000-01-002 are available and support the feasibility of the 
outlined starting dose regimens, the safety interim analysis will not be performed. 
Cohort A Study Schema 
 
TSR-042 
500 mg on Day 1 Q3W for 4 cycles, followed by 1,000 mg every other cycle (Q6W) beginning on Cycle 5 
Day 1 until PD or toxicity 
Bevacizumab 
15 mg/kg on Day 1 of every 21-day cycle (Q3W) for up to 15 months 
Niraparib 
Starting doses are as follows:  
- 300 mg in patients with screening actual body weight ≥77 kg AND screening platelet count ≥150,000/μL  
- 200 mg in patients with screening actual body weight <77 kg OR screening platelet count <150,000/μL  
administered on Days 1 to 21 Q3W until PD or toxicity 
Abbreviations: PD = progressive disease; Q3W = every 3 weeks; Q6W = every 6 weeks. 
Number of patients (planned):  
A total of 40 patients are planned for enrollment in Cohort A. 
Diagnosis and main criteria for inclusion:  
The overall list of eligibility criteria for entry into this study is provided in the master protocol. The 
following are additional cohort-specific eligibility criteria for this cohort. Patients must meet all criteria 
in both the master protocol and this cohort-specific supplement in order to be eligible for enrollment in 
this cohort. 
Patients will be eligible for entry in this cohort if all of the criteria for inclusion in the master protocol 
are met, as well as the following cohort-specific criteria: 

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A1. Patients must be resistant to the most recent platinum-based therapy, defined for the purpose 
of this protocol as progression within 6 months from completion of a minimum of 4 cycles of 
platinum-containing therapy. This should be calculated from the date of the last administered 
dose of platinum therapy to the date of the radiographic imaging showing disease 
progression. Patients with primary platinum-refractory disease as defined by those who 
progressed during or within 4 weeks of completion of first platinum-based chemotherapy are 
not eligible. 
A2. Patient must not have received any prior therapy for ovarian cancer with a PARP inhibitor 
A3. Patient has had 1 to 2 prior lines of anticancer therapy for ovarian cancer (The definition of 
prior lines of therapy is provided in section 8.1, inclusions 3 of the master protocol). 
A4. Patient is able to take oral medications. 
Main criteria for exclusion: 
Patients will not be eligible for entry in this cohort if any of the criteria for exclusion in the master 
protocol are met, or any of the following cohort-specific criteria: 
A1. Patient has known hypersensitivity to TSR-042, bevacizumab, niraparib, their components, 
or their excipients 
A2. Patient has a known history of myelodysplastic syndrome or acute myeloid leukemia. 
A3. Patient has active autoimmune disease that has required systemic treatment in the past 
2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment  
A4. Patient received prior treatment with an anti-programmed death-1 or anti-PD-L1 agent  
A5. Patient has received prior treatment with anti-angiogenic therapy with the exception of 
bevacizumab. (Patients who received prior bevacizumab are eligible only if they did not 
discontinue bevacizumab due to toxicity, as established by the Investigator.) 
A6. Patient has bowel obstruction, had bowel obstruction within the past 3 months, or is 
otherwise judged by the Investigator to be at high risk for bowel obstruction related to the 
underlying disease. Patient has any history of abdominal fistula, gastrointestinal perforation, 
or intra-abdominal abscesses. Evidence of recto-sigmoid involvement by pelvic examination 
or significant bowel involvement on computed tomography scan 
A7. Patient has proteinuria as demonstrated by urine protein:creatinine ratio ≥1.0 at screening or 
urine dipstick for proteinuria ≥2 (Patients discovered to have ≥2 proteinuria on dipstick at 
baseline should undergo 24-hour urine collection and must demonstrate <2 g of protein in 
24 hours to be eligible.)  
A8. Patient is at increased bleeding risk due to concurrent conditions (eg, major injuries or 
surgery within the past 28 days prior to start of study treatment, history of hemorrhagic 
stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically significant 
hemorrhage within the past 3 months) 
A9. Patient has a history of recent major thromboembolic event defined as follows: 
a. Pulmonary embolism diagnosed within 3 months of enrollment 
b. Lower extremity deep venous thrombosis diagnosed within 3 months of enrollment 
Note: Patients with a history of thromboembolic disease on stable therapeutic 
anticoagulation for more than 3 months prior to enrollment are eligible for this study. 

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Investigational product, dosage, and mode of administration:  
On days on which more than one study treatment is administered, TSR-042 will be administered first, 
followed by bevacizumab, and then niraparib, as applicable. 
TSR-042: 
TSR-042 will be administered via a 30-minute intravenous (IV) infusion on Day 1 every 3 weeks 
(Q3W) at 500 mg for 4 cycles followed by 1,000 mg every other cycle (every 6 weeks) beginning on 
Cycle 5 Day 1. The Pharmacy Manual contains descriptions of the packaging of TSR-042 and 
instructions for the preparation and administration of TSR-042. 
Bevacizumab: 
Bevacizumab 15 mg/kg will be administered via IV infusion on Day 1 of every 21-day cycle Q3W for 
up to 15 months. The Pharmacy Manual contains descriptions of the packaging of bevacizumab and 
instructions for the preparation and administration of bevacizumab. 
Niraparib: 
Niraparib will be supplied as 100-mg capsules and will be administered orally once daily continuously 
throughout each 21-day cycle at the assigned dose. The starting dose will be 300 mg in patients with a 
screening actual body weight ≥77 kg AND screening platelet count ≥150,000/μL, and 200 mg in 
patients with a screening actual body weight <77 kg OR screening platelet count <150,000/μL. On or 
after Cycle 3 Day 1, patients receiving the 200-mg niraparib starting dose may have their niraparib 
dose increased to 300 mg daily after discussion with medical monitor or designee if hemoglobin is ≥9 
g/dL, platelets are ≥100,000/µL, and neutrophils are ≥1500/µL for all laboratory evaluations performed 
during the first 2 cycles. Patients will be instructed to take niraparib at the same time each day. 
Bedtime administration may be a potential method for managing nausea. Patients must swallow and 
not chew all capsules. The consumption of water and food is permissible. Niraparib will be dispensed 
to patients on Day 1 of every cycle (every 21 days) until the patient discontinues study treatment. The 
Pharmacy Manual contains descriptions of the packaging of niraparib and instructions for the 
preparation and administration of niraparib. 
Duration of treatment:  
Treatment with TSR-042 and niraparib will continue until disease progression or toxicity. Treatment 
with bevacizumab will continue for a maximum of 15 months in the absence of disease progression or 
toxicity. Unless otherwise indicated, treatment with each combination agent will continue independent 
of dose adjustments, interruptions, or discontinuation of treatment for other combination agents. 
Reference therapy, dosage and mode of administration:  
Not applicable. 
Criteria for evaluation: 
Efficacy: 
Efficacy endpoints are described in the master protocol.  
Safety: 
Safety endpoints are described in the master protocol. 
Biomarkers: 
Tumor tissue, blood, and optional ascitic fluid samples will be assessed to identify potential 
biomarkers including BRCA status, HRR gene status, HRD score, PD-L1 expression, and other 
disease-related or treatment-related biomarkers that would associate with tumor responses to the 
combination of TSR-042, bevacizumab, and niraparib. Additionally, samples will be assessed to 
evaluate the evolution of the molecular profile of the tumor and tumor microenvironment in response 
to treatment. 

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Statistical methods: 
Sample size calculation was performed using SAS® version 9.4 with the EXACT method. A sample 
size of approximately 40 patients is estimated for this cohort to provide assessment of clinical activity 
of the treatment based on ORR. The null hypothesis that the true response rate is ≤25% (H0: p ≤ 0.25) 
will be tested against a 1-sided alternative of ≥45% (Ha: p ≥ 0.45). If there are 15 or more responses 
observed among 40 treated patients, it will be concluded that the lower bound of 80% confidence 
interval excludes H0 and the null hypothesis will be rejected. With 40 patients treated, the cohort has 
87% power to rule out a ≤25% ORR (null hypothesis) when the true ORR is 45% at the 10% type I 
error rate (1-sided). 
Enrollment will be stratified based on histology (epithelial vs carcinosarcoma). Enrollment of patients 
with carcinosarcoma will be limited to comprise approximately 10% of the cohort (ie, approximately 
4 patients).  
Statistical methods are further described in the master protocol. 
 

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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
2. 
SYNOPSIS ...................................................................................................................5 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............10 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15 
5. 
INTRODUCTION ......................................................................................................17 
5.1. 
Background .................................................................................................................17 
5.1.1. 
Background of TSR-042 .............................................................................................17 
5.1.1.1. 
Nonclinical Experience ...............................................................................................18 
5.1.1.2. 
Clinical Experience .....................................................................................................18 
5.1.2. 
Background of Bevacizumab ......................................................................................19 
5.1.3. 
Background of Niraparib ............................................................................................20 
5.1.4. 
Background of Combination of TSR-042 and Niraparib ...........................................20 
5.1.4.1. 
Nonclinical Experience ...............................................................................................20 
5.1.4.2. 
Clinical Experience .....................................................................................................21 
5.1.5. 
Background of Combination of Bevacizumab and Niraparib ....................................21 
5.1.6. 
Combination of TSR-042, Bevacizumab, and Niraparib ............................................22 
5.2. 
Rationale for Current Study ........................................................................................22 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................24 
6.1. 
Primary Objective .......................................................................................................24 
6.2. 
Secondary Objectives .................................................................................................24 
6.3. 
Exploratory Objectives ...............................................................................................24 
7. 
INVESTIGATIONAL PLAN .....................................................................................25 
7.1. 
Overall Study Design ..................................................................................................25 
7.2. 
Number of Subjects ....................................................................................................25 
7.3. 
Treatment Assignment ................................................................................................26 
7.4. 
Dose Adjustment Criteria ...........................................................................................26 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................26 

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7.4.1.1. 
TSR-042 ......................................................................................................................26 
7.4.1.2. 
Bevacizumab ...............................................................................................................28 
7.4.1.3. 
Niraparib .....................................................................................................................28 
7.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses ....................................31 
7.5. 
Criteria for Study Termination ...................................................................................31 
7.6. 
Study Conduct ............................................................................................................31 
7.6.1. 
Schedule of Events .....................................................................................................31 
7.6.2. 
Procedures by Visit .....................................................................................................31 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................37 
8.1. 
Subject Inclusion Criteria ...........................................................................................37 
8.2. 
Subject Exclusion Criteria ..........................................................................................37 
8.3. 
Subject Withdrawal Criteria .......................................................................................38 
8.3.1. 
Discontinuation from Treatment .................................................................................38 
8.3.2. 
Discontinuation from the Study ..................................................................................38 
9. 
TREATMENT OF SUBJECTS ..................................................................................39 
9.1. 
Description of Study Drug ..........................................................................................39 
9.2. 
Concomitant Medications ...........................................................................................39 
9.2.1. 
Prohibited Medications ...............................................................................................39 
9.2.2. 
Contraception ..............................................................................................................40 
9.2.3. 
Rescue Medications and Supportive Care Guidelines ................................................40 
9.2.3.1. 
Pneumonitis ................................................................................................................40 
9.2.3.2. 
Diarrhea/Colitis ...........................................................................................................41 
9.2.3.3. 
Type 1 Diabetes Mellitus or Grade 3 or 4 Hyperglycemia .........................................41 
9.2.3.4. 
Hypophysitis ...............................................................................................................41 
9.2.3.5. 
Hyperthyroidism or Hypothyroidism .........................................................................41 
9.2.3.6. 
Hepatitis ......................................................................................................................42 
9.2.3.7. 
Renal Failure or Nephritis ..........................................................................................42 
9.2.3.8. 
Management of Infusion-related Reactions ................................................................42 
9.2.4. 
Other Study Restrictions .............................................................................................43 
9.3. 
Treatment Compliance ................................................................................................43 
9.4. 
Randomization and Blinding ......................................................................................44 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................45 

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10.1. 
Study Drug ..................................................................................................................45 
10.1.1. 
TSR-042 ......................................................................................................................45 
10.1.2. 
Bevacizumab ...............................................................................................................45 
10.1.3. 
Niraparib .....................................................................................................................45 
10.2. 
Study Drug Packaging and Labeling ..........................................................................45 
10.3. 
Study Drug Storage .....................................................................................................45 
10.4. 
Study Drug Preparation ..............................................................................................45 
10.5. 
Administration ............................................................................................................45 
10.5.1. 
TSR-042 ......................................................................................................................45 
10.5.2. 
Bevacizumab ...............................................................................................................46 
10.5.3. 
Niraparib .....................................................................................................................46 
10.6. 
Study Drug Accountability .........................................................................................46 
10.7. 
Study Drug Handling and Disposal ............................................................................46 
11. 
ASSESSMENT OF EFFICACY ................................................................................47 
11.1. 
Primary Endpoint: Objective Response Rate .............................................................47 
11.2. 
Secondary Efficacy Endpoints ....................................................................................47 
11.3. 
Biomarker Endpoints ..................................................................................................47 
12. 
ASSESSMENT OF SAFETY .....................................................................................48 
12.1. 
Safety Parameters .......................................................................................................48 
12.2. 
Adverse Events and Special Situations .......................................................................48 
13. 
STATISTICS ..............................................................................................................49 
13.1. 
Sample Size Determination ........................................................................................49 
13.2. 
Planned Analysis ........................................................................................................49 
13.3. 
Biomarker Analysis ....................................................................................................49 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................51 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................52 
16. 
ETHICS ......................................................................................................................53 
17. 
DATA HANDLING AND RECORDKEEPING .......................................................54 
18. 
PUBLICATION POLICY ..........................................................................................55 
19. 
LIST OF REFERENCES ............................................................................................56 
 

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LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................15 
Table 2: 
Guidelines for Treatment of Immune-related Adverse Events of Interest .................27 
Table 3: 
Niraparib Dose Modifications for Nonhematologic Adverse Reactions ....................29 
Table 4: 
Niraparib Dose Reductions for Nonhematologic Toxicity .........................................29 
Table 5: 
Niraparib Dose Modifications for Hematologic Toxicity ..........................................30 
Table 6: 
Schedule of Events .....................................................................................................34 
Table 7: 
Investigational Product ...............................................................................................39 
Table 8: 
TSR-042 Infusion Reaction Treatment Guidelines ....................................................42 
 

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LIST OF FIGURES 
Figure 1: 
Cohort A Study Schema .............................................................................................25 
 
  

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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
ADP 
adenosine diphosphate 
AE 
adverse event 
AESI 
adverse event of special interest 
ASCO 
American Society of Clinical Oncology 
BIW 
twice weekly 
BRCA 
breast cancer susceptibility gene 
CBC 
complete blood count 
CI 
confidence interval 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
EOT 
End of Treatment 
EU 
European Union 
GCSF 
granulocyte colony-stimulating factor 
HR 
hazard ratio 
HRD 
homologous recombination deficiency 
HRR 
homologous recombination repair 
Ig 
immunoglobulin 
IL-2 
interleukin-2 
irAEI 
immune-related adverse event of interest 
IV 
intravenous 
mPD-1 
mouse programmed death-1 
MRI 
magnetic resonance imaging 
ORR 
objective response rate 
PARP 
poly(ADP-ribose) polymerase 
PD 
progressive disease 
PD-1 
programmed death-1 
PD-L1 
programmed death-ligand 1 

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Abbreviation or Specialist Term 
Explanation 
PD-L2 
programmed death-ligand 2 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PO 
orally 
PROC 
platinum-resistant ovarian cancer 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
Q6W 
every 6 weeks 
QD 
once daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
TEAE 
treatment-emergent adverse event 
TIL 
tumor-infiltrating lymphocyte 
TNBC 
triple-negative breast cancer 
US 
United States 
 

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5. 
INTRODUCTION 
The objective of this study is to evaluate the efficacy and safety of novel combinations of 
niraparib and agents with strong scientific rationale for synergistic activity in patients with 
recurrent ovarian cancer. An introduction to the overall study is provided in the master protocol.  
Most patients with ovarian cancer present with advanced disease at diagnosis, and the majority 
of these patients will relapse after initial treatment. Recurrence within 6 months of platinum-
based chemotherapy is defined as platinum-resistant disease, which confers a significantly worse 
prognosis, with median overall survival (OS) reported in clinical studies ranging from less than a 
year to 19 months.1, 2, 3, 4 Current treatment options for patients with recurrent platinum-resistant 
ovarian cancer (PROC) provide only modest benefit. The National Comprehensive Cancer 
Network guidelines recommend nonplatinum-based regimens such as docetaxel, oral etopside, 
gemcitabine, paclitaxel with or without pazopanib, liposomal doxorubicin with or without 
bevacizumab, paclitaxel/bevacizumab, or topotecan with and without bevacizumab.5 For patients 
who have a breast cancer susceptibility gene (BRCA) mutation, the guidelines recommend 
olaparib and rucaparib.5 Use of a single chemotherapeutic agent will yield a reported objective 
response rate (ORR) in the range of 10% to 30%, with relatively short-lived responses of less 
than 8 months.6, 7, 8, 9, 10, 11, 12 The anti-angiogenesis agent bevacizumab has a modest single-agent 
activity with an ORR of 15% and a median progression-free survival (PFS) of 4.4 months 
reported for patients with PROC.13 A more recent randomized Phase 2 study evaluated paclitaxel 
with or without the anti-angiogenic agent pazopanib in patients with PROC who had received 
1 to 2 prior lines of therapy, yielding ORRs of 56% and 25% and median PFSs of 6.4 and 
3.5 months, respectively.4 Chemotherapy with or without bevacizumab was evaluated in a 
Phase 3 study that demonstrated a median PFS of 3.4 months with chemotherapy alone versus 
6.7 months with combination of chemotherapy with bevacizumab, ORR (by Response 
Evaluation Criteria in Solid Tumors [RECIST]) was 11.8% versus 27.3%, respectively.3 A 
post-hoc analysis of this study suggested somewhat better outcomes in the paclitaxel and 
bevacizumab-treated patients (ORR of 53% and median PFS of 10.4 months).14 Based on these 
results, bevacizumab in combination with paclitaxel, pegylated liposomal doxorubicin, or 
topotecan was approved for the treatment of platinum-resistant recurrent epithelial ovarian, 
fallopian tube, or primary peritoneal cancer.15 
The objective of this cohort (Cohort A) is to evaluate the efficacy and safety of the novel 
combination of TSR-042, bevacizumab, and niraparib in patients with recurrent PROC not 
previously exposed to treatment with poly(adenosine diphosphate [ADP]-ribose) polymerase 
(PARP) inhibitors who had 1 to 2 prior lines of therapy. 
5.1. 
Background 
5.1.1. 
Background of TSR-042 
TSR-042 is an immunoglobulin (Ig)G4-κ humanized monoclonal antibody that binds with high 
affinity to programmed death-1 (PD-1), resulting in inhibition of binding to programmed 
death-ligand 1 (PD-L1) and programmed death-ligand 2 (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 
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(IL-2) production upon addition of TSR-042. Furthermore, TSR-042 has an acceptable safety 
profile based on toxicology studies in cynomolgus monkeys. Additional information on the 
nonclinical and clinical experience with TSR-042 can be found in the TSR-042 Investigator’s 
Brochure. 
5.1.1.1. 
Nonclinical Experience 
TSR-042 binds with high affinity to human and cynomolgus monkey PD-1. TSR-042 blocks 
binding of soluble ligands to human PD-1 expressed on the surface of Chinese hamster ovary 
cells, with a 50% maximum inhibitory concentration of approximately 1 nM. TSR-042 enhances 
T cell activation, as measured by the production of IL-2 from activated CD4+ T cells, with a 
50% maximum effective concentration of approximately 1 nM. Full PD-1 receptor occupancy 
achieved by TSR-042 in human and cynomolgus monkey T cells from peripheral blood 
mononuclear cells was determined to occur at concentrations of approximately 1 μg/mL. 
Linear pharmacokinetic (PK) was observed for TSR-042 over the dose range tested of 10 mg/kg 
to 100 mg/kg. Sex had no effect on exposure. The volume of distribution at steady state was low 
and suggested minimal tissue penetration, which is commonly observed for therapeutic 
monoclonal antibodies. Weekly administration resulted in approximately 2- to 3-fold increase in 
TSR-042 exposure. 
In a 4-week repeat-dose toxicology study in cynomolgus monkeys, administration of TSR-042 at 
doses of 0, 10, 30, or 100 mg/kg was well tolerated and did not result in any treatment-emergent 
adverse events (TEAEs) on clinical signs, body weight, food consumption, electrocardiograms, 
ophthalmology, safety pharmacology parameters, clinical pathology, gross pathology, organ 
weight, or histopathology. The no-observed-adverse-effects level was ≥100 mg/kg in this study. 
In a 13-week repeat-dose toxicology study in cynomolgus monkeys, weekly IV TSR-042 at 
doses of 0, 10, 30, and 100 mg/kg was well tolerated at 30 and 100 mg/kg. One male 
(10 mg/kg/week) was euthanized because of chronic, unresolved generalized skin findings 
associated with swollen and firm inguinal lymph nodes on both sides. Terminal necropsies of the 
remaining animals showed microscopic findings of an immune-mediated nature in the kidney, 
liver, and heart in animals dosed with TSR-042 at ≥10 mg/kg/week. Although these findings are 
commonly observed in cynomolgus monkeys, the severity of these findings was slightly 
increased in TSR-042-dosed animals compared to control animals. Considering the mechanism 
of action of TSR-042, these microscopic findings could be a result of the pharmacological effects 
of TSR-042. Because of the euthanasia of 1 male dosed in the 10 mg/kg dose group, the NOAEL 
could not be determined in this study. 
5.1.1.2. 
Clinical Experience 
TSR-042 has been evaluated as monotherapy in one Phase 1 study to date. Study 4010-01-001 
(NCT02715284) is an ongoing first-in-human Phase 1 study of TSR-042 to evaluate the safety 
and tolerability, PK, pharmacodynamics, and clinical activity of TSR-042 in patients with 
advanced solid tumors. The study is being conducted in 2 parts: 
• Part 1 (dose escalation) of the study used a modified 3 + 3 design to evaluate 
3 ascending weight-based doses of TSR-042 as follows: 1, 3, and 10 mg/kg 
administered every 2 weeks (Q2W) via IV infusion.  

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• Part 2 of the study is being conducted in 2 subparts (Part 2A and Part 2B) to explore 
the safety and clinical activity of TSR-042 administered as a fixed dose (ie, not 
weight based). 
 In Part 2A, following the completion of Part 1, the safety and tolerability of 
TSR-042 was evaluated at fixed doses of 500 mg every 3 weeks (Q3W) and 
1,000 mg every 6 weeks (Q6W) using a modified 6 + 6 design.  
 In Part 2B, the clinical activity, tolerability, and safety of TSR-042 at the 
recommended Phase 2 dose will be evaluated in patients with specific tumor 
types.  
As of 21 January 2018, 135 subjects with heavily pretreated advanced solid tumors have been 
treated with TSR-042 in Study 4010-01-001: 21 subjects in Part 1 and 114 subjects in Part 2A 
and 2B. 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. 
TSR-042 is also being studied in combination with other treatments, including TSR-022, an anti-
TIM3 antibody (4020-01-001) and TSR-033, an anti-LAG3 antibody (4040-01-001). As of 
January 2018, 28 subjects received TSR-042 in combination with TSR-022 in Study 4020-01-
001.  
5.1.2. 
Background of Bevacizumab 
Bevacizumab is an antiangiogenic recombinant humanized monoclonal Ig G1 antibody against 
the vascular endothelial growth factor protein. Bevacizumab (Avastin; Genentech/Roche United 
States [US]) has been approved in the US and European Union (EU) for the treatment of multiple 
tumor types in combination with certain other treatments. In the EU, bevacizumab is approved 
for the front-line treatment of adult patients with advanced (International Federation of 
Gynecology and Obstetrics Stages IIIB, IIIC, and IV) ovarian cancer. In the US, bevacizumab is 
approved for the treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary 
peritoneal cancer that is either platinum-resistant (in combination with paclitaxel, pegylated 
liposomal doxorubicin, or topotecan) or platinum-sensitive (in combination with carboplatin and 
paclitaxel or in carboplatin and gemcitabine, followed by Avastin as a single agent). 
Bevacizumab has been evaluated in multiple clinical studies, including in 361 patients with 
recurrent PROC as part of a Phase 3 study (AURELIA).3, 14 Patients receiving bevacizumab 
administered concurrently with single-agent chemotherapy (N=179) showed statistically 
significant improvement in PFS compared to chemotherapy alone (6.7 months vs 3.4 months; 
hazard ratio [HR], 0.48; p < 0.001) and statistically significant improvement in objective 
response rate (ORR) compared to chemotherapy alone (30.9% vs 12.6%; 95% confidence 

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interval [CI], 9.6-27.0; p < 0.001, by RECIST and/or Gynecology Cancer Intergroup cancer 
antigen 125 criteria). 
Statistically significant improvement with bevacizumab was observed regardless of 
chemotherapy regimen (paclitaxel: 10.4 months vs 3.9 months; HR, 0.46; 95% CI, 0.30-0.71; 
pegylated liposomal doxorubicin: 5.4 months vs 3.5 months; HR, 0.57; 95% CI, 0.39-0.83; and 
topotecan: 5.8 months vs 2.1 months; HR, 0.32; 95% CI, 0.21-0.49). 
Safety observations in this study were consistent with the safety profile of bevacizumab. 
Grade ≥2 hypertension and proteinuria were observed more frequently with bevacizumab than 
with chemotherapy alone. No new safety signals were observed. 
5.1.3. 
Background of Niraparib 
Overall clinical experience with niraparib is summarized in the master protocol. 
5.1.4. 
Background of Combination of TSR-042 and Niraparib 
5.1.4.1. 
Nonclinical Experience 
The efficacy and tolerability of niraparib in combination with anti-PD-1 therapy was evaluated in 
several nonclinical models. The combination was well tolerated in all of these studies. The 
combination was first tested in a homologous recombination-deficient ovarian cancer mouse 
model derived from breast cancer susceptibility gene (BRCA) null genetic background16, as 
PARP inhibition was previously shown to increase immune cell infiltration in BRCA-deficient 
models.17 In a study of an ovarian carcinoma mouse model18, niraparib (50 mg/kg orally [PO] 
once daily [QD]) and anti-mouse programmed death-1 (mPD-1; 5 mg/kg intraperitoneally twice 
weekly [BIW]) were administered to mice either alone or in combination for 16 days. The 
combination was tolerated with no treatment-related death. Almost all the tumors achieved 
complete regression upon treatment with niraparib, anti-mPD-1, and the combination. Complete 
regression was first observed on treatment Day 16 in 2 of 6, 1 of 6, and 4 of 6 mice from the 
niraparib, anti-mPD-1, and combination groups, respectively. These results suggest that the 
therapeutic approach of combining niraparib with a PD-1 inhibitor such as TSR-042 may provide 
additional benefit for patients with homologous recombination-deficient tumors.  
Niraparib and anti-PD-1 combination treatment has also been evaluated in several syngeneic 
models representing breast cancer 1 and breast cancer 2 (BRCA1/2) wild-type tumors, 1 of which 
was the breast cancer mouse model LPA1-T22. In study of a syngeneic transplant breast cancer 
model, niraparib (50 mg/kg PO QD) and anti-PD-1 antibody (10 mg/kg IV BIW) were 
administered to mice either alone or in combination for 15 days. While these tumors were 
moderately responsive to niraparib or anti-PD-1 antibody alone, with average tumor growth 
inhibition of approximately 50% for niraparib and 30% for PD-1 antibody, synergistic anti-tumor 
activity with near-complete tumor growth inhibition (>95%) was achieved with the 
combination.19 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-1 alone (30.5%).20 Together, these data support the therapeutic approach of 
combining niraparib with an anti-PD-1 agent. 

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5.1.4.2. 
Clinical Experience 
Combination treatment with TSR-042 and niraparib is currently being assessed in ongoing 
Study 3000-01-002 (NCT03307785); no clinical data are currently available for TSR-042 and 
niraparib combination treatment.  
Niraparib is also being evaluated in combination with another anti-PD-1 agent, pembrolizumab, 
in patients with triple-negative breast cancer (TNBC) or recurrent PROC as part of a Phase 1/2 
study (TOPACIO/KEYNOTE-162).21  
In Phase 1 of the study, 5 patients with TNBC and 9 patients with recurrent PROC received 
200 mg pembrolizumab via IV infusion on Day 1 of each 21-day cycle and 200 mg 
(Dose Level 1) or 300 mg (Dose Level 2) niraparib per day orally. DLTs included neutropenia, 
anemia, and thrombocytopenia in 1 patient at Dose Level 1 and thrombocytopenia in 2 patients at 
Dose Level 2. The recommended Phase 2 dose regimen was determined to be 200 mg niraparib 
per day orally (increasing to 300 mg after Cycle 2 in patients with no significant hematologic 
toxicities) in combination with 200 mg pembrolizumab via IV infusion on Day 1 of each 21-day 
cycle. Tumor responses included partial response or complete response in 5 of the 9 patients with 
recurrent PROC; the remaining 4 patients had stable disease.  
In Phase 2 of the study as of August 2017, no new safety signals have been observed. In 
36 patients with recurrent PROC, the most frequently reported Grade ≥3 TEAEs were anemia 
(16.7%), fatigue and platelet count decreased (5.6% each), and thrombocytopenia (2.8%).  
5.1.5. 
Background of Combination of Bevacizumab and Niraparib 
The combination of a PARP inhibitor and an angiogenesis inhibitor has the potential for 
improved PFS benefits in patients with or without homologous recombination deficiency (HRD).  
Tumor cells with a deficiency in homologous recombination are exquisitely sensitive to PARP 
inhibitors due to synthetic lethality. It has been observed that, for tumors without genetic or 
epigenetic defects in homologous recombination pathway genes, a functional state of HRD may 
be induced by hypoxia through transcriptional downregulation of homologous recombination-
related genes, including RAD51 and BRCA1. In addition, cyclic (acute) hypoxia and 
reoxygenation can induce both single-strand and double-strand deoxyribonucleic acid (DNA) 
breaks within tumor cells due to increased levels of reactive oxygen species.22, 23 These 
2 mechanisms working together lead to heightened sensitivity to PARP inhibitors when cells are 
under hypoxic stress exerted by angiogenesis inhibitors. It has been observed that PARP 
inhibitors selectively induce apoptosis in hypoxic tumor regions in vivo, supporting the idea of 
contextual synthetic lethality between hypoxia-induced functional HRD and PARP inhibition. In 
the clinical setting, preliminary evidence of clinical efficacy has been observed in patients with 
platinum-sensitive ovarian cancer treated with either niraparib combined with bevacizumab 
(ENGOT-OV24/AVANOVA trial24) or olaparib combined with cediranib (Phase 2), irrespective 
of their BRCA mutation or HRD status.25 These data provide a strong rationale for combining a 
PARP inhibitor with an angiogenesis inhibitor. 
To validate the hypothesis that tumors without HRD can be effectively treated with the 
combination of niraparib and bevacizumab, the HRD status for pretreatment tumor tissue will be 
determined using the Myriad research HRD assay. 

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The combination of niraparib and bevacizumab treatment is currently being explored in patients 
with recurrent platinum-sensitive ovarian cancer as part of an ongoing Phase 1/2 study 
(AVANOVA).24 Phase 1 of the study (dose escalation) has determined the recommended Phase 2 
dose in this population to be 300 mg niraparib orally once daily and 15 mg/kg bevacizumab via 
IV infusion Q3W. Results to date, although limited, indicate clinical activity of the combination 
in this patient population.  
Overall, the combination of niraparib and bevacizumab appears to be safe for administration, 
with a manageable safety profile. Adverse events (AEs) observed to date are consistent with 
those of the individual components and are readily managed through routine laboratory testing 
(ie, complete blood count), clinical surveillance (ie, blood pressure monitoring), and adherence 
to the recommended dose modifications. 
5.1.6. 
Combination of TSR-042, Bevacizumab, and Niraparib 
Combination treatment with TSR-042, bevacizumab, and niraparib is currently being assessed in 
ongoing Study 3000-01-002 (NCT03307785); no clinical data are currently available. However, 
the efficacy and safety of the combination of a PD-L1 inhibitor, a PARP inhibitor, and an 
anti-angiogenic agent have been studied in a Phase 1/2 study in women’s cancers.26 Data from 
the study indicates anticancer activity of the triplet combination, especially in ovarian cancer. At 
the dosing levels explored, the combination was tolerable and hematologic toxicity and 
cardiovascular toxicity observed in the study were consistent with PARP inhibitor-class and 
anti-vascular endothelial growth factor receptor treatments, respectively.   
5.2. 
Rationale for Current Study 
Over recent years, research has revealed the importance of tumor infiltrating lymphocytes in 
controlling the clinical progression of various cancers, and their presence in a tumor is associated 
with response to immune checkpoint inhibitors.27 In ovarian cancer, intraepithelial CD8+ T cells 
correlated with the presence of mutation or loss of expression of BRCA1 through promoter 
methylation.28 Ovarian cancer patients that were sensitive to agents targeting defects in DNA 
repair are likely to overlap with those tumors with an active yet checkpoint-blocked immune 
response. 
The activity of PD-1/PD-L1 inhibitors observed in ovarian cancer (ORR of 11% to 12% with 
single agent pembrolizumab or avelumab in small studies) has been modest so far.29, 30 However, 
preclinical data suggest there may be synergistic interaction between immune checkpoint 
inhibitors and PARP inhibitors. Nonclinical experiments in syngeneic mouse models have shown 
an increased response rate to the combination of anti-PD-1 and PARP inhibitors over either agent 
alone, providing additional support to investigate this combination in patients.31, 32 Exposure of a 
tumor in vivo to PARP inhibitor results in increased cancer cell death by 2 independent 
mechanisms. First, through the mechanism of synthetic lethality, the PARP inhibitor can kill 
tumors with HRD through apoptosis. Second, the PARP inhibitor can increase the number of 
CD8+ T cells and natural killer cells, as well as their production of interferon-γ and tumor 
necrosis factor-α.16, 33 Niraparib has also been shown to enhance immune responses in tumor 
microenvironment via activation of the stimulator of the interferon gene (STING) pathway, 
which renders tumors immunologically “hot” with an increase in infiltrating lymphocytes, 
resulting in an improved response to checkpoint blockade.31  

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Combination treatment with anti-PD-1 agent pembrolizumab and PARP inhibitor niraparib was 
evaluated in a dose escalation Phase 1b study and was shown to be tolerable with early signs of 
efficacy in patients with advanced solid tumors, including ovarian and breast cancers.34 A study 
to determine the safety, tolerability, and recommended Phase 2 dose of PD-1 inhibitor TSR-042 
in combination with niraparib (Study 3000-01-002, NCT03307785) is underway.  
The combination of niraparib and bevacizumab treatment is currently being explored in patients 
with recurrent platinum-sensitive ovarian cancer as part of an ongoing Phase 1/2 study 
(AVANOVA).24 Although limited, results to date indicate clinical activity of the combination in 
this patient population. 
In addition to a strong scientific rationale for the combinations of PARP inhibitors with immune 
checkpoint inhibitors as well as antiangiogenic agents, the approach of combining all 
3 mechanism of action was tested in a Phase 1/2 study of olaparib (PARP inhibitor), cediranib 
(anti-angiogenic agent), and durvalumab (PD-L1 inhibitor).35 This 3-drug combination showed 
acceptable safety data and early encouraging anticancer effects, supporting the potential 
synergistic effect of the combination. Among 9 patients treated, 3 (33%) had partial response 
(6, 6 plus, and 7 plus months, respectively) and 4 (44%) had stable disease (3, 7 plus, 9, and 
15 plus months, respectively).36 
Cohorts A and B of the present clinical study are designed to evaluate the novel triple 
combination of PD-1 inhibitor TSR-042, bevacizumab, and niraparib in the PROC patient 
population, based on the nonoverlapping safety and metabolic profiles and nonclinical and 
clinical data suggesting possible synergy. The safety and tolerability of this combination are 
currently being evaluated in Study 3000-01-002 (NCT03307785), and the results of 
Study 3000-01-002 will further support the justification of the starting dose in Cohort A of the 
current trial. 
Given recent as well as future anticipated approvals of several PARP inhibitors for treatment and 
maintenance in ovarian cancer, the treatment landscape in ovarian cancer will be changing 
significantly. The use of PARP inhibitors, initially approved for treatment in late lines of 
therapy, is expected to move into maintenance setting in earlier lines, especially for patients with 
BRCA mutation/HRD. However, the efficacy of re-treatment with the same mechanism of action 
for patients who previously progressed on PARP inhibitors is unknown. Therefore, Cohort A of 
the present protocol will be evaluating the efficacy of TSR-042, bevacizumab, and niraparib in 
patients with PROC not previously exposed to PARP inhibition, while Cohort B will evaluate if 
patients who previously progressed on PARP inhibitors can subsequently respond to a 
combination approach and be resensitized to PARP inhibitors through synergy with bevacizumab 
and PD-1 antibody. Given the expected treatment landscape evolution, Cohort A will focus on 
patients with early relapse (1 or 2 prior lines of therapy), and Cohort B will focus on the PROC 
patient population in later lines of therapy (2 to 3 prior lines of therapy). 

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6. 
TRIAL OBJECTIVES AND PURPOSE 
The following are the cohort-specific objectives for this study, which have been further specified 
from the overall study objectives presented in the master protocol. 
6.1. 
Primary Objective 
• To evaluate the efficacy of the combination of TSR-042, bevacizumab, and niraparib, 
as assessed by confirmed ORR, in patients with advanced, relapsed, high-grade 
ovarian, fallopian tube, or primary peritoneal cancer who have received 1 to 2 prior 
lines of anticancer therapy, are PARP inhibitor-naïve, and have platinum-resistant but 
not refractory disease. 
6.2. 
Secondary Objectives 
• To evaluate the following measures of clinical benefit for TSR-042, bevacizumab, 
and niraparib in patients with advanced, relapsed, high-grade ovarian, fallopian tube, 
or primary peritoneal cancer who have received 1 to 2 prior lines of anticancer 
therapy, are PARP inhibitor-naïve, and have platinum-resistant but not refractory 
disease: 
 Progression-free survival (PFS) 
 Overall survival (OS) 
 Duration of response (DOR) 
 Disease control rate (DCR) 
• To evaluate safety and tolerability in patients treated with TSR-042, bevacizumab, 
and niraparib. 
6.3. 
Exploratory Objectives 
• To identify potential biomarkers including BRCA status, homologous recombination 
repair (HRR) gene status, HRD score, PD-L1 expression, and other disease-related or 
treatment-related biomarkers that would associate with tumor responses to the 
combination of TSR-042, bevacizumab, and niraparib based on the molecular profile 
of tumor tissue, blood, and optional ascitic fluid samples. 
• To evaluate the evolution of the molecular profile of the tumor and tumor 
microenvironment in response to treatment. 

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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
The overall study design is described in the master protocol. 
In this cohort, all patients will receive treatment with TSR-042, bevacizumab, and niraparib 
(collectively referred to as “study treatment”) beginning on Cycle 1/Day 1 using the regimen 
detailed in Figure 1. 
As described in Section 5.1.6, combination treatment with TSR-042, bevacizumab, and niraparib 
is currently being assessed in ongoing Study 3000-01-002 (NCT03307785). If results from that 
study are not available at the initiation of treatment for this cohort, an interim safety analysis will 
be performed after a total of 12 patients are enrolled between Cohorts A and B and have 
completed 2 cycles of therapy. If results from Study 3000-01-002 are available and support the 
feasibility of the outlined starting dose regimens, the safety interim analysis will not be 
performed. 
Figure 1: 
Cohort A Study Schema 
 
TSR-042 
500 mg on Day 1 Q3W for 4 cycles, followed by 1,000 mg every other cycle (Q6W) beginning on 
Cycle 5 Day 1 until PD or toxicity 
Bevacizumab 
15 mg/kg on Day 1 of every 21-day cycle (Q3W) for up to 15 months 
Niraparib 
Starting doses are as follows:  
- 300 mg in patients with screening actual body weight ≥77 kg AND screening platelet count 
≥150,000/μL  
- 200 mg in patients with screening actual body weight <77 kg OR screening platelet count 
<150,000/μL  
administered on Days 1 to 21 Q3W until PD or toxicity 
Abbreviations:  PD = progressive disease; Q3W = every 3 weeks; Q6W = every 6 weeks. 
7.2. 
Number of Subjects 
A total of 40 patients are planned for enrollment in Cohort A. 

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7.3. 
Treatment Assignment 
All patients enrolled in this cohort will receive TSR-042, bevacizumab, and niraparib as 
indicated in Figure 1. 
7.4. 
Dose Adjustment Criteria 
7.4.1. 
Safety Criteria for Adjustment or Stopping Doses 
Dosing regimens for TSR-042, bevacizumab, and niraparib are described in Section 7.1. The 
rationale for the starting doses of TSR-042 and niraparib is provided in Section 5.1.4.2; the 
rationale for weight- and platelet-based dosing for niraparib is provided in Section 5.1.2.2 of the 
master protocol. Unless otherwise indicated, treatment with each combination agent will 
continue independent of dose adjustments, interruptions, or discontinuation of treatment for other 
combination agents. 
7.4.1.1. 
TSR-042 
AEs (both nonserious and serious) associated with TSR-042 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 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 will be permanently discontinued for any drug-related Grade 4 AE. TSR-042 
must be permanently discontinued for certain irAEIs as described in Table 2.  
The specific immune-related AEs typically observed with anti-PD-1 antibodies will be managed 
according to the guidelines summarized below.5 
The reason for interruption or discontinuation of TSR-042 should be recorded in the electronic 
case report form (eCRF). 
Immune-related Adverse Events of Interest and Guidelines for Management 
Given the mechanism of action of TSR-042, it is anticipated that activation of cellular immune 
system can be manifested as immune-related AEs. Based on available safety data from 
checkpoint inhibitors, TEAEs with the specific grades listed below were selected as irAEIs. The 
list of irAEIs may be updated upon emerging data. 
Refer to Table 2 for details on the management of TSR-042 dose delays and discontinuation for 
specific irAEIs. Detailed guidance for the administration of rescue medications and supportive 
care is available in Section 9.2.3. For all irAEIs listed in Table 2, TSR-042 should be withheld 
until the patient is clinically and metabolically stable and AEs have resolved to Grade ≤1. If 
systemic steroids are used as a part of irAEI management, the total dose of daily steroids should 
be equal to or less than prednisone 10 mg at the time of resuming TSR-042. 
All treatment delays (including any missed doses) and discontinuations, and the reason for delays 
or discontinuation of TSR-042, should be recorded in the eCRF. 

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Of note, if the attribution of an AE is not clear between TSR-042 and niraparib (examples might 
include diarrhea or aspartate aminotransferase or alanine aminotransferase elevation), both 
agents may be withheld and a discussion with the Sponsor’s Medical Monitor is recommended.  
Table 2: 
Guidelines for Treatment of Immune-related Adverse Events of Interest 
Toxicity 
Withhold Treatment for 
AE Grade 
Restarting Treatment/Discontinuation 
Diarrhea/colitis 
2 to 3 
Restart dosing when toxicity resolves to Grade 0 to 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) 
Restart dosing when toxicity resolves to Grade 0 to 1 (see 
exception below).a 
3 or 4  
(AST or ALT >5× ULN 
or total bilirubin 
>3× ULN) 
Permanently discontinue (see exception below).a 
T1DM or 
hyperglycemia 
3 or 4 hyperglycemia or 
T1DM (associated with 
metabolic acidosis or 
ketonuria) 
Restart dosing in appropriately managed, clinically and 
metabolically stable patients, insulin replacement therapy is 
required. 
Immune-related 
encephalitis 
Any grade 
Permanently discontinue. 
Hypophysitis 
2 to 4 
For Grade 2 to 3 AEs, hold 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. 
Hyperthyroidism 
3 
Restart dosing when toxicity resolves to Grade 0 to 1. 
4 
Permanently discontinue. 
Infusion-related 
reaction 
2b 
Restart dosing when toxicity resolves to Grade 0 to 1. 
3 or 4 
Permanently discontinue. 
Pneumonitis 
2 
Restart dosing when toxicity resolves to Grade 0 to 1. If 
Grade 2 recurs, permanently discontinue. 
3 or 4 
Permanently discontinue. 
Rash 
3 
Restart dosing when toxicity resolves to Grade 0 to 1. 
4 
Permanently discontinue. 

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Toxicity 
Withhold Treatment for 
AE Grade 
Restarting Treatment/Discontinuation 
Renal failure or 
nephritis 
2 
Restart dosing when toxicity resolves to Grade 0 to 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; 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; refer to Section 9.2.3 for further management 
details. 
7.4.1.2. 
Bevacizumab 
The Investigator is advised to consult the current bevacizumab label. Dose reductions of 
bevacizumab are not permitted in this study.15, 37 
Interrupt bevacizumab treatment for the following AEs: proteinuria, medically significant 
hypertension that cannot be adequately controlled with antihypertensive therapy, hypertension in 
the presence of posterior reversible encephalopathy syndrome, development of hypertensive 
crisis or hypertensive encephalopathy, or nephrotic syndrome. In case of uncontrolled 
hypertension, niraparib should also be held in addition to bevacizumab.  
Resume bevacizumab treatment only when 1) hypertension is controlled by hypertensive 
regimen, or 2) urine protein is <2 g per 24 hours urine collection.15 Niraparib should be resumed 
with bevacizumab when hypertension is controlled by hypertensive regimen. If hypersensitivity 
or infusion reactions occur during bevacizumab infusion, the infusion should be discontinued. 
Except in cases where permanent discontinuation of bevacizumab is indicated, resumption of the 
standard dose of bevacizumab upon resolution of other adverse reactions is at the discretion of 
the Investigator. 
Bevacizumab treatment should be withheld 4 weeks prior to elective surgery. In patients who 
experience wound healing complications during the study, treatment with bevacizumab should 
be withheld until the wound is fully healed.   
7.4.1.3. 
Niraparib 
Niraparib Dose Interruption and Modification 
Treatment must be interrupted for any nonhematologic Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 3 or 4 AE that the Investigator considers to be related to 
administration of niraparib (Table 3). If the nonhematologic toxicity is appropriately resolved to 
baseline or Grade ≤1 within 4 weeks (28 days) of the dose interruption period, the patient may 
restart treatment with niraparib but with a dose level reduction if prophylaxis is not considered 
feasible (see Table 4). If the event recurs at a similar or worse grade, treatment should be 

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interrupted again and, upon resolution, a further dose reduction must be made. No more than 
2 dose reductions will be permitted (ie, to a minimum dose of 100 mg QD).  
If the toxicity requiring dose interruption has not resolved completely or to CTCAE Grade 1 
during the maximum 4-week (28-day) dose interruption period, or the patient has already 
undergone a maximum of 2 dose reductions (to a minimum dose of 100 mg QD), the patient 
must permanently discontinue treatment with niraparib. 
Of note, if the attribution of an AE is not clear between TSR-042 and niraparib (examples might 
include diarrhea or aspartate aminotransferase or alanine aminotransferase elevation), both 
agents may be withheld and a discussion with the Sponsor’s Medical Monitor is recommended.  
The dose interruption and modification criteria for niraparib for hematologic parameters will be 
based on blood counts and are outlined in Table 5. If the hematologic toxicity has not recovered 
to the specified levels within 4 weeks (28 days) of the dose interruption period, or the patient has 
already undergone a maximum of 2 dose reductions (to a minimum dose of 100 mg QD), the 
patient must permanently discontinue treatment with niraparib. 
Table 3: 
Niraparib Dose Modifications for Nonhematologic Adverse Reactions 
Abnormality 
Intervention 
Nonhematologic CTCAE Grade ≥3 adverse reaction 
where prophylaxis is not considered feasible or adverse 
reaction persists despite treatment 
Withhold niraparib for a maximum of 28 days or until 
resolution of adverse reaction. 
Resume niraparib at a reduced dose per Table 4. Up to 
2 dose reductions are permitted for the starting dose of 
300 mg; only 1 dose reduction is permitted for the 
starting dose of 200 mg. 
CTCAE Grade ≥3 treatment-related adverse reaction 
lasting more than 28 days while patient is administered 
niraparib 100 mg/day 
Discontinue niraparib. 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events. 
 
Table 4: 
Niraparib Dose Reductions for Nonhematologic Toxicity 
 
Body weight <77 kg OR screening 
platelet count <150,000/μL 
Body weight ≥77 kg AND screening 
platelet count ≥150,000/μL 
Starting dose 
200 mg/day (two 100 mg capsules) 
300 mg/day (three 100 mg capsules) 
First dose reduction 
100 mg/day (one 100 mg capsule) 
200 mg/day (two 100 mg capsules) 
Second dose reduction 
Discontinue medication. 
100 mg/daya (one 100 mg capsule) 
Abbreviations: AE = adverse event; CTCAE = Common Terminology Criteria for Adverse Events; QD = once 
daily; SAE = serious adverse event. 
a If further dose reduction below 100 mg/day is required, discontinue niraparib. 

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Table 5: 
Niraparib Dose Modifications for Hematologic Toxicity 
Laboratory Abnormality 
Intervention 
Monitor complete blood counts weekly for the first cycle, once every treatment cycle thereafter  
Platelet count <100,000/μL 
First occurrence: 
Withhold niraparib for a maximum of 28 days and monitor blood counts 
weekly until platelet counts return to ≥100,000/μL. 
Resume niraparib at same or reduced dose.a 
If platelet count is <75,000/μL, resume niraparib at a reduced dose 
Second occurrence: 
Withhold niraparib for a maximum of 28 days and monitor blood counts 
weekly until platelet counts return to ≥100,000/μL. 
Resume niraparib at a reduced dose.a 
Discontinue niraparib if the platelet count has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the patient has 
already undergone dose reduction to 100 mg QD. 
Neutrophil count <1,000/μL 
Withhold niraparib for a maximum of 28 days and monitor blood counts 
until neutrophil counts return to ≥1,500/μL.  
Resume niraparib at a reduced dose.a 
Discontinue niraparib if neutrophil level has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the patient has 
already undergone dose reduction to 100 mg QD. 
Note: Prophylactic cytokines (ie, granulocyte colony-stimulating factor 
[GCSF]) should not be administered in the first cycle of the study but 
may be administered in subsequent cycles according to current American 
Society of Clinical Oncology (ASCO) guidelines. 
Hemoglobin ≤8 g/dL 
Withhold niraparib for a maximum of 28 days and monitor blood counts 
until hemoglobin returns to ≥9 g/dL.  
Resume niraparib at a reduced dose.a 
Discontinue niraparib if hemoglobin has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the patient has 
already undergone dose reduction to 100 mg QD. 
Hematologic adverse reaction 
requiring transfusion 
For patients with platelet count ≤10,000/μL, platelet transfusion should 
be considered. If there are other risk factors such as co-administration of 
anticoagulation or antiplatelet drugs, consider interrupting these drugs or 
transfusion at a higher platelet count. 
Red blood cell transfusion may be given at the discretion of the 
Investigator. 
Resume niraparib at a reduced dose.a 
Confirmed diagnosis of MDS or 
AML 
Permanently discontinue niraparib. 
Abbreviation: AML = acute myeloid leukemia; MDS = myelodysplastic syndrome; QD = once daily.  
a Niraparib dose must not be decreased below 100 mg daily. Additional details on dose reduction are described in 
Table 4.  
If dose interruption or modification is required at any point during study treatment because of 
hematologic toxicity, weekly blood draws for complete blood count (CBC) will be monitored 

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until the AE resolves to the specified blood count levels. To ensure the safety of the new dose, 
weekly blood draws for CBC will be required for an additional 4 weeks after the AE has 
resolved, after which monitoring every treatment cycle may resume.  
Any patient requiring transfusion of platelets or red blood cells (≥1 unit) must undergo a dose 
reduction upon recovery if study treatment is resumed. 
If a diagnosis of myelodysplastic syndrome/acute myeloid leukemia is confirmed by a 
hematologist, the patient must permanently discontinue study treatment. 
For major surgery while on study treatment, up to 4 weeks (28 days) of study treatment 
interruption is allowed.  
Once the dose of study treatment has been reduced, any re-escalation must be discussed with the 
Sponsor’s Medical Monitor. 
All dose interruptions and reductions (including any missed doses), and the reasons for the 
reductions/interruptions, are to be recorded in the eCRF. Reasons for the discontinuation of 
niraparib must also be recorded in the eCRF. 
7.4.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
Not applicable. 
7.5. 
Criteria for Study Termination 
Criteria for study termination are described in the master protocol. 
7.6. 
Study Conduct 
7.6.1. 
Schedule of Events 
The schedule of study procedures is provided in Table 6. 
7.6.2. 
Procedures by Visit 
Treatment Cycles 
Treatment cycles are 21 days (± 3 days) long. 
Visits should occur within ± 3 days of the scheduled visit. All times should be recorded using the 
24-hour clock (eg, 23:20, not 11:20 PM). 
Radiographic Evaluation for Primary Outcome 
All patients are required to undergo radiographic evaluation throughout the study as described in 
Table 6. Tumor imaging (chest, abdomen, and pelvis [plus head if clinically indicated]) should 
be performed by computed tomography (CT with IV contrast unless contraindication; preferred). 
Magnetic resonance imaging (MRI) should only be used if clinically appropriate, when CT is 
contraindicated, or for imaging of the head, 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. Positron emission tomography/CT may be used according to Response 
Evaluation Criteria in Solid Tumors (RECIST) v1.1 guidelines. If the chest or head CT/MRI is 

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clear at screening, repeat imaging of these areas is not required in the absence of clinical 
indication requiring follow‐up. Bone scans should be conducted per standard of care. 
Serum tumor marker data (eg, cancer antigen 125) will not be used for defining objective 
responses or disease progression; however, serum tumor marker data can be used for clinical 
decisions. Response to treatment will be based on Investigator evaluation of radiographic 
images. 
Radiographic evaluations to assess extent of disease will be conducted every 9 weeks (63 days 
± 7 days) while on study treatment, independent of cycle delays or dose interruptions, or at any 
time when progression of disease is suspected. After 1 year of radiographic assessments, patients 
will have imaging performed every 12 weeks (84 ± 14 days). Radiographic evaluations will 
continue until progressive disease (PD), start of alternate anticancer treatment, withdrawal of 
consent to study participation, becoming lost to follow-up, death, or end of the study. Per 
RECIST v1.1, complete response or partial response should be confirmed; tumor imaging for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of 
response or at the next scheduled scan (ie, 9 or 12 weeks later), whichever is clinically indicated. 
There is accumulating evidence indicating clinical benefit in a subset of patients treated with 
immunotherapy despite initial evidence of PD.38 Patients with PD may continue study treatment 
at the Investigator’s discretion only after discussion with the Sponsor, until the Investigator has 
determined that the patient is no longer experiencing clinical benefit or until study treatment is 
no longer tolerated by the patient. 
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 (ie, every 
9 weeks [63 ± 7 days] for the first year of treatment and every 12 weeks [84 ± 14 days] 
thereafter) until PD, start of alternate anticancer treatment, withdrawal of consent to study 
participation, becoming lost to follow-up, death, or end of the study. 
Biomarker Assessment 
Tumor tissue, blood, and optional ascitic fluid samples will be collected as indicated in Table 6 
to identify potential biomarkers.  
End of Treatment Visit and Safety Follow-up Visit 
All patients will undergo an End of Treatment (EOT) visit within 7 days after study treatment 
discontinuation. A safety follow-up visit will be conducted 30 days (± 7 days) after the last dose 
of study treatment. Safety follow-up visits are required only for those patients who have not 
started an alternate anticancer therapy. After the 30-day safety follow-up visit, all patients will 
enter the post-treatment follow-up period of telephone assessment for survival status and the 
occurrence of any treatment-related serious adverse events (SAEs) or adverse events of special 
interest (AESIs) every 90 (± 14 days), or as otherwise indicated in Section 12 and the master 
protocol, until patient discontinuation of study, withdrawal of consent, or death. Patients who 
discontinue the study due to treatment toxicity or intolerability and do not have PD will continue 
radiographic imaging until PD, start of alternate anticancer treatment, withdrawal of consent to 
study participation, becoming lost to follow-up, death, or end of the study.  
Safety Assessments 

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Safety assessments conducted during this study include collection of AEs, vital sign 
measurements, symptom-directed physical examinations, electrocardiograms, clinical laboratory 
assessments, and Eastern Cooperative Oncology Group performance status.  
 

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Table 6: 
Schedule of Events 
Cycle/Visita 
Screening 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Subsequent 
Cycles 
EOT 
Safety 
Follow
-up 
Survival 
Assessment 
Day 
Procedure 
-21 to -1 
1 
8 
15 
1 
1 
1 
1 
1 
1 
+7 
days 
post 
trt 
30 ±7  
days 
Every 90 
±14 days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, surgical, cancer, 
and medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor assessment 
(RECIST v1.1)  
X 
 
 
 
 
 
Xb 
 
 
Xb 
Xb 
 
Xbc 
Tumor tissue  
Xd 
 
 
 
Xd 
(C2D1-C3D1) 
 
 
 
 
 
 
 
Blood sample 
Xd 
 
 
 
Xd 
(C2D1-C3D1) 
 
 
 
 
 
 
 
Ascitic fluid (optional) 
Xe 
 
 
Laboratory assessments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBCf 
X 
Xg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum chemistry  
X 
Xg 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation  
X 
Xg 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy testh 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Urinalysis  
X 
Xg 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urine sample for proteini 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 

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Cycle/Visita 
Screening 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 
4 
Cycle 
5 
Cycle 
6 
Subsequent 
Cycles 
EOT 
Safety 
Follow
-up 
Survival 
Assessment 
Day 
Procedure 
-21 to -1 
1 
8 
15 
1 
1 
1 
1 
1 
1 
+7 
days 
post 
trt 
30 ±7  
days 
Every 90 
±14 days 
TSH, T3 or FT3, and 
FT4 or equivalentj 
X 
 
 
 
 
X 
 
X 
 
Xj 
X 
X 
 
Serum CA-125 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
ECG 
X 
As necessary according to standard of care 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Symptom-directed physical 
examination  
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Vital signs, height, and 
weightk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance status  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AE monitoringl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TSR-042 study treatment 
administeredm  
 
X 
 
 
X 
X 
X 
X 
 
Xn 
 
 
 
Bevacizumabm 
 
X 
 
 
X 
X 
X 
X 
X 
Xo 
 
 
 
Niraparib study treatment 
dispensed/collected 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Survival assessment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; C = cycle; CA-125 = cancer antigen 125; CBC = complete blood count; 
CT = computed tomography; D = day; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = End of Treatment; FT3 = free 
triiodothyronine; FT4 = free thyroxin; MRI = magnetic resonance imaging; PD = disease progression; RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event; T3 = triiodothyronine; TSH = thyroid-stimulating hormone. 

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a Treatment cycles are 21 days long, with visits on Day 1 of each cycle beyond Cycle 1, unless otherwise specified. Visits for subsequent cycles continue every 
21 days (±3 days) until study treatment discontinuation. Results of the laboratory evaluations (with the exception of thyroid studies) should be reviewed before 
study treatment administration.  
b Radiographic evaluations (CT/MRI of chest, abdomen, and pelvis) to assess extent of disease will be conducted every 9 weeks (63 days ± 7 days) while on 
study treatment independent of cycle delays and/or dose interruptions, and/or at any time when progression of disease is suspected. After 1 year of radiographic 
assessments, patients will have imaging performed every 12 weeks (84 ± 14 days). Radiographic evaluations will continue until PD, start of alternate anticancer 
treatment, withdrawal of consent to study participation, becoming lost to follow-up, death, or end of the study.   
c If a patient discontinues treatment for a reason other than progression or death, withdrawal of consent, loss to follow-up, or the end of the study, scans and 
cancer antigen 125 (CA 125) testing should continue at the specified intervals (ie, every 9 weeks for the first year of study and every 12 weeks thereafter until 
PD) 
d All patients included in the study must provide blood and tumor samples at screening. Tumor samples provided at screening need to be obtained after most 
recent disease progression or freshly biopsied. All patients included in the study must provide on-treatment tumor (provided it is deemed safe and feasible by 
the Investigator) and blood samples. The on-treatment tumor sample must be collected between Cycle 2 Day 1 and Cycle 3 Day 1, preferably from the same 
lesion used for the screening assessment. The blood sample must be collected at the same time (± 3 days) as when on treatment tumor samples are collected. 
Time and dose of last treatment before biopsy must be collected.  
e Ascitic fluid collection is optional but preferred when paracentesis is performed for clinical reasons between screening to EOT. 
f If dose interruption or modification is required at any point on study because of hematologic toxicity, weekly blood draws for CBC will be monitored until the 
AE resolves, and to ensure safety of the new dose, weekly blood draws for CBC also will be required for an additional 4 weeks after the AE has been resolved 
to the specified levels, after which monitoring every treatment cycle may resume. 
g If screening laboratory testing (CBC, serum chemistry, coagulation, urinalysis, and CA-125, and TSH, T3 or FT3, and FT4 or equivalent) is performed within 
72 hours of first dose of study treatment on Day 1, repeat testing is not required. 
h For women of childbearing potential only. 
i Urine dipstick or urine analysis for protein determination should be performed prior to each bevacizumab administration. Patients discovered to have ≥2 
proteinuria on dipstick should not be administered bevacizumab, should undergo a 24-hour urine collection, and must demonstrate <2 g of protein in 24 hours 
to be eligible for bevacizumab treatment to resume. 
j If TSH, T3 or FT3, or FT4 are not available, equivalent tests should be performed. TSH testing will be done at screening, Cycle 3, and every other cycle 
thereafter. 
k Vital signs include blood pressure, pulse, and temperature. Height obtained at screening only. Weight obtained at screening and Day 1 of each cycle only. 
l AEs are required to be captured through 30 days after cessation of study treatment, SAEs are required to be captured through 90 days after cessation of study 
treatment (or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy), and any pregnancies that occur within 180 days post 
treatment are to be captured. In conjunction with the survival assessment, AESIs (regardless of causality) and study-drug related SAEs will be collected every 
90 ± 14 days after the last dose of study treatment, or as otherwise indicated in Section 12 and the master protocol. 
m On days on which more than one study treatment is administered, TSR-042 will be administered first, followed by bevacizumab, and then niraparib, as 
applicable. 
n TSR-042 will be administered at a dose of 500 mg on Day 1 every 3 weeks for 4 cycles, followed by 1000 mg every other cycle (every 6 weeks) beginning on 
Cycle 5 Day 1, until progression or toxicity. 
o Bevacizumab will be administered for a maximum of 15 cycles. 
 

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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The overall list of eligibility criteria for entry into this study is provided in the master protocol. 
The following are additional cohort-specific eligibility criteria for this cohort. Patients must meet 
all criteria in both the master protocol and this cohort-specific supplement in order to be eligible 
for enrollment in this cohort. 
8.1. 
Subject Inclusion Criteria 
A1. Patients must be resistant to the most recent platinum-based therapy, defined for the 
purpose of this protocol as progression within 6 months from completion of a minimum 
of 4 cycles of platinum-containing therapy. This should be calculated from the date of the 
last administered dose of platinum therapy to the date of the radiographic imaging 
showing disease progression. Patients with primary platinum-refractory disease as 
defined by those who progressed during or within 4 weeks of completion of first 
platinum-based chemotherapy are not eligible. 
A2. Patient must not have received any prior therapy for ovarian cancer with a PARP 
inhibitor 
A3. Patient has had 1 to 2 prior lines of anticancer therapy for ovarian cancer (The definition 
of prior lines of therapy is provided in Section 8.1, inclusion 3 of the Master Protocol). 
A4. Patient is able to take oral medications. 
8.2. 
Subject Exclusion Criteria 
A1. Patient has known hypersensitivity to TSR-042, bevacizumab, niraparib, their 
components, or their excipients 
A2. Patient has a known history of myelodysplastic syndrome or acute myeloid leukemia 
A3. Patient has active autoimmune disease that has required systemic treatment in the past 
2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment  
A4. Patient received prior treatment with an anti-PD-1 or anti-PD-L1 agent 
A5. Patient has received prior treatment with anti-angiogenic therapy with the exception of 
bevacizumab. (Patients who received prior bevacizumab are eligible only if they did not 
discontinue bevacizumab due to toxicity, as established by the Investigator.) 
A6. Patient has bowel obstruction, had bowel obstruction within the past 3 months, or is 
otherwise judged by the Investigator to be at high risk for bowel obstruction related to the 
underlying disease. Patient has any history of abdominal fistula, gastrointestinal 
perforation, or intra-abdominal abscesses. Evidence of recto-sigmoid involvement by 
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A7. Patient has proteinuria as demonstrated by urine protein:creatinine ratio ≥1.0 at screening 
or urine dipstick for proteinuria ≥2 (Patients discovered to have ≥2 proteinuria on 
dipstick at baseline should undergo 24-hour urine collection and must demonstrate <2 g 
of protein in 24 hours to be eligible.)  
A8. Patient is at increased bleeding risk due to concurrent conditions (eg, major injuries or 
surgery within the past 28 days prior to start of study treatment, history of hemorrhagic 
stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically significant 
hemorrhage within the past 3 months) 
A9. Patient has a history of recent major thromboembolic event defined as follows: 
a. Pulmonary embolism diagnosed within 3 months of enrollment 
b. Lower extremity deep venous thrombosis diagnosed within 3 months of enrollment 
Note: Patients with a history of thromboembolic disease on stable therapeutic 
anticoagulation for more than 3 months prior to enrollment are eligible for this study. 
8.3. 
Subject Withdrawal Criteria 
8.3.1. 
Discontinuation from Treatment 
Examples of reasons for discontinuing study treatment applicable across cohorts are presented in 
the master protocol. Details of required dose modifications related to toxicity, including 
interruptions, reductions, and permanent discontinuations, are provided in Section 7.4.1. 
Unless otherwise indicated, treatment with each combination agent will continue independent of 
dose adjustments, interruptions, or discontinuation of treatment for other combination agents.  
8.3.2. 
Discontinuation from the Study 
Guidance on discontinuation of patients from the study is provided in the master protocol. 

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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
The investigational products for this cohort are described in Table 7. 
Table 7: 
Investigational Product 
 
Investigational Product 
Product name: 
TSR-042 
Bevacizumab 
(Avastin) 
Niraparib 
Dosage form: 
Solution for 
infusion 
Infusion 
Capsule 
Unit dose 
500 mg, 50 mg/mL 
15 mg/kg infusion 
100 mg per capsule 
Route of administration 
Intravenous 
Intravenous 
Oral 
Physical description 
Solution for 
intravenous 
infusion in 
single-use vial 
Clear to slightly 
opalescent, colorless 
to pale brown, 
sterile solution for 
intravenous infusion 
Capsules in 
high-density 
polyethylene bottles 
Manufacturer 
WuXi AppTec 
Genentech, Inc. 
QSP (Charles River 
Laboratories 
Contract 
Manufacturing) 
9.2. 
Concomitant Medications 
Details on the definition and recording of concomitant medications are provided in the master 
protocol. 
9.2.1. 
Prohibited Medications 
Known prior medications that exclude a patient from participating in this cohort are described in 
the exclusion criteria (see Section 8.2). 
Medications prohibited in the overall study are provided in the master protocol. The following 
additional therapies are prohibited during the screening and treatment phase for this cohort.  
• Investigational agents other than TSR-042, bevacizumab, and niraparib 
• 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 
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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. 
• Prophylactic cytokines (ie, granulocyte colony-stimulating factor [GCSF]) should not 
be administered in the first cycle of the study but may be administered in subsequent 
cycles according to current American Society of Clinical Oncology (ASCO) 
guidelines.39  
In addition, niraparib has been shown to weakly induce cytochrome P450 (CYP) 1A2 in vitro 
and is an insensitive substrate for P-glycoprotein. Therefore, Investigators and patients should be 
advised to use caution with drugs that are sensitive substrates of CYP1A2 with narrow 
therapeutic range, such as theophylline and tizanidine. The niraparib safety profile includes risk 
for thrombocytopenia, and bevacizumab may increase the potential for bleeding (hemorrhage); 
therefore, patients should be advised to use caution with anticoagulants (eg, warfarin) and 
antiplatelet drugs (eg, aspirin). Physicians should follow the current versions of the TSR-042 
Investigator’s Brochure, the Zejula® package insert39, the Avastin® [Genentech/Roche US] 
package insert40, and the niraparib Investigator’s Brochure for information on the general 
management of the patients receiving these therapies. 
9.2.2. 
Contraception 
Contraception guidelines are provided in the master protocol. 
9.2.3. 
Rescue Medications and Supportive Care Guidelines 
Supportive care measures for AEs during treatment with niraparib should be provided as deemed 
necessary by the treating Investigator according to local institutional practice and/or guidance in 
the appropriate prescribing information. 
During treatment with TSR-042, 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, GCSF) should not be administered in the first cycle 
of the study but may be administered in subsequent cycles according to current ASCO 
guidelines.39 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. 
9.2.3.1. 
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. 

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• Consider prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
9.2.3.2. 
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. 
9.2.3.3. 
Type 1 Diabetes Mellitus or Grade 3 or 4 Hyperglycemia 
For type 1 diabetes mellitus and for Grade 3 or 4 hyperglycemia associated with metabolic 
acidosis or ketonuria, insulin replacement therapy is required. 
9.2.3.4. 
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. 
9.2.3.5. 
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. 

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Pa g e 4 2  of 5 8  
•  Gra de 2 t o 4 H Y P Ot h yr oi dis m: T h yr oi d h or m o ne re place me nt t hera p y, wit h 
le v ot h yr o xi ne or li ot h yr o ni ne, is i n dicate d per sta n dar d of care. 
9. 2. 3. 6.  
He p atitis  
•  Treat wit h s yste mic c ort i c oster oi ds, oral f or Gra de 2 (i nitial d ose of 1 t o 2 m g/ k g/ da y 
of pre d nis o ne or e q ui vale nt) a n d I V f or Gra de 3 or 4 ( 1 t o 2 m g/ k g/ da y of pre d nis o ne 
or e q ui vale nt).  
•  Ta per c ortic oster oi ds w h e n s y m pt o ms i m pr o ve t o Gra de ≤1 o v er ≥4  wee ks.  
9. 2. 3. 7.  
Re n al F ail ure or Ne p hritis  
•  Treat wit h s yste mic c orti c oster oi ds, oral f or Gra de 2 (i nitial d ose of 0. 5 t o 
1  m g/ k g/ da y of pre d nis o ne or e q ui vale nt) a n d I V f or Gra de 3 or 4 ( 1 t o 2 m g/ k g/ da y 
of pre d nis o ne or e q ui vale nt).  
•  Ta per c ortic oster oi ds w h e n s y m pt o ms i m pr o ve t o Gra de ≤1 o v er ≥4  wee ks.  
9. 2. 3. 8.  
M a n a ge me nt of I nf usi o n -rel ate d Re a cti o ns  
Si g ns a n d s y m pt o ms us u all y de v el o p d uri n g or s h ortl y after dr u g i nf usi o n a n d ge nerall y res ol ve 
c o m pletel y wit hi n 2 4 h o urs of c o m pleti o n of i nf usi o n. Ta ble  8  s h o ws treat me nt g ui deli nes f or 
patie nts w h o e x perie nce i nf usi o n -relate d reacti o ns ass ociate d wit h a d mi nistrati o n of T S R-0 4 2.  
T a ble  8 : 
T S R -0 4 2 I nf usi o n Re a cti o n Tre at me nt  G ui deli nes  
C T C A E Gr a de  
Tre at me nt  
Pre me dic ati o n at S u bse q ue nt D osi n g  
Gr a de 1  
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t he p atie nt is 
dee m e d me dicall y sta ble i n t he o pi ni o n of 
t he I n vesti gat or. 
N o ne.  
Gr a de 2  
St o p i nf usi o n a n d m o nit or s y m pt o ms.  
A d diti o nal a p pr o priate me dical t hera p y 
ma y i ncl u de b ut is n ot li mite d t o:  
•  
I V fl ui ds 
•  
A nti hista mi nes  
•  
N S AI Ds  
•  
Aceta mi n o p he n  
•  
Narc otics  
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t he p atie nt is 
dee me d me d icall y sta ble i n t he o pi ni o n of 
t he I n vesti gat or. 
If s y m pt o ms res ol ve wit hi n 1 h o ur of 
st o p pi n g dr u g i nf usi o n, t he i nf usi o n ma y 
be restarte d at 5 0 % of t he ori gi nal i nf usi o n 
P atie nt ma y be pre me dicate d 1. 5  h o urs 
( ± 3 0  mi n) pri or t o i nf usi o n of T S R -0 4 2 
wit h t he f oll o wi n g:  
•  
Di p he n h y dra mi ne 5 0 m g 
P O ( or e q ui vale nt d ose of 
a nti hista mi ne)  
•  
Aceta mi n o p he n 5 0 0 t o 
1 0 0 0  m g P O ( or 
e q ui vale nt d ose of 
a nti p yretic)  
C CI
C CI

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C T C A E Gr a de  
Tre at me nt  
Pre me dic ati o n at S u bse q ue nt D osi n g  
rate (e g, fr o m 1 0 0 m L/ h t o 5 0 m L/ h). 
Ot her wise, d osi n g will be wit h hel d u ntil 
s y m pto ms res ol ve, a n d t he patie nt s h o ul d 
be pre me dicate d f or t he ne xt s c he d ule d 
d ose.  
P atie nts w h o de vel o p Gra de 2 t o xicit y 
des pite a d e q uate pre me dicati o n s h o ul d be 
per ma ne ntl y disc o nti n ue d fr o m f urt her 
st u d y treat me nt a d mi nistrati o n. 
Gr a de 3:  
 
Gr a de 4:  
St o p I nf usi o n.  
A d diti o nal a p pr o priate me dical t hera p y 
ma y i ncl u de b ut is n ot li mite d t o t he 
f oll o wi n g:  
•  
I V fl ui ds 
•  
A nti hista mi nes  
•  
N S AI Ds  
•  
Aceta mi n o p he n  
•  
Narc otics  
•  
O x y ge n  
•  
Press ors  
•  
C ortic oster oi ds  
•  
E pi ne p hri ne  
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t he p atie nt is 
dee me d me dicall y sta ble i n t he o pi ni o n of 
t he I n vesti gat or. 
H os pitalizati o n ma y be i n dicat e d.  
P atie nt is per m a ne ntl y disc o nti n ue d 
fr o m f urt her st u d y tre at me nt 
a d mi nistr ati o n.  
N o s u bse q ue nt d osi n g.  
A b bre viati o ns: C T C A E = C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts; I V = i ntra ve n o us; 
N S AI D  =  n o nster oi dal a nti -i nfla m mat or y dr u g; P O = orall y. 
N ote: A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a vaila ble i n t he r o o m a n d a p h ysicia n rea dil y a vaila ble d u ri n g 
t he peri o d of st u d y treat me nt a d mi nistrati o n. 
9. 2. 4.  
Ot her St u d y Restricti o ns  
Ot her st u d y restricti o ns are pr o vi de d i n t he master pr ot oc ol.  
9. 3.  
Tre at me nt C o m pli a nce  
O verall st u d y treat me nt c o m plia nce i nf or mati o n is prese nte d i n t he master pr ot oc ol. St u d y 
treat ment ( T S R -0 4 2, be v aciz u ma b, a n d nira pari b) will be a d mi nistere d b y i n vesti gati o nal site 
pers o n nel at i n vesti gati o nal sites as detaile d i n Secti o n  1 0. 5 . 
C CI
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9.4. 
Randomization and Blinding 
This study is not blinded. In order to minimize allocation bias, the sponsor may use randomized 
allocation for those patients meeting the eligibility criteria of more than 1 contemporarily 
enrolling treatment cohort as described in the master protocol. 

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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
10.1.1. 
TSR-042 
TSR-042 is an IgG4-κ humanized monoclonal antibody and will be supplied as a solution in 
vials containing 500 mg (50 mg/mL) TSR-042. 
10.1.2. 
Bevacizumab 
Bevacizumab (Avastin) is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 
solution for IV infusion.15 The excipients for bevacizumab are trehalose dihydrate, sodium 
phosphate, polysorbate 20, and water for injections. Bevacizumab is obtained from commercial 
sources according to local practice standards, and it is provided as a commercially available 
dosage. 
10.1.3. 
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. 
10.2. 
Study Drug Packaging and Labeling 
Overall study treatment packaging and labeling is described in the master protocol. 
10.3. 
Study Drug Storage 
Study treatment storage is described in the master protocol. 
10.4. 
Study Drug Preparation 
The Pharmacy Manual contains specific instructions for the preparation of each dose of the 
niraparib capsules and TSR-042 infusion solutions. Refer to local prescribing information for 
instructions for the preparation of bevacizumab. 
10.5. 
Administration 
On days on which  more than 1 study treatment is administered, TSR-042 will be administered 
first, followed by bevacizumab, and then niraparib, as applicable.  
10.5.1. 
TSR-042 
TSR-042 will be administered via a 30-minute IV infusion on Day 1 Q3W at 500 mg for 4 cycles 
followed by 1,000 mg every other cycle (Q6W) beginning on Cycle 5 Day 1.  
The Pharmacy Manual contains descriptions of the packaging of TSR-042 and instructions for 
the preparation and administration of TSR-042. 

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10.5.2. 
Bevacizumab 
Bevacizumab 15 mg/kg will be administered via IV infusion on Day 1 of every 21-day cycle 
Q3W for up to 15 months. 
Details on the administration of bevacizumab can be found in the bevacizumab prescribing 
information. 
10.5.3. 
Niraparib  
Niraparib will be supplied as 100-mg capsules and will be administered PO QD continuously 
throughout each 21-day cycle at the assigned dose. The starting dose will be  
• 300 mg in patients with a screening actual body weight ≥77 kg AND screening 
platelet count ≥150,000/μL 
• 200 mg in patients with a screening actual body weight <77 kg OR screening platelet 
count <150,000/μL. 
On or after Cycle 3 Day 1, patients receiving the 200-mg niraparib starting dose may have their 
niraparib dose increased to 300 mg daily after discussion with medical monitor or designee if 
hemoglobin is ≥9 g/dL, platelets are ≥100,000/µL, and neutrophils are ≥1500/µL for all 
laboratory evaluations performed during the first 2 cycles. 
Patients will be instructed to take niraparib at the same time each day. Bedtime administration 
may be a potential method for managing nausea. Patients must swallow and not chew all 
capsules. The consumption of water and food is permissible.  
Niraparib will be dispensed to patients on Day 1 of every cycle (every 21 days) until the patient 
discontinues study treatment.  
The Pharmacy Manual contains descriptions of the packaging of niraparib and instructions for 
the preparation and administration of niraparib. 
10.6. 
Study Drug Accountability 
Study treatment accountability is described in the master protocol. 
10.7. 
Study Drug Handling and Disposal 
Study treatment handling and disposal are described in the master protocol. 

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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Primary Endpoint: Objective Response Rate 
The primary endpoint, ORR, is described in the master protocol. 
11.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are described in the master protocol. 
11.3. 
Biomarker Endpoints 
Tumor tissue, blood, and optional ascitic fluid samples will be assessed to identify potential 
biomarkers including BRCA status, HRR gene status, HRD score, PD-L1 expression, and other 
disease-related or treatment-related biomarkers that would associate with tumor responses to the 
combination of TSR-042, bevacizumab, and niraparib. 
Details on tumor tissue, blood, and optional ascitic fluid sample collection, processing, and 
management can be found in the Study Laboratory Manual. Any remaining blood and tumor 
tissue samples may be stored for up to 15 years for future biospecimen research, which may 
include biomarker testing. 
Additionally, samples will be assessed to evaluate the evolution of the molecular profile of the 
tumor and tumor microenvironment in response to treatment. 

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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety parameters for this study are described in the master protocol. 
In addition, urine dipstick or urine analysis for protein determination will be performed at 
Screening and prior to each bevacizumab administration. Patients discovered to have 
≥2 proteinuria on dipstick should not be administered bevacizumab, should undergo a 24-hour 
urine collection, and must demonstrate <2 g of protein in 24 hours to be eligible for bevacizumab 
treatment to resume. 
12.2. 
Adverse Events and Special Situations 
Guidance on AEs and special situations is provided in the master protocol. 
With regard to AESIs, no AESIs have been reported to date for TSR-042, therefore all serious 
AEs assessed by the Investigator or Sponsor to be reasonably associated with the use of TSR-042 
are considered to be unexpected and should be reported as described in the master protocol. For 
bevacizumab, the local approved product label should be consulted. The AESIs for niraparib are 
described in the master protocol. 

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13. 
STATISTICS 
An overall description of the statistics for this study is provided in the master protocol. 
Additional details are provided in the Statistical Analysis Plan. 
13.1. 
Sample Size Determination 
Sample size calculation was performed using SAS® version 9.4 with the EXACT method. 
A sample size of approximately 40 patients is estimated for this cohort to provide assessment of 
clinical activity of the treatment based on ORR. The null hypothesis that the true response rate is 
≤25% (H0: p ≤ 0.25) will be tested against a 1-sided alternative of ≥45% (Ha: p ≥ 0.45). If there 
are 15 or more responses observed among 40 treated patients, it will be concluded that the lower 
bound of 80% confidence interval excludes H0 and the null hypothesis will be rejected. With 
40 patients treated, the cohort has 87% power to rule out a ≤25% ORR (null hypothesis) when 
the true ORR is 45% at the 10% type I error rate (1-sided). 
Enrollment will be stratified based on histology (epithelial vs carcinosarcoma). Enrollment of 
patients with carcinosarcoma will be limited to comprise approximately 10% of the cohort 
(ie, approximately 4 patients). 
13.2. 
Planned Analysis 
The primary analysis will occur 6 months after the last patient in the cohort has started study 
treatment. 
The final analysis will occur 1 year after the last patient in the cohort has received her last dose 
of study treatment.  
Additionally, an interim safety analysis may be performed after the first 12 patients are enrolled 
between Cohorts A and B and have completed 2 cycles of therapy. If results from 
Study 3000-01-002 (NCT03307785) are available and support the feasibility of the starting dose 
regimens in the current trial, the safety interim analysis will not be performed. 
13.3. 
Biomarker Analysis 
Exploratory endpoints of this trial include identification of potential biomarkers that would 
associate with tumor responses and evaluation of the tumor and tumor microenvironment 
changes in response to treatment. An attrition rate of up to 50% is expected in obtaining a 
pre- and on-treatment paired samples, as it might not be safe or feasible to repeat a tumor biopsy 
in certain patients. Additionally, some of the obtained core biopsy samples may not be evaluable. 
Therefore, it is anticipated there will be approximately 20 evaluable paired specimens for this 
cohort. 
As one of the measures of tumor microenvironment change in response to treatment, presence of 
tumor-infiltrating lymphocytes (TILs) will be quantified. Based on the literature report, a 
baseline CD8+ TIL of 15 cells/field (using a ×20 objective lens) is assumed, with a standard 
deviation of 15 cells/field.41 With 20 evaluable paired specimens, there will be 90% power to 
detect an increase in CD8+ TILs from 15 cells/field to 25 cells/fields (relative delta = 67% 

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increase) at the 5% type I error rate (1 sided) under an assumption of an additive shift model with 
a Gaussian common density function. 
The incidence/changes of biomarkers will be summarized using descriptive statistics. Correlation 
of clinical activity with biomarker subpopulations may be performed. 

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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Direct access to source data and documents is described in the master protocol. 

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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality control and quality assurance is described in the master protocol. 

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16. 
ETHICS 
Ethics is described in the master protocol. 

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17. 
DATA HANDLING AND RECORDKEEPING 
Data handling and recordkeeping is described in the master protocol. 

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18. 
PUBLICATION POLICY 
Publication policy is described in the master protocol. 

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19. 
LIST OF REFERENCES 
1. 
ten Bokkel Huinink W, Gore M, Carmichael J, et al. Topotecan versus paclitaxel for the 
treatment of recurrent epithelial ovarian cancer. J Clin Oncol. 1997;15(6):2183-2193. 
2. 
Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent 
epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal 
doxorubicin versus topotecan. J Clin Oncol. 2001;19(14):3312-3322. 
3. 
Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy 
for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized 
phase III trial. J Clin Oncol. 2014;32(13):1302-1308. 
4. 
Pignata S, Lorusso D, Scambia G, et al. Pazopanib plus weekly paclitaxel versus weekly 
paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer 
(MITO 11): a randomised, open-label, phase 2 trial. Lancet Oncol. 2015;16(5):561-568. 
5. 
NCCN. Clinical practice guidelines in oncology: ovarian cancer. National 
Comprehensive Cancer Network. 2017. 
6. 
Gordon AN, Tonda M, Sun S, Rackoff W, Doxil Study I. Long-term survival advantage 
for women treated with pegylated liposomal doxorubicin compared with topotecan in a 
phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol 
Oncol. 2004;95(1):1-8. 
7. 
Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III trial of gemcitabine compared with 
pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol. 
2008;26(6):890-896. 
8. 
Mutch DG, Orlando M, Goss T, et al. Randomized phase III trial of gemcitabine 
compared with pegylated liposomal doxorubicin in patients with platinum-resistant 
ovarian cancer. J Clin Oncol. 2007;25(19):2811-2818. 
9. 
Markman M. Pegylated liposomal doxorubicin: appraisal of its current role in the 
management of epithelial ovarian cancer. Cancer Manag Res. 2011;3:219-225. 
10. 
Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second-
line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a 
Gynecologic Oncology Group study. J Clin Oncol. 1998;16(2):405-410. 
11. 
Rose PG, Blessing JA, Ball HG, et al. A phase II study of docetaxel in paclitaxel-resistant 
ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 
2003;88(2):130-135. 
12. 
Miller DS, Blessing JA, Krasner CN, et al. Phase II evaluation of pemetrexed in the 
treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal 
carcinoma: a study of the Gynecologic Oncology Group. J Clin Oncol. 
2009;27(16):2686-2691. 
13. 
Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients 
with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 
2007;25(33):5180-5186. 
14. 
Poveda AM, Selle F, Hilpert F, et al. Bevacizumab combined with weekly paclitaxel, 
pegylated liposomal doxorubicin, or topotecan in platinum-resistant recurrent ovarian 
cancer: analysis by chemotherapy cohort of the randomized phase III AURELIA trial. J 
Clin Oncol. 2015;33(32):3836-3838. 
15. 
AVASTIN® (bevacizumab) solution for intravenous infusion [summary of product 
characteristics]. San Francisco, CA: Genetech Inc.; 2015. 

Niraparib 
 
 
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16. 
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. 
17. 
Meade M. Efficacy evaluation of niraparib and TSR-042 alone and in combination 
against subcutaneous BRKras-luc murine ovarian carcinoma in female FVB mice. 
Molecular Imaging;2016. TESA-201605b (MI2688). 
18. 
Mills G. Efficacy of niraparib as a single agent and in combination with PD-1 antibody 
in LPA1-T22 tumor model. TESARO, Inc.;2017. 
19. 
Efficacy and PD study in KLN205 subcutaneous lung squamous cell cancer model. 
Pharmaron;2016. PH-ON-TSB-KLN205-09032015. 
20. 
Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of 
conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015;28(6):690-
714. 
21. 
Konstantinopoulos PA, Sachdev JC, Schwartzberg L, et al. Dose-finding combination 
study of niarapib and pembrolizumab in patients (pts) with metastatic triple-negative 
breast cancer (TNBC) or recurrent platinum-resistant epithelial ovarian cancer (OC). Ann 
Oncol. 2017;28(5):403-427. 
22. 
Bindra RS, Schaffer PJ, Meng A, et al. Down-regulation of Rad51 and decreased 
homologous recombination in hypoxic cancer cells. Mol Cell Biol. 2004;24(19):8504-
8518. 
23. 
Chan N, Pires IM, Bencokova Z, et al. Contextual synthetic lethality of cancer cell kill 
based on the tumor microenvironment. Cancer Res. 2010;70(20):8045-8054. 
24. 
Mirza MR, Mortensen CE, Christensen RdP, et al. ENGOT-OV24/AVANOVA1 - A 
Phase 1 study of bevacizumab in combination with niraparib in patients with platinum-
sensitive epithelial ovarian cancer. Poster presented at the American Society of Clinical 
Oncology (ASCO) meeting June 3-7, 2016 in Chicago, Illinois. 
25. 
Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib 
alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 
study. Lancet Oncol. 2014;15(11):1207-1214. 
26. 
Lee JM, Zimmer ADS, Lipkowtiz S, Annunziata CM, Ho TW, Chiou VL. Phase I study 
of the PD-L1 inhibitor, durvalumab (MEDI4736; D) in combination with a PARP 
inhibitor, olaparib (O) or a VEGFR inhibitor, cediranib (C) in women's cancer 
(NCT02484404). J Clin Oncol. 2016;34(15):3015. 
27. 
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. 
28. 
Clarke B, Tinker AV, Lee CH, et al. Intraepithelial T cells and prognosis in ovarian 
carcinoma: novel associations with stage, tumor type, and BRCA1 loss. Mod Pathol. 
2009;22(3):393-402. 
29. 
Disis ML, Patel MR, Pant S, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, 
in patients with previously treated, recurrent or refractory ovarian cancer:  a phase Ib, 
open-label expansion trial. J Clin Oncol. 2015;33. 
30. 
Varga A, Piha-Paul SA, Ott PA, et al. Antitumor activity and safety of pembrolizumab in 
patients (pts) with PD-L1 positive advanced ovarian cancer:  interim results from a phase 
Ib study. J Clin Oncol. 2015;33. 
31. 
Data on file at Tesaro. 

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32. 
Jiao S, Xia W, Yamaguchi H, et al. PARP inhibitor upregulates PD-L1 expression and 
enhances cancer-associated immunosuppression. Clin Cancer Res. 2017;23(14):3711-
3720. 
33. 
Higuchi T, Flies D, Marjon N, et al. CTLA-4 blockade synergizes therapeutically with 
PARP inhibition in BRCA1-deficient ovarian cancer. Cancer Immunol  Res. 
2015;3(11):1257-1268. 
34. 
Friedlander M, Meniawy T, Markman M, Mileshkin LR, Harnett PR, Millward M. A 
phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination 
with the PARP inhibitor BGB-290 (290) in advanced solid tumors. J Clin Oncol. 
2017;35(15):3013. 
35. 
Zimmer A, Peer C, Cao L, et al. 390P - a phase I study of durvalumab (D) in combination 
with olaparib (O) and cediranib (C) in recurrent women's cancers. Ann Oncol. 
2017;28(5):122-141. 
36. 
Sabbatini P, Harter P, Scambia G, et al. Abagovomab as maintenance therapy in patients 
with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and 
GEICO--the MIMOSA study. J Clin Oncol. 2013;31(12):1554-1561. 
37. 
Colombo N, Creutzberg C, Amant F, et al. ESMO-ESGO-ESTRO consensus conference 
on endometrial cancer: diagnosis, treatment and follow-up. Ann Oncol. 2016;27(1):16-41. 
38. 
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. 
39. 
ZEJULA® (niraparib) capsules, for oral use [prescribing information]. Waltham, MA: 
TESARO; 2017. 
40. 
AVASTIN® (bevacizumab) solution for intravenous infusion [prescribing information]. 
San Francisco, CA: Genetech Inc.; 2016. 
41. 
Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a 
high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian 
cancer. Proc Natl Acad Sci U S A. 2005;102(51):18538-18543.