Clinical trial NCT05751629
Conditions: Ovarian Neoplasm
Keywords: Poly-ADP-ribose polymerase (PARP) Inhibitor Ovarian cancer Niraparib Bevacizumab TSR-042 Neoadjuvant treatment
Sponsor: Tesaro, Inc.
Start date: 2018-11-15; Completion date: 2022-04-01
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this sub study is to evaluate the efficacy of the combination of TSR-042, bevacizumab, and niraparib in participants 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.

This study is a sub study of the master protocol - OPAL (NCT03574779).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Dostarlimab intervention 2: Bevacizumab intervention 3: Niraparib
Intervention descriptions: intervention 1: Dostarlimab was administered. intervention 2: Bevacizumab was administered. intervention 3: Niraparib was administered.

Protocol documents:
Prot_000.pdf: 
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:  
 M D 
Cli nic al Rese arc h 
Or g a niz ati o n:  
N ot a p plica ble  
I N D N o.: 
1 0 0, 9 9 6  
E u dr a C T N o.:  
T o be deter mi ne d  
N C T N o.  
T o be deter mi ne d  
De vel o p me nt P h ase:  
2  
D ate of Ori gi n al P r ot oc ol:  
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
P P D


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 3 of 58 
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 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 4 of 58 
PROCEDURES IN CASE OF EMERGENCY 
Procedures in case of emergency are outlined in the master protocol. 
 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 5 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 6 of 58 
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: 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 7 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 8 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 9 of 58 
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. 
 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 10 of 58 
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 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 11 of 58 
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 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 12 of 58 
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 
 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 13 of 58 
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 
 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 14 of 58 
LIST OF FIGURES 
Figure 1: 
Cohort A Study Schema .............................................................................................25 
 
  


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 15 of 58 
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 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 16 of 58 
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 
 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 17 of 58 
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 
was confirmed in a mixed lymphocyte reaction assay, demonstrating enhanced interleukin-2 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 18 of 58 
(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.  


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 19 of 58 
• 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 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 20 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 21 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 22 of 58 
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  


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 23 of 58 
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). 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 24 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 25 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 26 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 27 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 28 of 58 
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 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 29 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 30 of 58 
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 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 31 of 58 
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 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 32 of 58 
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 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 33 of 58 
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.  
 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 Page 34 of 58 
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 
 
 
 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 Page 35 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 Page 36 of 58 
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. 
 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 37 of 58 
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 
pelvic examination or significant bowel involvement on computed tomography scan 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 38 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 39 of 58 
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 
asthma or chronic obstructive pulmonary disease exacerbation, prophylaxis for IV 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 40 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 41 of 58 
• 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. 


Nira pa ri b 
 
 
Cli nical St u d y Pr ot oc ol P R -3 0 0 0 -0 2 -0 0 5 Versi o n 1. 0  
 
C o nfi de ntial  
 
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


Nira pa ri b 
 
 
Cli nical St u d y Pr ot oc ol P R -3 0 0 0 -0 2 -0 0 5 Versi o n 1. 0  
 
C o nfi de ntial  
 
Pa g e 4 3  of 5 8  
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
C CI


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 44 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 45 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 46 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 47 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 48 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 49 of 58 
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% 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 50 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 51 of 58 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Direct access to source data and documents is described in the master protocol. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 52 of 58 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality control and quality assurance is described in the master protocol. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 53 of 58 
16. 
ETHICS 
Ethics is described in the master protocol. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 54 of 58 
17. 
DATA HANDLING AND RECORDKEEPING 
Data handling and recordkeeping is described in the master protocol. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 55 of 58 
18. 
PUBLICATION POLICY 
Publication policy is described in the master protocol. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 56 of 58 
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 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 57 of 58 
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. 


Niraparib 
 
 
Clinical Study Protocol PR-3000-02-005 Version 1.0 
 
Confidential 
 
Page 58 of 58 
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. 
 

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
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: 04-MAY-2022 
 
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 1 | 43 
STATISTICAL ANALYSIS PLAN 
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 
 
Protocol Number: 
3000-02-005 
Protocol Version and Date: 
v2.0 (Master), October 15, 2021  
v1.0 (Supplementary for Cohort A), March 20, 2018 
Study Drug Name: 
TSR-042, Niraparib and Bevacizumab 
Phase: 
Phase II 
Sponsor: 
GlaxoSmithKline plc 
Analysis Plan Date: 
May 04, 2022 
Analysis Plan Version: 
Version 2.0 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
All information contained in this document is privileged and confidential to 
GlaxoSmithKline plc. Any distribution, copying, or disclosure is strictly prohibited 
without prior written approval by GlaxoSmithKline plc. 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 2 | 43 
SPONSOR SIGNATURE PAGE 
Protocol Title: 
Phase 2 Multicohort Study to Evaluate the Safety and Efficacy 
of Novel Treatment Combinations in Patients with Recurrent 
Ovarian Cancer 
Protocol Number: 
3000-02-005 
Sponsor:  
GlaxoSmithKline plc 
1000 Winter Street 
Waltham MA 02451 
By signing this document, I acknowledge that I have read the document and approve of 
the planned statistical analyses described herein. I agree that the planned statistical 
analyses are appropriate for this study, are in accordance with the study objectives, and 
are consistent with the statistical methodology described in the protocol and all applicable 
regulatory guidance and guidelines. 
 
 
 
 
Approver:  
 
Ping Wang, PhD 
Biostatistician 
GlaxoSmithKline plc 
 
Signature:  
Date: 04 May 2022 
Vivek Samnotra, MD 
Senior Medical Director 
GlaxoSmithKline plc 
Signature:  
Date: 04 May 2022 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 3 | 43 
Table of Contents 
STATISTICAL ANALYSIS PLAN ..............................................................................................................1 
SPONSOR SIGNATURE PAGE ..................................................................................................................2 
Table of Contents ..........................................................................................................................................3 
LIST OF TABLES INCLUDED IN THE TEXT ......................................................................................6 
ABBREVIATIONS .......................................................................................................................................7 
1 
INTRODUCTION ................................................................................................................................9 
2 
STUDY DESIGN OVERVIEW .........................................................................................................10 
2.1 
Overall Study Design ......................................................................................................................10 
2.2 
Sample Size .....................................................................................................................................15 
2.3 
Randomization and Blinding ...........................................................................................................15 
3 
STUDY OBJECTIVES ......................................................................................................................16 
3.1 
Primary Objectives ..........................................................................................................................16 
3.2 
Secondary Objectives ......................................................................................................................16 
3.3 
Exploratory Objectives ....................................................................................................................16 
4 
STUDY ENDPOINTS AND EVALUATIONS .................................................................................17 
4.1 
Efficacy Endpoints and Evaluations ................................................................................................17 
4.2 
Safety Endpoints and Evaluations ...................................................................................................17 
4.3 
Biomarker Endpoints and Evaluations ............................................................................................17 
4.4 
Other Evaluations ............................................................................................................................17 
5 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .................................................19 
5.1 
Definition of Baseline......................................................................................................................19 
5.2 
Definition of Treatment Period .......................................................................................................19 
5.3 
Definition of Relative Study Days ..................................................................................................19 
5.4 
First Dose Date of Study Treatment ................................................................................................19 
5.5 
Analysis Visit Window....................................................................................................................19 
5.6 
Data Handling ..................................................................................................................................19 
5.6.1 
Handling of Repeated Clinical Laboratory Tests .................................................. 19 
5.6.2 
Handling of Partial Dates for AEs ......................................................................... 20 
5.6.3 
Handling of Partial Dates for Medications ............................................................ 20 
5.6.4 
Handling of Partial Dates for Prior Anti-cancer Treatment ................................... 21 
5.6.5 
Handling of Partial Dates for Follow-up Anti-cancer Treatment .......................... 21 
6 
PLANNED ANALYSIS .....................................................................................................................23 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 4 | 43 
6.1 
Changes from Planned Analyses in the Protocol .............................................................................23 
6.2 
Interim Analysis ..............................................................................................................................23 
6.3 
Final Analyses and Reporting .........................................................................................................23 
7 
ANALYSIS POPULATIONS AND APPLICATIONS .....................................................................24 
7.1 
All Patients Population ....................................................................................................................24 
7.2 
Safety Population.............................................................................................................................24 
7.3 
Efficacy Population .........................................................................................................................24 
7.4 
Response Evaluable Population ......................................................................................................24 
7.5 
Biomarker Population ......................................................................................................................24 
7.6 
Application of Analysis Populations ...............................................................................................24 
8 
STATISTICAL CONSIDERATIONS ...............................................................................................26 
8.1 
General Statistical Procedures .........................................................................................................26 
8.2 
Enrollment and Disposition .............................................................................................................27 
8.2.1 
Patients Enrollment ............................................................................................... 27 
8.2.2 
Patients Disposition ............................................................................................... 27 
8.2.3 
Protocol Deviations ............................................................................................... 27 
8.3 
Demographics and Baseline Characteristics ....................................................................................28 
8.3.1 
Demographics Characteristics ............................................................................... 28 
8.3.2 
Baseline Characteristics ......................................................................................... 28 
8.3.3 
Medical History ..................................................................................................... 28 
8.3.4 
Ovarian Cancer Pathology ..................................................................................... 29 
8.3.5 
Prior Anticancer Treatment ................................................................................... 29 
8.3.6 
Prior and Concomitant Medication and Procedures .............................................. 30 
8.4 
Efficacy Analysis.............................................................................................................................30 
8.4.1 
Objective Response Rate ....................................................................................... 30 
8.4.2 
Duration of Response ............................................................................................ 33 
8.4.3 
Disease Control Rate ............................................................................................. 34 
8.4.4 
Progression Free Survival ...................................................................................... 34 
8.4.5 
Overall Survival ..................................................................................................... 35 
8.5 
Biomarker Analysis .........................................................................................................................36 
8.5.1 
Analysis of BRCA, HRD, HRR, and PD-L1 ......................................................... 36 
8.5.2 
Analysis of CD8+ TIL ........................................................................................... 37 
8.6 
Safety Analysis ................................................................................................................................37 
8.6.1 
Adverse Events ...................................................................................................... 37 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 5 | 43 
8.6.2 
Study Drug Exposure ............................................................................................ 39 
8.6.3 
Clinical Laboratory Tests ...................................................................................... 42 
8.6.4 
Vital Signs ............................................................................................................. 43 
8.6.5 
Physical Examination Findings ............................................................................. 43 
8.6.6 
ECOG Performance Status .................................................................................... 43 
8.6.7 
Electrocardiogram (ECG) ...................................................................................... 43 
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 6 | 43 
LIST OF TABLES INCLUDED IN THE TEXT 
Table 1: Schedule of Events .......................................................................................................... 12 
Table 2: Application of Populations on Tables and Figures.......................................................... 24 
Table 3: Overall Response for Patients with Measurable Disease at Study Entry ........................ 31 
Table 4: Best Overall Response when Confirmation of CR and PR Required ............................. 32 
Table 5: Censoring Rules Used for DOR Analysis ....................................................................... 34 
Table 6: Censoring Rules Used for PFS Analysis ......................................................................... 35 
Table 7: Extent of Study Drug Exposure ...................................................................................... 41 
 
 
 
 
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 7 | 43 
ABBREVIATIONS  
Abbreviation 
Explanation 
ADP 
Adenosine Diphosphate  
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase 
ATC 
Anatomical Therapeutic Chemical 
BIL 
Bilirubin 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BRCA 
Breast Cancer Gene 
C2D1 
Cycle 2 Day 1 
C3D1 
Cycle 3 Day 2 
CA-125  
Cancer Antigen 125 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CPS 
Combined Positive Score 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCR 
Disease Control Rate 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronical Case Report Form 
EOT 
End of Treatment 
FT3 
Free Triiodothyronine 
FT4 
Free Thyroxine 
gBRCA 
Germline Breast Cancer Susceptibility Gene 
GSK 
GlaxoSmithKline 
H0 
Null Hypothesis 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 8 | 43 
Abbreviation 
Explanation 
Ha 
Alternative Hypothesis 
HRD 
Homologous Recombination Deficiency 
HRR 
Homologous Recombination Repair 
ID 
Identification  
KM 
Kaplan-Meier  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PARP 
Polymerase 
PD 
Progressive Disease 
PD-L1 
Programmed Death-Ligand 1  
PDV 
Protocol Deviation 
PFS 
Progression-Free Survival 
PR 
Partial Response 
PT 
Preferred Term  
Q3W 
Every 3 Weeks 
Q6W 
Every 6 Weeks 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors Version 1.1 
Rel 
Relative Study 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SOC 
System Organ Class 
STD 
Standard Deviation  
T3 
Triiodothyronine 
TEAE 
Treatment-Emergent Adverse Event 
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit of Normal 
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 9 | 43 
1 
INTRODUCTION  
This statistical analysis plan is designed to outline the statistical methods in evaluating 
the efficacy and clinical benefits of dostarlimab (TSR-042), bevacizumab, and niraparib 
in patients with advanced relapsed, high-grade ovarian, fallopian tube, or primary 
peritoneal cancer in Cohort A for GlaxoSmithKline (GSK) study protocol 3000-02-005.  
This document has been prepared based on Master Protocol, Protocol Supplement A 
dated 20 March 2018. Details will be described in this analysis plan to ensure that the 
data listings, summary tables and figures which will be produced, and the statistical 
methodologies that will be used, are complete and appropriate to allow valid conclusions 
regarding the study objectives.   
 
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 10 | 43 
2 
STUDY DESIGN OVERVIEW 
2.1 
Overall Study Design 
This is a multicenter, multicohort, open-label, Phase 2 study to evaluate the efficacy and 
safety of niraparib novel treatment combinations in patients with advanced, relapsed, 
high-grade ovarian, fallopian tube, or primary peritoneal cancer.  
Patients will be evaluated for eligibility to enter the study based on both the overall 
eligibility criteria presented in the master protocol and the eligibility criteria in the 
supplement protocol for cohort A.  
Cohort A includes 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.  
Treatment with hormonal agents alone are not counted in the number of lines of therapy. 
Treatment with single-agent bevacizumab or poly(ADP-ribose) polymerase (PARP) 
inhibitors given as maintenance is not counted as a separate line of therapy. If a 
therapeutic regimen is modified or changed for a reason other than lack of response or 
PD (such as allergic reaction, toxicity, or drug availability), this is not counted as a 
separate line of therapy. 
In this protocol, platinum-resistant disease is defined 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 are defined as those who progressed during or within 4 weeks 
of completion of first platinum-based chemotherapy. 
Cohort A will consist of a Screening Period (Day -21 to Day -1), a Treatment Period, an 
End of Treatment (EOT) Period occurring within 7 days when study treatment is 
discontinued for any reason, a Safety Follow-up Visit occurring 30 ± 7 days after the last 
dose of study treatment, and a Survival Assessment occurring every 90 ± 14 days after 
the last dose of study treatment until death or the end of study. 
Patients in Cohort A will receive treatment with TSR-042, bevacizumab, and niraparib 
beginning on Cycle 1/Day 1. The schedule of events is summarized in Table 1.   
Niraparib will be administrated at two dose levels as following: 
• 300 mg in patients with screening actual body weight ≥77 kg and screening 
platelet count ≥150,000/μL 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 11 | 43 
• 200 mg in patients with screening actual body weight <77 kg or screening platelet 
count <150,000/μL  
 
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005   
Dated: 04May2022, Version 2.0 
 
 
    Page 12 | 43 
Table 1: 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 
   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 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005   
Dated: 04May2022, Version 2.0 
 
 
    Page 13 | 43 
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. 
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 (except for 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 (i.e., every 9 weeks for the first year of treatment 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    


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005   
Dated: 04May2022, Version 2.0 
 
 
    Page 14 | 43 
  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 Protocol 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. 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 15 | 43 
2.2 
Sample Size  
Under hypothesis 
H0: ORR ≤ 25%   vs.  Ha: ORR ≥ 45% 
Approximately 40 patients are planned for enrollment to provide assessment of clinical 
activity of the treatment based on ORR. 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 the null hypothesis H0 and H0 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 of patients with carcinosarcoma will be limited to comprise approximately 
10% of the cohort (i.e., approximately 4 patients). 
Sample size calculation was performed using SAS® version 9.4 with the EXACT 
method.  
2.3 
Randomization and Blinding 
This is an open-label Phase 2 study. 
  


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 16 | 43 
3 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
• 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. 
3.2 
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 niraparib, TSR-042, 
and bevacizumab 
3.3 
Exploratory Objectives 
• 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. 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 17 | 43 
4 
STUDY ENDPOINTS AND EVALUATIONS  
4.1 
Efficacy Endpoints and Evaluations 
• Confirmed objective response rate (confirmed ORR)  
• Duration of response (DOR) 
• Disease control rate (DCR) 
• Progression-free survival (PFS) 
• Overall survival (OS) 
4.2 
Safety Endpoints and Evaluations 
The safety evaluations include:  
• Treatment emergent adverse events (TEAEs) 
• Clinical laboratory assessments  
− Hematology (CBC)  
− Serum chemistry 
− Coagulation factors 
− Pregnancy test 
− Urinalysis 
− Thyroid function  
- Serum CA-125 
• Physical examination findings 
• Vital signs (including weight and baseline height)  
• ECOG performance status  
• ECG 
4.3 
Biomarker Endpoints and Evaluations 
Exploratory endpoints of this trial include identification of potential biomarkers that 
would associate with tumor responses and evaluation of the tumor and tumor 
microenvironment. 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. Sample will be assessed to evaluate the evolution of the molecular profile of 
the tumor and tumor microenvironment in response to treatment.  
4.4 
Other Evaluations 
Other evaluations include: 
• Demographics and baseline characteristics 
• Medical history 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 18 | 43 
- General medical history 
- Primary and other cancer history 
- Prior blood disorders  
• Ovarian cancer pathology 
• Prior anticancer treatment 
- Primary anticancer treatment for primary cancer  
- Prior radiotherapy 
- Prior surgery for primary cancer treatment  
• Prior and concomitant medications and procedures 
- Prior non-anticancer medications  
- Concomitant medications 
- Prior and concomitant transfusions and growth factors 
• Subsequent anticancer treatment 
- Subsequent anticancer therapy 
- Subsequent radiotherapy 
- Subsequent surgery for cancer  


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 19 | 43 
5 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
5.1 
Definition of Baseline 
For all evaluations unless otherwise noted, baseline is defined as the most recent non-
missing measurement prior to or on the first administration of study drug. Baseline can be 
the same date as first dose, given the measurement is expected prior to first dose when 
only date information is available. 
5.2 
Definition of Treatment Period 
Treatment period is defined as the time from the first dose of study treatment through 
minimum of (last dose of study treatment + 21 days, start date of new anti-cancer therapy 
– 1 day). 
5.3 
Definition of Relative Study Days 
Unless otherwise noted, relative study days (Rel Days) of an evaluation are defined as 
number of days relative to the first dose date of study drug which is designated as Day 1, 
and the preceding day is Day -1, the day before that is Day -2, etc. Relative study days 
are calculated as an evaluation date minus first dose date of study drug, and plus 1 day if 
evaluation date is on or after first dose date.   
Relative study days take negative values if evaluation date occurs prior to first dose date 
and take positive values if evaluation date occurs on or after first dose date of study drug. 
5.4 
First Dose Date of Study Treatment 
The date of first dose of study treatment is defined as the earliest dose date of study drugs 
in the treatment regimen. 
5.5 
Analysis Visit Window 
For safety parameters as described in Section 4.2 excluding clinical laboratory data, 
measurements collected from unscheduled visits will not be included in the by-visit 
summary tables but will be included in the listings. Early termination visits for safety 
measurements will not be mapped to any scheduled post-baseline visit but will be used as 
the last assessment during treatment period.  
5.6 
Data Handling 
Missing observations will generally be treated as missing at random and will not be 
imputed, unless otherwise noted. 
5.6.1 Handling of Repeated Clinical Laboratory Tests 
For laboratories results at unscheduled visits, it will be treated as repeated laboratory 
results for the closest previous visit. The worst results (furthest outside of normal range, 
either high or low) within the visit will be used in the summary tables for that visit.  


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 20 | 43 
Lab results beyond the detectable limits will be reported as detectable limits for 
calculating descriptive statistics.  
All the laboratory test results will be included in the data listings as reported. 
5.6.2 Handling of Partial Dates for AEs   
When determining the treatment emergent AE, partial dates will be handled as follows.  
• If the day of the month is missing, the onset day will be set to the first day of the 
month unless it is the same month and year as first dose date. In this case, the 
onset date will be assumed to be the first date of treatment. 
• If the onset day and month are both missing, the day and month will be assumed 
to be January 1, unless the event occurred in the same year as the study treatment. 
In this case, the event onset will be coded to the day of treatment to 
conservatively report the event as treatment-emergent.  
• A missing onset date will be coded as the day of treatment. If the resulting onset 
date is after a reported date of resolution, the onset date will be set equal to the 
date of resolution.   
• Imputation of partial dates is used only to determine whether an event is 
treatment-emergent; data listings will present the partial date as recorded in the 
eCRF. 
Note: If the imputed date is greater than study end date or death date, then the earliest 
of these dates will be used as an end date. 
5.6.3 Handling of Partial Dates for Medications  
When determining prior or concomitant medications, partial dates will be handled as 
follows. Imputation of partial dates is used only to determine whether a medication is 
prior or concomitant; data listings will present the partial date as recorded in the eCRF. In 
the case of complete missing start date, medication will be assumed to be prior 
medication. 
Start dates: 
• If the day of the month is missing, the onset day will be set to the first day of the 
month unless it is the same month and year as first dose date. In this case, the 
onset date will be assumed to be the first date of treatment, unless the stop date 
contains a full date and the stop date is earlier than study treatment start date. In 
this case, the onset date will be set to the first day of the month.  
• If the onset day and month are both missing, the day and month will be assumed 
to be January 1, unless the event occurred in the same year as the study treatment. 
In this case, the event onset will be assumed to be the first date of treatment, 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 21 | 43 
unless the stop date contains a full date and the stop date is earlier than study 
treatment start date. In this case, the onset date will be set to January 1.  
End dates: 
• If the day of the month is missing, '28/29/30/31' will be used for the day 
(dependent on the month and year). 
• If the end day and month are both missing, the day and the month will be assumed 
to be December 31. 
Note: If the imputed date is greater than study end date or death date, then the earliest 
of these dates will be used as an end date. If the imputed end date is earlier than the 
start date, then the start date will be considered as the end date. 
5.6.4 Handling of Partial Dates for Prior Anti-cancer Treatment 
Partial dates of prior anticancer treatment will be handled as follows. 
• If the day of the month is missing, then impute day with first day of the month. 
• If the day and month are both missing, then impute as January 1st of that year.  
• If the date is completely missing, no imputation will be performed.  
Note: If the imputed end date is earlier than the start date, then the start date will be 
considered as the anti-cancer treatment end date. 
5.6.5 Handling of Partial Dates for Follow-up Anti-cancer Treatment 
• Partial dates of follow-up anticancer treatment will be handled as follows. 
• Completely missing start dates will remain missing, with no imputation applied.  
• Partial start dates will be imputed using the following convention:  
• If both month and day are missing, no imputation will be applied.  
• If only day is missing: 
o If the month of partial date is the same as the month of last dosing date, the 
minimum of (last dosing date + 1, last day of the month) will be used for the day. 
o If the month of partial date is the same as the month of last disease assessment 
and the last disease assessment is PD, minimum of (last date of disease 
assessment + 1, last day of the month) will be used for the day.  
o If both conditions above are met, the later date will be used for the day. 
o Otherwise, a ‘01’ will be used for the day. 
• Completely or partially missing end dates will remain missing, with no imputation 
applied.  


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 22 | 43 
Note: If end date is earlier than the imputed start date, then the start date will be 
considered as the therapy end date. 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 23 | 43 
6 
PLANNED ANALYSIS 
6.1 
Changes from Planned Analyses in the Protocol 
 
Data from a data cutoff date of July 24, 2020, was presented at SGO 2021. 
The final analysis will occur after Last Patient Last Visit instead of 1 year after the last 
patient in the cohort has received their last dose of study treatment.The primary efficacy 
analysis based on the investigator-assessed confirmed ORR per RECIST v1.1. at 6 
months after the last participant in the cohort has started study treatment will be reported.   
6.2 
Interim Analysis 
An interim safety analysis may be performed after the first 12 patients treated are 
enrolled 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. 
If interim analysis is to be performed, the safety analysis in Section 8.5 will be 
conducted. 
6.3 
Final Analyses and Reporting 
All final planned analyses per protocol and this analysis plan will be performed after 
database lock. 
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 24 | 43 
7 
ANALYSIS POPULATIONS AND APPLICATIONS  
7.1 
All Patients Population  
All Patients Population includes all patients who sign an informed consent form. 
7.2 
Safety Population 
Safety Population includes all patients who receive any amount of study drug.  
7.3 
Efficacy Population  
Efficacy Population includes all safety patients who have measurable disease at baseline.  
Measurable disease at baseline is defined by the existence of at least one target lesion at 
baseline tumor assessment. 
7.4 
Response Evaluable Population 
Response Evaluable Population includes all efficacy patients with at least one evaluable 
post-baseline tumor assessment. 
7.5 
Biomarker Population 
Biomarker Population includes all patients who have at least 1 follow-up tumor 
assessment and provide a tumor, blood, or optional ascitic fluid sample. . Here follow-up 
tumor assessment refers to post-baseline tumor assessment.  
7.6 
Application of Analysis Populations 
Unless otherwise noted, the analysis populations that will be used for creating the 
summary table(s) of each type is provided in Table 2.   
Table 2: Application of Populations on Tables and Figures 
Type 
All 
Safety 
Efficacy 
Response 
Evaluable 
 
 
Enrollment 
X 
 
 
 
 
Disposition 
 
X 
 
 
 
Demographics 
and 
baseline 
characteristics 
 
X 
 
 
 
Protocol deviations 
 
X 
 
 
 
Medical and disease history 
 
X 
 
 
 
Prior therapies/surgeries 
 
X 
 
 
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 25 | 43 
Type 
All 
Safety 
Efficacy 
Response 
Evaluable 
 
 
Prior and concomitant medications or 
procedures 
 
X 
 
 
 
Safety evaluations 
 
X 
 
 
 
Treatment exposure  
 
X 
 
 
 
Biomarker Analysis 
 
X 
 
X 
 
Efficacy evaluations 
 
 
 
 
 
      ORR, DOR and DCR 
 
 
X 
Xa 
 
      PFS and OS 
 
 
X 
 
 
Xa: The supportive analyses of ORR and DCR when applicable. 
 
 
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 26 | 43 
8 
STATISTICAL CONSIDERATIONS 
All analyses described in this plan are considered a priori analyses in that they have been 
defined prior to locking the database.  All other analyses, if any, designed subsequently to 
locking the database, will be considered post hoc analyses and will be described as 
exploratory analyses in the Clinical Study Report.  
All summaries and statistical analysis will be performed by SAS v9.3 or later.  
8.1 
General Statistical Procedures 
Frequency distributions for categorical variables will be provided as number of patients 
with a response in the category and the percentages out of the total number of patients in 
that column unless otherwise stated.  Percentages will be based on number of patients in 
the given population as noted. Percentages will be reported to one decimal place.  
A 2-sided 80% exact binomial (Clopper-Pearson) confidence interval (CI) for categorical 
variables without multiplicity adjustment will be provided where appropriate for efficacy 
analysis. 
The descriptive statistics for continuous variables will be number of patients, mean, 
standard deviation (STD), median, quartiles (Q1, Q3), minimum and maximum.   Mean, 
median, Q1, and Q3 will be reported to 1 more decimal place than the raw data, while the 
STD will be reported to 2 more decimal places than the raw data. Minimum and 
maximum will be reported the same as the original data.  
Time-to-event analyses will be performed using Kaplan-Meier methods and summarized 
by 25th, 50th, and 75th percentiles with associated 2-sided 95% confidence intervals (CIs), 
as well as the number and percent of censored observations. 
Otherwise stated, all data listings that contain an evaluation date will also contain relative 
study day (Rel days) which is defined as number of days relative to the first dose date of 
study drug (see Section 5.3 for details). 
In general, all listings will be ordered by patient ID and visit for available data unless 
otherwise specified in the text.   
Analysis visit windows and safety data handling (repeated laboratory tests, partial dates 
of AEs and medications) are described in Section 5.5 and Section 5.6.  
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 27 | 43 
8.2 
Enrollment and Disposition  
8.2.1 Patients Enrollment 
Number and percentage of patients will be provided for each analysis population. The 
denominators for percentages are the number of screened patients (who have signed 
informed consent).  
Enrollment information will be provided in a data listing for All Patients Population. 
8.2.2 Patients Disposition 
The treatment regimen is combination of study drug TSR-042, bevacizumab and 
niraparib. The treatment regimen is considered discontinued if patients discontinued all 
drugs in the regimen.   
Number and percentage of patients will be tabulated using Safety Population for:  
• Patients’ discontinuation from treatment and primary reasons  
• Patients’ discontinuation from study and primary reasons  
Discontinued patients from treatment and from study will be provided in a data listing for 
Safety Population. 
8.2.3 Protocol Deviations 
Important or significant protocol deviations (PDVs) will be assessed by sponsor 
personnel following GSK template 2010-00010-CLN “Protocol Deviations Standard 
Categories and Descriptions”.     
• A PDV is classified as important if there is the potential to impact the 
completeness, accuracy, and/or reliability of the study data, or affect a patient’s 
rights, safety, or well-being. The following are PDVs that will be considered 
important:  
o Failure to obtain informed consent for participation in the clinical trial  
o Enrollment of ineligible patient  
o Patient developed withdrawal criteria during the study but was not 
withdrawn 
o Patient received incorrect treatment (patient received non-study drug to 
treat ovarian cancer)  
o Incorrect or non-compliant dosing of a patient, i.e. dosing that is 
inconsistent with the protocol  
o Administration of an excluded concomitant treatment to a patient  
 
• An important PDV is classified as significant if it is confirmed to adversely 
impact the completeness, accuracy, and/or reliability of the study data, or affect a 
patient’s rights, safety, or well-being.  


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 28 | 43 
If a reported PDV does not meet classification criteria for importance or significance, the 
PDV will be reported as a protocol deviation without a classification.  
All PDVs will be identified and finalized prior to database lock and documented in a 
separate Medical Data Review Plan.   
Number and percentage of patients with a significant or important PDV will be 
summarized, then tabulated by type of deviation for Safety Population.  
All protocol deviations will be listed for All Patients  Population.  
8.3 Demographics and Baseline Characteristics 
8.3.1 Demographics Characteristics  
Demographic characteristics will be tabulated using descriptive statistics for Safety 
Population. The following variables will be included in the tables:  
• Age (years) at screening 
• Age category (18 to < 65, 65 to < 75; and ≥ 65, ≥ 75) 
• Childbearing status  
• Race  
• Ethnicity 
8.3.2 Baseline Characteristics  
Baseline (see Section 5.1 for baseline definition) characteristics will be tabulated using 
descriptive statistics for Safety Population, including: 
• Height (cm) 
• Weight (kg) 
• BMI (body mass index, kg/m2, calculated as Weight (kg) / Height (m)2) 
• ECOG performance status  
Conversions for height and weight are as follows: 
Height (cm) = Height (inches) x 2.54 
Weight (kg) = Weight (lb) x 0.4536 
Demographics and baseline characteristics will be listed for Safety Population. 
8.3.3 Medical History 
The medical history including general medical history will be coded using v24.1 or later  
of Medical Dictionary for Regulatory Activities (MedDRA) dictionary.  
The frequency count and percentage of patients experiencing any medical conditions will 
be tabulated by system organ classifications (SOC) and preferred term (PT) of MedDRA 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 29 | 43 
for Safety Population.  If a preferred term or system organ class was reported more than 
once for a patient, the patient would only be counted once in the incidence for that 
preferred term or system organ class.  
Patients’ primary cancer history will be summarized including: 
• Primary tumor site at initial diagnosis 
• Cancer stage at initial diagnosis 
• Time from first diagnosis to first dose of study treatment (months), defined as 
(first dose date of study drug – first diagnosis date + 1)/30.4375 
• Metastatic disease sites 
Patients’ history of blood disorder will be tabulated for Safety Population including 
• History of blood disorder 
• History of thrombocytopenia, leukopenia, anemia and neutropenia    
A data listing of medical history including general medical history, primary and other 
cancer history, and prior blood disorders history will be provided for Safety Population. 
8.3.4 Ovarian Cancer Pathology 
Patients’ ovarian cancer pathology will be summarized for Safety Population including: 
• gBRCA Status 
• Histology at initial and most recent diagnosis 
• Tumor grade at initial and most recent diagnosis 
Listing will be provided for Safety Population. 
8.3.5 Prior Anticancer Treatment 
Prior anticancer treatment will be tabulated for Safety Population. The following 
variables will be included in the tables:  
• Number of prior regimens 
• Number of lines of prior platinum-based therapy. Platinum-based therapy is 
defined as any drug where the question ‘Is this platinum based therapy?’ on the 
eCRF is answered ‘Yes’.  
• Duration of last platinum-based therapy (months), defined as (end date of last 
platinum-based therapy – start date of last platinum-based therapy + 1)/30.4375. 
The last platinum-based therapy is defined as the therapy with the latest end date. 
• Reason for discontinuation of last platinum-based therapy 
• Platinum-free interval: Time from end of last dose of prior platinum-based 
therapy to the date of progressive disease (months), defined as (date of 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 30 | 43 
progressive disease after last prior platinum-based therapy – stop date of last prior 
platinum-based therapy)/30.4375 
• Best response during last platinum-based therapy 
• Reason for administration of last therapy 
• Any surgeries related to primary cancer 
• Any radiotherapy prior to informed consent  
Handling of partial missing date in determination of duration of last platinum-based 
therapy and platinum-free interval is described in Section 5.6.4.  
A data listing of prior anticancer treatment including surgical/procedures, previous and 
concomitant radiotherapy will be provided for Safety Population. 
8.3.6 Prior and Concomitant Medication and Procedures 
All medications as documented by the investigator will be coded using Anatomical 
Therapeutic Chemical (ATC) classification based on the GSKDrug Dictionary (v4.0).  
Prior non-anticancer medications are defined as any medications, other than study 
treatment, prior medications for non-anticancer treatment and pre-medications for study 
treatment, which ended prior to the first dose date of study treatment. 
Concomitant medications are medications other than study treatments, being taken on or 
after the   initial study treatment dosing date through 30 days after the last dose or until 
the start of subsequent antitumor therapy.  
The count and percentage of patients who took prior and concomitant medications will be 
provided by GSK  Medication Class (ATC level 4 if non-missing, otherwise, ATC level 
3) and preferred term (PT) for Safety Population.  For the summary tables, if a patient has 
taken a prior or concomitant medication more than once, the patient will be counted only 
once for the medication. 
Patients’ prior and concomitant transfusions and growth factors will be summarized by 
count and percentage for the Safety Population.  
By-patient data listings will be provided for use of prior and concomitant medications, 
concomitant procedures, prior and concomitant transfusions and growth factors for Safety 
Population. 
8.4 
Efficacy Analysis 
8.4.1 Objective Response Rate 
The primary efficacy analysis will be based on the investigator-assessed confirmed ORR 
per RECIST v1.1.  At each evaluation, the criteria in Table 3 were used to define each 
patient’s overall response at that evaluation.  


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 31 | 43 
Table 3: Overall Response for Patients with Measurable Disease at Study Entry 
 Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease. 
Radiographic evaluations to assess extent of disease will be conducted every 9 weeks (63 
± 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). The 
minimum criteria for SD duration are at least 9 weeks minus 7 days (9 x 7 – 7 =56 days) 
from the date of first dose of study treatment. 
As confirmed CR/PR is required, the best overall response (BOR) will be determined as 
shown in Table 4. To confirm CR or PR response, tumor imaging may be performed at 
the earliest 4 weeks after the first indication of response or at the next scheduled scan 
(i.e., 9 or 12 weeks later), whichever is clinically indicated. Tumor imaging for 
confirmation of response occurred less than 4 weeks after the first indication of response 
of CR or PR may be used for clinical decision, but it will NOT be used for determination 
of BOR.  
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/Not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/Not 
evaluated 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 32 | 43 
Table 4: Best Overall Response when Confirmation of CR and PR Required 
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = 
stable disease. 
For each patient, BOR will be determined based on the overall responses at all time 
points between the date of first dose and the date of first documented radiological disease 
progression, or the date of subsequent anti-cancer therapy, or the date of study 
discontinuation, whichever occurs first. Specifically: 
• Day 1 can be determined from the “dose administration date” field on the 
“niraparib first dose” form. 
• The date of radiological disease progression can be determined by selecting the 
earliest date from the “date of the radiological scan or assessment on which the 
response evaluation was based” field on the “evaluation of response (RECIST)” 
form where “overall response” = PD. 
• Subsequent anti-cancer therapy can be determined by checking for any entries 
made on the “follow up anti-cancer therapy” form. 
Overall Response 
First Time Point 
Overall 
Response 
Subsequent 
Time 
Point  
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
SD 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
SD 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
SD 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, NE 
NE 
NE 
NE 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 33 | 43 
• The date of premature study discontinuation can be determined by using the “date 
of study discontinuation” field on the “discontinuation of study” form. This date 
should be compared to the date on the “discontinuation of treatment” forms where 
the primary reason for discontinuation is listed as “sponsor decision to terminate 
study”. If these dates differ, select the earlier date. 
• For each patient, select all “evaluation of response (RECIST)” forms meeting the 
following criteria: 
o The “date of the radiological scan or assessment on which the response 
evaluation was based” is after Day 1. 
o The “date of the radiological scan or assessment on which the response 
evaluation was based” is on or before the date of radiological disease 
progression, date that anti-cancer therapy first began, and the date of study 
discontinuation. If the patient did not experience radiological disease 
progression, begin anti-cancer therapy, or discontinue the study 
prematurely, select all forms after Day 1. 
ORR is defined as the proportion of patients who have achieved confirmed BOR of CR 
or PR.  
Number of responders, ORR, and its 2-sided 80% confidence interval along with a 1-
sided p-value for testing the null hypothesis based on the binomial distribution will be 
provided for Efficacy Population and Response Evaluable Population. The exact 
(Clopper-Pearson) method will be used to calculate 2-sided 80% CI. This can be 
programmed in SAS by appending the “/BINOMIAL(EXACT)” option to the end of the 
appropriate “TABLE” statement. 
The following plots will be provided using Response Evaluable Population: 
• Spider plots, which display the percent change from baseline in the sum of the 
diameter of all target lesions for each patient over the period of patient evaluation.  
• Waterfall plots, which display the best percentage change from baseline in the 
sum of the diameter of all target lesions. 
• Swim lane plots of time on study treatment with symbols indicating response 
start, progression, and withdrawal from study, where applicable. 
Unless otherwise stated, detailed tumor time-point response will be listed for Efficacy 
Population.   
8.4.2 Duration of Response  
DOR is defined as the time from the first documentation of response (CR or PR) until the 
time of the first documentation of disease progression by RECIST v1.1 based on 
investigator’s assessment or death by any cause, calculated as: 
(Date of Event or Censoring – Date of first confirmed CR or PR + 1)/30.4375  


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 34 | 43 
DOR will be calculated only for patients who responded to the study treatment using the 
censoring rules specified in Table 5.   
Due to small number of response events, DOR will be listed only for Efficacy Population 
and Response Evaluable Population and summarized descriptively for the Response 
Evaluable Population.  
Table 5: Censoring Rules Used for DOR Analysis 
Situation 
Date of Event or Censoring 
Outcome 
Start of subsequent anti-cancer therapy 
without 
a 
prior 
documented 
progression or death 
Date of last evaluable radiologic tumor 
assessment prior to or on the date of 
initiation of the subsequent anti-cancer 
therapy 
Censored 
No documented radiologic progression 
and no subsequent anti-cancer therapy 
started 
Date of last evaluable radiologic tumor 
assessment  
Censored 
Documented radiologic progression or 
death after two or more consecutive 
missing radiologic assessments 
Date of last evaluable radiologic tumor 
assessment before the missed tumor 
assessments 
Censored 
Documented radiologic progression or 
death 
Earliest date of documented radiologic 
progression or death 
Event 
8.4.3 Disease Control Rate  
DCR is defined as the proportion of patients who have achieved confirmed BOR of CR, 
PR, or stable disease (SD) per RECIST v1.1. 
DCR will be summarized using the same methods for ORR for Efficacy Population and 
Response Evaluable Population.   
8.4.4 Progression Free Survival  
PFS is defined as the time from the date of the first dose of study treatment to the earlier 
date of assessment of progression, or death by any cause in the absence of progression by 
RECIST v1.1. 
PFS in months will be calculated as following using the censoring rules specified in 
Table 6: 
• (Earlier Date of Event or Censoring – First dose date of study treatment + 
1)/30.4375 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 35 | 43 
The Kaplan-Meier (KM) method will be used to estimate the distribution of PFS for 
Efficacy Population SAS PROC LIFETEST with method = PL option (Kaplan-Meier 
estimates, also known as the product-limit estimates) will be used. The 25th, 50th, and 
75th percentiles of times-to-event with 95% CIs will be estimated using the Brookmeyer-
Crowley method (Brookmeyer & Crowley, Biometrics, Vol. 38, No. 1, Mar., 1982, pp. 
29-41). Summaries of the number and percentage of events and censored patients will 
also be provided. Survival risks at 6 and 12 months will be provided if applicable.  
 
A KM plot will be provided to graphically present the PFS. 
Table 6: Censoring Rules Used for PFS Analysis 
Situation  
Date of Event or Censoring 
Outcome  
No baseline tumor assessments 
First dose date 
Censored 
No post-baseline tumor assessments and no 
death  
First dose date 
Censored 
Start of subsequent anti-cancer therapy prior 
to a documented radiologic progression or 
death 
Date of last evaluable radiologic 
tumor assessment prior to or on the 
date of initiation of the subsequent 
anti-cancer therapy 
Censored 
No documented radiologic progression, no 
subsequent anti-cancer therapy started, and 
no death 
Date of last evaluable radiologic 
tumor assessment 
Censored  
Documented radiologic progression or death 
after two or more consecutive missing 
radiologic assessments 
Date of last evaluable radiologic 
tumor assessment before the missed 
tumor assessments 
Censored  
Documented radiologic progression or death  
Earliest 
date 
of 
documented 
radiologic progression or death 
Event  
8.4.5  Overall Survival  
Overall survival (OS) is defined as the time from first dose of treatment to the date of 
death of any causes. If the patient did not experience an event, he/she will be censored at 
the last follow-up date.  
The KM method will be used to estimate the distribution of OS for Efficacy Population. 
SAS PROC LIFETEST with method = PL option (Kaplan-Meier estimates, also known 
as the product-limit estimates) will be used. The 25th, 50th, and 75th percentiles of times-
to-event with 95% CIs will be estimated using the Brookmeyer-Crowley method 
(Brookmeyer & Crowley, 1982). Summaries of the number and percentage of events and 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 36 | 43 
censored patients will also be provided. Survival risks at 6 and 12 months will be 
provided if applicable.  
A KM plot will be provided to graphically present the OS. 
8.5 
Biomarker Analysis 
All biomarkers will be listed for Safety Population. Analysis for interested biomarkers is 
described as follows.  
8.5.1 Analysis of BRCA, HRD, HRR, and PD-L1 
BRCA, HRD status and HRR gene status are determined by tumor samples at screening 
via the Myriad myChoice Plus test. The PD-L1 expression is determined by tumor 
sample at screening via the PD-L1 IHC DAKO 22C3 test.  
HRR gene status may be explored if applicable.  
The ORR, DCR, and DOR will be summarized for following each type of biomarkers 
defined as following:  
• BRCA mutation status 
− BRCAmut: patients with BRCA deleterious or suspected deleterious mutation 
− BRCAwt: patients without BRCA deleterious or suspected deleterious 
mutation  
− BRCAunk: BRCA test result not available (e.g. test canceled, incomplete or 
inconclusive, or data missing for a patient, etc.) 
• HRD status 
− HRDpos:  BRCAmut or HRD score ≥ 42 
− HRDneg: BRCAwt/unknown and HRD score < 42 
− HRDunk: HRD unknown (e.g. test canceled, incomplete or inconclusive, or 
data missing for a patient, etc.) 
• HRR status  
− HRR positive:  patients with deleterious or suspected deleterious mutation in 
at least one of the Myriad IDE validated HRR gene panel (ATM, BARD1, 
BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, 
PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L) 
− HRR negative: patients without deleterious or suspected deleterious mutation 
in any of the Myriad IDE validated HRR gene panel (ATM, BARD1, BRCA1, 
BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, 
RAD51B, RAD51C, RAD51D, RAD54L) 
− HRR unknown: HRR gene mutation result not available (e.g. test canceled, 
incomplete or inconclusive, or data missing for a patient, etc.) 
• PD-L1 expression 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 37 | 43 
− PDL1-positive: PD-L1 CPS ≥ 1 (tumor that scores ≥ 1) 
− PDL1-negative: PD-L1 CPS < 1 (tumor that scores < 1) 
− PDL1-unk: PD-L1 CPS unknown. PD-L1 test result not available (e.g. test 
canceled, incomplete or inconclusive, or data missing for a patient. etc) 
8.5.2 Analysis of CD8+ TIL 
The CD8+ TIL density is determined by tumor samples at screening and on-treatment. 
Descriptive summary tables will be provided including:  
• Baseline CD8+ TIL: density of CD8+ TIL (count/mm2)in tumor sample collected 
at screening.  
• On-treatment CD8+ TIL: density of CD8+ TIL (count/mm2)in tumor samples 
collected on treatment between C2D1 to C3D1.  
8.6 
Safety Analysis 
8.6.1 Adverse Events 
AEs will be coded using MedDRA v24.1 or later and will be classified by SOC and PT of 
MedDRA. Severity of AEs will be assessed by investigators according to CTCAE 
(v4.03).  
A treatment-emergent AE (TEAE) will be defined as any new AE that begins, or any 
preexisting condition that worsens in severity from first dose date until 30 days after the 
last dose of study treatment (or until the start of new anticancer therapy, whichever 
occurred first).   
TEAEs are classified as Related or Unrelated to each study drug niraparib, TSR-042, and 
bevacizumab by the Investigator.  Any TEAEs for which the relationship to study drug is 
missing will be considered as related to study drug.  
The number and percentage of patients who experienced an AE will be summarized.  
The following types of summaries will be provided: 
• Overview of TEAEs 
• TEAEs by SOC and PT 
• TEAEs by PT in decreasing frequency 
• Immune-related TEAEs by PT in decreasing frequency 
• Drug-related TEAEs by PT in descending frequency 
- Niraparib-related TEAEs by PT in descending frequency 
- TSR-042-related TEAEs by PT in descending frequency 
- Bevacizumab-related TEAEs by PT in descending frequency 
• Drug-related AEs by PT in descending frequency 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 38 | 43 
- Niraparib-related AEs by PT in descending frequency 
- TSR-042-related AEs by PT in descending frequency 
- Bevacizumab-related AEs by PT in descending frequency 
• Drug-related TEAEs by SOC and PT 
- Niraparib-related TEAEs by SOC and PT 
- TSR-042-related TEAEs by SOC and PT  
- Bevacizumab-related TEAEs by SOC and PT 
• TEAEs by SOC, PT, and Maximum CTCAE toxicity grade 
• Drug-related TEAEs by SOC, PT, and Maximum CTCAE toxicity grade  
- Niraparib-related TEAEs by SOC, PT, and Maximum CTCAE toxicity grade  
- TSR-042-related TEAEs by SOC, PT, and Maximum CTCAE toxicity grade   
- Bevacizumab-related TEAEs by SOC, PT, and Maximum CTCAE toxicity 
grade  
• Serious AEs by SOC and PT 
• Non-serious AEs by SOC and PT 
• Drug-related serious AEs by SOC and PT 
- Niraparib-related Serious AEs by SOC and PT 
- TSR-042-related Serious AEs by SOC and PT  
- Bevacizumab-related Serious AEs by SOC and PT 
• TEAEs leading to study drug discontinuation by SOC and PT 
− TEAEs leading to Niraparib discontinuation by SOC and PT 
− TEAEs leading to TSR-042 discontinuation by SOC and PT 
− TEAEs leading to Bevacizumab discontinuation by SOC and PT 
• Drug-related TEAEs leading to study drug discontinuation by SOC and PT 
− Drug-related TEAEs leading to Niraparib discontinuation by SOC and PT 
− Drug-related TEAEs leading to TSR-042 discontinuation by SOC and PT 
− Drug-related TEAEs leading to Bevacizumab discontinuation by SOC and PT 
• TEAEs leading to Niraparib reduction or delay by SOC and PT 
• TEAEs leading to study drug interruption or delay by SOC and PT 
− TEAEs leading to TSR-042 infusion interruption or delay by SOC and PT 
− TEAEs leading to Bevacizumab infusion interruption or delay by SOC and PT 
• Death and primary reasons causing death 
• TEAEs of special interest by SOC and PT 
The AESIs for this study are myelodysplastic syndrome (MDS), acute myeloid leukemia 
(AML) and secondary cancers (new malignancies other than MDS/AMLTable 5 outlines the 
AESI with the criteria of mapping MedDRA PTs for each AESI using Standardized 
MedDRA Queries (SMQs), High Level Terms (HLTs), and/or PTs. 
 
 
 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 39 | 43 
Table 5: Adverse Events of Special 
Interest Group Term  
MedDRA V18.1 Criteria for Selection of 
Preferred Terms1  
AESI (MDS/AML events)  
MedDRA PTs associated with MDS/AML  
AESI (new malignancies other than MDS/AML)  
Malignant tumor SMQ (other than MDS/AML)  
Abbreviations: AESI = adverse event of special interest; AML = acute myelogenous leukemia; MDS = myelodysplastic 
syndrome; MedDRA = medical dictionary for regulatory activities; PT = preferred term; SMQ = Standardized 
MedDRA Query. 
If a preferred term or system organ class was reported more than once for a patient, the 
patient would only be counted once in the incidence for that preferred term or system 
organ class.  
In tabulation by severity (i.e., CTCAE toxicity grade),  
• For a given preferred term, only the most severe preferred term for each patient 
will be included.   
• For a given system organ class, only the most severe system organ class for each 
patient will be included.   
The following tables presented as listings will be provided: 
• Deaths 
• Serious AEs 
• TEAEs leading to dose reduction, interruption or delayed. 
• TEAEs leading to treatment discontinuation 
• Listing of COVID-19 assessment and symptom assessments for COVID-19 
positive subjects    
AEs will be listed for All Patients Population.  
 
8.6.2 Study Drug Exposure  
Study drug will be summarized using descriptive statistics including: 
• Duration of drug exposure 
• Number of treatment cycles (1 cycle, 2 cycles, etc.) 
• Actual dose intensity  
• Relative dose intensity  
Dose reduction, dose interruption or delay will be summarized by cycle: 
• Number of patients with infusion interruption for TSR-042 
• Number of patients with infusion delay for TSR-042 
• Number of patients with infusion interruption for Bevacizumab 
• Number of patients with infusion delay for Bevacizumab 
• Number of patients with Niraparib dose reduction  


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 40 | 43 
• Number of patients with Niraparib dose delay  
Duration of exposure and dose intensity will be calculated as described in Table 7 for 
each drug.   
Swimmer plots displaying the duration of treatment for each patient will be presented by 
including indicators:  
• Treatment status (ongoing or discontinued) 
• Response at each tumor assessment 
Details of study treatment exposure will be listed for Safety Population.  


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 41 | 43 
 
Table 7: Extent of Study Drug Exposure 
Parameter 
Niraparib 
TSR-042 
Bevacizumab 
Dosing 
schedule  
Dose level 1: 200mg daily 
Dose level 2: 300mg daily 
500mg Q3W (first 4 cycles), 
followed by 1,000mg Q6W 
beginning on Cycle 5 Day 1 
15 mg/kg Q3W 
Intended dose  (mg/day) 
Dose level 1: 200/1   
Dose level 2: 300/1 
(mg/day) 
First 4 Cycles: 500/21   
After Cycle 5: 1000/42 
(mg/kg /day) 
15/21 
Duration of 
Treatment 
(unit) 
(day) 
Last dose date - Start dose date +1 
(day) 
First 4 cycles: 
Last dose date prior to cycle 5 
– Start dose date + 21  
 
After cycle 5: 
Last dose date – First Dose 
Date at or after Cycle 5 + 42  
(day) 
Last dose date - 
Start dose date + 21 
 
Actual 
Cumulative 
Dose (unit) 
(mg) 
Sum of the doses (mg) consumed 
by a patient during the treatment 
period 
 
The sum of the doses consumed 
(mg) is the total number of 
capsules consumed multiplying 
by 100. 
The total number of capsules 
consumed is the sum of the 
number of capsules dispensed less 
the sum of the number of capsules 
returned by the patient during the 
study. Unused capsules not 
returned will be assumed to have 
been consumed 
(mg) 
Sum of the doses (mg) 
administered to a patient 
during the treatment period 
 
Calculated separately for the 
first 4 cycles and cycles after 
cycle 5 
 
(mg/kg) 
Sum of the doses 
(mg/kg) 
administered to a 
patient during 
the treatment period 
Actual Dose 
Intensity 
(unit) 
(mg/day)  
Actual Cumulative Dose / 
Duration of treatment 
(mg/day) 
Actual Cumulative Dose 
/Duration of treatment 
Calculated separately for the 
first 4 cycles and cycles at or 
after cycle 5 
(mg/kg/day) 
Actual Cumulative 
Dose /Duration of 
treatment 
 
Relative Dose 
Intensity (%) 
Actual Dose Intensity/Intended Dose   
Note for TSR-042, it needs to be calculated separately for the first 4 cycles and cycles 
after cycle 5 
Abbreviations: Q3W = every 3 weeks; Q6W = every 6 weeks; 


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 42 | 43 
 
8.6.3 Clinical Laboratory Tests 
All laboratory parameters collected at each center’s local laboratory will be normalized 
by converting values in original units to values in SI units and classified as normal, low, 
or high based on normal ranges supplied by the local laboratories and upon employing 
standardization.  
For hematology, coagulation, serum chemistry, thyroid function and serum CA-125 
laboratory parameters which are normalized in SI units, descriptive summary tables for 
observed values and changes from baseline will be provided by visit for Safety 
Population.  
The laboratory test results will be categorized according to NCI CTCAE v4.03 toxicity 
grades.  Shift tables will be provided from baseline toxicity to maximum post-baseline 
toxicity grade ONLY for each applicable hematology and chemistry laboratory parameter 
in Safety Population.  
Urinalysis laboratory parameters at each visit will be summarized. The categorical 
urinalysis parameters will be summarized using frequency table.  
Liver function tests will be summarized for the following categories. To be counted in the 
denominator, the patient must have at least one post-baseline lab chemistry measurement 
for the specified lab tests (e.g. in the ‘ALT ≥3xULN and BIL ≥2xULN’ category, the 
denominator should include subjects who had both a post-baseline ALT value AND a 
post-baseline BIL value that was up to 28 days after ALT).   
• ALT ≥ 3×ULN and BIL ≥ 2×ULN  
• ALT ≥3xULN and INR >1.5 
• ALT ≥ 3×ULN and BIL ≥ 2×ULN and ALP < 2×ULN 
• Hepatocellular injury is defined as ((ALT/ALT ULN)/(ALP/ALP ULN)) ≥5 and 
ALT 
3xULN. ALT and ALP values must occur on the same day. The 
denominator should include subjects who had both a post-baseline ALT and ALP 
on the same day.   
• Hepatocellular injury and BIL ≥2xULN. The denominator should include subjects 
who had both a post-baseline ALT and ALP on the same day as well as BIL on or 
up to 28 days of that day.   
• ALT ≥ 3×ULN, ALT ≥5×ULN, ALT ≥10×ULN, ALT ≥20×ULN 
The BIL elevation must occur on or up to 28 days after the ALT elevation. Categories are 
not mutually exclusive.  ULN is the upper limit of normal.  


GlaxoSmithKline plc  
Confidential  
Statistical Analysis Plan 
Protocol No: 3000-02-005    
 
Dated: 04May2022, Version 2.0 
 
 
    Page 43 | 43 
A scatter plot of maximum total bilirubin versus maximum ALT will be generated, as 
well as a scatter plot of maximum vs baseline for ALT. 
Separate listings will be provided for all laboratory tests including pregnancy testing for 
Safety Population.   
8.6.4 Vital Signs 
The vital signs parameters will be summarized in a change from baseline descriptive 
summary table by visit for the Safety Population.  
A patient-detailed listing of vital signs including systolic and diastolic blood pressure 
(mmHg), pulse (bmp), temperature (oC)) and weight (kg) will be provided for Safety 
Population.  
Conversion of temperature is as following: 
Temperature (ºC) = (Temperature (ºF) – 32) x 5/9 
8.6.5 Physical Examination Findings 
Physical examination will be presented in listing for Safety Population. 
8.6.6 ECOG Performance Status  
The number and percentage of ECOG performance status by each visit will be 
summarized. The denominators for calculating the percentages will be based on the 
number of patients with non-missing values. 
The ECOG shift from baseline grade to worst (highest) post-baseline grade during the on-
treatment period will be summarized for Safety Population.  
Listings will be presented for Safety Population. 
8.6.7 Electrocardiogram (ECG) 
ECG findings will be listed for Safety Population.