A Single-Arm Phase-II Study of Niraparib in Locally Advanced or Metastatic Solid Tumor Patients With PALB2 Mutations
Phase: PHASE2
Conditions: Solid Tumor, Breast Tumor, Colon Tumor, Malignant, Lung Tumor, Urologic Cancer, Pancreatic Cancer, Melanoma, Metastatic Cancer, Locally Advanced Solid Tumor, Esophageal Cancer, Endometrial Cancer, Head and Neck Cancer
Sponsor: Tempus AI

Protocol Cover Page 
NCT05169437 
Title: A Single-Arm Phase-II Study of Niraparib in Locally Advanced or Metastatic Solid 
Tumor Patients with PALB2 Mutations 
Date: 06December2021 

TMPS-101 Amendment 1  
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    December 06, 2021 
 
 
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TITLE PAGE 
 
Protocol Title: 
A Single-Arm Phase-II Study of Niraparib in Locally 
Advanced or Metastatic Solid Tumor Patients with 
PALB2 Mutations  
 
Protocol Number: 
TMPS-101 
Compound Name: 
Niraparib (GSK3985771) 
Brief Title: 
Niraparib in the Treatment of Patients with Advanced 
PALB2 Mutated Tumors 
Study Phase: 
Phase II 
Sponsor Name and Legal 
Registered Address:  
Tempus Labs, Inc. 
600 West Chicago Ave., Suite 510,  
Chicago, Illinois 60654 
 
Regulatory Agency 
Identification Numbers: 
IND Number: 159142 
Approval Date: 
December 06, 2021 
Version:  
Amendment 1  
. 
 

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SPONSOR SIGNATORY 
Protocol Title: 
A Single-Arm Phase-II Study of Niraparib in Locally 
Advanced or Metastatic Solid Tumor Patients with PALB2 
Mutations  
 
Protocol Number: 
TMPS-101 
Version:  
Amendment 1  
Compound Name: 
Niraparib (GSK3985771) 
 
 
Medical Director, TEMPUS  
Signature: 
Date:  
The signed page is a separate document. 
Medical Monitor Name and 
Contact Information: 
Can be found in the Study Manual 
 
 

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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
Document History  
Document History Document  
Date  
Amendment 01  
06 December 2021   
Original Protocol  
29 October 2021 
Overall Rationale for the Amendment  
Amendment 01 is a global amendment created to address regulatory feedback and provides 
important clarity to facilitate study conduct.  
A description and brief rationale for each change is provided below.  
Summary of Changes for the Amendment  
Summary of Changes for 
Amendment 01 Section(s) 
Affected  
Description of Change  
Brief Rationale  
Headers, cover page, Protocol 
Amendment Summary of 
Changes, Appendix 12. Protocol 
Amendment History (new), and 
throughout  
Headers and cover page were 
updated with new document 
number and amendment 
information; Protocol 
Amendment Summary of 
Changes section was updated to 
include rationale for this 
amendment.  
Re-versioning of the document 
to Amendment 1.  
Section 1.1. Synopsis 
(Exploratory Objectives) 
Section 1.3. Schedule of 
Activities (Table 4: Schedule of 
Activities, footnote m) 
Section 3 Study Objectives and 
Endpoints  
(Table 8 Objectives and 
Endpoints for Study TMPS-101) 
Section 8.25 Pharmacokinetic 
Sample Collection 
9.4.4 Exploratory Endpoints 
Add sparse PK sampling for all 
study participants.  
Added new Section 8.25 
Pharmacokinetic Sample 
Collection.  
Updated 9.4.4 Exploratory 
Endpoints section to add PK 
analysis.  
In response to FDA feedback, 
the Sponsor has committed to 
conduct sparse PK sampling for 
all study participants. 
Section 1.1. Synopsis 
Section 1.2 Schedule of 
Activities (SoA) (Table 3: 
Schedule of Activities – 
Screening Biomarker PALB2 
Testing) 
Updated ‘Laboratory Manual’ to 
‘NGS Laboratory Manual’  
Updated List of Abbreviations 
and Definitions of Terms to add 
NGS. 
Administrative change to 
provide clarity between different 
trial laboratory manuals. 

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Section 8.1.2. Biomarker 
Testing for PALB2 and 
Translational Research   
Appendix 5: List of 
Abbreviations and Definitions of 
Terms 
Section 1.1 Synopsis (Criteria 
for Inclusion & Methodology)  
Section 2.1 Study Rationale  
Section 4.1 Study Design 
Section 5.1 Participant Inclusion 
Criteria 
 
Updated title for patient 
population clarification.  
Updated Methodology for 
patient population clarification.  
Replaced Inclusion #6  
Renumbered following inclusion 
criteria appropriately.  
Updated Study Rationale & 
Study Design for patient 
population clarification.  
In response to FDA feedback, 
the Sponsor has added an 
inclusion criterion to further 
specify that patients must have 
progressed on all available 
therapies known to confer 
clinical benefit for their tumor 
type prior to study participation.  
Protocol updated to clarify the 
study population.  
Section 1.1 Synopsis (Criteria 
for Inclusion) 
Section 5.1 Participant Inclusion 
Criteria 
Added clarification around mild 
and moderate hepatic 
impairment definition to 
Inclusion #10.  
Administrative change for 
clarity. 
Section 1.1 Synopsis (Criteria 
for Inclusion & Criteria for 
Exclusion:)  
Section 5.2 Participant 
Exclusion Criteria 
 
Add new Exclusion #27.  
Edited Exclusion #25  
Removed Exclusion #27 
Renumbered exclusion criteria 
appropriately.  
In response to FDA feedback, 
the Sponsor has updated the 
protocol to include select 
patients with HIV. 
Section 4.3 Dose Justification 
Section 11. References  
Section 1.1 Synopsis 
(Investigational Product, 
Dosage, and Mode of 
Administration – Niraparib) 
Add new Section 4.3 Dose 
Justification. 
Updated references section.  
Clarification made to dosing 
regimen in synopsis.  
In response to FDA feedback, 
the Sponsor has updated the 
protocol to include dose 
justification.  
Administrative change for 
clarity. 
Section 6.2.3 Niraparib 
Administration 
Section 6.2.5 Study Drug 
Handling and Disposal  
Updated ‘Study Manual’ to 
‘niraparib product guidelines 
document’ to clarify niraparib 
instructions document.  
Administrative change for 
clarity.  
Section 8.1.2 Biomarker Testing 
for PALB2 and Translational 
Research   
Further clarified requirements 
regarding new biopsy sample 
collection.  
In response to FDA feedback, 
the Sponsor has updated the 
protocol to provide clarification 
regarding new biopsy sample 
collection.  
 
 
 

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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ................................................................................................................. 9 
1.1. 
SYNOPSIS ..................................................................................................................................... 9 
1.2. 
SCHEMA ..................................................................................................................................... 19 
1.3. 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 19 
2. 
INTRODUCTION ............................................................................................................................ 28 
2.1. 
STUDY RATIONALE .................................................................................................................... 28 
2.1.1. PALB2 in the HRR pathway .................................................................................................. 29 
2.1.2. Hereditary/Germline PALB2 Mutations (gPALB2) .............................................................. 29 
2.1.3. Somatic PALB2 Mutations (sPALB2) ................................................................................... 30 
2.1.4. Comprehensive Genomic Testing .......................................................................................... 30 
2.1.5. PALB2 Mutation Prevalence ................................................................................................. 30 
2.2. 
BACKGROUND ON PARP INHIBITORS AND NIRAPARIB ............................................................. 32 
2.3. 
PARPI MECHANISM OF ACTION ................................................................................................ 32 
2.3.1. Biomarkers of PARPi Response ............................................................................................ 34 
2.3.2. Niraparib Preclinical Data ................................................................................................... 34 
2.3.3. Niraparib Safety Data ........................................................................................................... 35 
2.3.4. Niraparib Approved Indications and Registrational Trial Overviews .................................. 35 
2.3.5. Niraparib Clinical Trials Outside of Approved Indications ................................................. 36 
2.3.6. Other Approved PARPi ......................................................................................................... 37 
2.3.7. Clinical Trials of PARPi in PALB2-mutated Tumors ........................................................... 38 
2.4. 
BENEFIT / RISK ASSESSMENT .................................................................................................... 38 
2.4.1. Chemotherapy Agents Approved for Use in Advanced Cancers ........................................... 38 
2.4.2. Benefit of PARPi in PALB2-mutated cancers ....................................................................... 39 
2.4.3. Risk Assessment ..................................................................................................................... 40 
2.4.4. Overall Benefit/Risk Conclusion ........................................................................................... 41 
3. 
STUDY OBJECTIVES AND ENDPOINTS .................................................................................. 41 
4. 
STUDY DESIGN .............................................................................................................................. 43 
4.1. 
OVERALL DESIGN ...................................................................................................................... 43 
4.2. 
NUMBER OF PARTICIPANTS ....................................................................................................... 44 
4.3. 
DOSE JUSTIFICATION ................................................................................................................. 44 
4.4. 
DOSE ADJUSTMENT CRITERIA ................................................................................................... 45 
4.4.1. Niraparib ............................................................................................................................... 45 
4.5. 
END OF STUDY ........................................................................................................................... 45 
4.6. 
STUDY CONDUCT ....................................................................................................................... 45 
4.6.1. Procedures by Visit ............................................................................................................... 45 
5. 
STUDY POPULATION ................................................................................................................... 46 
5.1. 
PARTICIPANT INCLUSION CRITERIA .......................................................................................... 46 
5.2. 
PARTICIPANT EXCLUSION CRITERIA ......................................................................................... 48 
5.3. 
LIFESTYLE CONSIDERATIONS .................................................................................................... 50 
5.4. 
SCREEN FAILURES ..................................................................................................................... 50 
6. 
STUDY TREATMENT(S) AND CONCOMITANT THERAPY ................................................ 50 
6.1. 
STUDY TREATMENT(S) ADMINISTERED..................................................................................... 50 
6.1.1. Niraparib ............................................................................................................................... 50 
6.2. 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY .......................................................... 51 

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6.2.1. Study Drug Packaging and Labeling .................................................................................... 51 
6.2.2. Study Drug Storage ............................................................................................................... 51 
6.2.3. Niraparib Administration ...................................................................................................... 51 
6.2.4. Study Drug Accountability .................................................................................................... 52 
6.2.5. Study Drug Handling and Disposal ...................................................................................... 52 
6.3. 
STUDY TREATMENT COMPLIANCE ............................................................................................ 52 
6.4. 
TREATMENT OF OVERDOSE ....................................................................................................... 53 
6.5. 
CONCOMITANT THERAPY .......................................................................................................... 53 
6.5.1. Prohibited Medications ......................................................................................................... 54 
6.5.2. Contraception ........................................................................................................................ 55 
6.5.3. Other Study Restrictions ....................................................................................................... 56 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................................... 57 
7.1. 
DISCONTINUATION FROM STUDY TREATMENT ......................................................................... 57 
7.2. 
WITHDRAWAL OF CONSENT ...................................................................................................... 58 
7.3. 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY ........................................ 58 
7.4. 
LOST TO FOLLOW-UP ................................................................................................................ 59 
7.4.1. Further Research Maintaining Confidential Participant Information .................................. 59 
8. 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 60 
8.1. 
SCREENING AND CRITICAL BASELINE ASSESSMENTS ............................................................... 60 
8.1.1. Baseline Assessments at Screening ....................................................................................... 60 
8.1.2. Biomarker Testing for PALB2 and Translational Research ................................................. 60 
8.1.3. Baseline CT/MRI ................................................................................................................... 61 
8.2. 
ASSESSMENT OF EFFICACY ........................................................................................................ 61 
8.2.1. Primary Efficacy Endpoint .................................................................................................... 61 
8.2.2. Radiographic Evaluation of Tumor Response....................................................................... 61 
8.2.3. Secondary Efficacy Endpoints ............................................................................................... 63 
8.2.4. Patient-Reported Outcome Measures ................................................................................... 63 
8.2.5. Pharmacokinetic Sample Collection ..................................................................................... 63 
8.3. 
ASSESSMENT OF SAFETY ........................................................................................................... 64 
8.3.1. Safety Parameters ................................................................................................................. 64 
8.3.2. Demographic/Medical History .............................................................................................. 64 
8.3.3. Physical Examination ............................................................................................................ 64 
8.3.4. Vital Signs, Height, and Weight ............................................................................................ 64 
8.3.5. Laboratory Assessments ........................................................................................................ 65 
8.3.6. HIV, Hepatitis B, and Hepatitis C Testing ............................................................................ 67 
8.3.7. ECOG Performance Status ................................................................................................... 67 
8.4. 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES), AND OTHER SAFETY 
REPORTING ............................................................................................................................................. 67 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information .................................. 67 
8.4.2. Method of Detecting AEs and SAEs ...................................................................................... 67 
8.4.3. Follow-Up of AEs and SAEs ................................................................................................. 68 
8.4.4. Pregnancy ............................................................................................................................. 68 
8.4.5. Cardiovascular and Death Events ........................................................................................ 69 
8.4.6. Adverse Events of Special Interest (AESIs) ........................................................................... 69 
9. 
STATISTICAL CONSIDERATIONS ............................................................................................ 70 
9.1. 
STATISTICAL HYPOTHESES ........................................................................................................ 70 
9.2. 
SAMPLE SIZE DETERMINATION ................................................................................................. 70 

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9.3. 
ANALYSIS POPULATIONS ........................................................................................................... 71 
9.4. 
STATISTICAL ANALYSES ............................................................................................................ 72 
9.4.1. General Considerations ........................................................................................................ 72 
9.4.2. Primary Endpoints ................................................................................................................ 72 
9.4.3. Secondary Endpoints ............................................................................................................. 72 
9.4.4. Exploratory Endpoints .......................................................................................................... 73 
9.4.5. Safety Analyses ...................................................................................................................... 74 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......... 75 
11. 
REFERENCES ............................................................................................................................. 75 
12. 
APPENDICES .............................................................................................................................. 80 
APPENDIX 1. REGULATORY, ETHICAL, AND STUDY CONSIDERATIONS ................................................. 80 
APPENDIX 2. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND PREGNANCIES: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, FOLLOW UP, AND REPORTING ...................................... 85 
APPENDIX 3. CONTRACEPTION GUIDELINES .......................................................................................... 91 
APPENDIX 4. LIVER SAFETY REQUIRED ACTIONS AND FOLLOW-UP ASSESSMENTS ............................. 94 
APPENDIX 5. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................................... 98 
APPENDIX 6. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS V1.1 ........................................... 101 
APPENDIX 7. PATIENT-REPORTED OUTCOMES ..................................................................................... 104 
APPENDIX 8. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS .......................... 105 
APPENDIX 9. ESTIMATION OF CREATININE CLEARANCE WITH THE COCKCROFT-GAULT FORMULA .. 105 
APPENDIX 10. DOSAGE ADJUSTMENTS FOR ADVERSE REACTIONS ................................................... 106 
 
LIST OF TABLES 
TABLE 1. ORGAN/BONE MARROW FUNCTION INCLUSION CRITERIA 
11 
TABLE 2. OPTIMIZED STOPPING BOUNDARIES BASED ON BOP2 DESIGN 
17 
TABLE 3. SCHEDULE OF ACTIVITIES – SCREENING BIOMARKER PALB2 TESTING 
20 
TABLE 4. SCHEDULE OF ACTIVITIES – SCREENING PERIOD THROUGH END OF STUDY FOR 
ALL COHORTS 
21 
TABLE 5. PALB2 MUTATION PREVALENCE BY TUMOR TYPE 
31 
TABLE 6. SINGLE-AGENT CHEMOTHERAPY ORR, TTP OR DOR BY TUMOR TYPE 
39 
TABLE 7. SUMMARY OF RISKS AND MITIGATIONS FOR THE PRODUCT 
40 
TABLE 8. OBJECTIVES AND ENDPOINTS FOR STUDY TMPS-101 
41 
TABLE 9. ORGAN/BONE MARROW FUNCTION INCLUSION CRITERIA 
46 
TABLE 10. INVESTIGATIONAL PRODUCT DETAILS 
50 
TABLE 11. NIRAPARIB DOSING CRITERIA 
52 
TABLE 12. TIMING OF CONTRACEPTION AND SPERM DONATION 
56 
TABLE 13. OVERVIEW OF IMAGING REQUIREMENTS BY VISIT 
62 
TABLE 14. LABORATORY ASSESSMENTS 
66 
TABLE 15. OPERATING CHARACTERISTICS 
71 

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TABLE 16. STATISTICAL ANALYTICAL METHODS - SAFETY 
74 
TABLE 17. CONTRACEPTIVES ALLOWED DURING THE STUDY 
92 
TABLE 18. PHASE III-IV LIVER CHEMISTRY STOPPING CRITERIA AND REQUIRED FOLLOW-
UP ASSESSMENTS 
94 
TABLE 19. PHASE III-IV LIVER CHEMISTRY STOPPING CRITERIA AND REQUIRED FOLLOW-
UP ASSESSMENTS (CONTINUED) 
95 
TABLE 20. PHASE III-IV LIVER CHEMISTRY INCREASED MONITORING CRITERIA WITH 
CONTINUED THERAPY 
97 
TABLE 21. ABBREVIATIONS AND SPECIALIST TERMS 
98 
TABLE 22. EVALUATION OF RESPONSE FOR PARTICIPANTS WITH MEASURABLE DISEASE 
(IE, TARGET DISEASE) 
102 
TABLE 23. EVALUATION OF RESPONSE FOR PARTICIPANTS WITH NON-MEASURABLE 
DISEASE (IE, NON-TARGET DISEASE) 
102 
TABLE 24. ECOG PERFORMANCE STATUS GRADING 
105 
TABLE 25. COCKCROFT-GAULT FORMULA FOR SERUM CREATININE CLEARANCE 
105 
TABLE 26. RECOMMENDED DOSE MODIFICATIONS FOR ADVERSE REACTIONS 
106 
TABLE 27. DOSE MODIFICATIONS FOR NON-HEMATOLOGIC ADVERSE REACTIONS 
106 
TABLE 28. DOSE MODIFICATIONS FOR HEMATOLOGIC ADVERSE REACTIONS 
106 
 
 
 LIST OF FIGURES 
FIGURE 1: OVERALL STUDY SCHEMA 
19 
FIGURE 2: DNA DOUBLE-STRAND BREAK REPAIR MECHANISMS AND PARPI FUNCTION 
(CORTESI ET AL., 2021) 
33 
 

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1. 
PROTOCOL SUMMARY 
1.1. Synopsis 
Name of Sponsor/Company: Tempus Labs 
Name of Investigational Product: Niraparib  
Name of Active Ingredient: Niraparib  
Title of Study:  A Single-Arm Phase-II Study of Niraparib in Locally Advanced or Metastatic 
Solid Tumor Patients with PALB2 Mutations  
Study Center(s): Multicenter 
Planned Duration (Projected):  
Estimated date first participant enrolled: Q1 2022 
Estimated date of first analysis: Q3 2023 
Estimated date of final analysis: Q3 2025 
Phase of development:  
Phase II 
 
Study Rationale: 
The purpose of this study is to further evaluate the efficacy and safety of niraparib in patients 
with locally advanced or metastatic solid tumors and a pathogenic or likely pathogenic tumor 
PALB2 (tPALB2) mutation.  
Objectives:  
Primary Objective: 
● To evaluate overall response rate (ORR) as assessed by Independent Central 
Review (ICR) using RECIST v1.1 
Secondary Objectives: 
● To evaluate duration of response (DOR) as assessed by ICR using RECIST v1.1  
● To evaluate progression-free survival (PFS) as assessed by ICR using Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) 
● To evaluate ORR as assessed by Investigator using RECIST v1.1 
● To evaluate DOR as assessed by Investigator using RECIST v1.1 
● To evaluate PFS as assessed by Investigator using RECIST v1.1  
● To evaluate Clinical Benefit Rate (CBR) as assessed by ICR and Investigator  
● To evaluate intracranial ORR and PFS in participants with untreated measurable 
CNS lesions as assessed by ICR and Investigator using RECIST v1.1 
● To evaluate safety and tolerability per the National Cancer Institute Common 
Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) 
● To evaluate overall survival (OS)  
Exploratory Objectives: 
● To evaluate health-related quality of life (HRQoL) and symptoms as assessed by 
EORTC QLQ-C30 and EuroQol EQ-5D-3L 
● To evaluate exploratory biomarkers in tumor and/or blood that may be predictive 
of response including clinical factors 
● To evaluate niraparib concentration or pharmacokinetics (PK)  

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Methodology:  
This is a multicenter study of niraparib in participants with locally advanced or metastatic 
solid tumors and a confirmed pathogenic or likely pathogenic tPALB2 mutation. Participants 
must have received all standard therapies appropriate for their tumor type and stage of disease 
or, in the opinion of the Investigator, the patient would be unlikely to tolerate or derive 
clinically meaningful benefit from appropriate standard of care therapy, or the participant has 
no satisfactory alternative treatments.  
● Baseline: eligibility scan(s) conducted within 28 (± 7) days prior to enrollment 
● Overall progression will be assessed using RECIST v1.1 by ICR and Investigator to 
measure PFS. ORR will be assessed using RECIST v1.1 by Investigator and ICR.  
● Imaging every 8 weeks (56±7 days) from date of enrollment through until radiographic 
progressive disease (PD) is documented per RECIST v1.1. 
● Complete blood count (CBC) will be monitored weekly for the first 4 weeks of the 
treatment period, and blood pressure (BP) and heart rate will be monitored at least 
weekly for the first 2 months, then monthly for the first year and periodically 
thereafter. 
● All AEs and serious adverse events (SAEs) will be collected and recorded for each 
participant from the day of signing the main study informed consent form (ICF) until 
30 days after last dose of study treatment. All AEs and SAEs experienced by a 
participant, irrespective of the suspected causality, will be monitored until the AE or 
SAE has resolved, until abnormal laboratory values have returned to baseline or 
normalized, until there is a satisfactory explanation for the changes observed, until the 
participant is lost to follow-up, or until the participant has died. All SAEs assessed by 
the Investigator as related to the study treatment and adverse events of special interest 
(AESIs) will be collected and reported until study closeout. Any pregnancies that occur 
within 180 days post-treatment will be reported. 
● Patient-reported outcomes (PROs) will be collected in a coordinated fashion with 
imaging while participants remain on study treatment. For participants who 
discontinue all study treatment, the PROs should be collected at the End-of-Treatment 
(EOT) Visit. 
● Each participant will have an EOT Visit at the time of discontinuation from study 
treatment, Safety Follow-up Visits at 30 (±7) days, and Survival Follow-up 
assessments which may be conducted via telephone, email, in person visits to the clinic 
or back-up contacts every 90 (±14) days for 1 year after last dose and then every 180 
(±14) days that will continue until death or the end of study data collection. If 
available, participants continuing niraparib treatment at the time of final analysis may 
be offered the option to continue to receive access to treatment. 
● Data Review:  
o Investigators will assess efficacy for their enrolled participants. An aggregated 
data set will be established based on the assessments of each investigator.   
o An ICR will be performed as an independent review and assessment of the 
efficacy data. An interim and final efficacy analysis will be performed (see 
Statistical Methods). 
Number of Participants (Planned): Approximately 110 participants enrolled based on 
approximately 140 participants screened.  

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Diagnosis and Main Criteria for Inclusion:  
Criteria for Inclusion: 
Participants will be eligible for study entry if all of the following criteria are met: 
1. Participants must be ≥18 years of age. 
2. Participants must have a histologically or cytologically confirmed diagnosis of locally 
advanced or metastatic solid tumor(s). This study will enrich for lung, breast, and colon 
cancers; targeting approximately 10 participants for each of these cancer types.  
3. Participants must have tested positive for a pathogenic or likely pathogenic tPALB2 gene 
mutation using a CLIA-certified laboratory as described in the NGS Laboratory Manual.  
4. Participants who have stable and asymptomatic CNS disease must be receiving a stable 
(for at least 7 days) or decreasing corticosteroid dose at the time of study entry. 
5. Participants must submit fresh or archived (collected within 24 months of enrollment) 
FFPE tumor sample to the central laboratory for post-enrollment confirmation of tPALB2 
status.  
6. Participants must have received all standard therapies appropriate for their tumor type and 
stage of disease or, in the opinion of the Investigator, the patient would be unlikely to 
tolerate or derive clinically meaningful benefit from appropriate standard of care therapy, 
or the participant has no satisfactory alternative treatments. 
7. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1. 
8. Participants must have a life expectancy of at least 12 weeks. 
9. Participants must have adequate organ and bone marrow function defined below. 
Treatment may be delayed up to 3 weeks from enrollment to allow for these criteria to be 
met. 
Table 1. Organ/Bone Marrow Function Inclusion Criteria 
Absolute neutrophil count: 
≥1,500/μL 
Platelets: 
≥100,000/μL 
Hemoglobin: 
≥9 g/dL or 5.6 mmol/L 
Creatinine clearance (CLCr): 
>30 mL/min as estimated by the Cockcroft-Gault equation  
Total bilirubin*: 
  
≤1.5×upper limit of normal (ULN) (except in participants with 
Gilbert’s syndrome. Participants with Gilbert’s syndrome: total 
bilirubin >1.5×ULN is acceptable if bilirubin is fractionated and 
direct bilirubin is <35%). 

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Aspartate aminotransferase 
(AST) and alanine 
aminotransferase (ALT)*: 
≤ 2.5×ULN (unless liver metastases are present, in which case they 
must be ≤5×ULN) 
Note: CBC test should be obtained without transfusion or receipt of colony-stimulating factors 
within 4 weeks prior to obtaining sample. 
*Participants with mild to moderate hepatic impairment are allowed on the study.  
Mild hepatic impairment is defined as total bilirubin ≤1.5×upper limit of normal (ULN), any 
aspartate aminotransferase (AST); and an alanine aminotransferase (ALT) ≤2.5×ULN.   
Moderate impaired hepatic function is defined as total bilirubin >1.5× and ≤3×ULN, any level 
of AST; and an ALT ≤2.5×ULN.  
10. Participants must be able to swallow and retain orally administered study treatment. 
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least one of the following conditions applies: 
● Is not a woman of childbearing potential (WOCBP). 
or 
● Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), with low user dependency, during the intervention 
period and for at least 180 days after the last dose of study treatment and agrees not 
to donate eggs (ova, oocytes) for the purpose of reproduction during this period. 
The Investigator should evaluate the effectiveness of the contraceptive method in 
relation to the first dose of study treatment. 
● A WOCBP must have a negative pregnancy test (either a highly sensitive urine or a 
serum pregnancy test as required by local regulations) within 72 hours before the 
first dose of study treatment. 
● If a highly sensitive urine test cannot be confirmed as negative (eg, an ambiguous 
result), a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive. 
● The Investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
12. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 90 days after the last dose of study treatment:  
● Refrain from donating sperm 
plus, either: 
● Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent  
or 
● Must agree to use contraception/barrier as detailed below: 

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● Agree to use a male condom (and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom 
may break or leak) when having sexual intercourse.  
● Participants must be able to understand the study procedures and agree to 
participate in the study by providing written informed consent. Participants 
must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent to participate in the study. 
 
Criteria for Exclusion: 
Participants will be excluded from study entry if any of the following criteria are met: 
1. Participants have other active concomitant malignancy that warrants systemic, biologic, or 
hormonal therapy.  
2. Participants who have ovarian or prostate cancer. 
3. Participants who have variants of undetermined significance (VUS), but not pathogenic 
variants of PALB2, at the time of screening.  
4. Participants who relapsed while receiving platinum based therapy in the adjuvant/curative 
setting. 
5. Participants progressing within 14-18 weeks while receiving platinum based therapy in the 
metastatic setting. 
6. Participants who have received PARP inhibitor(s) in prior lines of treatment.  
7. Participants with leptomeningeal disease, carcinomatous meningitis, symptomatic brain 
metastases, or radiologic signs of CNS hemorrhage. 
8. Participants with germline or somatic BRCA1 or BRCA2 mutations. 
9. Participant has systolic BP >140 mmHg or diastolic BP >90 mmHg, despite optimal 
medical therapy. 
10. Participants who have any clinically significant gastrointestinal abnormalities that may 
alter absorption such as malabsorption syndrome or major resection of the stomach and/or 
bowels. 
11. Participants with current active liver or biliary disease are excluded (with the exception of 
Gilbert’s syndrome or asymptomatic gallstones, liver cancer/metastases, or otherwise 
stable chronic liver disease per Investigator assessment).  
12. Participants who are receiving chronic systemic steroids (prednisone >20 mg per day). 
Participants with asthma who require intermittent use of bronchodilators or inhaled 
steroids; or with medical conditions who require topical, local steroid application or 
injections, would not be excluded from the study. 
13. Participants have previously or are currently participating in a treatment study of an 
investigational agent within 3 weeks of the first dose of therapy preceding the study.  
14. Participants have received prior systemic cytotoxic chemotherapy, biological therapy, or 
hormonal therapy for cancer, or received radiation therapy within 3 weeks of the first dose 
therapy preceding the study.  

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15. Participants with toxicity from prior cancer therapy must have recovered to Grade 1. (A 
participant with Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion 
and qualify for this study.) 
16. Participants have known hypersensitivity to the components of niraparib or their 
formulation excipients. 
17. Participants have undergone major surgery within 4 weeks of starting the first dose of 
study treatment or have not recovered from any effects of any major surgery. 
18. Participants have other active concomitant malignancy that warrants systemic, biologic, or 
hormonal therapy. 
19. Participants have received a live vaccine within 30 days of study enrollment. 
20. Participants have current active pneumonitis or any history of pneumonitis requiring 
steroids (any dose) or immunomodulatory treatment within 90 days of planned start of the 
study. 
21. Participants who have any clinically significant concomitant disease or condition (such as 
transfusion-dependent anemia or thrombocytopenia) that could interfere with, or for which 
the treatment might interfere with, the conduct of the study or that would, in the opinion of 
the Investigator, pose an unacceptable risk to the participants in this study. 
22. Participants who have any psychological, familial, sociological, or geographical condition 
potentially hampering compliance with the study requirements and/or follow up 
procedures. Those conditions should be discussed with the participants before study entry. 
23. Participants have high medical risk due to a serious, uncontrolled medical disorder; 
nonmalignant systemic disease; or active, uncontrolled infection (including COVID-19). 
Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent 
(within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable 
spinal cord compression, superior vena cava syndrome, active uncontrolled coagulopathy, 
bleeding disorder, or any psychiatric disorder that prohibits obtaining informed consent. 
24. Participants who are pregnant, breastfeeding, or expecting to conceive children while 
receiving study treatment and/or for up to 180 days after the last dose of study treatment. 
25. Participants have presence of hepatitis B surface antigen or a positive hepatitis C antibody 
test result at screening or within 3 months prior to first dose of study treatment. 
Participants with presence of hepatitis B core antibody should also be excluded.  
26. Participants have a known history or current diagnosis of myelodysplastic syndrome 
(MDS), acute myeloid leukemia (AML) or posterior reversible encephalopathy syndrome 
(PRES). 
27. Participant is immunocompromised. Participants with splenectomy are allowed. 
Participants with known human immunodeficiency virus (HIV) are allowed if they meet 
the following criteria: 
• Cluster of differentiation 4 ≥350/μL and viral load <400 copies/mL. 
• No history of acquired immunodeficiency syndrome-defining opportunistic infections 
within 12 months prior to enrollment. 
• No history of HIV-associated malignancy for the past 5 years. 

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• Concurrent antiretroviral therapy as per the most current National Institutes of Health 
(NIH) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents 
Living with HIV [NIH, 2021] started <4 weeks prior to study enrollment. 
 
Investigational Product, Dosage, and Mode of Administration - Niraparib: 
The dosing regimen for niraparib will be the approved individualized starting dose regimen, 
which is 300 mg in participants with a baseline body weight ≥77 kg AND baseline platelet 
count ≥150,000/μL or 200 mg in participants with a baseline body weight <77 kg or baseline 
platelet count <150,000/μL and for participants with moderate hepatic impairment at baseline. 
Niraparib will be taken orally once daily throughout each 28-day cycle. 
All supplies indicated above will be provided centrally by the Sponsor or locally by the study 
site, subsidiary, or designee, depending on local country operational or regulatory 
requirements. For any commercially available product that is provided by the study site, 
subsidiary, or designee, every attempt will be made to source these supplies from a single 
lot/batch number. The study site will be responsible for recording the lot number, 
manufacturer, and expiry date of any locally purchased product. The Investigator will take 
responsibility for maintaining the investigational product and will take all steps necessary to 
maintain appropriate records and ensure appropriate supply, storage, handling, distribution, 
and usage of study treatments in accordance with the protocol and any applicable laws and 
regulations. 
Duration of Treatment:  
Participants will continue to receive treatment until radiographic PD is documented per 
RECIST v1.1 unacceptable toxicity, death, withdrawal of consent, or becoming lost to follow-
up, whichever comes first.  
Treatment with niraparib will continue until radiographic PD is documented per RECIST v1.1 
or another treatment discontinuation criterion is met. If available, participants continuing 
niraparib treatment at the time of final analysis may be offered the option to continue to 
receive access to treatment. 
Criteria for Evaluation: 
Efficacy Analysis 
Primary Efficacy Endpoint 
This study has the primary efficacy endpoint of ORR. ORR is defined as the proportion of 
participants who have a partial or complete response to therapy and will be assessed by ICR. 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be evaluated: 
● DOR, defined as the time between initial response to therapy and subsequent disease 
progression or relapse by ICR using the RECIST v.1.1 criteria.   
● PFS, defined as the time from the date of enrollment to the date of first radiographic 
progression or death from any cause in the absence of progression, whichever occurs first. 
Progression will be assessed by ICR using the RECIST v.1.1 criteria.  
● ORR will be assessed by Investigator. 
● DOR will be assessed by Investigator.  

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● PFS will be assessed by Investigator.  
● CBR as assessed by ICR and Investigator. CBR is defined as the percentage of participants 
who have achieved complete response, partial response and stable disease.  
● Intracranial ORR and PFS in participants with untreated measurable CNS lesions as 
assessed by ICR and Investigator using RECIST v1.1  
● OS, defined as the time from enrollment to the date of death by any cause. Participants 
who are alive will be censored at the date of last contact. OS includes the following: death 
attributable to any cause, including primary cancer, secondary cancer, or unknown cause.  
Safety Analysis  
Safety will be evaluated based on the incidence of AEs, SAEs, and AESIs, the incidence of 
treatment discontinuations, dose interruptions, and dose reductions due to AEs, SAEs, or 
AESIs, changes in ECOG performance status, changes in clinical laboratory results 
(hematology, chemistry, thyroid function, and urinalysis), vital sign measurements, 
observations during physical examination, and use of concomitant medications. All AEs will 
be coded using the current version of the Medical Dictionary for Regulatory Activities coding 
system. The severity of AEs will be graded utilizing the National Cancer Institute Common 
Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0). 
 
Statistical Methods: 
Statistical Hypotheses 
The primary efficacy endpoint ORR will be assessed using the Bayesian Optimal Phase 2 
(BOP2) design (Zhou, Lee and Yuan, 2017). Based on available data the expected ORR in this 
population is assumed to be at best 15% under standard of care (SOC). Niraparib would be 
considered promising in this population if an ORR=30% would be achieved. Therefore, if 
𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒 denotes the ORR, the null hypothesis is 𝐻𝐻0: 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒≤0.15,, under which the treatment is 
deemed as not promising and unacceptable and the alternative hypothesis 𝐻𝐻1: 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒≥0.3, 
where the treatment is considered promising. These hypotheses will be tested at a one-sided 
α=0.025 with about 90% power. 
 
Sample Size Determination 
For the sample size determination, the BOP2 design will be used with one interim analysis.  
The following stopping boundaries will be applied (see Table 2) which achieve a statistical 
power of 0.932 if 90 participants are evaluable for ORR under 𝐻𝐻1 and a type I error of one-
sided α=0.025. For the primary analysis these stopping criteria (non-binding) will be applied 
to the overall population, combining all tumor types as it is assumed that this population 
represents a homogeneous population and results are expected to be similar across the 
different tumor types.  
 
 
 

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Table 2. Optimized stopping boundaries based on BOP2 design 
Analysis 
Sample size  
Stop if # responses ≤ 
Interim  
40 
5 
Final  
90 
20 
 
In order to achieve 90 evaluable participants a total of approximately 110 participants will be treated. 
Analysis Populations 
● The All Screened Population will consist of all participants who signed the main study 
ICF to participate in the clinical study. Participants in this population will be used for 
screen failure summary. 
● The Intent-to-Treat (ITT) Population: all participants who were enrolled in the study 
and who received at least one dose of study treatment. This population will be the 
secondary population for the analysis of efficacy data. Any participant who receives a 
treatment number will be considered to have been enrolled. 
● The Response Evaluable Population: all participants who received at least one dose of 
study treatment, who have an adequate baseline tumor assessment and at least one 
follow-up tumor assessment will be considered evaluable for anti-tumor efficacy using 
RECIST version 1.1 criteria. Participants who are treated and removed from study 
prior to on-study tumor assessment because of disease progression will be considered 
evaluable for efficacy and counted as failures. This population will be considered the 
primary population for the analysis of efficacy data. 
● The Safety Population will consist of all participants who took at least 1 dose of study 
treatment. 
Statistical Analyses - Efficacy 
A BOP2 design will be applied to assess the primary endpoint ORR based in the IRC 
assessment. An interim analysis at 40 participants will be performed to assess the stopping 
criteria presented in Table 2. If six or more participants in the Response Evaluable Population 
demonstrate tumor response the study could continue to enroll a total of 90 participants. If at 
the interim analysis five or less responders are observed the study could be stopped for futility. 
At the final analysis for ORR, it can be concluded that niraparib is promising if at least 21/90 
responders are observed. In addition to the estimated response rate at each analysis, 95% 
confidence intervals (CI) will be calculated   
ORR is defined as the proportion of participants with a confirmed CR or confirmed PR 
according to RECIST 1.1 definitions, relative to the response evaluable population as well as 
the safety population. Confirmed responses are those that persist on repeat tumor assessments 
for at least 4 weeks after initial documentation or response. Otherwise, the participant will be 
counted as a non-responder in the assessment of ORR. Assessment of ORR will be based on 
the ICR assessment. The response evaluable analysis set will be the primary analysis set for 
ORR. The CBR as assessed by ICR and Investigator will be evaluated as well including the 
95% CI. 

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DOR, PFS, and OS will be analyzed by the Kaplan-Meier method and survival estimates such 
as median survival and landmark rates at 6, 12, 18 and 24 months reported along with 
respective 95% CIs. 
The primary analysis will be applied to the overall population (response evaluable population), 
combining all tumor types as it is assumed that this population represents a homogeneous 
population and results are expected to be similar across the different tumor types. In addition, 
ORR will be evaluated for each tumor type. 
The study will be monitored on an ongoing basis to permit the early decision to proceed to the 
end of the study. The formal futility decision will be made at the pre-specified interim analysis 
with less than 6 responders out of 40 patients. 
 
Statistical Analyses - Safety 
Adverse events will be graded by the Investigator according to the NCI CTCAE most current 
version and coded using the Medical Dictionary for Regulatory Activities (MedDRA) most 
current version. The focus of AE summaries will be on treatment-emergent AEs, those with 
initial onset or increasing in severity after the first dose of study medication. The number and 
percentage of participants who experienced any AE, treatment-emergent AEs, SAE, treatment-
related AE, and treatment-related SAE, AEs leading to treatment discontinuation, adverse 
events of special interest, will be summarized according to worst toxicity grades. The 
summaries will present AEs both on the entire study period and by cycle (Cycle 1 and cycles 
beyond 1). Serious AEs will be listed separately. This analysis will be performed for all 
participants pooled regardless of tumor type. 
A more detailed description of the analyses of safety including other endpoints like laboratory 
data, vital signs, ECG will be described in a separate SAP. 
 
Interim analysis  
One interim analysis is planned when 40 participants have completed their assessment of 
efficacy (ORR assessed by IRC). According to the BOP2 design the stopping criteria at time 
of the interim analysis will be if ≤5 responders are observed, the study could be stopped for 
futility. 
 
Handling of missing data  
As a general rule, missing data will not be imputed in the study. Conventions on how to 
manage missing data in the analysis will be detailed in the SAP. 
 
 
 
 
 
 

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1.2. Schema 
 Figure 1: 
Overall Study Schema 
 
1.3. Schedule of Activities (SoA) 
The schedule of activities (SoA) for this study are presented in Table 3 and Table 4. 
The study will be conducted in conformance with the protocol, Good Clinical Practice (GCP), 
and applicable regulatory requirements. Regulatory, ethical, and study oversight considerations 
are provided in the protocol.

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Table 3. Schedule of Activities – Screening Biomarker PALB2 Testing   
Visit: 
Information or 
Procedure: 
Screening 
Notes 
Clinical report from a 
validated genetic test 
X 
Results from local next generation sequencing (NGS) testing from tissue and/or 
blood performed by a CLIA-certified laboratory as described in the NGS 
Laboratory Manual may be used to meet molecular eligibility. Test report must 
state that the participant has a PALB2 mutation classified as pathogenic or likely 
pathogenic. 
Tumor tissue* 
X 
30 FFPE slides or 1 block equivalent of tumor tissue collected from the 
most recent biopsy (sample collected within the past 24 months of 
enrollment) must be provided. For participants with only germline PALB2 
mutations, archival tissue from a primary or metastatic tumor may be 
provided. For participants with somatic PALB2 mutations, a metastatic 
tissue sample is requested; if not available, a primary tumor sample may be 
provided and a new biopsy will be requested, though optional, so that a 
metastatic disease sample may be submitted for testing. 
Pathology report 
submitted 
X 
Pathology reports will be submitted with tumor tissue. 
Blood sample for 
assessing PALB2 and 
biomarkers associated 
with PALB2* 
X 
3 tubes with stabilization solution (e.g. Streck cfDNA tubes); ~ 30 mLs of 
peripheral blood 
 
Abbreviation: FFPE=formalin-fixed paraffin-embedded 
*All samples will be collected and managed centrally, when possible, and distributed either directly or subsequently to designated translational 
research laboratories for biomarker testing as needed. Details on tissue and blood sample description, collection, processing, storage, shipping, and 

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c Blood samples for PK analysis will be collected on Cycle 1/Day 1, and Cycle 2/Day 1 predose (within 1 hour prior to dosing) and 3 hours postdose (±15 
minutes). Additional predose blood samples on Cycle 4/Day 1 and Cycle 7/Day 1 will be collected (within 1 hour before scheduled dose). dose). Blood will be 
also collected at the EOT visit if the participant discontinued before Cycle 7. If study treatment is held 1 day prior to and on Cycle 2/Day 1, PK sample collection 
on that day is not required. Participants will be instructed to hold their niraparib dose until the predose PK sample has been taken.  See the study-specific 
laboratory manual for additional details  
d CT scan of the chest, and IV contrast enhanced CT of the abdomen, and pelvis; IV contrast-enhanced MRI of the abdomen and pelvis plus noncontrast CT of 
the chest should only be conducted if clinically indicated (eg, if participant is sensitive to IV CT contrast). If MRI is performed at Baseline, it should be 
preferentially continued throughout the study. The same imaging and anatomical coverage should be used throughout the study. If scans are performed outside of 
the 8 weeks (± 7 day) window interval and the participant has not progressed, every attempt should be made to perform the subsequent scans at their scheduled 
time points. If a participant discontinues study treatment for any reason other than death, withdrawal of consent, or loss to follow-up, then scans should continue 
at the specified intervals until disease progression is confirmed. If an equivocal new lesion is observed on a postbaseline radiological assessment, a follow-up 
scan should be acquired at least 4 weeks later to reassess. On the follow-up scan, if the equivocal new lesion becomes unequivocal, the date of progression is the 
date of the scan when the new lesion first appeared (refer to Appendix 3).  
All radiological images/scans, scheduled and unscheduled, must be submitted (preferably electronically) to a central imaging vendor for QC, storage, and 
analysis by ICR (refer to section 8.2.2). 
Abbreviations: AE=adverse event; AESI=AE of special interest; AJCC=American Joint Committee on Cancer; ICR= independent central review; BP=blood 
pressure; C=cycle; CBC=complete blood count; CRF=case report form; CT=computed tomography; D=day; DFS=disease-free survival; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire; EOT=End of Treatment; EQ-5D-3L=European Quality of Life 5-Dimensions 3‑Level Scale 
FUP=Follow-up Period; HIV=human immunodeficiency virus; ICF=informed consent form; MRI=magnetic resonance imaging; n=number of subsequent cycles; 
PK= pharmacokinetic; PRO=patient-reported outcome; QC=quality control; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse 
event; WOCBP=women of childbearing potential.

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2. 
INTRODUCTION 
Advanced solid tumors harboring PALB2 mutations have been associated with a variety of 
cancer types. Beyond first-line, standard of care, systemic therapies, patients with advanced 
disease and PALB2 mutations have limited options for effective treatment. Because PALB2 is a 
potent regulator of the homologous recombination repair (HRR) pathway, one potential avenue 
to treat this population is with poly (ADP-ribose) polymerase inhibitors (PARPi), which prevent 
DNA damage repair and promote cancer cell cytotoxicity.  
 
Niraparib is an orally available, potent, highly selective PARP-1 and -2 inhibitor that is dosed 
once daily. Niraparib is approved in 36 countries worldwide including the US, EU, Switzerland, 
Australia, Canada, and Saudi Arabia. Niraparib was approved by the Food and Drug 
Administration (FDA) on 27 March 2017 (NDA 208447) and received European Commission 
approval on 16 November 2017 as maintenance therapy for women with recurrent epithelial 
ovarian, fallopian tube, or primary peritoneal cancer who are in complete response or partial 
response to platinum-based chemotherapy. Additionally, niraparib was approved by the FDA on 
23 October 2019 for patients with advanced ovarian, fallopian tube, or primary peritoneal cancer 
treated with three or more prior chemotherapy regimens and whose cancer is associated with 
homologous recombination deficiency (HRD)-positive status. In 2020, the use of niraparib was 
further expanded as maintenance therapy for patients with advanced ovarian, fallopian and 
primary peritoneal carcinomas which have shown prior complete/partial response to 
chemotherapy (Zejula USPI. Zejula (niraparib) US Prescribing Information. 2021). 
2.1. Study Rationale  
Efficacious treatment options for patients with advanced, PALB2-mutated solid tumors remains 
a high unmet need. Therapy is needed with an acceptable safety profile that delivers clinically 
meaningful improvement in ORR, DoR, and PFS.  
 
This study will evaluate the efficacy of niraparib monotherapy in participants with advanced or 
metastatic solid tumors harboring a confirmed pathogenic or likely pathogenic tumor PALB2 
mutation (tPALB2). Tumors in patients with PALB2 pathogenic mutations have deficiencies in 
Homologous Recombination, and therefore are sensitive to growth inhibition by knocking out 
the PARP pathway.   Participants must have received all standard therapies appropriate for their 
tumor type and stage of disease or, in the opinion of the Investigator, the patient would be 
unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care 
therapy, or the participant has no satisfactory alternative treatments. By limiting eligible 
participants to those with a pathogenic or likely pathogenic tPALB2 alteration in a tumor-
agnostic setting, a genetically homogenous patient group with limited standard therapy options 
will be enrolled.  

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Niraparib has shown an acceptable clinical and nonclinical safety profile. The proposed 
evaluation of niraparib at the approved dose in advanced solid tumors harboring PALB2 
mutations is based on clinical data demonstrating a favorable benefit-risk ratio of niraparib in 
patients with tumors having mutations in a similar Homologous Recombination gene, BRCA 
1/2.Furthermore, the study builds on preclinical and clinical data describing PALB2 mutations 
leading to HRD-positive tumors, which should bestow similar sensitivity to niraparib in PALB2 
mutated tumors as what has been demonstrated in BRCA 1/2 mutated cancers.  
 
2.1.1. 
PALB2 in the HRR pathway  
While BRCA mutations are the most well-characterized, several other genes are involved in the 
HRR pathway. Following data of improved survival in HRD-positive tumors with and without 
gBRCA mutations, there has been a new effort to identify HRR-related biomarkers beyond 
gBRCA1/2 that may indicate sensitivity to PARPi. PALB2 has recently been studied given its 
role as the localizer of BRCA2. Acting as a signal mediator between BRCA1 and the 
BRCA2/RAD51 complex, PALB2 facilitates HRR by recruiting BRCA2 and RAD51 to the sites 
of DNA double-strand breaks (Xia et al., 2006).  
 
 
 
 
 
2.1.2. 
Hereditary/Germline PALB2 Mutations (gPALB2)  
PALB2 plays a critical role in DNA repair as a partner and nuclear localizer of BRCA2. Because 
of its biologic function, mutations in PALB2 have been described as susceptibility gene 
mutations for hereditary breast, ovarian, and pancreatic cancer (Rahman et al., 2007 & Yang et 
al., 2020). Although gPALB2 mutations are present at a much lower frequency than other HRR-
related genes, the alteration is still associated with an increased risk of cancer development. 
About 35% of females carrying gPALB2 mutations may develop breast cancer before turning 70 
years old, and the risk increases to 58% in carriers with a history of breast cancer (Antoniou et 
al., 2014). When compared to non-PALB2 mutation carriers, data support that patients with 
gPALB2 mutations have a shorter 10-year survival (Cybulski, et al., 2015). Given this increased 
risk associated with gPALB2 and the increased sensitivity of PALB2-deficient cells to platinum-
based chemotherapy and PARPi, HRD-targeting treatments such as niraparib can potentially 
provide clinical benefit to breast cancer patients with gPALB2 mutations (Nikkila, et al., 2013; 
Foo et al., 2017; Isaac et al., 2018).   
Besides breast cancer, gPALB2 mutations can increase risk for the development of other cancer 
types such as ovarian and pancreatic cancers (Yang, 2020). In ovarian cancer, gPALB2 carriers 
had a risk rising from <1% at age 50 to 5% in age 80, 5x higher than that of the general 
population. In addition, the risk of developing ovarian cancer by age 80 in gPALB2 carriers was 
5% for women without a family history of ovarian cancer but increased to 16% for women with 
a family history of ovarian cancer. Regarding pancreatic cancer, the risk of disease development 

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in gPALB2 carriers at age 80 was 2.2% for women and 2.8% for men. In both cases, this was 
>2x the risk than observed in the general population.  
Based on the known increased risk of developing cancers for individuals with gPALB2 
mutations, the American College of Medical Genetics and Genomics (ACMG) developed 
guidelines for surveillance and treatment (Tischkowitz et. al. 2021). Recommendations include 
(1) Enhanced breast surveillance as offered for patients with BRCA1/2 mutations and 
consideration for risk-reducing interventions on an individualized risk basis, (2) surveillance for 
ovarian cancer is not recommended (insufficient evidence of testing sensitivity) but 
consideration of risk-reducing interventions for those <50 years old, and (3) surveillance for 
pancreatic cancer in the clinical trial setting.  In addition, PALB2 heterozygotes should be 
evaluated for treatment or clinical trials similar to those with BRCA1/2, in particular PARPi 
therapy. 
2.1.3. 
Somatic PALB2 Mutations (sPALB2) 
Like many hereditary predisposition mutations, PALB2 mutations are typically germline but 
somatic mutations can exist. Data is limited and the incidence of sPALB2 mutations is unclear; 
however, in a recent publication regarding breast cancer tumors, the frequency of germline 
mutations was noted as much higher than somatic mutations (Hu et al., 2020). To further 
understand the incidence of somatic mutations, large-scale, unbiased genomic sequencing data 
needs to be compiled. For example, a study from Memorial Sloan Kettering Cancer Center used 
MSK-IMPACT whole-exome sequencing (WES) with matched normal DNA, allowing for the 
detection of somatic alterations that would have otherwise been missed (Zehir et al., 2017).  
2.1.4. 
Comprehensive Genomic Testing 
Testing for PALB2 increased with its inclusion on multigene cancer panels starting around 
2012–2013 (Tischkowitz, 2021). In line with the findings from MSK-IMPACT, PALB2 
mutations can be differentially detected from germline or somatic sources with a combined test 
using a tumor and normal samples (Zehir et al., 2017). Germline PALB2 mutations are stable 
over time, therefore the use of archival tissue in this study is appropriate. For patients assumed to 
have a gPALB2 mutation, a fresh blood draw taken at any time can be used to confirm (Ong, 
2019). Regarding somatic mutations, on the other hand, FFPE tissue is typically utilized for 
archival samples (Wang et al., 2015).   
 
2.1.5. 
PALB2 Mutation Prevalence  
 
According to the AACR Project GENIE, PALB2 mutations are present in only 1.52% of all 
malignant solid tumors (AACR Project GENIE Consortium, 2017). The MSK-IMPACT clinical 
sequencing cohort exhibits a similar overall prevalence at 1.3% (Zehir et al., 2017). The GENIE 

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2.2. Background on PARP Inhibitors and Niraparib  
 
Due to their broad applicability across cancer types, distinct biomarkers, and demonstration of 
clinical efficacy, PARPi have emerged as a promising treatment option in the precision oncology 
space. PARPi are a distinctive group of antineoplastic agents which target the DNA 
repair/damage pathways to promote cytotoxicity in cancer cells. In combination with other 
agents or underlying genetic mutations, PARPi lead to extensive DNA damage and consequently 
cell death. This synergy between cellular defect and drug-induced effect has been referred to as 
synthetic lethality (Kaelin, 2005), and has been harnessed to apply PARPi as antitumor agents in 
a variety of cancers (Rose et al., 2020).   
2.3. PARPi Mechanism of Action  
DNA repair is accomplished by several mechanisms in healthy cells, including but not limited to 
HRR, non-homologous end joining (NHEJ), and base excision repair (BER) (Dantzer et. al., 
1999 & Dantzer et al., 2000). Some cells are incapable of HRR due to the inactivation of genes 
such as BRCA1 or BRCA2. In the absence of HRR, these cells must rely on alternative DNA 
repair mechanisms such as pathways regulated by PARP-1 and PARP-2. PARP-1 and PARP-2 
are zinc-finger DNA-binding proteins that detect damaged DNA and promote DNA repair by 
several mechanisms. For example, after detecting DNA damage, PARP activates the BER 
pathway via an intracellular signaling mechanism (Hanzlikova et al, 2017).  
 
By preventing PARP-1 and PARP-2 from activating the BER pathway, PARPi block DNA 
repair. Thus, PARP inhibition in cells incapable of HRR leads to irreparable double-strand DNA 
breaks, collapsed replication forks, and an increased use of the NHEJ pathway (Sun et. al., 
2020). These disruptions result in genomic instability and, ultimately, cell death. Treatment with 
PARPi represents an opportunity to selectively kill cancer cells with deficiencies in HRR and 
other DNA repair mechanisms (Cortesi et al., 2021). Figure 2 illustrates PARPi function in 
HRR-proficient versus HRR-deficient pathways.  
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 2: DNA Double-strand Break Repair Mechanisms and PARPi Function (Cortesi et 
al., 2021)  
(A) PARP-dependent DNA repair mechanisms are activated at DNA single-strand breaks (SSB). (B) 
PARPi stop PARP recruitment to DNA SSB and PARP-dependent DNA repair systems. This results in 
DNA fork replication collapse and DNA double-strand breaks (DSB). (C) In HRR-proficient cells, the 
DSB is repaired via the ‘error-free’ HRR system of proteins, including PALB2 - the BRCA2 localizer. 
(D) In HRR-deficient cells, the DSB is repaired via ‘error-prone’ non-homologous end-joining 
mechanisms and leads to incorrect DSB repair. 
 
 
 

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2.3.1. 
Biomarkers of PARPi Response 
The rationale for employing PARPi to selectively eliminate cancer cells is supported by 
nonclinical ex vivo and in vivo experiments demonstrating that PARPi are more potent 
cytotoxicity inducers in tumors with homozygous inactivation of BRCA1 or BRCA2 than in 
BRCA-replete counterparts. Germline and somatic BRCA1/2 mutations are well-defined 
biomarkers for PARPi response in a number of cancer types, including breast, ovarian, 
pancreatic, and prostate cancer (Tung & Garber, 2018). Multiple studies examining PARPi have 
demonstrated promising results in the treatment of BRCA-mutated breast and ovarian cancer, 
and PARPi have been studied both as monotherapy and in combination with cytotoxic therapy or 
radiotherapy (Hu et al., 2020 & Swisher et al., 2021).  
Recently, however, HRR-related mutations besides BRCA1/2 have also shown promise as 
treatment-directing biomarkers for PARPi therapy. For example, a recent study of the PARPi 
olaparib demonstrated an increased PFS in patients with tumors harboring PALB2 mutations. In 
TBCRC 048, a Phase II study of olaparib for metastatic breast cancer and mutations in HRR 
somatic or germline genes, patients received olaparib until progression or unacceptable toxicity. 
The data showed that patients with germline PALB2 mutations had an ORR of 82% (9/11) and a 
median PFS of 13.3 months (Tung et al., 2020).   
 
 
 
 
2.3.2. 
Niraparib Preclinical Data  
Niraparib is an orally available, potent, highly selective PARP-1 and PARP-2 inhibitor. 
Niraparib co-crystallizes with the human PARP-1 catalytic domain and has been shown to inhibit 
PARP-1 and PARP-2 activity in vitro with a half-maximal inhibitory concentration (IC50) of 3.8 
and 2.1 nM, respectively. In cultured cells, niraparib inhibited PARP-dependent PARylation 
stimulated by DNA damage with an IC50 of 4 nM and a 90% inhibitory concentration (IC90) of 
40 nM.  
Niraparib demonstrated a 25- to 200-fold increased cytotoxicity against cancer cell lines that 
were engineered to be HRD via BRCA1 or BRCA2 silencing or that carried BRCA1 or BRCA2 
mutations, as compared to control cell lines capable of homologous recombination. Treatment of 
xenograft-bearing mice with clinically relevant doses resulted in tumor regression in BRCA- and 
ATM-mutant tumor models. At the doses used in these studies, 90% PARP inhibition was 
observed in tumors for up to 24 hours after a single dose. Additionally, PARP inhibition in tumor 
tissue was greater and more durable than PARP inhibition in the corresponding PBMCs, where 
inhibition levels were ≤50% 24 hours after dosing.  
 
 
 
Niraparib has also been evaluated in more than 30 ovarian cancer patient-derived xenograft and 
tumor cell line-derived xenograft models. Tumor regression has been observed in BRCA1- and 
BRCA2-mutant xenografts and in HRD-positive, wild-type BRCA models. Additionally, tumor 

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growth inhibition was observed in some models that were HRD negative as defined by the 
Myriad myChoice HRD test. 
For more information on preclinical data, please refer to the Investigator’s Brochure.  
2.3.3. 
Niraparib Safety Data  
In addition to the preclinical data described above, numerous clinical trials have led to FDA 
approvals of niraparib over the past decade. A total of 20 clinical studies investigating the safety 
and efficacy of niraparib have been conducted, ranging from Phase I to Phase III. From these 
studies, 2,244 patients have received at least one dose of niraparib. Most of these patients 
(n=1,606) participated in ovarian cancer studies, and the remaining 638 participated in non-
ovarian studies. Niraparib’s safety and efficacy has been studied as a single agent, as well as in 
combination with other agents, and adverse events (AEs) related to the treatment have been 
assessed extensively in both contexts.   
The well-established AE profile of niraparib consists of AEs that are commonly managed in the 
patient population of advanced cancer. The key safety concerns included hematological 
toxicities, hypertension, and potential risks of MDS/AML and secondary malignancies. Common 
AEs, including Grade 3 and higher, were generally manageable with dose modification and 
clinical treatment. Furthermore, most AEs were resolved without discontinuation of niraparib. 
Additional information on safety data can be referenced in the Investigator’s Brochure.  
2.3.4. 
Niraparib Approved Indications and Registrational Trial Overviews  
Niraparib was initially approved in 2017 for the maintenance of patients with recurrent ovarian, 
fallopian, or primary peritoneal carcinoma who have had a complete/partial response to 
chemotherapy, regardless of BRCA mutational status (Mirza et al., 2016). The approval was 
expanded in 2019 for the treatment of patients with HRD-positive, advanced ovarian, fallopian, 
or primary peritoneal carcinomas after 3 or more prior lines of therapy, independent of 
sensitivity to prior chemotherapy (Moore et al., 2019). Most recently in 2020, use of niraparib 
was further expanded as maintenance therapy for patients with advanced ovarian, fallopian, or 
primary peritoneal carcinomas that have shown prior complete/partial response to chemotherapy, 
regardless of mutational status (Gonzalez-Martin et al., 2019). These approved indications for 
niraparib were based mainly on data from the NOVA, PRIMA, and QUADRA trials.  
The NOVA study explored the efficacy of niraparib as maintenance treatment in patients with 
platinum-sensitive, recurrent ovarian cancer in a randomized, double-blind, placebo-controlled 
Phase III trial. It also characterized the importance of biomarker-based patient selection for 
maintenance treatment with PARPi in this patient population. The PFS was significantly longer 
for participants who received niraparib compared to those who received placebo in both cohorts. 
Within the gBRCA-mutated cohort, the median PFS was 21.0 months with niraparib versus 5.5 

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months with placebo (HR: 0.27; 95% CI:0.173 to 0.410; p<0.001). In the non-gBRCA-mutated 
cohort, the median PFS was 9.3 months with niraparib versus 3.9 months with placebo (HR: 
0.45; 95% CI: 0.338 to 0.607; p<0.001). In the HRD group of the non-gBRCA-mutated cohort, 
PFS was also significantly longer with niraparib than with placebo (median: 12.9 months versus 
3.8 months; HR: 0.38; 95% CI: 0.243 to 0.586; p<0.001). The findings from this non-gBRCA-
mutated, HRD-positive population support the exploration of non-BRCA HRR-related mutations 
as markers of PARPi treatment eligibility.      
In the Phase III, double-blind, randomized, placebo-controlled PRIMA study, niraparib was 
tested in patients with ovarian, fallopian tube, or primary peritoneal cancer at high risk for 
progressive disease after response to first-line platinum-based chemotherapy. The data from 
PRIMA indicated a reduced hazard of death or disease progression and prolonged median PFS in 
participants who received niraparib compared to those who received placebo. Median PFS based 
on RECIST (version 1.1) was 21.9 months in the niraparib arm and 10.4 months in the placebo 
arm (HR 0.43 [95% CI: 0.310 to 0.588]; p<0.0001). Overall survival was also shown to be 
favorable in the niraparib arm (HR 0.70 [95% CI: 0.442 to 1.106]; p=0.1238). 
Additionally, the QUADRA study examined the efficacy and safety of niraparib in participants 
with advanced ovarian cancer treated with 3 or more prior chemotherapy regimens. Overall, the 
results indicated clinical benefit as reflected by clinical and molecular biomarkers. The highest 
response rates were observed among participants with tumors that were HRD-positive and 
platinum-sensitive or BRCA-mutated regardless of platinum sensitivity status. Within the 
biomarker-defined population of 98 participants with 3 or more prior lines of treatment, the ORR 
was 25.5%, and median DoR was 8.3 months. The findings suggest that ORR was higher than 
the expected ORR associated with approved chemotherapy in late-line disease setting, including 
for participants with BRCA-mutated disease regardless of platinum sensitivity (ORR: 28.6%; 
median DoR: 9.2 months) and participants with non-BRCA-mutated/HRD-positive, platinum-
sensitive disease (ORR: 20%; median DoR: 6.6 months) 
2.3.5. 
Niraparib Clinical Trials Outside of Approved Indications  
Niraparib is currently being developed as a monotherapy agent or in combination with 
cytotoxic/radiotherapy/biologic agents to treat other solid tumors, including triple-negative breast 
cancer (TNBC), non-small cell lung cancer, and prostate cancer.  
The TOPACIO study evaluated the efficacy of niraparib in combination with pembrolizumab 
from 47 evaluable participants with advanced or metastatic TNBC. The ORR was 21% (90% CI: 
12% to 33%) with a disease control rate (DCR) of 49% (90% CI: 36% to 62%). In 15 evaluable 
participants with tumor BRCA mutations, ORR was 47% (90% CI: 24% to 70%), DCR was 80% 
(90% CI: 56% to 94%), and median PFS was 8.3 months (95% CI: 2.1 months to not estimable). 
In 27 evaluable participants with BRCA-wild-type tumors, ORR was 11% (90% CI: 3% to 26%), 

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DCR was 33% (90% CI: 19% to 51%), and median PFS was 2.1 months (95% CI: 1.4 to 2.5 
months). Another study in breast cancer, BRAVO, supported niraparib as an active agent for the 
treatment of patients with gBRCA-mutated metastatic breast cancer, and for the TNBC 
subpopulation.  
The GALAHAD study, which is an ongoing open-label Phase II study, is examining niraparib in 
patients with metastatic castration-resistant prostate cancer (mCRPC) and DNA-repair gene 
defects (DRD) with disease progression on taxane and androgen receptor-targeted therapy. The 
results at the interim analysis have pointed at clinical activity and durable responses in patients 
with treatment-refractory mCRPC, specifically in biallelic BRCA mutation carriers. At the time 
of the interim analysis, 165 patients were enrolled and median follow-up in the BRCA- and non-
BRCA-mutated groups was 7.3 and 6.4 months, respectively. In the BRCA-mutated 
subpopulation, ORR was 41%, CRR was 63%, and median DoR was 5.5 months (range: 3.5–
9.2). Median radiographic PFS and OS in the BRCA-mutated group were 8.2 and 12.6 months, 
respectively. In the non-BRCA-mutated population, objective response was noted in 2/22 
patients and CRR was 17%; DoRs were 3.8 and 6.5 months, respectively (Smith et al., 2019).  
There are currently no approved therapies specifically targeting PALB2. Based on its well-
understood safety profile and demonstrated efficacy in numerous tumor types, however, we 
hypothesize that niraparib may offer greater clinical benefit over existing options in this 
population of advanced or metastatic cancer patients harboring germline or somatic PALB2 
mutations. In addition to the niraparib data summarized above, the totality of data across PARPi 
datasets also serves as evidence for the possible favorable benefit/risk profile, particularly in the 
PALB2-mutated population.  
2.3.6. 
Other Approved PARPi  
 
 
Olaparib (Lynparza) was the first PARPi approved by the FDA and EMA in 2014 as a 
monotherapy for the treatment of advanced, gBRCA-mutated ovarian cancer (Kaufman et al., 
2015). In 2017, this was extended to include maintenance therapy of recurrent ovarian, fallopian, 
and primary peritoneal tumors, regardless of BRCA mutational status (Pujade-Lauraine et al., 
2017; Friedlander et al., 2018). In addition, olaparib was approved for the treatment of 
gBRCA1/2-mutated HER2-negative breast cancer and metastatic pancreatic cancer in 2018 and 
2019, respectively (Moore et al., 2018; Golan et al., 2019; Robson et al., 2019). In 2020, olaparib 
was approved for the treatment of HRD-positive mCRPC (de Bono et al., 2020).   
Other PARPi, namely rucaparib (Rubraca) and talazoparib (Talzenna), have been approved in 
similar tumor types. In 2016, rucaparib was granted an accelerated approval for the treatment of 
germline or somatic BRCA1/2-mutated advanced ovarian carcinomas after patients received 
multiple chemotherapy treatments (Oza et al., 2017). Later, rucaparib maintenance therapy was 
approved in 2018 for recurrent ovarian, fallopian, and primary peritoneal cancers, regardless of 

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BRCA mutational status (Coleman et al., 2017). In 2020, rucaparib gained FDA approval for the 
treatment of BRCA1/2-mutated mCRPC (Abida et al., 2019). 
 
2.3.7. 
Clinical Trials of PARPi in PALB2-mutated Tumors   
Recent studies have demonstrated that patients with metastatic breast, melanoma, and pancreatic 
cancers with germline and/or somatic PALB2 mutations benefit from treatment with PARPi. 
Accordingly, PARPi have been studied as a subsequent line of therapy in breast cancer and 
melanoma. For TBCRC 048, a Phase II study of olaparib for metastatic breast cancer and 
mutations in HRR-related somatic or germline genes, patients received no prior PARPi nor 
progressed on a platinum-based therapy. All patients received olaparib until progression or 
unacceptable toxicity. As stated above, the data showed that patients with PALB2 mutations had 
an ORR of 82% (9/11) and a median PFS of 13.3 months (Tung et al., 2020). Additionally, a 
Phase II trial in gPALB2-mutated advanced and heavily pretreated breast cancers showed 
talazoparib monotherapy was associated with single-agent activity. For the 5 patients with 
gPALB2 mutations, all 5 had a reduction in target lesions > 20% and 3 of 5 achieved a RECIST 
1.1 response (Gruber, et al., 2019). In melanoma, a case report of a patient with metastatic 
melanoma and an sPALB2 mutation who failed immunotherapy demonstrated an ongoing partial 
response at 6 months with olaparib (Lau, Menzies & Joshua, 2021). 
Efficacy data for PARP inhibition in PALB2-mutated tumors also exists in the maintenance 
setting. In a Phase II study of rucaparib as maintenance therapy in advanced pancreatic cancer 
with germline or somatic pathogenic variants, patients with gPALB2 achieved an ORR of 3 out 
of 6 (50%) and the median PFS was 14.5 months (Reiss et al., 2021). 
2.4. Benefit / Risk Assessment  
2.4.1. 
Chemotherapy Agents Approved for Use in Advanced Cancers  
Chemotherapy offers limited efficacy and significant toxicity in patients with advanced solid 
tumors and PALB2 mutations who have progressed on at least one systemic therapy. Aggregate 
data in advanced solid tumors demonstrates ORRs with single-agent chemotherapeutics in the 
15% range and DoRs generally less than 6 months. Table 6 demonstrates representative data 
regarding on-label responses and time to progression (TTP) or PFS following single-agent 
chemotherapy that is FDA approved for advanced/metastatic tumors (Cancer.gov, 2021). The 
data in the table below reflect various solid tumor types which can harbor PALB2 mutations.  
 
 
 

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2.4.3. 
Risk Assessment  
More detailed information about the known and expected benefits and risks, as well as the 
reasonably expected AEs of niraparib may be found in the current version of the Investigator’s 
Brochure. 
Table 7. Summary of Risks and Mitigations for the Product 
Risks of Clinical Significance 
(Identified or Potential) 
Summary of Data / Rationale 
for Risk 
Mitigation Strategy 
Thrombocytopenia 
Anemia 
Leukopenia 
Neutropenia 
Pancytopenia 
Based on nonclinical and 
clinical observations as well as 
identified risk with PARPi, 
niraparib  
Protocol has inclusion criteria that 
participants must have adequate 
organ and bone marrow function; 
randomization and treatment may 
be delayed up to 3 weeks to allow 
for these criteria to be met.  
Protocol provides guidelines for 
monitoring hematologic labs and 
adverse reactions.  
Protocol provides Investigator 
guidance for the clinical 
management of these events.  
Protocol provides guidance for 
dose modification (Appendix 10) 
and discontinuation of study 
(Section 7.1).  
Hypertension, Including 
Hypertensive Crisis 
Cases reported with niraparib 
Protocol provides monitoring and 
stopping criteria for 
discontinuation of study 
treatment. 
 
Protocol includes exclusion 
criteria for participants who have 
systolic BP >140 mmHg or 
diastolic BP >90 mmHg that has 
not been adequately treated or 
controlled. 
Second Primary Malignancy 
Myelodysplastic Syndrome / 
Acute Myeloid Leukemia 
Embryofetal Toxicity  
Based on nonclinical and 
clinical observations as well as 
identified with PARPi, 
niraparib 
Protocol provides monitoring and 
stopping criteria for 
discontinuation of study 
treatment. 
Protocol excludes participants that 
are pregnant or breastfeeding and 
provides detailed guidance on 
contraception.  

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Posterior Reversible 
Encephalopathy Syndrome 
(PRES) 
Cases reported with niraparib 
Protocol provides monitoring and 
stopping criteria for 
discontinuation of study 
treatment. 
Abbreviation: PARP=poly (adenosine diphosphate-ribose) polymerase. 
 
There have been rare reports of niraparib-treated patients developing signs and symptoms that 
are consistent with Posterior Reversible Encephalopathy Syndrome (PRES), a treatable acute 
neurologic illness characterized by rapid onset headache, visual disturbance, altered 
consciousness, seizures, hypertension, and imaging findings of white matter, parietal, and 
posterior occipital vasogenic edema. In patients developing PRES, treatment of specific 
symptoms including control of hypertension is recommended, along with discontinuation of 
niraparib. 
2.4.4. 
Overall Benefit/Risk Conclusion  
Based on the available clinical data, the benefit/risk profile of niraparib is anticipated to be 
favorable in the populations targeted in this study with utilization of the risk mitigation strategies 
as outlined in the study protocol. The goal of this trial is to determine whether niraparib 
treatment will demonstrate a favorable therapeutic index for this rare subset of tumor-agnostic 
patients. There is a vast amount of efficacy and safety data for PARPi and, specifically, niraparib 
in many indications. Overall, niraparib has a favorable benefit/risk profile when assessing the 
current landscape of single-agent chemotherapeutic options. By targeting pathogenic or likely 
pathogenic tPALB2 mutations in this population of advanced cancer patients, niraparib may 
offer greater clinical benefit over existing options.  
3. 
STUDY OBJECTIVES AND ENDPOINTS 
Table 8. Objectives and Endpoints for Study TMPS-101 
Objectives 
Endpoints 
Primary 
To evaluate ORR as assessed by ICR using 
RECIST v1.1 
ORR is defined as the proportion of participants 
who have a partial or complete response to 
therapy and will be assessed by ICR using the 
RECIST v.1.1 criteria. 
 

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Secondary 
To evaluate DOR as assessed by ICR using 
RECIST v1.1  
DOR is defined as the time between initial 
response to therapy and subsequent disease 
progression or relapse and will be assessed by 
ICR using the RECIST v.1.1 criteria. 
To evaluate PFS as assessed by ICR using 
Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST v1.1) 
PFS is defined as the time from first dose to the 
date of first radiographic progression or death 
from any cause in the absence of progression, 
whichever occurs first. Progression will be 
assessed by ICR using the RECIST v.1.1 criteria.  
To evaluate ORR as assessed by Investigator 
using RECIST v1.1 
 
ORR is defined as the proportion of participants 
who have a partial or complete response to 
therapy and will be assessed by Investigator.  
 
To evaluate DOR as assessed by Investigator 
using RECIST v1.1 
DOR is defined as the time between initial 
response to therapy and subsequent disease 
progression or relapse and will be assessed by 
Investigator using the RECIST v.1.1 criteria.   
To evaluate PFS as assessed by Investigator using 
RECIST v1.1  
PFS is defined as the time from first dose to the 
date of first radiographic progression or death 
from any cause in the absence of progression, 
whichever occurs first. Progression will be 
assessed by Investigator using the RECIST v.1.1 
criteria.  
To evaluate CBR as assessed by ICR and 
Investigator 
CBR is defined as the percentage of participants 
who have achieved complete response, partial 
response and stable disease, and will be assessed 
by ICR and Investigator. 
To evaluate Intracranial ORR and PFS in 
participants with untreated measurable CNS 
lesions as assessed by ICR and Investigator using 
RECIST v1.1  
ORR is defined as the proportion of participants 
who have a partial or complete intracranial 
response to therapy as assessed by ICR and 
Investigator using RECIST v1.1. 
PFS is defined as the time from first dose to the 
date of first radiographic progression or death 
from any cause in the absence of progression, 
whichever occurs first, and will be assessed by 
ICR and Investigator using RECIST v1.1 

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To evaluate safety and tolerability per the 
National Cancer Institute Common Terminology 
Criteria for Adverse Events version 5.0 (NCI-
CTCAE v5.0) 
Assess the incidence of AEs, SAEs, and AESIs 
To evaluate OS  
OS is a secondary efficacy endpoint in this study 
is defined as the time from first dose to the date 
of death by any cause. Participants who are alive 
will be censored at the date of last contact. OS 
includes the following: death attributable to any 
cause, including primary cancer, secondary 
cancer, or unknown cause.  
Exploratory  
To evaluate health-related quality of life 
(HRQoL) and symptoms as assessed by EORTC 
QLQ-C30 and the EuroQol EQ-5D-3L 
The EORTC QLQ-C30 and EuroQol EQ-5D-3L 
will be analyzed descriptively by changes from 
baseline in overall score, sub scores, and 
individual items when applicable. 
To evaluate exploratory biomarkers in tumor 
and/or blood that may be predictive of response 
including clinical factors  
Blood and tissue samples for the evaluation of 
exploratory biomarkers will be obtained at 
screening. The incidence of biomarkers will be 
summarized using descriptive statistics. 
Comparisons of efficacy endpoints between 
biomarker subpopulations may be performed.  
To evaluate niraparib concentration or PK   
Plasma concentrations or PK parameters of 
niraparib, as data permit. 
 
4. 
STUDY DESIGN 
4.1. Overall Design 
This is a multicenter study of niraparib in participants with locally advanced or metastatic solid 
tumors and a confirmed pathogenic or likely pathogenic tPALB2 mutation. Participants must 
have received all standard therapies appropriate for their tumor type and stage of disease or, in 
the opinion of the Investigator, the patient would be unlikely to tolerate or derive clinically 
meaningful benefit from appropriate standard of care therapy, or the participant has no 
satisfactory alternative treatments. 
To participate in this study, participants eligibility will be confirmed via scan(s) conducted 
within 28 days prior to enrollment. While on-study, imaging will be performed every 8 weeks 
(every 56 [±7] days) from the date of enrollment until disease progression. If at any time 
radiographic PD is documented per RECIST v1.1 the participant will come off study.   

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Complete blood count (CBC) will be monitored weekly for the first 4 weeks of the treatment 
period, and blood pressure (BP) and heart rate will be monitored weekly for the first 2 months of 
the treatment period. Patient-reported outcomes (PROs) will be collected in a coordinated 
fashion with imaging while participants remain on study treatment. For participants who 
discontinue all study treatment, all PROs should be collected at the End-of-Treatment (EOT) 
Visit. 
Each participant will have an EOT Visit at the time of discontinuation from study treatment, 
Safety Follow-up Visits at 30 (±7) days, and Survival Follow-up Assessments which may be 
conducted via telephone, email, in person visits to the clinic or back-up contacts every 
90 (±14) days for 1 year after last dose and then every 180 (±14) days that will continue until 
death or the end of study data collection. 
4.2. Number of Participants 
Approximately 110 participants will be enrolled based on approximately 140 participants 
screened.  
4.3. Dose Justification  
Niraparib monotherapy has demonstrated efficacy in the homologous recombination deficiency 
(HRd) and homologous recombination proficient (HRp) cancer populations at both the fixed 
starting dose of 300 mg or an individualized starting dose of 200 or 300 mg based on baseline 
weight and platelet count in ovarian cancer (Gonzalez-Martin et al., 2019). Therefore, the 
individualized starting dose regimen is expected to be suitable for a population of patients with 
PALB2 mutations as PALb2 is a Homologous Recombination Repair gene. Pathogenic 
mutations in PALB2 result in a HRd state within the tumor (Nyugen et al., 2020). 
Niraparib has a demonstrated acceptable benefit/risk ratio across tumor types when prescribed as 
an individualized starting dose regimen across tumor types.  In this study, the dosing regimen for 
niraparib is the approved individualized starting dose regimen, which is 300 mg of niraparib in 
participants with a baseline body weight ≥77 kg AND baseline platelet count ≥150,000/μL or 
200 mg in participants with a baseline body weight <77 kg OR baseline platelet count 
<150,000/μL, given once daily (QD), in participants with normal hepatic function or mild 
hepatic impairment.  
Retrospective exploratory statistical multivariable analysis of data from the NOVA trial (Study 
213356) identified baseline body weight and platelet counts as predictors of adverse events that 
required dose modification in patients treated with niraparib at 300 mg QD. Participants with a 
body weight <77 kg or platelet counts <150,000/μL at baseline had higher rates of Grade 3 
thrombocytopenia (35% versus 12%) and were more likely to require dose modification to 200 
mg within the first two months of treatment, with only 17% of participants with these baseline 
characteristics remaining on 300 mg by Month 4. In prospective evaluation in the PRIMA study 
in advanced ovarian cancer patients (Study 213359), the individualized starting dose regimen 
allowed participants to achieve comparable efficacy to a fixed starting dose of 300 mg, with a 
substantially lower incidence of thrombocytopenia and anemia, and this individualized starting 
dose regimen is approved for first-line maintenance treatment in advanced ovarian cancer. 

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4.4. Dose Adjustment Criteria 
4.4.1. 
Niraparib 
To manage adverse reactions, Investigators may consider interruption of treatment, dose 
reduction, or discontinuation, consistent with the following guidance.  
Niraparib dose interruption is allowed for up to 28 days. Participants should be placed back on 
study therapy within 28 days of the scheduled interruption, unless otherwise discussed with the 
Sponsor.  In this case, the medical monitor, in agreement with the sponsor, can allow delays of 
greater than 28 days. If, in the opinion of the investigator, a participant cannot safely restart 
therapy within 28 days, they will be discontinued from the study. All treatment interruptions and 
dose reductions (including any missed doses) and the reasons for the reductions/interruptions are 
to be recorded in the electronic Case Report Form (eCRF). 
For participants whose initial dose is 300 mg/day, dose reductions to 200 mg/day and 
subsequently to 100 mg/day will be allowed. No further dose reduction will be allowed. 
For participants whose initial dose is 200 mg/day, dose reduction to 100 mg/day will be allowed. 
No further dose reduction will be allowed. 
4.5. End of Study 
The end of the study is defined as the date of the last scheduled procedure shown in the SoA for 
the last participant in the study. A participant is considered to have completed the study if he/she 
has completed all study assessments, including the last scheduled procedure as reflected in the 
SoA (including survival assessment). 
The Sponsor may terminate this study at any time. The Sponsor will notify the Investigators 
when the study is to be placed on hold, completed, or terminated. 
4.6. Study Conduct 
4.6.1. 
Procedures by Visit 
Prior to participation, all participants must sign the main study ICF. Baseline and on-study 
imaging for all participants will include the chest, abdomen, pelvis, CNS as applicable, and other 
sites as clinically indicated. Imaging studies performed prior to informed consent as part of 
routine clinical management are also acceptable for use as initial imaging if they are of 
diagnostic quality, meet the protocol imaging requirements, and are performed within 28 (± 7) 
days prior to enrollment. Note that source documents must clearly identify the standard of care 
tests/procedures that are used for study Screening and the results of these tests/procedures must 
be entered in the eCRF (documentation of study-related procedures and study data will be 
captured in the eCRFs). 

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5. 
STUDY POPULATION 
5.1. Participant Inclusion Criteria 
Participants will be eligible for study entry if all of the following criteria are met: 
1. Participants must be ≥18 years of age. 
2. Participants must have a histologically or cytologically confirmed diagnosis of locally 
advanced or metastatic solid tumor(s). This study will enrich for lung, breast, and colon 
cancers; targeting approximately 10 participants for each of these cancer types.   
3. Participants must have tested positive for a pathogenic or likely pathogenic tPALB2 
mutation using a CLIA-certified laboratory as defined in the NGS Laboratory Manual. 
4. Participants who have stable and asymptomatic CNS disease must be receiving a stable 
(for at least 7 days) or decreasing corticosteroid dose at the time of study entry. 
5. Participants must submit fresh or archived (collected within 24 months of enrollment) 
FFPE tumor sample to the central laboratory for post-enrollment confirmation of tPALB2 
status.  
6. Participants must have received all standard therapies appropriate for their tumor type and 
stage of disease or, in the opinion of the Investigator, the patient would be unlikely to 
tolerate or derive clinically meaningful benefit from appropriate standard of care therapy, 
or the participant has no satisfactory alternative treatments. 
7. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1. 
8. Participants must have a life expectancy of at least 12 weeks. 
9. Participants must have adequate organ and bone marrow function defined below. 
Treatment may be delayed up to 3 weeks from enrollment to allow for these criteria to be 
met. 
Table 9. Organ/Bone Marrow Function Inclusion Criteria 
Absolute neutrophil count: 
≥1,500/μL 
Platelets: 
≥100,000/μL 
Hemoglobin: 
≥9 g/dL or 5.6 mmol/L 
Creatinine clearance (CLCr): 
>30 mL/min as estimated by the Cockcroft-Gault equation  
Total bilirubin*: 
  
≤1.5×upper limit of normal (ULN) (except in participants with 
Gilbert’s syndrome. Participants with Gilbert’s syndrome: isolated 
bilirubin >1.5×ULN is acceptable if bilirubin is fractionated, and 
direct bilirubin is <35%). 

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Aspartate aminotransferase 
(AST) and alanine 
aminotransferase (ALT)*: 
≤ 2.5×ULN (unless liver metastases are present, in which case they 
must be ≤5×ULN) 
Note: CBC test should be obtained without transfusion or receipt of colony-stimulating factors within 
4 weeks prior to obtaining sample.  
*Participants with mild to moderate hepatic impairment are allowed in the study. 
Mild hepatic impairment is defined as total bilirubin ≤1.5×upper limit of normal (ULN), any aspartate 
aminotransferase (AST); and an alanine aminotransferase (ALT) ≤2.5×ULN.   
Moderate impaired hepatic function is defined as total bilirubin >1.5× and ≤3×ULN, any level of AST; 
and an ALT ≤2.5×ULN. 
 
10. Participants must be able to swallow and retain orally administered study treatment. 
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
● Is not a woman of childbearing potential (WOCBP). 
or 
● Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, during the intervention period and 
for at least 180 days after the last dose of study treatment and agrees not to donate 
eggs (ova, oocytes) for the purpose of reproduction during this period. The 
Investigator should evaluate the effectiveness of the contraceptive method in relation 
to the first dose of study treatment. 
● A WOCBP must have a negative pregnancy test (either a highly sensitive urine or a 
serum pregnancy test as required by local regulations) within 72 hours before the first 
dose of study treatment. 
● If a highly sensitive urine test cannot be confirmed as negative (eg, an ambiguous 
result), a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive. 
● The Investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
12. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 90 days after the last dose of study treatment:  
● Refrain from donating sperm 
plus, either: 
● Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent  
or 
● Must agree to use contraception/barrier as detailed below: 

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● Agree to use a male condom (and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom may 
break or leak) when having sexual intercourse  
● Participants must be able to understand the study procedures and agree to 
participate in the study by providing written informed consent. Participants must 
be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent to participate in the study. 
5.2. Participant Exclusion Criteria 
Participants will be excluded from study entry if any of the following criteria are met: 
1. Participants have other active concomitant malignancy that warrants systemic, biologic, 
or hormonal therapy.  
2. Participants who have ovarian or prostate cancer. 
3. Participants who have variants of undetermined significance (VUS), but not pathogenic 
variants of tPALB2, at the time of screening. 
4. Participants who relapsed while receiving platinum based therapy in the adjuvant/curative 
setting. 
5. Participants progressing within 14-18 weeks while receiving platinum based therapy in 
the metastatic setting. 
6. Participants who have received PARP inhibitor(s) in prior lines of treatment.  
7. Participants with leptomeningeal disease, carcinomatous meningitis, symptomatic brain 
metastases, or radiologic signs of CNS hemorrhage. 
8. Participants with germline or somatic BRCA1 or BRCA2 mutations. 
9. Participant has systolic BP >140 mmHg or diastolic BP >90 mmHg, despite optimal 
medical therapy. 
10. Participants who have any clinically significant gastrointestinal abnormalities that may 
alter absorption such as malabsorption syndrome or major resection of the stomach and/or 
bowels. 
11. Participants with current active liver or biliary disease are excluded (with the exception of 
Gilbert’s syndrome or asymptomatic gallstones, liver cancer/metastases, or otherwise 
stable chronic liver disease per Investigator assessment).  
12. Participants who are receiving chronic systemic steroids (prednisone >20 mg per day). 
Participants with asthma who require intermittent use of bronchodilators or inhaled 
steroids; or with medical conditions who require topical, local steroid application or 
injections, would not be excluded from the study. 
13. Participants have previously or are currently participating in a treatment study of an 
investigational agent within 3 weeks of the first dose of therapy preceding the study.  
14. Participants have received prior systemic cytotoxic chemotherapy, biological therapy, or 
hormonal therapy for cancer, or received radiation therapy within 3 weeks of the first 
dose therapy preceding the study.  

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15. Participants with toxicity from prior cancer therapy must have recovered to Grade 1. (A 
participant with Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion 
and qualify for this study.) 
16. Participants have known hypersensitivity to the components of niraparib or their 
formulation excipients. 
17. Participants have undergone major surgery within 4 weeks of starting the first dose of 
study treatment or have not recovered from any effects of any major surgery. 
18. Participants have other active concomitant malignancy that warrants systemic, biologic, 
or hormonal therapy. 
19. Participants have received a live vaccine within 30 days of study enrollment. 
20. Participants have current active pneumonitis or any history of pneumonitis requiring 
steroids (any dose) or immunomodulatory treatment within 90 days of planned start of the 
study. 
21. Participants who have any clinically significant concomitant disease or condition (such as 
transfusion-dependent anemia or thrombocytopenia) that could interfere with, or for 
which the treatment might interfere with, the conduct of the study or that would, in the 
opinion of the Investigator, pose an unacceptable risk to the participants in this study. 
22. Participants who have any psychological, familial, sociological, or geographical condition 
potentially hampering compliance with the study requirements and/or follow up 
procedures. Those conditions should be discussed with the participants before study 
entry. 
23. Participants have high medical risk due to a serious, uncontrolled medical disorder; 
nonmalignant systemic disease; or active, uncontrolled infection (including COVID-19). 
Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent 
(within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable 
spinal cord compression, superior vena cava syndrome, active uncontrolled coagulopathy, 
bleeding disorder, or any psychiatric disorder that prohibits obtaining informed consent. 
24. Participants who are pregnant, breastfeeding, or expecting to conceive children while 
receiving study treatment and/or for up to 180 days after the last dose of study treatment. 
25. Participants have presence of hepatitis B surface antigen or a positive hepatitis C 
antibody test result at screening or within 3 months prior to first dose of study treatment. 
Participants with presence of hepatitis B core antibody should also be excluded.  
26. Participants have a known history or current diagnosis of myelodysplastic syndrome 
(MDS), acute myeloid leukemia (AML) or posterior reversible encephalopathy syndrome 
(PRES). 
27. Participant is immunocompromised. Participants with splenectomy are allowed. 
Participants with known human immunodeficiency virus (HIV) are allowed if they meet 
the following criteria: 
• Cluster of differentiation 4 ≥350/μL and viral load <400 copies/mL. 
• No history of acquired immunodeficiency syndrome-defining opportunistic infections 
within 12 months prior to enrollment. 
• No history of HIV-associated malignancy for the past 5 years. 

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• Concurrent antiretroviral therapy as per the most current National Institutes of Health 
(NIH) Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living 
with HIV [NIH, 2021] started <4 weeks prior to study enrollment. 
5.3. Lifestyle Considerations 
Cases of photosensitivity have been reported for patients on niraparib treatment. Participants 
must be informed on measures to decrease exposure to ultraviolet light, such as minimizing time 
in direct sunlight unless wearing hats and long-sleeves and application of sun protection creams. 
5.4.      Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demographics, screen failure details, eligibility criteria, any 
protocol deviations, and any SAEs. 
A participant that has previously screen failed may be rescreened for the study. Participants who 
are rescreened are required to sign a new ICF. Rescreened participants should be assigned a new 
participant number for every Screening/Rescreening event. 
6. 
STUDY TREATMENT(S) AND CONCOMITANT THERAPY 
6.1. Study Treatment(s) Administered 
Table 10. Investigational Product Details 
Product name 
Niraparib 
Dosage form 
Capsules 
Unit dose 
100 mg 
Route of administration 
Oral 
Physical description 
Capsules will be packaged in high-density polyethylene bottles 
Manufacturer 
GlaxoSmithKline 
6.1.1. 
Niraparib 
Niraparib ([3S]-3-[4-[7-(aminocarbonyl)-2H-indazol-2-yl] phenyl] piperidine [tosylate 
monohydrate salt]) is an orally available, potent, and highly selective PARP1 and PARP2 
inhibitor. The excipients for niraparib are lactose monohydrate and magnesium stearate. 

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Niraparib will be supplied as 100-mg capsules. The starting dose will be based upon the 
participant’s baseline body weight and/or baseline platelet count. 
Participants with a baseline body weight ≥77 kg and baseline platelet count ≥150,000 µL will be 
administered niraparib 300 mg daily. Participants with a baseline body weight <77 kg or baseline 
platelet count <150,000 µL will be administered niraparib 200 mg daily. 
6.2. Preparation/Handling/Storage/Accountability 
6.2.1. 
Study Drug Packaging and Labeling 
Niraparib capsules will be packaged in high-density polyethylene bottles with child-resistant 
closures. Participants will be provided enough capsules to accommodate 28 days of dosing with 
up to +3 days for visit flexibility.      
The label text of the study treatments will comply with Good Manufacturing Practice and 
national legislation to meet the requirements of the participating countries.  
6.2.2. 
Study Drug Storage 
All study treatment supplies must be stored in accordance with instructions and package labeling 
as contained within the Study Manual. Until dispensed or administered to the participants, the 
study treatment will be stored in a securely locked area that is accessible only to authorized 
personnel. 
The Investigator shall take responsibility for and shall take all steps necessary to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
6.2.3. 
Niraparib Administration 
Niraparib will be taken orally once a day, continuously throughout the 28-day cycle starting on 
Cycle 1/Day 1. Two capsules of 100-mg strength (200 mg/day) or 3 capsules of 100-mg strength 
(300 mg/day), based on baseline body weight and/or platelet count, will be taken at each dose 
administration. Participants will be instructed to take their niraparib dose in the morning at 
approximately the same time each day, except on clinic visit days. On these days, participants 
will be instructed to hold their niraparib dose until their visit; it will be administered at the site. 
Niraparib may be taken with or without food or water. Participants must swallow and not chew 
the capsules. If a participant vomits or misses a dose of niraparib, a replacement dose should not 
be taken. Bedtime administration may be a potential method for managing nausea. 
Niraparib will be dispensed to participants on Day 1 of every cycle (every 28 days) thereafter 
until radiographic PD is documented per RECIST v1.1 or other treatment discontinuation 
criterion is met. The niraparib product guidelines document contains descriptions of the 
packaging of niraparib and instructions for administration of niraparib. 
Complete instructions for collection, processing, shipping, and handling are described in the 
Manual. 
 

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Table 11. Niraparib Dosing Criteria 
Baseline Criteria 
Starting Dose 
Weight <77 kg or platelets <150,000/μL, or both 
200 mg daily (two 100-mg capsules) 
Weight ≥77 kg and platelets ≥150,000/μL 
300 mg daily (three 100-mg capsules) 
6.2.4. 
Study Drug Accountability 
The Investigator or designee is responsible for maintaining accurate dispensing records of the 
study treatments throughout the clinical study. 
Details of maintaining drug accountability, including information on the accountability log, will 
be provided in the Study Manual. 
The Pharmacist will dispense study treatment for each participant according to the protocol and 
Study Manual. 
6.2.5. 
Study Drug Handling and Disposal 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Receipt and dispensing of study treatment must be recorded by an 
authorized person at the study site. Refer to the niraparib product guidelines document for full 
niraparib handling precautions. 
The Investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the participants, and the 
amount remaining at the conclusion of the study. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. At the 
end of study, when all participants have stopped protocol treatment, complete drug reconciliation 
per batch should be available at the site for verification in order to allow drug destruction or 
return procedure. After receiving Sponsor approval in writing, the investigational site is 
responsible for destruction of study treatment according to local regulations. If a site does not 
have the capability for onsite destruction, the Sponsor will provide a return for destruction 
service through a third party. Both the unused and expired study treatment must be destroyed, 
upon authorization of the Sponsor, according to local regulations and procedures, and a copy of 
the destruction form must be filed in the study binder. 
The treatment provided for this study is to be used only as indicated in this protocol and only for 
the participants entered in this study. 
6.3. Study Treatment Compliance 
Compliance with inclusion and exclusion criteria will be assessed as outlined in Sections 5.1 and 
5.2.  
Study treatment will be administered by site personnel at study sites as detailed in Section 6.2.3.  

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When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. 
When participants self-administer study intervention at home, compliance with niraparib will be 
assessed by direct questioning or counting returned capsules during the site visits and recording 
in the source document and relevant forms. Deviation(s) from the prescribed dosage regimen 
should be recorded. 
A record of the quantity of study treatment dispensed to and administered by each participant 
must be maintained and reconciled with study intervention and compliance records. Intervention 
start and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded. 
Study treatment accountability will be monitored with a patient dosing diary.  
6.4. Treatment of Overdose 
For this study, a dose of niraparib greater than indicated in this protocol within the specified 
administration window will be considered an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until the 
investigational product can no longer be detected systemically. 
3. Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
6.5. Concomitant Therapy 
Any medication the participant takes during the study other than the study treatments, including 
herbal and other non-traditional remedies, is considered a concomitant medication. All 
concomitant medications must be recorded in the eCRF. The following information must be 
recorded in the eCRF for each concomitant medication: generic name, route of administration, 
start date, stop date, dosage, and indication. Any changes in the dosage or regimen of a 
concomitant medication must be recorded in the eCRF. 
At Screening, participants will be asked what medications they have taken during the last 
30 days. At each subsequent study visit, participants will be asked what concomitant medications 
they are currently taking or have taken since the previous visit. 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the course of this study. All treatment interventions that the Investigator considers 
medically necessary for a participant’s wellbeing may be administered at the discretion of the 
Investigator in keeping with the community standards of practice. If there is a clinical indication 

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for any medication or vaccination specifically prohibited during the study, discontinuation of 
study treatment may be required. The final decision on any supportive medications or 
vaccination is the responsibility of the Investigator and/or the participant’s primary physician. 
The decision to continue the participant on the study treatment schedule requires the mutual 
agreement of the Investigator, the Sponsor, and the participant. 
6.5.1. 
Prohibited Medications 
Known prior medications that exclude a participant from participating in the study are described 
in the exclusion criteria. 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment phase of this study:  
● Systemic anticancer or biological treatment 
● Immunotherapy not specified in this protocol 
● Chemotherapy not specified in this protocol 
● Investigational agents other than niraparib 
● Prophylactic cytokines (eg, GCSF) should not be administered in the first cycle of the 
study but may be administered in subsequent cycles according to local guidelines. 
● Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in this clinical study 
● Chronic systemic steroids (prednisone >20 mg per day) 
The data on niraparib in combination with cytotoxic medicinal products are limited. Therefore, 
caution should be taken if niraparib is used in combination with vaccines, immunosuppressant 
agents or with other cytotoxic medicinal products. 
No other anticancer treatment is permitted during the course of the study treatment for any 
participant. Palliative radiotherapy (excluding palliative radiotherapy encompassing >20% of the 
bone marrow within 1 week of the first dose of study treatment) is allowed for pre-existing small 
areas of painful bone metastases that cannot be managed with local or systemic analgesics, as 
long as no evidence of disease progression is present. 
The niraparib safety profile includes risk for thrombocytopenia; therefore, participants should be 
advised to use caution when taking anticoagulants (eg, warfarin) and antiplatelet drugs 
(eg, aspirin). 
Caution is recommended when niraparib is combined with active substances the metabolism of 
which is cytochrome P450 enzyme (CYP)3A4-dependent and, notably, those having a narrow 
therapeutic range (eg, cyclosporine, tacrolimus, alfentanil, ergotamine, pimozide, quetiapine, and 
halofantrine). 
Caution is recommended when niraparib is combined with active substances the metabolism of 
which is CYP1A2-dependent and, notably, those having a narrow therapeutic range (eg, 
clapzine, theophylline, and ropinirole). Caution is then recommended when niraparib is 
combined with substrates of breast cancer resistance protein (eg, rosuvastatin, simvastatin, 
atorvastatin, and methotrexate). 

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Niraparib is an inhibitor of multidrug and toxin extrusion transporter (MATE)1 and MATE2 
with a half maximal inhibitory concentration of 0.18 µM and ≤0.14 µM, respectively. Increased 
plasma concentrations of coadministered medicinal products that are substrates of these 
transporters (eg, metformin) cannot be excluded. 
Caution is recommended when niraparib is combined with active substances that undergo an 
uptake transport by organic cation transporter 1 (eg, metformin). 
Physicians should follow the current versions of the niraparib Investigator’s Brochure for 
information on the general management of the participants receiving this therapy. 
6.5.2. 
Contraception 
Niraparib is known to have properties that require participants to use contraception. For details 
on niraparib, refer to the current niraparib Investigator’s Brochure. 
Based on its mechanism of action, niraparib may cause teratogenicity and/or embryo-fetal death 
when administered to a pregnant woman. 
Participants of childbearing potential may only be enrolled if they have a negative serum 
pregnancy test within 72 hours prior to taking study treatment. Note: A highly sensitive urine 
pregnancy test may be performed if the serum pregnancy result is not available before dosing. 
Participants must agree to abstain from activities that could result in pregnancy from Screening 
through 180 days after the last dose of study treatment, be willing to use effective contraception, 
or be of non-childbearing potential. 
Participants should be informed that taking the study treatment may involve unknown risks to the 
fetus if pregnancy were to occur during the study. To participate in the study, they must adhere 
to the contraception requirements described above. If there is any question that a participant will 
not reliably comply with the requirements for contraception, that participant should not be 
enrolled in the study. 
Male participants must use an adequate method of contraception and not donate sperm starting 
with the first dose of study treatment through 90 days after the last dose of study treatment. 
Abstinence is acceptable if this is the established and preferred contraception for the participant. 
 
 
 
 
 
 
 
 
 
 

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Table 12. Timing of Contraception and Sperm Donation 
Parameter 
Timeframe 
Contraception use, 
female participants 
Starting with the Screening visit through 180 days after the last dose of study 
treatment 
Contraception use, 
male participants 
Starting with the first dose of study treatment through 90 days after the last 
dose of study treatment 
Sperm donation 
Starting with the first dose of study treatment through 90 days after the last 
dose of study treatment 
6.5.3. 
Other Study Restrictions 
Participants who are blood donors should not donate blood during the study and for 90 days after 
the last dose of study treatment. 
Participants should maintain a normal diet, unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting. 

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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1. Discontinuation from Study Treatment 
Participants may be discontinued from study treatment at any time. Participants who discontinue 
from study treatment or from the study will not be replaced. Participants who discontinue from 
study treatment will attend the EOT Visit within 7 days after the last dose of study treatment, 
Safety Follow-up Visits at 30 (±7) days, and Survival Follow-up assessments which may be 
conducted via telephone, email, in person visits to the clinic or back-up contacts every 
90 (±14) days for 1 year after last dose and then every 180 (±14) days that will continue until 
death or the end of study data collection (provided that this allows the opportunity for 
completion of all 90-day follow-up assessments).  
Specific reasons for discontinuing study treatment include the following: 
● AE 
− If a participant has any treatment-related NCI-CTCAE v5.0 Grade 3 or 4 AEs that 
have not reverted to NCI-CTCAE v5.0 Grade 1 or better within 28 days. 
− If upon re-challenge with study treatment at the lowest allowable dose any NCI-
CTCAE v5.0 Grade 3 or 4 AEs recur, the participant must be discontinued from 
niraparib treatment. 
● Liver chemistry stopping criteria are met per Appendix 4: Liver Safety Required 
Actions and Follow-up Assessments  
● Thrombocytopenia, if the platelet count has not returned to ≥100,000/µL within 
28 days of dose interruption 
● Neutropenia, if the neutrophil counts has not returned to ≥1,500/mcL within 28 days 
of dose interruption 
● Anemia, if the hemoglobin has not returned to ≥9 g/dL within 28 days of dose 
interruption 
● MDS, AML or PRES 
● New primary malignancy other than MDS or AML 
● Risk to the participant as judged by the Investigator, Sponsor, or both 
● Severe non-compliance with protocol as judged by the Investigator, Sponsor, or both 
● Pregnancy 
● Withdrawn consent 
● Lost to follow-up 
● Death 
● PD as indicated by radiographic evidence per RECIST v1.1 
Treatment with niraparib will continue until radiographic PD is documented per RECIST v1.1 or 
another treatment discontinuation criterion is met.  
If a participant discontinues treatment for any reason other than radiographic PD per RECIST 
v1.1, then tumor assessment scans should continue at the specified intervals until radiographic 
PD is documented per RECIST v1.1 or until the start of subsequent anticancer treatment. 

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Participants who discontinue from study treatment will continue to receive follow-up 
assessments as part of the study unless they are discontinued from the study.  During follow-up, 
contact to assess survival may be made via another form of communication (eg, telephone, 
email). 
7.2. Withdrawal of Consent 
Participants may withdraw consent at any time. If a participant withdraws consent, the 
Investigator is to determine whether the participant is willing to be followed up for subsequent 
procedures in the safety and survival follow-up periods and for OS. Such participants will be 
required to indicate whether they agree to continue these procedures as well as whether they 
agree to the collection of their disease history information until the end of the study and to the 
use of the blood and tumor samples they provided for the study for research purposes; this 
information will be recorded on the appropriate eCRF page. 
Documentation of participant consent for further research will be captured in the eCRFs. Any 
specimens for which such an informed consent cannot be verified will be destroyed, as will those 
requested to be destroyed at time of consent withdrawal. 
7.3. Participant Discontinuation/Withdrawal from the Study 
Specific reasons for discontinuing from the study include the following: 
● Withdrawal of consent by the participant, who is at any time free to discontinue 
participation in the study, without prejudice to further treatment 
● Loss to follow-up 
● Death from any cause 
● Sponsor’s decision to terminate study 
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or compliance 
reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an EOT Visit should be conducted, as 
shown in the SoA. See SoA for data to be collected at the time of study discontinuation and 
follow up and for any further evaluations, including survival status, that need to be completed. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
A participant may choose to stop receiving study treatment and still be involved in the study. In 
this case, study staff may contact the participant (or other representatives [eg, caregiver, doctor] 
if the participant cannot be reached directly) by telephone or email (every 90 days for 1 year 
after last dose and then every 180 days) to make health inquiries, which may help to inform long-
term effects of the study treatment. 

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7.4. Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
● The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the study. 
● Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
● Regarding collection of date for death/survival status, a back-up contact, if 
documented by the participant, or public databases can be used to provide the 
information.  
● Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
7.4.1. 
Further Research Maintaining Confidential Participant Information 
The Sponsor will conduct further research on specimens collected during this study. This 
research may include genetic/genomic, proteomic, metabolomic, and transcriptional analyses. 
The data generated may be combined with clinical and histological image analysis. Such 
research helps to address emergent questions not described in the protocol and will only be 
conducted on specimens from properly consented participants. 
In an effort to optimize the research that can be conducted with further research specimens, it is 
essential to link study participant clinical study data with further research test results. The 
clinical study data allow specific analyses to be conducted. Knowing participant characteristics 
like gender, age, medical history, treatment type, and treatment outcomes are critical to 
understanding the clinical context of further research analytical results. 
To maintain privacy of information collected from specimens obtained for further research, the 
Sponsor has developed secure policies and procedures. All specimens will be single coded per 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) E15 guidelines, “Definitions for Genomic Biomarkers, Pharmacogenomics, 
Pharmacogenetics, Genomic Data and Sample Coding Categories”. 
At the clinical study site, unique codes will be placed on the further research specimens for 
transfer to the storage facility. This first code is a random number that does not contain any 
personally identifying information embedded within it in order to maintain participant privacy. 
The link (or key) between participant identifiers and this first unique code will be held at the 
study site. No personal identifiers will appear on the specimen tube. 

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Participants may withdraw their consent for further research and have their specimens and all 
derivatives destroyed. Participants may withdraw consent at any time by contacting the 
Investigator. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. Screening and Critical Baseline Assessments  
8.1.1. 
Baseline Assessments at Screening 
Refer to the Schedule of Activities (Table 3 and Table 4) for the full list of assessments collected 
during Screening. Tumor characteristics to be collected during Screening include, but are not 
limited to, histologic tumor type, tumor grade, tumor stage (both clinical and pathologic staging 
as per the American Joint Committee on Cancer (AJCC) and response to chemotherapy (as 
applicable). Primary pathology reports will be collected from biopsy. 
8.1.2. 
Biomarker Testing for PALB2 and Translational Research  
Screening Testing  
An individual must have a PALB2 somatic or germline mutation to be eligible for enrollment.  
Results from local NGS testing from tissue and/or blood performed by a CLIA-certified 
laboratory as described in the NGS Laboratory Manual will be used to meet molecular eligibility.  
If an individual is enrolled based on local testing, tissue and blood samples must be submitted for 
retrospective confirmation of PALB2 status (where applicable), diagnostic development, and 
biomarker research. 30 FFPE slides or 1 block equivalent of tumor tissue collected from the most 
recent biopsy (sample collected within the past 24 months of enrollment) must be provided.  For 
participants with only germline PALB2 mutations, archival tissue from a primary or metastatic 
tumor may be provided. For participants with somatic PALB2 mutations, a metastatic tissue 
sample is requested; if not available, a primary tumor sample may be provided and a new biopsy 
will be requested, though optional, so that a metastatic disease sample may be submitted for 
testing. To obtain the new biopsy sample a core or needle biopsy may be performed; however, 
more invasive procedures should not be utilized for the purpose of this trial.  
In addition, a total of 3 tubes with stabilization solution of peripheral blood, ~ 30 mL, will be 
collected for biomarker testing in accordance with Table 3.  
Longitudinal Testing  
Additional blood samples (2 tubes with stabilization solution, ~ 20 mL, of peripheral blood) for 
exploratory biomarker testing will be collected at the time points specified in the SoA to evaluate 

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genomic, gene expression, proteomic, or other signatures to investigate predictive biomarkers for 
response and mechanisms of resistance as well as for exploratory research.  
If a participant discontinues study treatment for any reason other than disease progression per 
RECIST v1.1, death, withdrawal of consent, or loss to follow-up, then biomarker blood sample 
collection should continue at the specified intervals until disease recurrence is confirmed. 
8.1.3. 
Baseline CT/MRI  
A CT scan of the chest, and IV contrast-enhanced CT of the abdomen, and pelvis will be 
conducted within 28 (± 7) days prior to randomization. An IV contrast-enhanced MRI of the 
abdomen and pelvis plus noncontrast CT of the chest should only be conducted if clinically 
indicated (eg, if the participant is sensitive to IV CT contrast). For participants with CNS lesions, 
brain MRI will also be conducted within 28 (± 7) days prior to randomization. The same imaging 
modality, method, and anatomical coverage should be used throughout the study. 
8.2. Assessment of Efficacy 
8.2.1. 
Primary Efficacy Endpoint 
This study has the efficacy endpoint ORR, which is defined as the proportion of participants who 
have a partial or complete response to therapy and will be assessed by ICR. 
8.2.2. 
Radiographic Evaluation of Tumor Response 
Images of the chest, abdomen, pelvis, CNS as applicable, and other sites as clinically indicated 
will be used to determine extent of disease. The same imaging method and anatomical coverage 
should be used throughout the study. 
The preferred method used for chest, abdomen and pelvis assessments is cross-sectional imaging 
by CT scan. CT scans should be performed with IV contrast, unless contraindicated for medical 
reasons, in which case MRIs are acceptable. MRI of the chest should not be substituted for CT of 
the chest, even if IV contrast is contraindicated. In such a case, CT will be performed without IV 
contrast to evaluate the lung parenchyma. Premedication (including steroids) is permitted prior to 
CT scans for participants with a documented history of IV contrast allergy. 
Imaging of the CNS (brain only, unless otherwise clinically indicated) will be performed for all 
participants with documented CNS disease by MRI at baseline and all CNS assessments 
throughout the study. However, CT is acceptable if MRI is not possible. 
Participants who are known to have bone metastasis or who display clinical or laboratory signs 
(eg, serum alkaline phosphatase >1.5×ULN) of bone metastasis may undergo additional imaging 
(eg, radionuclide bone scan, CT scan, MRI, PET scan, Xray) as clinically indicated, in the 
judgment of the Investigator. 
Overall progression will be assessed by the Investigator per RECIST v1.1 and verified by ICR to 
measure PFS.  
Imaging will be collected/conducted per Table 13.  
 

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Table 13. Overview of Imaging Requirements by Visit 
Imaging Visit 
Description 
Baseline 
● Performed within 28 [±7] days prior to randomization 
● Performed by CT of chest, abdomen, and pelvis. MRI of the brain is 
necessary for imaging participants with CNS lesions. 
● Assessed by ICR and Investigator per RECIST v1.1 
● Imaging assessment conducted prior to consent as part of routine care may 
be used if it is performed within the 28 (± 7)-day window 
Treatment Period 
● Performed every 8 weeks (every 56[±7] days) from the date of study start 
● Participants with either a PR or CR should have an additional set of scans 
to confirm the response at least 28 (+7) days after scans showing the PR or 
CR 
● Performed more frequently if clinically indicated  
● Brain scan required for participants with documented CNS disease every 8 
weeks (every 56[±7] days) from the date of study start to assess 
intracranial ORR and PFS in participants with untreated measurable CNS 
lesions (all scans must be the same as the initial scan type) 
● Assessed by ICR and Investigator per RECIST v1.1 
EOT 
● For participants who discontinue study treatment due to ICR-verified 
progression, additional imaging assessment is not required at EOT 
● For participants who begin a subsequent anticancer treatment prior to 
ICR-verified progression, EOT imaging assessment must be performed 
within 4 weeks of the date of study treatment discontinuation 
Post-Treatment 
Follow-Up 
● Participants who discontinue study treatment for any reason other than 
radiographic PD per RECIST v1.1 should continue monitoring disease 
status by tumor imaging every 8 weeks (every 56 [±7] days) until 
radiographic PD is documented per RECIST v1.1 or until the start of 
subsequent anticancer treatment. 
Abbreviations: ICR= independent central review; CNS=central nervous system; CR=complete response; 
CT=computed tomography; EOT=End-of-Treatment; MRI=magnetic resonance imaging; PD=progressive 
disease; PR=partial response; RECIST v1.1=Response Evaluation Criteria in Solid Tumors version 1.1; 
SD=stable disease; TTP=time to progression. 
 
Tumor assessments and timing should occur according to this schedule regardless of treatment 
interruptions. Imaging should not be delayed due to delays in cycle starts or extension. 
All imaging will be submitted to the imaging vendor for ICR. Two independent radiologists 
(along with an adjudicator, as necessary) will conduct reads using RECIST v1.1 criteria for the 
determination of response.  

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8.2.3. 
Secondary Efficacy Endpoints 
This study has the following secondary efficacy endpoints: ORR, DOR, PFS, CBR and OS. 
ORR is defined as the proportion of participants who have a partial or complete response to 
therapy and will be assessed by Investigator as a secondary efficacy endpoint. 
 
DOR is defined as the time between initial response to therapy and subsequent disease 
progression or relapse and will be assessed by ICR and Investigator using the RECIST v.1.1 
criteria.   
 
PFS is defined as the time from first dose to the date of first radiographic progression or death 
from any cause in the absence of progression, whichever occurs first. Progression will be 
assessed by ICR and Investigator using the RECIST v.1.1 criteria.  
 
CBR is defined as the percentage of participants who have achieved complete response, partial 
response, and stable disease, and will be assessed by ICR and Investigator. 
 
Intracranial ORR and PFS in participants with untreated measurable CNS lesions as assessed by 
ICR and Investigator using RECIST v1.1.   
OS is a secondary efficacy endpoint in this study is defined as the time from first dose to the date 
of death by any cause. Participants who are alive will be censored at the date of last contact. OS 
includes the following: death attributable to any cause, including primary cancer, secondary 
cancer, or unknown cause.  
8.2.4. 
Patient-Reported Outcome Measures 
Summaries of the PRO instruments for EORTC QLQ-C30 and EQ-5D-3L are provided in 
Appendix 7.  
The PRO questionnaires should be conducted in the clinic, on the day of study treatment 
administration, prior to dosing or clinical procedures during the Treatment Period. They may be 
administered by telephone in follow up if the participant is no longer actively returning to the 
site. 
The questionnaires will be administered to participants based on the availability of translated 
versions. 
Participants will be instructed on the completion of the questionnaires by site personnel who 
have been trained on their implementation. 
8.2.5. 
Pharmacokinetic Sample Collection 
Blood samples for niraparib PK will be collected at the time points specified in Table 4 for all 
study participants with sparse PK sampling. Each PK sample must be collected as close as 
possible to the planned time relative to the dose administered to the participant on PK sampling 

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days. 
Plasma prepared from the blood samples will be analyzed for niraparib concentrations for PK 
Evaluation. 
Complete instructions for collection, processing, shipping, and handling of PK samples are 
detailed in a study-specific Laboratory Manual. 
8.3. Assessment of Safety 
8.3.1. 
Safety Parameters 
Safety parameters will include the incidence of AEs, SAEs, and AESIs, the incidence of 
treatment discontinuations, dose interruptions, and dose reductions due to AEs, SAEs, or AESIs, 
changes in ECOG performance status, changes in clinical laboratory results (hematology, 
chemistry and urinalysis), vital sign measurements, observations during physical examination, 
and use of concomitant medications. 
8.3.2. 
Demographic/Medical History 
Demographic and baseline characteristics consist of those variables that are assessed at 
Screening/baseline. Participant demographics consist of age at Screening, race, ethnicity, 
smoking status (nonsmoker, former smoker, and current smoker), and sex. Medical history will 
include disease history, medical and surgical history, previous and concomitant medications, and 
any other relevant information. Information regarding standard of care induction chemotherapy 
and cancer history will also be collected. 
8.3.3. 
Physical Examination 
Physical examinations and symptom-directed physical examinations will be performed in 
accordance with the standard of care for oncology patients and in accordance with local-regional 
standards of practice. 
A full physical examination will include, at a minimum, assessments of respiratory, 
cardiovascular, gastrointestinal, and neurological systems. 
Symptom-directed, targeted physical examinations will include, at a minimum, assessments of 
the skin, heart, lungs, and abdomen (including liver and spleen), along with a neurological 
assessment. Investigators should pay special attention to clinical signs related to previous serious 
illness and to emerging AEs. Abnormal findings should be reassessed at subsequent visits. 
Any physical examination or vital sign abnormalities assessed as clinically significant should be 
recorded as an AE or SAE. If SAE criteria are met or the abnormality is an AESI, the finding 
should be recorded and reported according to the SAE reporting process. 
8.3.4. 
Vital Signs, Height, and Weight 
Vital signs, including BP, temperature, heart rate, respiratory rate, weight, and height will be 
measured. Any abnormal vital signs assessed as clinically significant should be recorded as an 

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AE or SAE. If SAE criteria are met or the abnormality is an AESI, the event should be recorded 
and reported according to the SAE reporting process. Height will be measured at Screening only. 
Weight will be measured at Screening and at every visit indicated in the schedule. Heart rate and 
BP must be monitored weekly for the first 2 months, then on Day 1 of each subsequent cycle. 
Blood pressure and heart rate collection methodology can occur during on-site scheduled clinic 
visits, at a local laboratory/clinic, or may also be reported to the site by a home nurse, or by 
another method deemed by the investigator and sponsor to be reliable. Three readings of BP and 
heart rate should be performed at a clinic visit. The first reading should be rejected and the 
second and third averaged to give the measurement to be recorded in the CRF. 
 
8.3.5. 
Laboratory Assessments 
These tests will be performed by the local laboratory at the clinical site. 
Any abnormal laboratory value assessed as clinically significant should be recorded as an AE. 
Evaluation by Investigators should be given to clinically significant laboratory values that begin 
before the start of study treatment but after obtaining main study ICF for determination regarding 
whether values should be recorded as medical history/current medical conditions. If SAE criteria 
are met or if the laboratory abnormality is an AESI, the event should be recorded and reported 
according to the SAE reporting process. 
Hematologic, blood chemistry and coagulation factor testing may occur more frequently than is 
specified, if medically indicated per Investigator judgment or if the event meets the criteria for 
study treatment dose modification. Additional tests may be performed at a laboratory facility 
other than the study site, but the test results must be reported to the study site, the study site must 
keep a copy of test results with the participant’s study file, and the results must be entered into 
the eCRF. 
Any suspected case of MDS/AML reported while a participant is receiving treatment or followed 
for post-treatment assessments must be referred for evaluation to a local hematologist to perform 
bone marrow aspirate and biopsy as per local practice. The study site must receive a copy of the 
hematologist’s report of aspirate/biopsy findings, which must include a classification according 
to WHO, and other sample testing reports related to MDS/AML. Report data will be entered in 
the appropriate eCRF pages, and the site must keep a copy of all reports with the participant’s 
study file. If a diagnosis of MDS/AML is confirmed by a hematologist, the participant must 
permanently discontinue study treatment. 
Any suspected case of secondary cancer (new malignancies other than MDS/AML) reported 
while a participant is receiving treatment or followed for post-treatment assessments must be 
investigated, including obtaining and documenting a histological diagnosis. Testing completed as 
part of standard of care is sufficient as long as the methods are deemed acceptable after 
consultation with the Sponsor’s Medical Monitor. 

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Table 14. Laboratory Assessments 
Hematology 
Coagulation 
Factorsa 
Chemistry 
Chemistry 
Urinalysis 
Other 
WBC – total and 
differential 
PT/INR 
Sodium 
Calcium 
Specific gravity 
Serum β-
hCGb 
Hemoglobin 
PTT/aPTT 
Potassium 
Magnesium 
Blood 
FT4 
Hematocrit 
 
Chloride 
Phosphorus 
Glucose 
 
Platelet countc 
 
CO2 or 
bicarbonated 
Albumin 
Ketones 
 
Absolute 
neutrophil count 
 
BUN or 
ureae 
 
Total 
Protein 
Protein 
 
Absolute 
lymphocyte Count 
 
Uric acid 
Alkaline 
phosphatase 
Nitrite 
 
 
 
Creatinine 
ALT 
Leukocyte esterase 
 
 
 
Glucose 
AST 
Urobilinogen 
 
 
 
 
Amylase 
Bilirubin 
 
 
 
 
Total 
Bilirubin 
Microscopic exam, if 
abnormal results are 
noted 
 
 
 
 
 
Urine pregnancy test 
 
Abbreviations: β-hCG=beta-human chorionic gonadotropin; ALT=alanine aminotransferase; 
aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
CO2=carbon dioxide; FT4=free thyroxine; INR=international normalized ratio; PT=prothrombin time; 
PTT=partial thromboplastin time; WBC=white blood cell. 
a Coagulation factors (PT/INR and aPTT/PTT) should be tested as part of the screening procedures for all 
participants. Any participant receiving anticoagulant therapy should have coagulation factors monitored 
closely throughout the study. 
b Perform β-hCG on women of childbearing potential only. Urine pregnancy test is preferred. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
c Mean platelet volume is optional but encouraged, especially for participants with high-grade 
thrombocytopenia. 
d If CO2 or bicarbonate in the chemistry panel are not done as part of standard of care in your region, then 
these tests do not need to be performed. 
e BUN is preferred; if not available, urea may be tested. 
 

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8.3.6. 
HIV, Hepatitis B, and Hepatitis C Testing 
HIV, hepatitis B virus, and hepatitis C virus testing will be done at Screening and performed 
consistent with local regulations, where applicable. 
8.3.7. 
ECOG Performance Status 
Performance status will be assessed using the ECOG scale in Appendix 8. The same observer 
should assess ECOG performance status each time. 
8.4. Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally appointed representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE, SAE, or AESI according to CTCAE v5.0 and 
remain responsible for following up all events. 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
● All AEs and SAEs will be collected from the signing of the main study ICF until 
30 days after the last dose of study treatment at the time points specified in Table 4. 
However, any SAEs assessed as related to study participation (eg, study treatment, 
protocol-mandated procedures, invasive tests, or change in existing therapy) or 
related to study treatment will be collected and reported until study closeout as 
specified in Table 4. 
● AESIs will be collected and reported from the signing of the main study ICF until 
study closeout at the time points specified in Table 4 and as described in 8.4.6. 
● Adverse Events that begin before the start of study treatment but after obtaining 
informed consent will be recorded as Medical History/Current Medical Conditions. 
● All SAEs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours. The Investigator will submit any 
updated SAE data to the Sponsor or designee within 24 hours of it being available. 
● Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of the study participation. However, if the Investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, 
and he/she considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the Sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence. 

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8.4.3. 
Follow-Up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs and SAEs will be followed until the event is 
resolved, stabilized, or otherwise explained; until the participant is lost to follow-up; or until the 
participant has died.  
Regulatory Reporting Requirements for SAEs 
● Prompt notification by the Investigator to the Sponsor and GSK of an SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 
● The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
● An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
● Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) as applicable and in accordance with regional reporting 
requirements. Sponsor policy and applicable provision to Investigators as necessary 
should also apply. 
8.4.4. 
Pregnancy 
● Details of all pregnancies in female participants and female partners of male 
participants who receive study treatment will be collected after the start of study 
treatment and until 180 days after the last dose of study treatment in female 
participants and 90 days after the last dose of study treatment for female partners of 
male participants. 
● If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the 
pregnancy of the female participant or female partner of male participant (after 
obtaining the necessary signed informed consent from the female partner). While 
pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE 
or SAE. 
● Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
● The participant/pregnant female partner will be followed to determine the outcome of 
the pregnancy. The Investigator will collect follow-up information on the 

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participant/pregnant female partner and the neonate, and the information will be 
forwarded to the Sponsor. 
● Any post-study pregnancy-related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor. While the Investigator is 
not obligated to actively seek this information in former study participants/pregnant 
female partners, he or she may learn of an SAE through spontaneous reporting. 
● Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment. 
8.4.5. 
Cardiovascular and Death Events 
For any cardiovascular (CV) events detailed in Appendix 2 and all deaths, whether or not they 
are considered SAEs, specific sections of the eCRF will be required to be completed. These 
sections include questions regarding cardiovascular (including sudden cardiac death) and non-
cardiovascular death. 
The CV-related eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be recorded 
in the specific cardiovascular section of the eCRF within 1 week of receipt of a CV Event data 
query prompting its completion. 
The death-related eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week of when 
the death is reported. 
8.4.6. 
Adverse Events of Special Interest (AESIs) 
Selected non-serious AEs and SAEs are also known as Adverse Events of Special Interest 
(AESI). Serious AESIs must be recorded as such on the eCRF and reported to the Sponsor within 
24 hours of the Investigator becoming aware of them. 
The AESIs for niraparib should be reported as follows: 
● MDS or AML, along with other secondary cancers (new malignancies other than 
MDS or AML), should be reported to the Sponsor until death or loss to follow up. 

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9. 
STATISTICAL CONSIDERATIONS 
ORR is the only endpoint for which a formal statistical test will be performed according to the 
Bayesian Optimal Phase 2 (BOP2) design, for all other endpoints the statistical analyses will be 
descriptive only. 
Continuous data will be summarized for the overall population using descriptive statistics 
(number, mean, standard deviation [Std], minimum, median and maximum). Categorical data 
will be summarized by treatment group using frequency tables (number and percentage). Where 
appropriate 95% CI will be calculated and presented in addition to the point estimates. 
9.1. Statistical Hypotheses 
The primary efficacy endpoint ORR will be assessed using the BOP2 design (Zhou, Lee and 
Yuan, 2017). Based on historical data the expected ORR in this population is assumed to be at 
best 15% under standard of care (SOC). Niraparib would be considered promising in this 
population if an ORR=30% would be achieved. Therefore, if 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒 denotes the ORR, the null 
hypothesis is 𝐻𝐻0: 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒≤0.15, under which the treatment is deemed as not promising and 
unacceptable and the alternative hypothesis 𝐻𝐻1: 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒≥0.3, where the treatment is considered 
promising. These hypotheses will be tested at a one-sided α=0.025 with about 90% power.  
9.2. Sample Size Determination 
The primary efficacy endpoint ORR will be assessed using the Bayesian Optimal Phase 2 
(BOP2) design (Zhou, Lee and Yuan, 2017). Specifically, let 𝑛𝑛 denote the interim sample size 
and 𝑁𝑁 denote the maximum sample size. Let 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒 denote the ORR and define the null hypothesis 
𝐻𝐻0: 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒≤0.15, under which the treatment is deemed as not promising and unacceptable. The 
trial will stop enrolling participants and claim that the treatment is unacceptable if 
𝑃𝑃𝑃𝑃(𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒> 0.15|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) < 𝜆𝜆ቀ𝑛𝑛
𝑁𝑁ቁ
𝛼𝛼
, 
where 𝜆𝜆 =0.96 and 𝛼𝛼 =1 are design parameters optimized to maximize power under the 
alternative hypothesis  𝐻𝐻1: 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒= 0.3, (i.e., the probability of correctly claiming that the 
treatment is acceptable under 𝐻𝐻1), while controlling the type I error rate (i.e., the probability of 
incorrectly claiming that the treatment is acceptable under 𝐻𝐻0) at 0.024. This optimization is 
performed assuming a vague prior Beta (0.15,0.85) for 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒. The above decision rule leads to the 
following stopping boundaries and yields a statistical power of 0.932 under 𝐻𝐻1 when 90 
participants are included as evaluable participants for ORR described in Table 2.  
Based on Table 2, the interim analysis will be performed when a total of 40 participants have 
completed their efficacy assessment on ORR. If 5 or less responders are observed in these 40 
participants, the study could be stopped for futility. If 6 or more responders are observed among 
the 40 participants, the study could continue to enroll a total of 90 participants.  At the end of the 
study the null hypothesis would be rejected and concluded that the treatment is promising if at 
least 21 responders are observed in the total of 90 participants; otherwise, it will be concluded 
that the treatment is not promising in the overall population. The go/no-go criteria in Table 2 are 

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non-binding. In order to achieve 90 evaluable participants a total of approximately 110 
participants will be treated. 
In Table 15 the operating characteristics of the design are presented for different response rates 
using the BOP2 web application (BOP2 V1.4.8.0), which is available at 
http://www.trialdesign.org. 
Table 15. Operating characteristics 
Scenario 
Response Rate 
Early Stopping (%) 
Claim Promising (%) 
Average Sample Size 
1 
0.150 
43.25 
2.36 
68.4 
2 
0.175 
27.60 
9.53 
76.2 
3 
0.200 
16.13 
24.68 
81.9 
4 
0.225 
8.69 
46.04 
85.7 
5 
0.250 
4.33 
67.53 
87.8 
 
9.3. Analysis Populations 
● All Screened Population: all participants who signed the main study ICF to participate 
in the clinical study. Participants in this population will be used for screen failure 
summary. 
● The Intent-to-Treat (ITT) Population: all participants who were enrolled in the study 
and who received at least one dose of study treatment. This population will be the 
secondary population for the analysis of efficacy data. Any participant who receives a 
treatment number will be considered to have been enrolled. 
● The Response Evaluable Population: –all participants who received at least one dose 
of study treatment, who have an adequate baseline tumor assessment and at least one 
follow-up tumor assessment will be considered evaluable for anti-tumor efficacy 
using RECIST version 1.1 criteria. Participants who are treated and removed from 
study prior to on-study tumor assessment because of disease progression will be 
considered evaluable for efficacy and counted as failures. This population will be 
considered the primary population for the analysis of efficacy data. 
● The Safety Population will consist of all participants who took at least 1 dose of study 
treatment. 

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9.4. Statistical Analyses 
9.4.1. 
General Considerations  
All statistical analysis will be performed using SAS® version 9.4 or later, unless otherwise 
stated.  
Descriptive statistics (i.e., mean, standard deviation, median, minimum, maximum, etc.) will be 
provided for all continuous variables; frequencies and percentages will be tabulated for incidence 
and categorical variables and 95% CIs based on the Clopper-Pearson exact method provided as 
appropriate. For parameters measured over time, observed values and changes from baseline will 
be described for each time point. For time to event endpoints Kaplan-Meier estimates will be 
provided. 
The study will be monitored on an ongoing basis to permit the early decision to proceed to the 
end of the study. The formal futility decision will be made at the pre-specified interim analysis 
with less than 6 responders out of 40 patients. 
A Statistical Analysis Plan (SAP) describing statistical analyses in detail will be provided as a 
separate document. The SAP will be finalized prior to major analyses of the study. 
9.4.2. 
Primary Endpoints 
The primary endpoint ORR is defined as the proportion of participants with a confirmed CR or 
confirmed PR according to RECIST version 1.1 definitions, as assessed by the ICR. Confirmed 
responses are those that persist on repeat tumor assessments for at least 4 weeks after initial 
documentation of response. Otherwise, the participant will be counted as a non-responder in the 
assessment of ORR. The frequency and proportion of participants with ORR will be summarized 
for the response evaluable population as well as the safety population and 95% CI be calculated.  
Rates for CR and PR will also be presented in addition to ORR. As a secondary analysis the ORR 
based on non-confirmed responses will be presented as well. 
● Sensitivity analyses for ORR will be defined in the SAP to account for intercurrent events 
which can affect the availability of data for the ORR analysis or affect the interpretation of 
the results. 
9.4.3. 
Secondary Endpoints 
The first secondary endpoint considered is DOR as assessed by ICR and is defined as the time 
from the first documentation of objective tumor response (CR or PR) that is subsequently 
confirmed to the first documentation of objective tumor progression or to death due to any cause, 
whichever occurs first. Participants with ongoing response will be censored at time of data cut-off 
for the analysis. Kaplan-Meier estimates will be provided along with 95% CIs for the median DOR. 
These analyses will be presented for the ICR assessments as well as the investigator assessments. 

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For other secondary endpoints measured as frequencies and percentages will be presented as well 
with 95% CIs for the response evaluable population as well as the safety population for the 
following endpoints: 
● ORR as assessed by the investigator 
● CBR as assessed by ICR and investigator, defined as CR+PR+SD at 6- and 12 months  
● Intracranial response and control in participants with untreated measurable CNS lesions 
as assessed by ICR and investigator 
PFS is defined as the time from the first dose to the first progression of disease (PD) or death for 
any reason in the absence of documented PD. PFS will be summarized in the safety analysis set. 
PFS data will be censored on the date of the last tumor assessment on study for participants who 
do not have objective tumor progression and who do not die while on study. Participants lacking 
an evaluation of tumor response after enrollment will have their PFS time censored on the date of 
first dose with a duration of 1 day. Participants who are treated and removed from study prior to 
on-study tumor assessment because of disease progression will be considered evaluable for 
efficacy and counted as an event at the time of progression. Additionally, participants who start a 
new anti-cancer therapy prior to documented PD will be censored at the date of the last tumor 
assessment prior to the start of the new therapy. PFS (in months) will be calculated as (date of 
progression or death − date of first dose +1)/30.4.  PFS will be summarized for the response 
evaluable population as well as the safety population and 95% CI be calculated.  This analysis will 
be performed separately based on ICR assessment as well as the investigator assessment. Kaplan-
Meier estimates for PFS will be provided including median PFS, 6- and 12 months PFS together 
with 95% CIs. 
Sensitivity analyses will be defined in the SAP to account for intercurrent events which can affect 
the availability of data for the PFS analysis or affect the interpretation of the results. 
OS is defined as the time from the date of first dose of study medication to the date of death due 
to any cause. OS (in months) is calculated as (date of death − date of first dose +1)/30.4. For 
participants still alive at the time of the analysis, for those who are lost to follow-up, and those 
who withdraw consent for additional follow-up, the OS will be censored on the last date that 
participants were known to be alive. Participants lacking data beyond the first dose will have their 
OS censored at the date of first dose. Kaplan-Meier estimates for OS will be provided including 
median OS, 6- and 12 months OS together with 95% CIs. 
9.4.4. 
Exploratory Endpoints 
The changes from baseline in health-related quality of life (HRQoL) and symptoms as assessed 
by EORTC QLQ-C30 and EuroQol EQ-5D-3L will be analyzed for each timepoint by presenting 
descriptive statistics as mean, standard deviation, median, minimum, maximum. 
Exploratory statistical analyses of Biomarkers will be defined in the SAP. 
Niraparib plasma concentration-time data will be plotted and summarized (if appropriate) by 
planned time point. Niraparib plasma concentration-time data may be combined with data from 
other studies and analyzed using a population PK approach. Summary exposure measures (e.g., 
maximum concentration [Cmax], area under the concentration-time curve [AUC]) may also be 

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computed. Results of this analysis may be provided in a separate report. If deemed appropriate 
and if data permit, exposure-response relationships between niraparib exposure (e.g., dose, 
Cmax, or AUC) and clinical activity and/or toxicity (e.g., response, safety event, biomarkers) 
may be explored using population methods. 
9.4.5. 
Safety Analyses 
The safety analyses are described in Table 16. All safety analyses will be performed on the 
Safety Population. 
Table 16. Statistical Analytical Methods - Safety 
Endpoint 
Statistical Analysis Methods 
Secondary 
AEs: All AEs, whether serious or non-serious, will be reported from the start of 
treatment until 30 days after the last dose of study treatment, until the participant 
withdraws consent for study participation, or until the participant starts subsequent 
anticancer treatment, whichever occurs first. AEs will be recorded using standard 
medical terminology and graded according to the NCI-CTCAE v5.0. For AE reporting, 
the verbatim term used in the eCRF by Investigators to identify AEs will be coded using 
the latest version of MedDRA coding dictionary. 
AEs and SAEs will be summarized by frequency and proportion of total participants, by 
system organ class and preferred term. Separate summaries will be given for all AEs, 
common (>5%) AEs, and AESIs. 
The incidence of deaths and the primary cause of death will be summarized. 
 
Additional summaries will be provided for treatment-related AEs and AEs leading to 
dose reduction, interruption, an/or discontinuation of study treatment. AEs, if listed in 
the NCI-CTCAE v5.0, will be summarized by the maximum grade. 
Clinical laboratory evaluation: The evaluation of clinical laboratory tests will focus on 
selected laboratory analytes from the hematology and blood chemistry panel and will 
include the toxicity grading by NCI-CTCAE. The worst-case toxicity grade in 
hematology and chemistry result during the treatment will be summarized 
Descriptive statistics (mean, standard deviation, median, range) will be used to 
summarize change from baseline in observed value at each scheduled visit. 
 
Other Safety Measures: Data for ECG and vital signs will be summarized. For 
continuous variables, these summaries will include sample size, mean, median, standard 
deviation, minimum, and maximum. These summary statistics will be provided for 
absolute values as well as change from baseline.  For categorical variables, the 
summaries will include frequencies and corresponding percentages. Details will be 
provided in the SAP. 
 
Abbreviations: AE=adverse event; AESI=adverse event of special interest; eCRF=electronic case report form; NCI-
CTCAE v5.0=National Cancer Institute - Common Terminology Criteria for Adverse Events version 5.0; 
SAE=serious adverse event; SAP=Statistical Analysis Plan. 
Abbreviations: cum.=cumulative; HR=hazard ratio; IA=interim analysis; OS=overall survival; PFS=progression-
free survival.

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
The Regulatory and ethical considerations of the study are outlined in Appendix 1. 
11. 
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12. 
APPENDICES 
Appendix 1. 
REGULATORY, ETHICAL, AND STUDY CONSIDERATIONS 
This study will be conducted in accordance with the protocol and with: 
● Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
● Applicable ICH Good Clinical Practice (GCP) Guidelines 
● Applicable laws and regulations 
● The protocol, protocol amendments, ICFs, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will comply with  health 
authority requirements.  
● The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC 
− Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local 
regulations 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 

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Informed Consent Process 
● The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
● Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent which meets the requirements of 21 
CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. 
● The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 
● A copy of the ICF(s) must be provided to the participant. 
TEMPUS (alone or working with others) may use participant’s coded study data and samples 
and other information to carry out this study, understand the results of this study, learn more 
about the study treatments or about the study disease, publish the results of these research efforts, 
and work with government agencies or insurers to have the study treatments approved for 
medical use or approved for payment coverage. 
The ICF contains a section that addresses the use of participant data and remaining samples for 
further research, as approved by the IRB. The Investigator or authorized designee will inform 
each participant of the possibility of further research not related to the study/disease. In 
accordance with the IRB approved ICF, participants may be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the storage 
period. The participant’s decision to participate in further research will be indicated in the ICF. 
Sponsor will notify GSK in the event consent is withheld by a participant. 
 
Data Protection 
● Participants will be assigned a unique identifier by the Sponsor. Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier. 
● The participant must be informed that his/her personal study-related data will be used 
by the Sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant, who will be required to give consent for 
their data to be used as described in the informed consent. 
● The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 

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Secondary Use of Biospecimens  
Tempus (or people or companies working with Tempus) will store the biomarker and exploratory 
research samples in a secure storage space with adequate measures to protect confidentiality. The 
samples will be retained while research on niraparib (or drugs of this class) or this disease and 
related conditions continues but may be destroyed 20 years after study completion. Some portion 
of samples may remain after their use in the study. Tempus may use or direct use of these 
residual samples for secondary use, such as validation, bridging studies, and other purposes to 
the extent permitted by applicable law. 
 
Reporting Product Complaints for GSK Products 
Any written, electronic or oral communication that alleges dissatisfaction related to 
manufactured clinical drug product with regards to its manufacturing, testing, labeling, 
packaging, or shipping, must be reported by the Sponsor Institution or qualified designee to GSK 
within 1 working day of first becoming aware of the possible defect to 
. The product and packaging components in question, if available, must 
be stored in a secure area under specified storage conditions until it is determined whether the 
product is required to be returned for investigation of the defect.  If the product complaint is 
associated with an SAE, the SAE must be reported separately in accordance with the protocol, 
and the SAE report should mention the product quality complaint. 
 
Data Quality Assurance 
● All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
● Quality tolerance limits (QTLs) will be predefined in the Study Manual to identify 
systematic issues that can impact participant safety and/or reliability of study results. 
These pre-defined parameters will be monitored during the study and deviations from 
the QTLs and remedial actions taken will be summarized in the CSR. 
● The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
● Monitoring details describing strategy including definition of study critical data items 
and processes (eg, risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, or on-site monitoring) are provided 
in the Monitoring Plan. 
● The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Detailed information about the study data 
collection and management process, including systems used, can be found in the 
study Data Management Plan. 

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● The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations [CROs]). 
● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the Investigator for 25 years from the issue of the final 
CSR/equivalent summary unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of the Sponsor. No records may be transferred to another 
location or party without written notification to the Sponsor. 
Source Documents 
● Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site. 
● Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
● The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
● Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site Termination 
Tempus or designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of Tempus. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
For study termination: 

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● Discontinuation of further study treatment development 
For site termination: 
● Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
● Inadequate or no recruitment of participants (evaluated after a reasonable amount of 
time) by the Investigator 
● If the study is prematurely terminated or suspended, the Sponsor shall promptly 
inform the Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) 
used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up 
Publication Policy 
● Subject to the terms of the applicable study agreement, the results of this study may 
be published or presented at scientific meetings. If this is foreseen, the Investigator 
agrees to submit all manuscripts or abstracts to the Sponsor in accordance with the 
terms of the applicable study agreement. Review allows the Sponsor to protect 
proprietary information and to provide comments. 
● The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 

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Appendix 3. 
CONTRACEPTION GUIDELINES 
Definitions 
A woman in either of the following categories is considered a woman of childbearing potential 
(WOCBP) (fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently sterile 
(see below) 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
● A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
● Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Permanent sterilization methods (for the purpose of this study) include: 
● Documented hysterectomy 
● Documented bilateral salpingectomy 
● Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator discretion 
should be applied to determining study entry. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study treatment, additional evaluation should be considered. 

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Abbreviations: CTFG=Clinical Trial Facilitation Group; IUD=intrauterine device; IUS=intrauterine 
hormone-releasing system; LAM=lactational amenorrhea method. 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM are not acceptable methods of contraception for this study. Male 
condom and female condom should not be used together (due to risk of failure with friction). 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from 
those when used consistently and correctly. 
c Male condoms must be used in addition to hormonal contraception. If locally required, in accordance 
with CTFG guidelines, acceptable contraceptive methods are limited to those that inhibit ovulation as the 
primary mode of action. 

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Appendix 4. 
LIVER SAFETY REQUIRED ACTIONS AND FOLLOW-UP ASSESSMENTS 
Phase III to IV liver chemistry stopping, and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the United States 
Food and Drug Administration’s premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM174090.pdf). 
Table 18. Phase III-IV Liver Chemistry Stopping Criteria and Required Follow-up 
Assessments  
Liver Chemistry Stopping Criteria –Liver Stopping Event 
Participant with entry criteria ALT≤2.5×ULN 
ALT-absolute 
ALT ≥8×ULN 
ALT Increase 
ALT ≥5×ULN but <8×ULN persists for ≥2 weeks 
ALT ≥3×ULN but <5×ULN persists for ≥4 weeks 
Bilirubina,b 
ALT ≥3×ULN and bilirubin ≥2×ULN (>35% direct bilirubin)  
INRb 
ALT ≥3×ULN and INR >1.5, if INR measured 
Cannot Monitor 
ALT ≥5×ULN but <8×ULN and cannot be monitored weekly for ≥2 weeks 
ALT ≥3×ULN but <5×ULN and cannot be monitored weekly for ≥4 weeks 
Symptomaticc 
ALT ≥3×ULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
Including participants with documented liver metastases/tumor infiltration at baseline and entry criteria 
ALT>2.5×ULN but ≤5×ULN 
ALT-absolute 
Both ALT ≥8×ULN and ≥2×baseline value 
ALT Increase 
Both ALT ≥3×ULN and ≥1.5×baseline value that persists for ≥4 weeks 
Bilirubina,b 
ALT ≥3×ULN and bilirubin ≥2×ULN (>35% direct bilirubin)  
INRb 
ALT ≥3×ULN and INR >1.5, if INR measured 
Cannot Monitor 
Both ALT ≥3×ULN and ≥1.5×baseline value and cannot be monitored weekly 
for ≥4 weeks 
Symptomaticc 
Both ALT ≥3×ULN and ≥1.5×baseline value associated with symptoms (new 
or worsening) believed to be related to liver injury or hypersensitivity 

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Table 19. Phase III-IV Liver Chemistry Stopping Criteria and Required Follow-up 
Assessments (Continued) 
Required Actions and Follow up Assessments following Any Liver Stopping Event 
Actions 
Follow Up Assessments 
● Immediately discontinue study treatment  
● Report the event to Sponsor within 24 hours 
● Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAEb 
● Perform liver event follow up assessments  
● Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below) 
● Do not restart/rechallenge participant with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted 
● If restart/rechallenge not allowed or not 
granted, permanently discontinue study 
treatment and may continue participant in the 
study for any protocol specified follow up 
assessments  
MONITORING: 
For bilirubin or INR criteria:  
● Repeat liver chemistries (include ALT, AST, 
ALP, bilirubin) and perform liver event 
follow up assessments within 24 hours 
● Monitor participants twice weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline 
● A specialist or hepatology consultation is 
recommended 
For all other criteria:  
● Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
to 72 hours 
● Monitor participants weekly until liver 
chemistries resolve, stabilize, or return to 
within baseline 
● Viral hepatitis serologyd 
● Only in those with underlying chronic hepatitis 
B at study entry (identified by positive hepatitis 
B surface antigen) quantitative hepatitis B DNA 
and hepatitis delta antibodye 
● Blood sample for PK analysis, obtained within 3 
hours (±15 minutes) after last dosef 
● Serum CPK and LDH 
● Fractionate bilirubin, if total bilirubin ≥2×ULN 
● Obtain complete blood count with differential to 
assess eosinophilia 
● Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on 
the AE report form 
● Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications. 
● Record alcohol use on the liver event alcohol 
intake case report form 
For bilirubin or INR criteria: 
● Antinuclear antibody, antismooth muscle 
antibody, Type 1 antiliver kidney microsomal 
antibodies, and quantitative total 
immunoglobulin G (IgG or gamma globulins). 
● Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution 
to liver injury in participants with definite or 
likely acetaminophen use in the preceding week 
(James, 2009)).  
● Liver imaging (ultrasound, MRI, or CT) and/or 
liver biopsy to evaluate liver disease; complete 
Liver Imaging and/or Liver Biopsy eCRF forms. 
 

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Abbreviations: AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; CPK=serum creatine phosphokinase; eCRF=electronic case report 
form; CT=computed tomography; GSK=GlaxoSmithKline; HPLC=high performance liquid 
chromatography; IgG=immunoglobulin G; IgM=immunoglobulin M; INR=international normalized ratio; 
LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PCR=polymerase chain reaction; 
PK=pharmacokinetics; SAE=serious adverse event; SM=Study Manual; ULN=upper limit of normal. 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation 
is not immediately available, discontinue study treatment for that participant if ALT ≥3×ULN and 
bilirubin ≥2×ULN. Additionally, if serum bilirubin fractionation testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
b All events of ALT ≥3×ULN and bilirubin ≥2×ULN (>35% direct bilirubin) or ALT ≥3×ULN and 
INR>1.5, if INR measured, which may indicate severe liver injury (possible “Hy’s Law”), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not 
required, and the threshold value stated will not apply to participants receiving anticoagulants. 
c New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as 
fever, rash, or eosinophilia). 
d Includes: Hepatitis A IgM antibody, hepatitis B surface antigen, hepatitis B core antibody (IgM), 
hepatitis C RNA, cytomegalovirus IgM antibody, Epstein-Barr viral capsid antigen IgM antibody (or if 
unavailable, obtain heterophile antibody or monospot testing), and hepatitis E IgM antibody. 
e If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR assay of hepatitis D 
RNA virus (where needed) (Le Gal, 2005). 
f Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 
prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated or a PK sample 
cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SRM. 

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Table 20. Phase III-IV Liver Chemistry Increased Monitoring Criteria with Continued 
Therapy  
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
Participant with entry criteria ALT≤2.5×ULN: 
ALT ≥5×ULN and <8×ULN and bilirubin 
<2×ULN without symptoms believed to be 
related to liver injury or hypersensitivity, and 
who can be monitored weekly for 2 weeks 
or 
ALT ≥3×ULN and <5×ULN and bilirubin 
<2×ULN without symptoms believed to be 
related to liver injury or hypersensitivity, and 
who can be monitored weekly for 4 weeks 
Participant with documented liver 
metastases/tumor infiltration at baseline AND 
entry criteria ALT >2.5×ULN but ≤5×ULN: 
ALT ≥3×ULN and ≥1.5×baseline value but 
ALT <8×ULN and 2×baseline value and 
bilirubin <2×ULN without symptoms believed 
to be related to liver injury or hypersensitivity, 
and who can be monitored weekly for 4 weeks 
 
Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss participant 
safety 
Participant can continue study treatment  
Participant must return weekly for repeat liver 
chemistries (ALT, AST, ALP, bilirubin) until they 
resolve, stabilize or return to within baselinea  
If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above 
For participant with entry criteria ALT≤2.5×ULN: 
If ALT decreases from ALT ≥5×ULN and <8×ULN 
to ≥3×ULN but <5×ULN, continue to monitor liver 
chemistries weekly 
If, after 4 weeks of monitoring, ALT <3×ULN and 
bilirubin <2×ULN, monitor participants twice 
monthly until liver chemistries normalize or return to 
within baseline 
For participants with documented liver 
metastases/tumor infiltration at baseline and entry 
criteria ALT >2.5×ULN but ≤5×ULN: 
If, after 4 weeks of monitoring, ALT <3×ULN and 
<1.5× baseline value, and bilirubin <2×ULN, 
monitor participants twice monthly until liver 
chemistries normalize or return to within baselinea 
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; GSK=GlaxoSmithKline; ULN=upper limit of normal. 
a For the purpose of these guidelines, “baseline” refers to laboratory assessments performed closest and 
prior to first dose of study treatment. 

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Appendix 5. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 21. Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
β-hCG   
beta-human chorionic gonadotropin 
AE 
adverse event 
AESI 
adverse event of special interest 
AJCC 
American Joint Committee on Cancer 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
aPTT 
 activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ICR 
independent central review 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
BM 
brain metastases 
BOP2 
Bayesian Optimal Phase 2 
BP 
blood pressure 
BRCA 
breast cancer susceptibility gene 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CI 
confidence interval 
CLCr 
creatinine clearance 
CNS 
central nervous system 
CO2 
carbon dioxide 
CPK 
serum creatine phosphokinase 
CR 
complete response 
CRF 
case report form  
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT 
computed tomography 

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CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
cardiovascular event 
CYP 
cytochrome P450 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC QLQ-C30 
European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire 30-item Core module  
EOT 
End-of-Treatment 
EQ-5D-3L 
European Quality of Life 5-Dimensions 3-Level Scale 
EU 
European Union 
FDA 
(United States) Food and Drug Administration 
FFPE 
formalin-fixed, paraffin-embedded 
FT4 
free thyroxine 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
HR 
hazard ratio 
HRD (pos) 
homologous recombination deficiency (positive) 
HRQoL 
health-related quality of life 
HPLC 
high performance liquid chromatography 
IA 
interim analysis  
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG4 
immunoglobulin G4 
IMP 
investigational medicinal product 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
intravenous 
LDH 
lactate dehydrogenase 
mAb 
monoclonal antibody 
MDS 
myelodysplastic syndrome 

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MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NA 
not applicable 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for 
Adverse Events 
NGS 
Next Generation Sequencing  
ORR 
objective response rate 
OS 
overall survival 
PARP 
poly (adenosine diphosphate-ribose) polymerase 
PALB2 
partner and localizer of BRCA2 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PK 
pharmacokinetics 
PFS 
progression-free survival 
PR 
partial response 
PRES 
Posterior Reversible Encephalopathy Syndrome 
PRO 
patient-reported outcome 
PRO-CTCAE 
Patient-Reported Outcomes version of the Common Term 
Criteria for Adverse Events 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QoL 
quality of life 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SM 
Study Manual  
SoA 
Schedule of Activities 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event 
tPALB2  
tumor partner and localizer of BRCA2 
TTP 
time to progression 
ULN 
upper limit of normal 

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US 
United States 
WBC  
white blood count 
WOCBP 
woman of childbearing potential 
Appendix 6. 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS V1.1 
Response Criteria by RECIST v1.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered 
progressions.) 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Not Applicable (NA): No target lesions at baseline. 
Not Evaluable (NE): Cannot be classified by one of the 5 preceding definitions. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s). 
Progressive Disease (PD): Appearance of 1 or more new lesions and/or unequivocal progression 
of existing non-target lesions. A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to quality for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 
NA: No non-target lesions at baseline. 
NE: Cannot be classified by one of the 5 preceding definitions. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression (taking as reference for PD the smallest measurements recorded since the treatment 
started). The participant's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 

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Table 22. Evaluation of Response for Participants with Measurable Disease (ie, Target 
Disease) 
Target Lesions 
Non-Target Lesions 
New Lesionsa 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required 
CR 
CR or NA 
No 
CR 
>4 weeks confirmationb 
CR 
Non-CR/Non-PD or 
NE 
No 
PR 
>4 weeks confirmationb 
CR 
NE 
No 
PR 
PR 
Non-CR/Non-PD/NE No 
PR 
SD 
Non-CR/Non-PD/NE No 
SD 
Documented at least once 
>4 weeks from baselineb 
NE 
Non-CR/Non-PD or 
NA 
No 
NE 
 
PD 
Any 
Yes or No 
PD 
No prior SD, PR, or CR 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR=complete response; NA=not applicable; NE=not evaluable; PD=progressive disease; PR=partial 
response; RECIST v1.1=Response Evaluation Criteria in Solid Tumors version 1.1; SD=stable disease. 
Note: Participants who are CR following standard of care induction treatment (at baseline) will be assigned a status 
of “no disease” or “NA,” and evidence of any new lesion at a follow-up time point will constitute PD. Participants 
with a global deterioration of health status requiring discontinuation of treatment without objective evidence of 
disease progression at that time should be reported as “symptomatic deterioration.” Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
a See RECIST v1.1 manuscript for further details on what is evidence of a new lesion. 
b Only for non-randomized studies with response as primary endpoint. 
 
Table 23. Evaluation of Response for Participants with Non-Measurable Disease (ie, Non-
Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
NE 
No 
not evaluated 

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Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
Abbreviations: CR=complete response; NE=not evaluable; PD=progressive disease; SD=stable disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target disease since SD is increasingly 
used as an endpoint for assessment of efficacy in some studies so to assign this category when no lesions 
can be measured is not advised. 
Duration of Response (DOR) 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or PD is objectively documented (taking as reference for PD the smallest measurements 
recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that PD is objectively documented. 

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Appendix 7. 
PATIENT-REPORTED OUTCOMES 
EORTC QLQ-C30 
The EORTC QLQ-C30 was developed to assess the quality of life of patients with cancer, and it 
is the most widely used cancer-specific, health-related quality of life (HRQoL) instrument. 
The EORTC QLQ-C30 is a 30-item questionnaire used to measure HRQoL in participants with 
cancer; it has been translated and validated in over 100 languages and has been used in more 
than 3,000 studies worldwide (http://groups.eortc.be/qol/eortc-qlq-c30). The EORTC QLQ-C30 
is composed of both multi-item scales and single-item measures. These include 5 functional 
scales (Physical functioning, Role functioning, Emotional functioning, Cognitive functioning, 
and Social functioning), 3 symptom scales (Fatigue, Nausea and vomiting, and Pain), 6 single 
items (Dyspnea, Insomnia, Appetite loss, Constipation, Diarrhea, and Financial difficulties), and 
a global health status/HRQoL scale. The EORTC QLQ-C30 employs a 1-week recall period for 
all items and a 4-point scale for the functional and symptom scales/items with response 
categories of “Not at all,” “A little,” “Quite a bit,” and “Very much.” The 2 items assessing 
global health status/quality of life utilize a 7-point scale ranging from 1 (“Very Poor”) to 7 
(“Excellent”) (Aaronson, 1993). 
 
EuroQol Questionnaire (EQ-5D-3L) 
The EQ-5D-3L is a standardized instrument for use as a measure of health utility. It is designed 
for self-completion or interview administration and is cognitively simple, taking only a few 
minutes to complete. 
The EQ-5D-3L self-assessment questionnaire has 2 parts. The first part consists of 5 items 
covering 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). Each dimension is measured by a 3-point Likert scale (no problems, some 
or moderate problems, and unable or extreme problems). Participants are asked to choose one 
level that reflects their "own health state today" for each of the 5 dimensions. Participants can be 
then classified into 1 of 243 distinct health states. The second part is a 20-cm visual analogue 
scale (EQ-VAS) that has endpoints labelled "best imaginable health state" and "worst imaginable 
health state" anchored at 100 and 0, respectively. 
The EQ-5D-3L will provide data for use in economic models and analyses including developing 
health utilities or quality-adjusted life-years. The EQ-5D-3L will be completed by participants 
last after completing all other PRO assessments. 
 

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Appendix 8. 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS 
Table 24. ECOG Performance Status Grading 
Description 
Grade 
Fully active, able to carry on all pre-disease performance without restriction 
0 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (ie, light house work, office work). 
1 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
4 
Dead 
5 
Source: (Oken, 1982) 
Abbreviation: ECOG=Eastern Cooperative Oncology Group. 
Appendix 9. 
ESTIMATION OF CREATININE CLEARANCE WITH THE COCKCROFT-GAULT 
FORMULA 
The Cockcroft-Gault formula is a commonly used equation for calculating estimated creatinine 
clearance (CLCr) and employs creatinine measurements and a participant’s weight (in kilograms) 
to predict the clearance (Cockcroft, 1976). As estimated by the Cockcroft-Gault equation, mild 
renal impairment is considered CLCr of 60 to 89 mL/min and moderate renal impairment is 
considered CLCr of 30 to 59 mL/min. 
Table 25. Cockcroft-Gault Formula for Serum Creatinine Clearance 
Serum Creatinine 
Units 
Formula 
mmol/L 
(Q × (140 - age [years]) × actual body weight [kg]a) ÷ (48816 × serum creatinine 
[mmol/L]) 
mg/dL 
(Q × (140 - age [years]) × actual body weight [kg]a) ÷ (72 × serum creatinine 
[mg/dL]) 
Note: Q=0.85 for females, Q=1.0 for males. 
a Calculation of ideal body weight using the Devine formula (McCarron, 1974) as follows: 
Male participants: 50.0 kg + (2.3 kg × each inch over 5 feet) or 50.0 kg + (0.906 kg × each cm over 152.4 
cm) 

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Female participants: 45.5 kg + (2.3 kg × each inch over 5 feet) or 45.5 kg + (0.906 kg X each cm over 
152.4 cm) 
If a participant is below ideal body weight, use actual body weight in the calculation to estimate CLCr. 
If a participant is obese (>30% over ideal body weight), use ideal body weight in the calculation to 
estimate CLCr. For example, for a male participant with actual body weight of 90.0 kg and height of 68 
inches, the calculation is as follows: 
Ideal body weight=50.0 kg + (2.3 kg × (68 - 60))=68.4 kg 
This participant’s actual body weight is >30% over ideal body weight. In this case, the participant’s ideal 
body weight of 68.4 kg should be used in calculating estimated CLCr. 
Appendix 10. 
DOSAGE ADJUSTMENTS FOR ADVERSE REACTIONS 
Table 26. Recommended Dose Modifications for Adverse Reactions 
Starting Dose Level 
200 mg 
300 mg 
First dose reduction 
100 mg/daya 
(one 100-mg capsule) 
  
200 mg/day 
(two 100-mg capsules) 
Second dose reduction 
Discontinue niraparib. 
100 mg/daya 
(one 100-mg capsule) 
  
a If further dose reduction below 100 mg/day is required, discontinue niraparib. 
  
Table 27. Dose Modifications for Non-Hematologic Adverse Reactions 
Non-hematologic CTCAE ≥Grade 3 
adverse reaction that persists despite 
medical management 
• Withhold niraparib for a maximum of 
28 days or until resolution of adverse 
reaction. 
• Resume niraparib at a reduced dose per 
Table 26. 
CTCAE ≥Grade 3 treatment-related adverse 
reaction lasting more than 28 days while 
patient is administered niraparib 100 
mg/day 
Discontinue niraparib. 
CTCAE = Common Terminology Criteria for Adverse Events. 
  
Table 28. Dose Modifications for Hematologic Adverse Reactions 

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Monitor complete blood counts weekly for the first month, monthly for the next 11 
months of treatment, and periodically after this time. 
Platelet count <100,000/mcL 
First occurrence: 
• Withhold niraparib for a maximum of 28 
days and monitor blood counts weekly until 
platelet counts return to ≥100,000/mcL. 
• Resume niraparib at same or reduced dose 
per Table 26. 
• If platelet count is <75,000/mcL, resume 
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/mcL. 
• Resume niraparib at a reduced dose per 
Table 26. 
• Discontinue niraparib if the platelet count 
has not returned to acceptable levels within 
28 days of the dose interruption period or if 
the patient has already undergone dose 
reduction to 100 mg once daily.a 
Neutrophil <1,000/mcL or hemoglobin <8 
g/dL 
• Withhold niraparib for a maximum of 28 
days and monitor blood counts weekly until 
neutrophil counts return to ≥1,500/mcL or 
hemoglobin returns to ≥9 g/dL. 
• Resume niraparib at a reduced dose per 
Table 26. 
• Discontinue niraparib if neutrophils and/or 
hemoglobin have not returned to acceptable 
levels within 28 days of the dose 
interruption period or if the patient has 
already undergone dose reduction to 100 
mg once daily.a 

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Hematologic adverse reaction requiring 
transfusion 
• For patients with platelet count 
≤10,000/mcL, platelet transfusion should be 
considered. If there are other risk factors 
such as coadministration of anticoagulation 
or antiplatelet drugs, consider interrupting 
these drugs and/or transfusion at a higher 
platelet count. 
• Resume niraparib at a reduced dose. 
a If myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) is confirmed, 
discontinue niraparib.