Niraparib Plus Carboplatin in Patients With Homologous Recombination Deficient Advanced Solid Tumor Malignancies
Phase: PHASE1
Conditions: Solid Tumor, Adult, Homologous Recombination Deficiency
Sponsor: Georgetown University

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Niraparib Plus Carboplatin in Patients with Homologous 
Recombination Deficient Advanced Solid Tumor Malignancies 
 
Georgetown Protocol #:   
2017-0085 (CRC #112016-01) 
Clinicaltrials.gov #: 
 
NCT03209401 
Initial Protocol Version Date:  
Version 1.0, 10/20/2016 
 
Amended Version Dates: 
Version 1.1 (Amendment 1), 12/16/2016 
 
  
 
 
 
Version 1.2 (Amendment 2), 02/09/2017 
 
  
 
 
 
Version 1.3 (Amendment 3), 06/10/2017 
 
  
 
 
 
Version 1.4 (Amendment 4), 09/24/2017 
 
  
 
 
 
Version 1.5 (Amendment 5), 06/18/2018 
 
  
 
 
 
Version 1.6 (Amendment 6), 08/17/2020 
 
Version 2.0 (Amendment 7), 07/26/2021 
 
Version 2.1 (Amendment 8), 08/08/2022 
 
Version 3.0 (Amendment 9), 07/03/2023 
 
Principal Investigator (PI): 
Claudine Isaacs, MD 
 
  
 
 
 
Lombardi Comprehensive Cancer Center 
 
  
 
 
 
Georgetown University Medical Center 
3800 Reservoir Road, NW 
Washington, DC 20057 
Telephone (202) 444-3677 
Fax (202) 444-1229 
E-Mail: isaacsc@georgetown.edu 
 
Study Chair(s): 
 
 
Michael Pishvaian, MD, PhD 
 
  
 
 
 
E-Mail: mpishva1@jhmi.edu 
 
 
Arielle Heeke, MD 
 
  
 
 
 
Levine Cancer Institute 
 
Carolinas Healthcare System  
 
  
 
Correlative Science PI:  
Jonathan Brody, PhD 
 
  
 
 
 
Oregon Health and Science University (OHSU) 
E-Mail: brodyj@ohsu.edu 
 
  
 
Biostatistician: 
 
 
Hongkun Wang, PhD 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
Funding Sources: 
 
GlaxoSmithKline (GSK) 
Study Drug: 
 
 
Niraparib capsule 
IND Number: 
 
 
132931 
Clinical Phase: 
 
 
Ia/Ib 
Number of Subjects: 
 
18-146 
 
 

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The study will be conducted according to the protocol and in compliance with Good Clinical Practice 
 
(GCP), with the Declaration of Helsinki, and with other applicable regulatory requirements including 
 
but not limited to Institutional Review Board/Ethics Committee (IRB/EC) approval. 
 
 
 
Confidentiality Statement 
 
All information contained in this document is privileged and confidential. Any distribution, 
 
copying, or disclosure is strictly prohibited without prior written approval by the Sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
 
Title: Niraparib Plus Carboplatin in Patients with Homologous Recombination Deficient Advanced Solid Tumor 
Malignancies  
 
 
 
 
This study protocol was subjected to critical review and has been approved by the Sponsor. The information it 
contains is consistent with the current risk/benefit evaluation of the investigational product as well as with the 
moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki and 
the guidelines on Good Clinical Practice. 
 
 
 
_____________________________________ _____________________ 
Claudine Isaacs, MD                                           Date 
Lombardi Comprehensive Cancer Center 
Georgetown University Medical Center 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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INVESTIGATOR SIGNATURE PAGE 
 
Declaration of the Investigator 
 
Title: Niraparib Plus Carboplatin in Patients with Homologous Recombination Deficient Advanced Solid Tumor 
Malignancies  
 
 
 
 
I have read this study protocol, including all appendices. By signing this protocol, I agree to conduct the clinical 
study, following approval by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), in 
accordance with the study protocol, the current International Conference on Harmonisation (ICH) Guideline for 
Good Clinical Practice (GCP), and applicable regulatory requirements. I will ensure that all personnel involved 
in the study under my direction will be informed about the contents of this study protocol and will receive all 
necessary instructions for performing the study according to the study protocol. 
 
 
 
 
_____________________________________ ______ 
 
_______________ 
Investigator Name:  
 
                                           
 
 Date 
Site Name: 
 
 
 
 
 

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TABLE OF CONTENTS 
 
 
 
 
 
 
 
          Page 
Table of Contents 
 
 
 
 
 
 
 
 
 
 
5 
Figures and Tables  
 
 
 
 
 
 
 
 
 
7 
Glossary of Abbreviations and Definition of Terms 
 
 
 
 
 
8 
Study Synopsis 
 
 
 
 
 
 
 
 
 
 
10 
1.0  Background and Justification  
 
 
 
 
 
 
 
20 
1.1 DNA Repair 
 
 
 
 
 
 
 
 
 
20 
1.2 Homologous Recombination Defects 
 
 
 
 
 
 
20 
1.3 PARP inhibition 
 
 
 
 
 
 
 
 
 
23 
 
1.3.1 PARP Inhibition in Breast Cancer 
 
 
 
 
 
23 
 
1.3.2 PARP Inhibition in Ovarian Cancer 
 
 
 
 
 
24 
 
1.3.3 PARP Inhibition in Other Malignancies  
 
 
 
 
24 
 
1.3.4 PARP Inhibition Effect on Homologous Recombination 
 
 
24 
 
1.3.5 PARP Inhibition in Addition to Chemotherapy  
 
 
 
24 
 
1.3.6 PARP Inhibition Resistance 
 
 
 
 
 
 
25 
1.4 Niraparib Activity and Pharmacokinetic Profile  
 
 
 
 
25 
 
1.4.1 Niraparib Overview 
 
 
 
 
 
 
 
25 
 
1.4.2 Niraparib in vitro Pharmacology 
 
 
 
 
 
26 
 
1.4.3 Niraparib in vivo Pharmacology 
 
 
 
 
 
26 
 
 
1.4.4 Non-Clinical Pharmacokinetics and Metabolism 
 
 
 
27 
 
1.4.5 Human Pharmacokinetics, Metabolism and Efficacy  
 
 
27 
1.4.6 Safety Pharmacology and Toxicity 
 
 
 
 
 
29 
1.5 Carboplatin 
 
 
 
 
 
 
 
 
 
30 
 
1.5.1 Carboplatin Pharmacokinetics  
 
 
 
 
 
30 
 
1.5.2 Human Efficacy and Safety of Carboplatin 
 
 
 
 
31 
1.6 Rationale for the Current Study  
 
 
 
 
 
 
31 
2.0  Study Objectives 
 
 
 
 
 
 
 
 
 
32 
 
2.1 Primary Objectives 
 
 
 
 
 
 
 
 
32 
 
2.2 Secondary Objectives 
 
 
 
 
 
 
 
 
32 
 
2.3 Indication  
 
 
 
 
 
 
 
 
 
32 
3.0  Subject Population 
 
 
 
 
 
 
 
 
 
33 
3.1 Subject Population, Number of Subjects, and Feasibility 
 
 
 
33 
 
3.2 Inclusion Criteria  
 
 
 
 
 
 
 
 
33 
3.3 Exclusion Criteria  
 
 
 
 
 
 
 
 
35 
3.4 Additional Study Restrictions 
 
 
 
 
 
 
 
36 
3.5 Other Prior and Concomitant Therapy 
 
 
 
 
 
 
37 
3.6 Removal/Replacement of Subjects from Therapy or Assessment 
 
 
38 
3.7 Multi-Institutional Trial Coordination 
 
 
 
 
 
 
39 
4.0  Study Procedures: Molecular Assessment and Treatment Assignment  
 
40 
4.1 Study Overview 
 
 
 
 
 
 
 
 
 
40 
 
4.1.1 Phase Ia Procedures 
 
 
 
 
 
 
 
41 
 
 
4.1.1.1 Alternative Schedules 
 
 
 
 
 
42 
 
4.1.2 Phase Ib Procedures 
 
 
 
 
 
 
 
44 
4.2 Patient Screening and Enrollment 
 
 
 
 
 
 
45 
4.3 Treatment Assignment and Tumor Assessment  
 
 
 
 
46 
4.4 Detailed Patient Assessments 
 
 
 
 
 
 
 
49 
5.0  Dosages and Dispensation of Drugs  
 
 
 
 
 
 
69 
 
5.1 Dispensation of Study Drugs and Treatments Administered 
 
 
 
69 
 
5.2 Packaging and Labeling of Niraparib 
 
 
 
 
 
 
69 
 
5.3 Storage and Disposition of Niraparib and Carboplatin 
 
 
 
 
69 
5.4 Treatment Compliance 
 
 
 
 
 
 
 
 
70 
5.5 Drug Accountability 
 
 
 
 
 
 
 
 
70 
5.6 Selection of Doses in the Study (Niraparib Investigator’s Brochure) 
 
 
70 
5.7 Carboplatin Dosing 
 
 
 
 
 
 
 
 
70 
6.0  Safety Variables and Toxicity Assessment  
 
 
 
 
 
71 

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6.1 Adverse Events Assessment 
 
 
 
 
 
 
 
71 
6.2 Study Monitoring  
 
 
 
 
 
 
 
 
71 
6.3 Adverse Event and Toxicity Definitions  
 
 
 
 
 
72 
 
6.4 Adverse Event Collection Period  
 
 
 
 
 
 
74 
6.5 Adverse Event Reporting  
 
 
 
 
 
 
 
75 
6.6 Reporting Product Quality Complaints for Niraparib 
 
 
 
 
75 
6.7 Pregnancy 
 
 
 
 
 
 
 
 
 
75 
6.8 Potential Risks of Niraparib 
 
 
 
 
 
 
 
76 
 
 
6.9 Toxicity Management and Dose Adjustments 
 
 
 
 
 
76 
6.10 General Management of Significant Toxicities  
 
 
 
 
78 
 
 
7.0  Measurement of Effect  
 
 
 
 
 
 
 
 
84 
7.1 Definitions  
 
 
 
 
 
 
 
 
 
84 
7.2 Methods of Measurement 
 
 
 
 
 
 
 
84 
7.3 Response Criteria  
 
 
 
 
 
 
 
 
85 
7.4 Evaluation of Best Overall Response 
 
 
 
 
 
 
85 
7.5 Definition of Disease Progression 
 
 
 
 
 
 
86 
8.0  Statistical Considerations 
 
 
 
 
 
 
 
 
87 
8.1 Objectives  
 
 
 
 
 
 
 
 
 
87 
8.2 Study Design 
 
 
 
 
 
 
 
 
 
87 
8.3 Sample Size Considerations 
 
 
 
 
 
 
 
88 
8.4 Endpoints  
 
 
 
 
 
 
 
 
 
88 
8.5 Analysis Plan 
 
 
 
 
 
 
 
 
 
89 
9.0  Correlative Research and Tumor Sample Management 
 
 
 
 
90 
 
9.1 Sample Labeling Overview 
 
 
 
 
 
 
 
90 
 
9.2 Timing and Utilization of Tumor Biopsies 
 
 
 
 
 
90 
 
9.3 Correlates  
 
 
 
 
 
 
 
 
 
91 
 
 
9.3.1 RAD51 Foci Formation  
 
 
 
 
 
 
91 
 
 
9.3.2 ᵞH2AX Foci Formation  
 
 
 
 
 
 
92 
 
 
9.3.3 PARP Trapping Assay  
 
 
 
 
 
 
93 
 
 
9.3.4 Resistance Mechanisms 
 
 
 
 
 
 
93 
 
 
9.3.5 Additional Correlates 
 
 
 
 
 
 
 
93 
10.0  Ethical Considerations 
 
 
 
 
 
 
 
 
94 
10.1 Institutional Review Board (IRB) 
 
 
 
 
 
 
94 
10.2 Ethical Conduct of the Study 
 
 
 
 
 
 
 
94 
10.3 Subject Information and Consent 
 
 
 
 
 
 
94 
10.4 Ethical Consideration for Enrollment 
 
 
 
 
 
 
94 
10.5 Protection of Patient Confidentiality 
 
 
 
 
 
 
94 
11.0  References 
 
 
 
 
 
 
 
 
 
 
95 
12.0  Appendices 
 
 
 
 
 
 
 
 
 
 
100 
 
 
Appendix A: Eligibility Checklist (Including ECOG Performance Status Table) 
 
100 
Appendix B: Patient Registration Form 
 
 
 
 
 
 
103 
Appendix C: Data sharing Plan 
 
 
 
 
 
 
 
104 
Appendix D: Sample Shipment Addresses  
 
 
 
 
 
106 
Appendix E: Patient Drug Diary 
 
 
 
 
 
 
 
107 
Appendix F: Safety Reporting Information 
 
 
 
 
 
 
108 
 

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FIGURES AND TABLES 
 
 
 
 
 
 
 
          Page 
Figure 1:  Phase 1a Trial Design (Schedule #1) 
 
 
 
 
 
 
13, 41 
Figure 2 : Phase 1a Trial Design, 1st Alternative Schedule (Schedule #2)  
 
 
14, 43 
Figure 3 : Phase 1a Trial Design, 2nd Alternative Schedule  (Schedule #3) 
 
 
14, 44 
Figure 4 : Components of DNA DSB Repair Pathways 
 
 
 
 
 
21 
Figure 5 : Chemical Structure of Niraparib 
 
 
 
 
 
 
 
26 
Figure 6 : Chemical Structure of Carboplatin  
 
 
 
 
 
 
30 
 
Table 1 : Phase 1a Dose Schedule (Schedule #1)  
 
 
 
 
 
13, 42 
Table 2 : Phase 1a Dose Schedule, 1st Alternative Schedule (Schedule #2) 
 
  
14, 43 
Table 3 : Phase 1a Dose Schedule, 2nd Alternative Schedule (Schedule #3) 
 
 
14, 44 
Table 4a: Study Activities, Phase Ia (Schedule #1)  
 
 
 
 
 
53 
Table 4b: Study Activities, Phase Ia (Schedule #2)  
 
 
 
 
 
55 
Table 4c: Study Activities, Phase Ia (Schedule #3)  
 
 
 
 
 
57 
Table 4d: Study Activities, Phase Ib  
 
 
 
 
 
 
 
59 
Table 5a: Study Activities Checklist, Ia (Schedule #1) 
 
 
 
 
 
61 
Table 5b: Study Activities Checklist, Ia (Schedule #2) 
 
 
 
 
 
63 
Table 5c: Study Activities Checklist, Ia (Schedule #3) 
 
 
 
 
 
65 
Table 5d: Study Activities Checklist, Ib 
 
 
 
 
 
 
 
67 
Table 6 : Niraparib Dispensation by Dose Level 
 
 
 
 
 
 
69 
Table 8 : Criteria for Defining DLTs for Phase 1a 
 
 
 
 
 
 
77 
Table 9: Dose Modifications for Toxicities Related to Niraparib or Carboplatin 
 
 
79 
Table 10: Response Evaluation 
 
 
 
 
 
 
 
 
85 
Table 11: ECOG Performance Status 
 
 
 
 
 
 
 
102 
 
 
 
 
 

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GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS 
ALP 
 
 
Alkaline phosphatase 
ALT 
 
 
Alanine aminotransferase 
AML 
 
 
Acute myeloid leukemia 
ANC 
 
 
Absolute neutrophil count 
ASCO  
 
American Society of Clinical Oncology 
AST 
 
 
Aspartate aminotransferase 
ATM 
 
 
Ataxia telangiectasia mutated (ATM),  
ATR 
 
 
Ataxia telangiectasia and Rad3 related (ATR) 
ATRX  
 
Alpha thalassemia/mental retardation X-linked 
AUC 
 
 
Area under the curve 
BAP1  
 
BRCA1-binding protein 
BARD1 
 
BRCA1-associated RING domain 
BER 
 
 
Base excision repair 
β-hCG  
 
β-human chorionic gonadotropin 
BRIP1   
 
BRCA1 interacting protein C-terminal helicase 1 
BUN 
 
 
Blood urea nitrogen 
CBC 
 
 
Complete blood count 
CHEK1/CHEK2 
Checkpoint kinase 1 and 2  
Cis 
 
 
Cisplatin 
CLIA  
 
Clinical laboratory improvement amendments 
CNS 
 
 
Central nervous system 
COE 
 
 
Centers of excellence 
CR 
 
 
Complete response 
pCR 
 
 
Pathologic complete response 
CRC 
 
 
Colorectal cancer 
CRF 
 
 
Case Report Form 
CRO  
 
Clinical research organization 
CT 
 
 
Computed tomography 
CYP 
 
 
Cytochrome P450 
DCR 
 
 
Disease control rate 
DDR 
 
 
DNA damage response 
DLT 
 
 
Dose-limiting Toxicity 
DNA 
 
 
Deoxyribonucleic acid 
DSMB  
 
Data and safety monitoring review board 
ECOG  
 
Eastern Cooperative Oncology Group 
ECG 
 
 
Electrocardiogram 
FFPE  
 
Formalin-fixed, paraffin embedded 
GCP 
 
 
Good clinical practice 
GGT 
 
 
Gamma-glutamyl transpeptidase 
GI 
 
 
Gastrointestinal 
HIV 
 
 
Human immunodeficiency virus 
HR 
 
 
Hazard ratio 
HR 
 
 
Homologous recombination 
HRD 
 
 
Homologous repair deficiency 
ICH 
 
 
International Conference on Harmonisation 
IEC 
 
 
Independent ethics committees 
IHC 
 
 
Immunohistochemistry 
INR 
 
 
International normalized ratio 
IV 
 
 
Intravenously 
LCCC  
 
Lombardi Comprehensive Cancer Center 
LD 
 
 
Longest diameter 
LFT 
 
 
Liver profile 
LLN 
 
 
Lower limit of normal 
LMWH  
 
Low molecular weight heparin 

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LOH 
 
 
Loss of heterozygosity 
LSST  
 
Large scale state transition 
MDS  
 
Myelodysplastic syndrome 
MRI 
 
 
Magnetic resonance imaging 
MRN  
 
MRE11-RAD50-NBS1 
MSI 
 
 
Microsatellite instability 
MSS 
 
 
Microsatellite stable 
MTD 
 
 
Maximum tolerated dose 
MTT 
 
 
Molecularly-tailored therapy 
NCI CTCAE 
 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
NER 
 
 
Nucleotide excision repair  
NGS 
 
 
Next-Generation Sequencing 
NHEJ  
 
Non-homologous end joining 
NR 
 
 
Not Reported 
ORR  
 
Objective response rate 
OS 
 
 
Overall survival 
PALB2  
 
Partner and localizer of BRCA2 
PARP  
 
Poly (ADP-ribose) polymerase 
PET 
 
 
Positron emission tomography 
PD 
 
 
Progressive disease 
PDX 
 
 
Patient-derived xenografts 
PFS 
 
 
Progression-free survival 
PGP 
 
 
P-glycoprotein 
PI 
 
 
Principal investigator 
PK 
 
 
Pharmacokinetics 
PO 
 
 
By mouth 
POR 
 
 
Proof of receipt 
PR 
 
 
Partial response 
PS 
 
 
Performance Status 
PT 
 
 
Paclitaxel 
PT 
 
 
Prothrombin time 
PTT 
 
 
Partial thromboplastin time 
RCB 
 
 
Residual cancer burden 
RECIST 
 
Response Evaluation Criteria in Solid Tumors 
RP2D  
 
Recommended Phase II Dose 
RR 
 
 
Response rate 
SAE 
 
 
Significant adverse event 
SD 
 
 
Stable disease 
SRS 
 
 
Stereotactic radiosurgery 
SSB 
 
 
Single-strand break 
SUSAR 
 
Suspected unexpected serious adverse reactions 
TAI 
 
 
Telomeric allelic imbalance 
TJU 
 
 
Thomas Jefferson University 
TLS 
 
 
Translesion synthesis 
TNBC  
 
Triple negative breast cancer 
ULN 
 
 
Upper limit of normal 
WHO  
 
World Health Organization 
 

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STUDY SYNOPSIS 
Title 
Niraparib Plus Carboplatin in Patients with Homologous Recombination Deficient 
Advanced Solid Tumor Malignancies  
Short Title 
Niraparib Plus Carboplatin in HR Deficient Advanced Solid Tumors 
Protocol  
Number 
2017-0085 (Georgetown University Parent IRB); (CRC #112016-01) 
Clinicaltrials.gov 
number 
NCT03209401 
Phase 
Phase Ia/Ib 
Investigational 
Agents 
1. Niraparib, an oral PARP inhibitor (GSK) 
2. Carboplatin 
FDA IND number 
132931 
Indication 
Advanced solid tumor malignancies with evidence of homologous recombination 
deficiency (HRD). 
Study Overview 
This is a multi-institutional Phase I dose-escalation and dose-expansion trial for 
patients with advanced, solid tumor malignancies who have pre-identified 
deleterious germline or somatic mutations in the homologous recombination 
deoxyribonucleic acid (DNA) repair pathway (HR deficient). The trial is designed 
to assess the efficacy and safety of niraparib plus carboplatin in patients with 
evidence of HRD. The primary endpoint will be identifying the recommended 
phase 2 dose (RP2D) and schedule of niraparib plus carboplatin, as well as 
establishing the anti-tumor efficacy of niraparib plus carboplatin as determined by 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. 
 
Patients will be pre-identified from participating centers as having either a 
germline deleterious mutation or tumor expression of a deleterious mutation in 
one of the genes listed below, as determined by Next-generation DNA 
sequencing (NGS) only, completed prior to enrollment in this protocol. Patients 
with advanced solid tumor malignancies with the presence of somatic or germline 
deleterious mutation in a gene(s) critical to DNA repair through homologous 
recombination, including but not limited to: RAD50/51/51B, BARD1, BLM, 
BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, or BAP1, and who have 
an adequate performance status (PS), bone marrow, hepatic, and renal function 
as well as biopsiable and measurable disease will be screened for enrollment.   
  
Appropriate patients will be enrolled in a 3+3 alternating dose escalating fashion, 
to a maximum dose of niraparib of 300mg daily and a maximum dose of 
carboplatin area under the curve (AUC) of 4. The 3+3 schema will be employed 
to ensure safety and tolerability.  
 
Once the RP2D and schedule are identified, a Phase Ib expansion cohort of 20 
additional patients will be enrolled as a pilot subgroup to determine efficacy.  Of 
the 20 patients in this Phase Ib cohort, no more than 10 patients will have 
underlying breast cancer; and additionally no more than 10 patients may harbor 
BRCA1 or BRCA2 mutations.  
 
To assess the efficacy of poly (ADP-ribose) polymerase (PARP) inhibition and 
the extent of DNA damage, patients will undergo serial tumor biopsies to measure 
DNA damage as quantified by levels of ᵞH2AX and RAD51 foci formation, as well 
as an assessment of PARP inhibitory activity. Tumor biopsies will also be used 
to assess the mechanisms of resistance to PARP inhibitor-based therapy.  
Assessment of safety including blood tests, clinic visits and exams will occur 
weekly at the start of therapy, then will transition to every 3-week clinic visits and 

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exams at the beginning of cycle 4. For the Phase Ib portion, patients will undergo 
weekly lab work and clinic visits for cycle 1 only. We hypothesize that in this HR 
deficient patient population, the addition of niraparib to carboplatin will lead to 
significant anti-tumor responses with acceptable toxicities. 
Study Duration 
48 – 60 months 
Study Center(s) 
 Georgetown University, Lombardi Comprehensive Cancer Center  
Washington, DC 
 Additional participating centers to be added upon activation 
Objectives 
Phase Ia (dose-escalation phase) Primary Objective:  
To identify the RP2D and schedule of niraparib plus carboplatin for patients with 
homologous recombination deficient advanced solid tumor malignancies 
 
Phase Ib (dose-expansion phase) Primary Objective:  
To determine the anti-tumor efficacy of niraparib plus carboplatin in a non-disease 
specific cohort of patients with homologous recombination deficient advanced 
solid tumor malignancies, as determined by RECIST v1.1 
 
Secondary Objectives: 
Clinical: 
a. To evaluate the safety and tolerability of niraparib plus carboplatin 
b. To determine evidence of any disease specificity with this combination 
c. To assess the anti-tumor efficacy of combined therapy as determined by 
RECIST v1.1 
d. To assess the anti-tumor efficacy of combined therapy as determined by 
measurement of overall survival (OS) and progression free survival (PFS) 
 
Scientific: 
a. To assess the effects of niraparib alone, and niraparib plus carboplatin 
on pharmacodynamic markers of DNA damage and repair, including 
γH2AX/RAD51 foci formation, and as measured by the PARP trapping 
assay 
b. To explore predictive markers of response and/or resistance to therapy in 
serial tumor biopsy samples  
Number of 
Subjects 
A minimum of 18 patients (assuming 6 patients at the lowest dose of the 3 
schedules) 
A maximum of 146 patients (assuming 6 patients in each cohort and each 
schedule (21 cohorts) PLUS a 20 patient Phase Ib portion) 
 
The anticipated number of patients will be approximately 80, accounting for dose 
escalation to the RP2D, utilization of the alternative schedules, and the 20 patient 
expansion group. 
Diagnosis and 
Main Inclusion 
and Exclusion 
Criteria 
Key Inclusion Criteria 
1) Histologically confirmed advanced solid tumor malignancy that is amenable 
to biopsy - A patient’s biopsied lesion must be at least 1cm in diameter (in at least 
one dimension) 
2) Pre-identified presence of somatic or germline deleterious mutation in a 
gene(s) critical to DNA repair through homologous recombination, including but 
not limited to: RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, 
FANCA/C/D2/E/F/G/L, PALB2, or BAP1 
3) Radiographically measurable disease by RECIST v1.1 
4) Age ≥ 18 years 
5)    Life expectancy of more than 3 months 
5) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 
6) Signed informed consent form 

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7) Adequate hepatic, bone marrow, and renal function as defined below in the 
body of the protocol 
 
Key Exclusion Criteria 
1) Prior exposure to PARP inhibitor-based therapy 
2)  Prior disease progression while receiving platinum chemotherapy; or disease 
progression within 6 months of any platinum chemotherapy (including adjuvant 
or neoadjuvant) except for breast cancer where disease progression cannot have 
occurred within 12 months of the last platinum chemotherapy 
3) Active severe infection, or known chronic infection with human 
immunodeficiency virus (HIV) or hepatitis B virus 
4) Cardiovascular disease problems including unstable angina, therapy for life-
threatening ventricular arrhythmia, or myocardial infarction, stroke within the last 
3 months, or a diagnosis of congestive heart failure 
5) Women who are pregnant or breastfeeding 
6) Patients with known untreated central nervous system (CNS) metastases 
7)    Patients with clinical significant neuropathy, grade 2 or greater 
8)  Patients with history of another active malignancy within the past 2 years, 
excluding non-melanoma carcinoma of the skin 
9)    Patients receiving any other investigational agents 
 
Study Design 
 
This study is a single-arm, open-label, multi-institutional Phase I trial with a dose-
escalation (Ia) and dose-expansion (Ib) portion evaluating the combination of 
niraparib plus carboplatin in homologous recombination deficient advanced solid 
tumor malignancies. 
 
Phase Ia Portion 
The Phase Ia portion of the study will be used to determine the RP2D and 
schedule for niraparib plus carboplatin. Patients will be evaluated weekly for the 
first 3 cycles (9 weeks) and then every 3 weeks thereafter on Day 1 of subsequent 
cycles. Niraparib will be given daily days 1-14 out of a 21 day cycle with the dose 
determined by the patient cohort. Carboplatin at a maximum AUC of 4 will be 
administered on Day 2 of every cycle sparing cycle 1 (cycle 1 will be Niraparib 
alone) (Figure 1). A standard 3+3 design will be employed to ensure safety and 
tolerability, in which patients are enrolled in cohorts of 3 patients each. If there 
are less than 2 dose-limiting toxicities (DLTs) in the first 3 patients, then 3 
additional patients will be enrolled to the current dose level cohort. If there are 
less than 2 dose-limiting toxicities (DLTs) in these 6 patients, then 3 additional 
patients will be enrolled in the next dose level (Table 1), and so on. If there are 
greater than or equal to 2 DLTs in a given 6 patient cohort, then the dose level 
below will be considered the maximum tolerated dose (MTD) and will be 
employed as the RP2D and schedule. If dose level 1 is not tolerated, then an 
alternative schedule will be pursued.  
 
 
 
 
 
 
 

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Figure 1: Treatment and Biopsy Schedule: Niraparib (Days 1-14) 
 
 
Dose 
Cohort 
Niraparib 
(mg Daily) 
Carboplatin 
(AUC) 
1 
100 
2 
2 
100 
3 
3 
100 
4 
4 
200 
2 
5 
200 
3 
6 
200 
4 
7 
300 
2 
8 
300 
3 
9 
300 
4 
Table 1: Dose Escalation for Carboplatin and Niraparib 
(Niraparib Dosing Days 1-14) 
 
Alternative Dosing Schedules 
Given concerns over the potential for combinatorial toxicity, especially on 
myelosuppression, two alternative dosing schedules will be considered. The 
decision to pursue one or both of these alternative schedules will be determined 
by the PIs and will take into account toxicities observed to date, as well as the 
pharmacodynamic effects observed on serial tumor biopsies.  
 
Thus, for example, if dose level 1 is too toxic in Schedule #1 (i.e. with 2 or more 
DLTs), then patients will be enrolled according to Schedule #2. If Schedule #2 
remains too toxic, then Schedule #3 will be employed.   
 
However, the investigators will also be reviewing the pharmacodynamic 
assessments of DNA damage, and will have the opportunity to compare these 
results to the clinical efficacy.  If these pharmacodynamics assessments suggest 
that an alternative schedule may be more efficacious, or that an alternative 
schedule merits scientific exploration, then the investigators may choose as a 
group to pursue one or both of the alternative schedules.  Ultimately, the schedule 
and the dose must be selected by the investigators prior to enrollment of the 
Phase Ib expansion cohort – as patients in the Phase Ib expansion cohort will be 
enrolled in only one RP2D and schedule. 
 
In the first alternative schedule, niraparib will only be dosed on Days 1-7 of an 
every 21 day cycle (Figure 2).  The dose escalation will be otherwise similar 
(Table 2). Carboplatin at a maximum AUC of 4 will still be administered on Day 2 
of every cycle sparing cycle 1 (cycle 1 will be Niraparib alone). 

Version 3.0 (Amendment 9), 7/3/2023 
14
 
Figure 2: Treatment and Biopsy Schedule: Niraparib (Days 1-7) 
 
Dose 
Cohort 
Niraparib 
(mg Daily) 
Carboplatin 
(AUC) 
1 
100 
2 
2 
100 
3 
3 
100 
4 
4 
200 
2 
5 
200 
3 
6 
200 
4 
7 
300 
2 
8 
300 
3 
9 
300 
4 
Table 2: Dose Escalation of Carboplatin and Niraparib 
(Niraparib Dosing Days 1-7) 
 
In the second alternative schedule, patients will receive carboplatin AUC 2 weekly 
for 2 weeks on, 1 week off of every q3week cycle. In addition, the niraparib will 
only be given for 4 days, each of the first two weeks (Days 1-4, and 8-11).  The 
carboplatin will be given on Days 2 and 9 (Figure 3). For this alternative schedule, 
there will be no dose escalation of the carboplatin – only the niraparib will be 
dose-escalated (Table 3). 
 
 
Figure 3: Treatment and Biopsy Schedule: Weekly Carboplatin 
 
Dose      
Cohort 
Niraparib 
(mg Daily) 

Version 3.0 (Amendment 9), 7/3/2023 
15
1 
100 
2 
200 
3 
300 
Table 3: Dose Escalation – Weekly Carboplatin 
Patients will be evaluated, including laboratory testing, weekly until the first 
restaging analysis.  Restaging will occur every 9 weeks. If at first restaging there 
is no evidence of progressive disease (PD), as determined by RECIST v1.1 
criteria, and the patient is tolerating therapy, then patient will continue with study 
therapy, with clinic visits and lab work on Day 1 only of future cycles, and 
restaging imaging every 9 weeks. Patients will continue to remain on study as 
long as there is no evidence of PD (according to RECIST v1.1 criteria) and the 
therapy is adequately tolerated.   
 
Pharmacodynamic studies will be directed toward an assessment of DNA 
damage including ᵞH2AX and RAD51 foci formation, as well as an assessment of 
PARP inhibitory activity, as measured by a PARP-trapping assay. In addition, a 
portion of all tumor samples will be used in ex vivo models (e.g. organoids) for 
further analysis of mechanism of resistance and to identify combinatorial 
therapies that can overcome resistance. 
 
Phase Ib Portion 
There will be a Phase Ib expansion cohort including 20 patients to further assess 
the efficacy of niraparib plus carboplatin, using the RP2D and schedule from 
Phase Ia.  Twenty patients with tumors harboring deleterious mutations in the HR 
repair pathway (similar to Phase Ia), with no more than 10 patients with breast 
cancer and no more than 10 patients with BRCA1 or BRCA2 mutations will be 
enrolled.  
 
All patients in the Phase Ib portion will be evaluated with clinic visits, physical 
exams, and blood tests weekly for the first cycle, then on Day 1 of subsequent 
cycles only, unless clinically indicated sooner. Restaging will occur every 9 
weeks. If at first restaging there is no evidence of PD, as determined by RECIST 
v1.1 criteria, and the patient is tolerating therapy, then patient will continue with 
study therapy. Patients will continue to remain on study as long as there is no 
evidence of PD (according to RECIST v1.1 criteria) and the therapy is adequately 
tolerated.   
 
All patients in the Phase 1b portion will undergo three serial tumor biopsies to 
assess the pharmacodynamic effects of niraparib, and then niraparib plus 
carboplatin on DNA repair.  An off study/at progression tumor biopsy will also be 
required. Correlative studies for the serial tumor biopsies will be the same as for 
the Phase Ia. 
 
Timing and Utilization of Tumor Biopsies 
Pre-Treatment Biopsy 
Following successful screening and enrollment of patients with an advanced solid 
tumor malignancy and known deleterious mutations in selected DNA repair 
genes, a pre-treatment tumor biopsy will be obtained (within 4 weeks of Day 1 of 
study treatment).   
 
Second & Third Biopsies (For patients in the Phase Ib portion) 
The second biopsy will occur on C1D14 (range C1D10-14) in schedule #1 (the 
timing of the biopsies in the alternative schedules will differ, as outlined in the full 
protocol), on niraparib therapy alone. The third biopsy will occur on C2D14 (range 
C2D10-14) on niraparib and carboplatin therapy. There can be some flexibility 

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with the timing of the biopsies, but it is important that the second and third 
biopsies take place on a day that the patient received a dose of niraparib. 
 
 
Biopsy Upon Progression 
All patients whose disease has NOT rapidly progressed on trial will undergo a 
biopsy upon disease progression for ongoing correlative studies.  Specifically, 
patients who meet the following conditions will have a biopsy upon progression: 
- 
The patient experiences a RECIST 1.1 confirmed partial or complete 
response at any point, and then subsequently experiences disease 
progression 
Or 
- 
The patient experiences stable disease of ≥27 weeks (to comport with the 
timing of restaging imaging), and then subsequently experiences disease 
progression 
Tissue Utilization and Prioritization 
A rigorous tumor collection algorithm will be instituted for this protocol. Shipping 
details and addresses are all summarized in Appendix D. 
 
For each biopsy, 5 individual cores will be obtained with an 18-20 gauge needle.  
The utilization of the cores differs depending upon which biopsy is being obtained. 
Please refer to Section 4.3.2 and the Lab Manual for details 
 
Additional Exploratory Correlative Analyses 
During the course of therapy, patients will undergo blood sample collection for 
additional correlative analyses: 
- 
Patients will submit a 10mL sample of blood in a red top heparinized tube 
for future research on Cycle 1 Day 1 and every 3 weeks until progression.  
These samples will be processed to isolate serum, which will be batched 
and shipped to Dr. Brody’s lab at OHSU. 
 
Initiation of Treatment, Patient Assessment, and Response Assessment 
Prior to treatment initiation, all patients will undergo baseline imaging within 4 
weeks of initiating therapy and screening for enrollment within 2 weeks of initiating 
therapy.  At the screening evaluation, the patient’s performance status will be 
confirmed, and standard laboratory tests will be obtained. Patients must have 
measurable, metastatic disease, as per RECIST v1.1 and the index lesions could 
not have been previously treated with local therapy, such as radiation.   
 
Treatment will be initiated on Cycle 1 Day 1, and patients will be evaluated weekly 
while on therapy for the first 3 cycles (9 weeks) and then every 3 weeks on Day 
1 of subsequent cycles. These “protocol defined visits” will include a history and 
physical, update of concomitant medications, assessment of treatment toxicities, 
laboratory evaluations and may or may not coincide with the regular visits that a 
physician may wish to have with the patient – BUT these will be required visits 
used for data collection. Laboratory evaluation will continue weekly through the 
first 3 cycles for the Phase Ia portion of study and then on D1 only of subsequent 
cycles unless clinically indicated sooner. For the Phase Ib portion of study, 
laboratory evaluation will continue weekly through the first cycle only and then on 
D1 only of subsequent cycles unless clinically indicated sooner. Radiologic 
response will occur every 9 weeks. Following the first response assessment, any 
patient with stable or responding disease as per RECIST v1.1 may stay on 
therapy, and will be evaluated every 9 weeks until disease progression, at which 
point he/she will be removed from the study.  

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Longitudinal Outcomes Assessment 
Subsequent therapies will be administered at the discretion of the treating 
physician.  All patients will be followed until death for assessment of overall 
survival. 
Multi-Institutional 
Trial 
Coordination 
Georgetown University’s LCCC Consortium IIT Office will oversee the multi-
institutional coordination. 
 
Patient Enrollment 
Enrollment at the sites will be competitive.  If a patient is being screened for 
enrollment, the local research coordinator must send an email within 24 hours 
containing the patient’s initials to the local principal investigator (PI), to Dr. Isaacs, 
and to Georgetown University’s LCCC Consortium IIT Office.  If a patient is 
successfully screened, the local research coordinator must send all supporting 
documentation to Georgetown University’s LCCC Consortium IIT Office by 
secure email to confirm eligibility.  Patients should not start therapy until Dr. 
Isaacs and Georgetown University’s LCCC Consortium IIT Office have reviewed 
the patient’s records and confirmed that the patient is indeed eligible for 
enrollment. 
 
Data Collection and Management  
Patient data will be entered into the on-line accessible database.  This database 
is housed at Lombardi-Georgetown, but is accessible anywhere there is internet 
access.  The data manager and research coordinator at each site will attend an 
on-line training session so that they may learn how to enroll data into the data 
base.  All screening data should be entered prior to starting therapy, and all 
ongoing patient data should be entered within 10 business days of each patient 
visit.   
 
Conference Calls 
A monthly conference call will be held between Lombardi-Georgetown and the 
other sites to review patient enrollment, toxicity, and response assessment. In 
addition, a separate conference call will be held between OHSU and the other 
sites to review sample collection, tissue coordination, and tissue analysis.  This 
will include an ongoing review of the success rate of the tumor biopsies, and of 
the ex-vivo tumor samples.  
 
Trial Auditing 
Georgetown University’s LCCC Consortium IIT Office will arrange all primary 
source documents for the patients to be audited.  This will include collecting 
copies of the primary source data for any patients treated at other sites. 
 
Duration of 
therapy 
All drugs will be administered until disease progression or unacceptable toxicity 
is observed. 
 
Statistical 
Design,  
Feasibility, and 
Trial Duration 
This study is a single-arm, open-label, multi-institutional Phase I trial of the 
combination of niraparib and carboplatin in patients with advanced solid tumor 
malignancies with deleterious mutation(s) in DNA damage repair genes. The 
Phase Ia portion of the trial will be conducted in a 3+3 design, enrolling patients 
in cohorts of 3 patients each to ensure safety and tolerability. If there are less 
than 2 dose-limiting toxicities (DLTs) in the first 3 patients, then 3 additional 
patients will be enrolled to the current dose level cohort. If there are less than 2 

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dose-limiting toxicities (DLTs) in these 6 patients, then 3 additional patients will 
be enrolled in the next dose level (Table 1), and so on. If there are greater than 
or equal to 2 DLTs in a given 6 patient cohort, then the dose level below will be 
considered the maximum tolerated dose (MTD) and will be employed as the 
RP2D and schedule. If dose level 1 is not tolerated, then an alternative schedule 
will be pursued. 
 
There will be a Phase Ib expansion cohort including 20 patients to further assess 
the efficacy of niraparib plus carboplatin, using the RP2D and schedule from 
Phase Ia.  Twenty patients with tumors harboring deleterious mutations in the HR 
repair pathway (similar to Phase Ia), with no more than 10 patients with breast 
cancer and no more than 10 patients with BRCA1 or BRCA2 mutations will be 
enrolled.  
 
Efficacy for both Phase Ia and Phase Ib will be assessed by radiologic 
assessment every 9 weeks for objective response. All patients meeting the 
eligibility criteria and who have signed a consent form, have begun treatment, are 
not lost to follow-up, and are not taken off study for reasons other than 
progression or death before 9 weeks will be considered evaluable for the 
assessment. The primary endpoint for Phase Ia will be the number of grade 3 and 
4 toxicities according to the National Cancer Institute Common Toxicity Criteria 
for Adverse Events Version 5.0 [NCI CTCAE v5.0], and the primary endpoint for 
Phase Ib will be anti-tumor efficacy of niraparib plus carboplatin by ORR. 
Secondary endpoints for both portions of study will include PFS and OS, disease 
control rate, quantification of DNA damage and repair, quantification of PARP 
inhibition, and exploration of predictive markers of response and/or resistance to 
therapy in serial tumor biopsy samples. Interim analyses to assess secondary 
endpoints of OS and PFS will be scheduled to occur at 12 months and 24 months. 
Between 18 and 126 patients will be enrolled in the Phase Ia portion of the study, 
depending on whether DLTs occur and dose de-escalation and/or utilization of 
the alternative schedules is required. Twenty patients will be enrolled in the Phase 
Ib portion of the study. With 20 evaluable patients in the Phase Ib portion, 
combined with a minimum of 18 to a maximum of 126 patients enrolled strictly in 
the Phase Ia portion of the trial, there will be up to 146 patients enrolled. It is 
anticipated that approximately 80 patients, however, will need to enroll to 
complete the trial.  At an expected accrual rate of 2-3 patients per month (roughly 
30 patients per year), the expected accrual duration will be approximately 48 – 
60 months.  
 
Descriptive statistics will be used to summarize patients’ experienced toxicity. 
Patients’ adverse events and toxicities will be tabulated according to their grades 
and attributions. PFS and OS will be estimated using the Kaplan-Meier method. 
As a pilot study with a heterogeneous patient population, no meaningful efficacy 
statistics can be generated, rather an observation of efficacy. ORR by RECIST 
v1.1 criteria will be estimated with its 95% exact confidence interval, and will be 
assessed overall and by tumor subtype (breast/gynecologic, gastrointestinal 
[esophageal, gastric, colorectal, anal], pancreatobiliary, GU, other). The main 
purpose of Phase Ib is not hypothesis testing but rather observing the efficacy. 
However, if we observe at least 5 or more out of the 20 patients who obtain a PR, 
CR or SD at 9 weeks, this would be equivalent to a one-stage Phase II testing of 
the response rate of 0.1 vs. at least 0.3 at a 0.05 one-sided alpha level. The 
sample size of 20 patients would give 80% to reject the null hypothesis of 
the response rate at 0.1. If, in this study, 6, 7 or 8 patients obtain a PR, CR or SD 
at 9 weeks, then we are 80% confident that the response rate would be within the 
range of 16.6%-46.6%, 21.2%-51.2%, or 24.8%-56.8%, respectively.  

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Number of Centers 
Because the qualifying mutation rate is expected to be 5-10%, it will be critical to 
have access to a large pool of potential patients to be able to recruit between 18 
and 146 evaluable patients for this trial.  Thus, we propose a multi-institutional 
trial, with centers enrolling gradually following identification of patients with 
advanced solid tumor malignancies and deleterious DNA repair gene mutations. 
Georgetown-Lombardi will act as the primary site, and Georgetown University’s 
LCCC Consortium IIT Office will oversee patient enrollment and on study 
activities at other sites.  Georgetown-Lombardi will also be responsible for 
generation of the case report forms, which can be accessed through an on-line 
data entry portal (Training for this portal can be done on-line).  
 
 
 

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1.0 BACKGROUND AND JUSTIFICATION 
 
 
1.1 Deoxyribonucleic acid (DNA) Repair  
Each of the more than 70 trillion cells in the human body endures tens of thousands of DNA lesions per day1. 
Upon DNA damage, a complex DNA damage response (DDR) pathway is initiated.  This includes cell-cycle 
arrest, transcriptional and post-transcriptional activation of a subset of genes including those associated with 
DNA repair, and sometimes programmed cell death. If not repaired or repaired incorrectly, DNA lesions can lead 
to wider scale DNA aberrations, resulting in genomic instability, which is widely accepted as the fundamental 
etiology of cancer.  
 
DNA lesions are a result of both endogenous and exogenous. Oxidative stress and production reactive oxygen 
species are a major endogenous source of DNA damage, as well as lipid peroxidation, hydrolytic reactions, and 
non-enzymatic methylations which generate thousands of DNA-base lesions per cell per day. DNA damage can 
result from exogenous causes including UV light, ionizing radiation, tobacco-containing products, and 
environmental/occupational exposures. Reactive oxygen and nitrogen compounds can lead to adducts that 
impair base-pairing, block DNA replication and transcription, and result in base loss or DNA single-strand breaks 
(SSBs). DNA double stranded breaks are often formed by exogenous sources of DNA damage, specifically 
ionizing radiation. Additionally, DSBs can be formed under mechanical stress, when two SSBs arise in close 
proximity or when the DNA-replication fork encounters a SSB or other lesions, or at the end of chromosomes as 
a result of impaired metabolism of telomeres. Of the many types of DNA damage, DSB are probably the most 
lethal2-4. In metazoa, just one DSB can result in cell death if it inactivates an essential gene and causes 
apoptosis5. Furthermore, DSBs are of importance because they are difficult to repair, and have been associated 
with induction of mutations and chromosomal translocations. 
 
For the myriad of DNA lesions, there are many distinct DNA repair mechanisms.  For DSB repair, two   
mechanisms are used: non-homologous end-joining (NHEJ) and homologous recombination (HR). These are 
distinct but complimentary pathways which function to repair DSBs. In NHEJ, DSBs are recognized by the Ku 
protein that then binds and recruits protein kinase DNA-PKcs, leading to recruitment of Xrcc4 DNA ligase IV. 
This process results in ligation of two DNA DSBs and does not require extensive sequence homology6. There is 
often some limited processing or DNA polymerization which takes place before NHEJ occurs, which is error 
prone and results in deletions of DNA sequence.   HR is initiated by ssDNA generation, which is promoted by 
various proteins including the MRE11-RAD50-NBS1 (MRN) complex. RAD51, BRCA1 and BRCA2 catalyze 
ssDNA invades undamaged template and, following the actions of polymerases, nucleases, helicases and other 
components, DNA ligation and substrate resolution ensue. HR is also used to restart stalled replication forks and 
to repair interstrand DNA crosslinks. 
 
1.2 Homologous Recombination Defects 
BRCA1 and BRCA2 genes encode protein(s) that are involved in repair of DNA double-strand breaks and cross-
linking DNA damage including those induced by various chemotherapy agents through the homologous 
recombination pathway. DNA damage leads to localization of BRCA tumor suppressors to the nucleus, formation 
of RAD51 foci and subsequent DNA damage repair7-8. Therefore, the functional status of BRCA genes is thought 
to impact sensitivity to chemotherapy. The sensitivity of BRCA-deficient cells to PARP inhibition may be more 
related to a defect in homologous recombination by gene conversion (loss or depletion of several other HR-
related genes), rather than directly due to BRCA 1/2 deficiency9. 
 
Beyond BRCA 1 and 2 mutations, defects in homologous recombination repair can also be caused by loss of 
function of proteins, including the RecA homologue RAD51, ataxia telangiectasia mutated (ATM), ataxia 
telangiectasia and Rad3 related (ATR), and checkpoint kinase 1 and 2 homologue (CHEK1 and CHEK2) proteins, 
as well as components of the Fanconi’s anemia repair pathway. The inactivation of these various genes, which 
participate in the precise repair of breaks in double-stranded DNA by homologous recombination, lead to 
development of breast and other cancers. The process is initiated when ATM and CHEK2 protein kinases 
phosphorylate proteins such as BRCA1, which signals double stranded breaks in DNA and causes BRCA1 to 
localize to the site of DNA repair. BRCA2 carries the DNA-recombination enzyme RAD51 to the same site. The 
cascade of activity of these proteins ultimately leads to error-free DNA repair by recombination10.  
 

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Figure 4. Components of DNA DSB repair pathways. 
NHEJ: Ku binds a DSB, followed by recruitment and activation of DNA-PKcs. XRCC4 and 
ligase IV are recruited directly or indirectly by the DNA-PK holoenzyme and/or are activated by 
DNA-PK−mediated phosphorylation. HR: proteins involved in mammals are indicated. The 
strand-exchange reaction catalyzed by Rad51 is facilitated by Rad52 through direct interaction. 
Rad54, a DNA-dependent ATPase, also interacts directly with Rad51 and stimulates its 
activity. Rad51-related proteins (Rad51B-D, Xrcc2 and Xrcc3) are also involved in HR. There 
is a direct interaction between Xrcc3 and Rad51, and Rad51B and Xrcc3 interact with Rad51C. 
Rad51 also interacts with Brca2 and indirectly with Brca1 through Brca2. The c-Abl tyrosine 
kinase modulates Rad51 strand exchange activity through phosphorylation. Brca1 and c-Abl 
are phosphorylated by ATM. The Mre11/Rad50/Nbs1 complex, which participates in both 
NHEJ and HR, is also indicated. 
                         Nature Genetics  27, 247 - 254 (2001) 
 
RAD51 is a protein that plays a major role in homologous recombination of DNA during double-strand break 
repair11. It localizes to the DNA replication fork and stimulates a DNA strand exchange reaction between 
homologous sequences. RAD51 mutants are associated with dysfunction in replication and repair mechanisms, 
chromosomal aberrations, and high sensitivity to cell death by cross-linking agents such as mitomycin C and 
cisplatin12-13. RAD51 interacts directly with XRCC2, XRCC3, BRCA1, and BRCA2 to form complexes that allow 
for DNA damage repair via the homologous recombination pathway, and that promote chromosomal stability. 
Mutations in different components of these complexes can lead to defective homologous recombination and 
generate a high-risk environment for cancer development. For example, XRCC2 mutations have been 
associated with a significantly increased risk of breast cancer14. 
 
ATM and ATR are members of the phosphoinositol 3-kinase–related kinase family and are involved in mediating 
the cellular response to double strand DNA breaks and replication dysfunction. Deficiencies in ATM and 
reduction of ATR kinase activity result in defects in homologous recombination15-16. Heterozygous ATM mutation 
carriers have shown an association with a moderately increased risk of breast cancer17-18. Studies have 
elucidated a potential role of ATR mutations in endometrial, colorectal and gastric cancer subsets with 
microsatellite instability19. In endometrial cancer, truncated ATR mutations are associated with a naturally more 
aggressive disease biology shown by significantly reduced disease-free and overall survival20. 
 
Fanconi anemia is a genetic disease associated with a greatly increased risk of cancer. In response to DNA 
damage, several Fanconi anemia proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, and FANCM) 
form a nuclear core complex, which interacts with FANCL and leads to FANCD2 monoubiquitination. This 
process is integral for the repair of DNA and the accumulation of FANCD2 at sites of DNA damage where it 
interacts with BRCA1 and BRCA216,21-25. Cells with defects in Fanconi anemia genes including FANCA, FANCC, 
FANCG, or FANCD2 have demonstrated deficient homologous recombination26-29. 
 
The partner and localizer of BRCA2 (PALB2) gene (also known as FANCN) encodes a protein that binds to and 
co-localizes with BRCA2 in nuclear foci, promotes its stabilization and enables DNA repair30-31. PALB2 also 

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regulates the interaction between BRCA1 and BRCA232. Similar to BRCA2 mutants, PALB2-deficient cells 
demonstrate decreased homologous recombination capability and hypersensitivity to cross-linking agents33. 
Furthermore, PALB2-deficient cells have demonstrated sensitivity to PARP inhibitors34. Biallelic germline loss-
of-function mutations in PALB2 cause Fanconi’s anemia, whereas monoallelic mutations are associated with an 
increased risk of breast cancer and pancreatic cancer35-39. 
 
Similar to PALB2, Abraxas (FAM175), BRCA1-associated RING domain (BARD1), and BRCA1 interacting 
protein C-terminal helicase 1 (BRIP1) have been identified as an important genes involved in BRCA1/2 DNA 
damage repair and homologous recombination. Abraxas, BARD1, Rap80, and BRCA1 form a complex that 
engages at sites of DNA damage and is dedicated to ubiquitin chain recognition and hydrolysis at DNA DSBs 
via the homologous recombination pathway40. BRIP1 is a Fanconi anemia group protein which also interacts 
with BRCA1/2 in homologous recombination, with BRCA1/2 serving as the scaffolding protein41. Germline 
mutations in BRIP1 have been associated with an increased risk of epithelial ovarian cancer42.  
 
BRCA1-binding protein BRCA1-associated deubiquitylase (BAP1) is a deubiquitinating enzyme with C-terminal 
active hydrolase domain (UCH) and N-terminal nuclear localization signals (NLS1, NLS2) and is mutated in 
several cancers, most notably mesothelioma and melanoma, where it is thought to promote oncogenesis.   BAP1 
mediates PARP-dependent recruitment of the polycomb deubiquitylase complex PR-DUB to sites of DNA 
damage.  BAP1 also serves as a phosphorylation target for the DDR kinase ATM. BAP1 promotes repair of DNA 
double-strand breaks, enhancing cell survival after DNA damage43. Given this role in DNA repair, we hypothesize 
those tumors which harbor this mutation may be amenable to platinum based chemotherapy.  
 
MRE11A forms the MRN protein complex with RAD50 and NBN that initially processes and resects damaged 
DNA to allow for DNA repair by the homologous recombination repair pathway. In patients with mutations in 
MRE11A, for example, there is a higher frequency of cancers in comparison to the general population and this 
mutation has been linked to the Ataxia-Telangectasia-Like Disorder. In mouse models, MRE11A mutations are 
associated with extensive oncogene-induced breast mammary hyperplasia with frequent progression to invasive 
breast cancer44. In vitro, loss of the MRE11 protein has been shown to predict sensitivity to PARP-inhibitor 
therapy45. 
 
Both WRN and BLM are also involved in the MRN complex and its role in DNA damage resection via HR repair, 
accumulating at sites of DSBs in human cells46. In patients with Werner syndrome, in which they have an 
inherited mutation in the WRN gene, this defect is manifested as severe premature aging due to severe genomic 
instability47.  
 
CDKN1A plays an essential role in DNA damage repair, by direct inhibition of DNA replication, inducing cell cycle 
arrest, and by regulation of apoptosis and transcription. These functions are performed through the ability of p21 
to interact with a number of proteins involved in these processes. Despite an initial controversy, during the last 
years several lines of evidence have also indicated that p21 may be directly involved in DNA repair. In particular, 
the participation of p21 in nucleotide excision repair (NER), base excision repair (BER), and DNA translesion 
synthesis (TLS)48. CDKN2A overexpression impairs the recruitment of RAD51 to the site of DNA damage by 
downregulating cyclin D1 protein expression. Studies have shown decreased expression of cyclin D1 in CDKN2a 
overexpressing cells impaired the recruitment of RAD51 to damaged DNA and impeded the homologous 
recombination DNA repair49. 
 
ATRX (alpha thalassemia/mental retardation X-linked) is a choramtin remodeler, and mutations in this gene 
cause alternating length of telomeres. The resulting persistent telomere cohesion promotes recombination 
between sister telomeres, while it suppresses inappropriate recombination between non-sisters. Forced 
resolution of sister telomere cohesion induces excessive recombination between non-homologs, genomic 
instability, and therefore inadequate DNA repair50. 
 
ARID1A is a member of the SWI-SNF chromatin remodeling complex which plays a role in various cellular 
processes including development, differentiation, proliferation, DNA repair and tumor suppression51. The 
complex uses the energy of ATP hydrolysis to facilitate access of transcription factors to regulatory DNA 
sequences. BAF250a is the protein encoded by ARID1A and is a subunit of the SWI-SNF complex thought to 

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contribute specificity to gene expression regulation 52-53. It has been postulated that ARID1A has tumor 
suppressor function; ARID1A rearrangement has been shown in a breast cancer cell line, and an ARID1A 
deletion has been observed in a lung cancer cell line54. ARID1a is mutated in ~50% of ovarian clear cell 
carcinomas, 30% of endometriosis-associated ovarian carcinomas, and 40% of uterine low-grade endometrioid 
carcinomas55-57. ARID1A mutations have also been described in gastric, hepatocellular, breast, pancreatic, 
colorectal and prostate cancer58-61. 
 
The MLL2 gene encodes a protein which functions as a histone methyltransferase that methylates the Lys-4 
position of histone H3, and is part of a multi-protein complex involved in gene regulation (beta-globin and 
estrogen receptor genes) and embryonic development62-64. In vitro, MLL2 complex has been shown to associate 
with Pax7, a transcription factor, and activate myogenic genes through H3 K4 methylation65. In vivo, MLL2 is 
shown to be required for normal embryonic development in mice66. MLL2 plays a role in regulation of gene 
expression programs related to cell proliferation and invasion67 and altered expression of MLL2 is seen in human 
breast and colon tumors68. Additionally, studies have shown that aberrations in histone lysine methylation may 
have clinical relevance to breast, ovarian, and pancreatic cancer69. 
 
SLX4 is involved in homologous recombination in several ways and serves as an important scaffold for proteins 
involved in the repair of damaged DNA via homologous recombination70. Biallelic mutations in SLX4 have been 
seen in patients with Fanconi anemia and hereditary breast cancer71. 
 
The role of PTEN in homologous recombination is less clear, but it is responsible for phosphorylation of AKT 
substrates including CHEK1, which in turn is responsible for delaying cell cycle progression to allow for DNA 
damage repair. In vitro, PTEN-deficient cell lines are hypersensitive to PARP inhibitors, highlighting its role in 
homologous recombination72.  
 
1.3 PARP Inhibition 
Poly (ADP-ribose) polymerase (PARP) is an enzyme involved in DNA base excision repair via binding to single-
strand breaks in DNA and bringing DNA repair proteins to the damaged site73. The mechanisms of action of 
PARP inhibitors include trapping of PARP enzyme on DNA and inhibition of base excision repair, leading to 
induction of DSBs74-76. Thus PARP inhibition results in less efficient DNA repair following a cytotoxic insult.  DNA 
damaging agents, including cytotoxic chemotherapy and radiation therapy, remain a mainstay of cancer therapy, 
and cancer cells are often genetically unstable and/or exhibit deficiencies in DNA repair systems77-78.  These 
deficiencies render cells more dependent on PARP for DNA repair and thus more sensitive to PARP inhibition78.  
Additionally, higher expression of PARP in cancer cells compared to normal cells has been linked to drug 
resistance and the overall ability of cancer cells to sustain genotoxic stress79.  Consequently, PARP inhibitors 
are proposed as sensitizing agents for ionizing radiation therapy and a variety of DNA-damaging agents including 
platinums, alkylators, and topoisomerase inhibitors. 
 
Tumors which are characterized by a defect in homologous DNA repair function, including germline or somatic 
BRCA 1/2 mutations, appear to be susceptible to PARP inhibitors74. 
 
Studies in breast and ovarian cancers with BRCA 1/2 mutations have demonstrated tumor responses and 
progression-free survival benefit with olaparib and other PARP inhibitors80-85. In patients with ovarian cancer, an 
association between platinum sensitivity and extent of olaparib response has been observed86. Furthermore, 
there have been reports of responses to PARP inhibitors in BRCA 1/2-mutated prostate and pancreatic 
cancers87-88.  
 
1.3.1 PARP Inhibition in Breast Cancer 
In a 2010 Lancet article, Tutt et al described the clinical efficacy of olaparib, which was demonstrated in a Phase 
2 study including 54 patients with BRCA carriers with advanced breast cancer who had received a median of 3 
prior chemotherapy regimens to be efficacious. The ORR was 41% (11/27 patients) in the cohort assigned to 
400 mg twice daily, and 22% (6/27) in the cohort assigned to 100 mg twice daily. Median duration of response 
was ~140 days80. 
 
 

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1.3.2 PARP Inhibition in Ovarian Cancer 
Data supporting the activity of PARP inhibitors in BRCA mutant ovarian cancer is steadily growing. In December 
2014, olaparib was approved as monotherapy for the treatment of patients with germline BRCA mutated 
advanced ovarian cancer who have previously received three or more lines of chemotherapy89-90. In a larger 
cohort of patients with ovarian cancer (n=193) published in JCO by Kaufman et al, the tumor response rate was 
31.1%, the median progression-free survival was 7 months, and median overall survival was 16.6 months. Tumor 
response rates for breast, pancreatic, and prostate cancers were 12.9% (8/62; 95% CI, 5.7-23.9), 21.7% (5/23; 
95% CI, 7.5-43.7), and 50.0% (4/8; 95% CI, 15.7-84.3) respectively91.  
 
The NOVA study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study of niraparib 
(administered once daily continuously during a 28-day cycle) as maintenance in platinum-sensitive ovarian 
cancer patients who have either gBRCA mutation or a tumor with high-grade serous histology and who have 
responded to their most recent platinum-containing chemotherapy regimen. Design of these two independent 
cohorts is based on the hypothesis that patients with gBRCA mutations have more pronounced responses to 
niraparib. Primary endpoint is PFS92. 
 
1.3.3 PARP Inhibition in Other Malignancies 
A durable antitumor effect with PARP inhibitors has been seen in metastatic castrate-resistant prostate cancer 
and germline BRCA2 mutations85,87,93. A  study published in the New England Journal of Medicine in October 
2015 by Mateo et al demonstrated that in patients with prostate cancer whose tumors were no longer responding 
to standard therapies and harbored defects in DNA-repair genes (including BRCA 1/2, ATM, Fanconi’s anemia 
genes and CHEK2), treatment with olaparib led to a high response rate (88%)94. 
 
1.3.4 PARP Inhibition Effect on Homologous Recombination 
The loss of DNA homologous recombination repair mechanism (homologous recombination deficiency) leads to 
genomic instability and culminates in tumor cell growth95-96. The development of this deficiency can be due to 
loss of function or inactivation of genes involved in DNA repair as described above including BRCA 1/2, RAD51 
or ATM. In a tumor cell which is already affected by one of these deleterious mutations, PARP inhibitors will 
exploit this mechanism, and effectively lead to cell death by the accumulation of genomic aberrations and 
defective DNA repair. This concept, where two pathway defects alone can be tolerated but when combined 
become lethal is known as synthetic lethality74-75,97. Homologous recombination deficiency is more common in 
ovarian cancers compared to BRCA1/2 mutations, 40-50% versus 15% respectively98. Causative factors in the 
case of homologous recombination deficiency include somatic BRCA 1/2 mutations, BRCA1 methylation (which 
leads to inactivation of the gene), and mutations in other genes implicated in the DNA repair via homologous 
recombination pathway98-99. Thus, there is a clinical need to uncover those biomarkers that can identify patients 
whose tumors may respond better to PARP inhibition. 
 
In a 2006 study by McCabe et al, the hypothesis that other tumors deficient in integral HR genes would also be 
sensitive to PARP inhibitors. They were able to show deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, 
ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity10. 
  
1.3.5 PARP Inhibition in Addition to Chemotherapy  
While single agent PARP inhibitors have been effective in breast and ovarian cancer, the addition of 
chemotherapy may provide more benefit and certain cancer types may require chemo. The activity of combined 
olaparib and chemotherapy was investigated in a randomized Phase 2 study in patients with platinum sensitive, 
recurrent, high-grade serous ovarian cancer who had received up to 3 previous courses of platinum-based 
chemotherapy and were progression-free for at least 6 months. Pts were randomized in a 1:1 fashion to either 
olaparib plus chemotherapy then olaparib monotherapy (olaparib plus chemotherapy group) or chemotherapy 
alone. Primary endpoint was PFS, and prespecified exploratory analyses included efficacy by BRCA mutations 
status. PFS was significantly longer in the olaparib plus chemotherapy group (median 12.2 months) than in the 
chemotherapy alone group (median 9.6 months), especially in patients with BRCA mutations.  
 
In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus 
chemotherapy than with chemotherapy included  alopecia, nausea, neutropenia, diarrhea , headache, peripheral 
neuropathy, and dyspepsia. Most were of mild-to-moderate intensity. The most common grade 3 or higher 

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adverse events during the combination phase were neutropenia (in 43% of 81 patients in the olaparib plus 
chemotherapy group versus 35% of 75 in the chemotherapy alone and anemia (0% versus 7%, respectively).  
Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 
16 of 75 (21%) patients in the chemotherapy alone group84. 
 
1.3.6 PARP Inhibition Resistance 
Though there is great enthusiasm for the benefit of PARP inhibitor-based therapy in patients with metastatic 
breast cancer who are BRCA1 or -2 mutation carriers, it is clear that not all patients benefit, and all eventually 
develop tumor progression.  Thus there are both intrinsic and acquired mechanisms of resistance.  The 
mechanisms underlying responsiveness to treatment are critical to further identifying candidates for this therapy, 
as well as opening potential avenues to overcome resistance to these agents. 
 
Secondary BRCA mutations have been reported and have been shown to restore BRCA function. In the study 
by Norquist et al, six carboplatin-resistant patients with ovarian cancer carrying BRCA mutations were 
subsequently treated with the PARP inhibitor olaparib. Of these patients, two exhibited de novo resistance to 
olaparib, two showed a partial response (PR) and two showed a complete response (CR). The patients who 
were de novo resistant to olaparib both had secondary mutations, one with reversion to the wild-type allele and 
one with a 1-bp insertion; both of these mutations restored the BRCA2 open reading frame. Of the two patients 
with a PR, one exhibited a reversion of a BRCA2 allele to the wild-type sequence, whereas the other was not 
found to have a secondary BRCA2 mutation. The two patients who showed a CR to olaparib did not show any 
signs of secondary mutation100. 
 
There are preclinical models which also suggest one mechanism of resistance to PARP inhibitor olaparib was 
conferred by increased efflux of the drug by ABC transporter P-glycoprotein (PgP) due to increased expression 
of PgP. This was supported by studies in mice which showed enhanced long-term response to PARP inhibition 
when PgP was genetically inactive. Newer PARP inhibitors (AZD2461) which were poor PgP substrates showed 
improved antitumor response compared to response with olaparib101. 
 
Reduced/absent 53BP1 expressions results in partial restoration of HR. Loss of 53BP1 was identified by 
immunohistochemistry in 3 of 11 olaparib-resistant tumors and in 3 of 12 AZD2461-resistant tumors. Expression 
loss was explained by truncating mutations, duplications, frame-shifts, and silencing. This was supported by 
previous in vitro studies loss of 53BP1 partially restores the HR defect that BRCA-1 deletion confers102. 
 
A more recent article by Choi et al suggested that resistance mechanism by which a microRNA, miR-622, 
induces resistance to PARP inhibitors and platinum in BRCA1 mutant HGSOCs by targeting the Ku complex and 
restoring HR-mediated DSB repair. Physiologically, miR-622 inversely correlates with Ku expression during the 
cell cycle, suppressing non-homologous end-joining and facilitating HR-mediated DSB repair in S phase. 
Importantly, high expression of miR-622 in BRCA1-deficient HGSOCs is associated with worse outcome after 
platinum chemotherapy, indicating microRNA-mediated resistance through HR rescue103. 
 
1.4 Niraparib Activity and Pharmacokinetic Profile104 
1.4.1 Niraparib Overview 
Please refer to the most recent Investigator Brochure for the current information on Niraparib. 
 
Niraparib (formerly MK-4827) is an oral small molecule, selective inhibitor of PARP-1 and PARP-2. PARP-
1/PARP-2 are zinc-finger DNA-binding enzymes that are activated by binding to DNA double- or single-strand 
breaks, leading to the conversion of DNA damage into intracellular signals that either activate DNA repair by the 
base excision repair (BER) or NHEJ pathway, or triggers cell death in the presence of extensive DNA damage. 
In tumors with defects in homologous repair (HR), the activity of PARP-1 and PARP-2 are required for BER and 
NHEJ. With PARP inhibition, this alternative pathway is shut down, leading to ongoing DNA damage and 
ultimately cell death. PARP inhibition also leads to increased tumor cell death when combined with cytotoxic 
chemotherapy such as cisplatin, carboplatin, alkylating or methylating agents, radiation therapy, and 
topoisomerase I inhibitors; PARP activity is also required for repair of DNA damage induced by standard cytotoxic 
chemotherapy. As such, niraparib has been developed as a treatment for tumors with defects in the HR DNA 

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repair pathway, as well as a sensitizing agent in combination with cytotoxic agents and radiotherapy. In Phase I 
clinical testing, niraparib is generally safe and well tolerated.  
 
 
Figure 5. Chemical structure of niraparib 
 
1.4.2 Niraparib in vitro Pharmacology 
Niraparib inhibits PARP-1 and PARP-2 enzymes with 50% inhibition (IC50) values of 3.8 nM (PARP-1) and 2.1 
nM (PARP-2) in biochemical assays, with a 100-fold window for PARP-1/PARP-2 over the other PARP family 
members (IC50 of 1300 PARP-3 and 570 TANK-1). Niraparib inhibits intracellular PARP-1 and PARP-2 activity 
with IC50 vales of 4 nM and IC90 values of 50 nM.  
 
Niraparib has selective anti-proliferative activity for cancer cell lines (HeLa and A549) silenced for BRCA-1 or 
BRCA-2, or that carry BRCA-1 or BRCA-2 mutations. The cytotoxic concentration (CC50) for HeLa BRCA-1-
deficient cells was 34 nM, with a 25-fold selectivity window over the wild-type BRCA-1 matched pair HeLa cells 
(CC50 = 852 nM). In BRCA-2 silenced A549 cells, niraparib lead to a CC50 of 11 nM with more than a 100-fold 
selectivity window over wild-type BRCA-2 matched pair cells (CC50 = 1760 nM). The 3 cell lines carrying BRCA-
1 mutations (MDA-MB-436, SUM149PT, SUM1315MO2) had a CC50 of approximately 20 nM, whereas the 
BRCA-2 mutation cell line (CAPAN-1) had a CC50 of 70 nM. The effect of niraparib on normal human cells without 
BRCA mutations is weak, with a CC50 of 2900 to >5000 in human renal, prostate and mammary epithelial cells. 
The mechanisms by which niraparib kills BRCA-deficient or mutated cells has been assessed, and exposure to 
niraparib led to G2/M cell cycle arrest for BRCA-1/BRCA-2-deficient cell lines and BRCA-1 mutant cells. 
Additionally, in the BRCA-1 mutated cells, treatment with niraparib led to significant apoptosis following cell cycle 
G2/M arrest. 
 
1.4.3 Niraparib in vivo Pharmacology 
Niraparib was overall efficacious and well-tolerated in BRCA1/2 mutated and deficient mouse Xenograft models, 
with less than 10% body weight loss seen over the duration of treatment. In MDA-MB0436 BRCA-1-mutant mice, 
niraparib administered orally at 100mg/kg daily or 50mg/kg twice daily dosing led to a significant reduction in the 
average tumor volume in both treatment groups, with a maximal 50% reduction of tumor volume after 33 days, 
and 3 and 4 weeks of therapy was more efficacious in comparison to 1 and 2 weeks of therapy. In CAPAN-1 
BRCA-2-mutant mice, niraparib administered orally at 90mg/kg daily resulted in a 55-60% growth inhibition (by 
both tumor volume and weight) at Day 35. In mice with OVCAR3 Xenografts mimicking BRCA-1 and BRCA-2 
deficiency, niraparib administered orally at 10, 25, and 50 mg/kg daily for 5 days significantly reduced tumor size 
at the end of a 4-week evaluation period, particularly with the 50mg/kg dose. 
 
Niraparib has also been evaluated in high-grade ovarian cancer patient-derived Xenograft (PDX) mice models 
as single agent primary and maintenance therapy. Regarding primary use, in model PDX077 bearing a BRCA2 
mutation, daily oral niraparib 100mg/kg was effective in leading to tumor regression. Regarding maintenance 
use, after regression of tumors observed in PDX077 models treated with 50mg/kg daily of niraparib in 
combination with carboplatin and paclitaxel, mice remained on maintenance 100mg/kg daily niraparib for 21 
weeks, with associated prolonged recurrence-free survival. Daily oral treatment of tumor-bearing mice with 
100mg/kg of niraparib also demonstrated anticancer activity in tumors that were BRCA wild-type but exhibited 
protein deficiencies or mutations in other genes known to be involved with homologous repair, with high 
myChoiceTM HRD scores (myChoiceTM HRD testing utilizes NGS to detect variants of BRCA1 and BRCA2 genes 
and to quantitate the genomic instability of the tumor).  In 27 breast carcinoma PDX models, niraparib single 

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agent at 50mg/kg daily over 28 days led to significant inhibition of tumor growth in 9 out of 19 HRDpos models 
(47%), in comparison to 9 out of 30 models overall (30%). In breast cancer,18 luminal B and 27 triple negative 
PDX models were evaluated. Niraparib caused tumor regression in 2 out of 18 luminal B models (11%) overall 
and 2 out of 9 HRDpos models (22%), and 3 out of 25 triple negative models (8%) overall and 2 out of 16 HRDpos 
models (12%). 
 
More recently, the combination of niraparib with irinotecan was studied in microsatellite instable (MSI) and 
microsatellite stable (MSS) colorectal cancer (CRC) models, and the combination was shown to be more 
efficacious than irinotecan or niraparib alone in both MSI and MSS CRC cell lines. In this evaluation, mice were 
given 10, 25, or 50mg/kg daily of niraparib for 3, 5, or 7 days alone or in combination with 100mg/kg irinotecan 
intraperitoneally weekly for 4 weeks. Mice that received both study drugs had an average tumor volume at the 
end of the study period of 120mm3 in the highest niraparib dose group versus 225mm3 with irinotecan alone105. 
 
Ex vivo pharmacokinetic (PK)/pharmacodynamic (PD) studies demonstrated dose-related inhibition of PARP-1 
in Xenograft tumor homogenate following treatment with niraparib. At both 50 and 100mg/kg oral dosing of 
niraparib, PARP activity in CAPAN-1 tumors was inhibited effectively – 90% inhibited for at least 8 hours with 
the 50mg/kg dose and maximal inhibitory PARP activity sustained for 24 hours with the 100mg/kg dose (decline 
in inhibition noted after 48 hours). 
 
1.4.4 Non-clinical Pharmacokinetics and Metabolism of Niraparib 
Pharmacokinetics of niraparib were evaluated in male Sprageu-Dawley rats and male beagle dogs following IV 
and oral administration. Niraparib exhibited moderate to high clearance (28 and 31 mL/min/kg), a high volume 
of distribution (6.9 and 12.3 L/kg), and moderate half-lives (3 and 6 hours). Niraparib is moderately bound to 
plasma proteins (16% unbound in rat, 28% in dog, and 17% in human) and distributes to the brain. The oral 
bioavailability was reasonable in rats (27%) and dogs (57%), with minimal blood-to-plasma concentrations (1.1-
1.8). Niraparib is excreted predominately unchanged in rates (equally excreted in bile, urine and feces [24-30% 
each]), and is excreted predominately as pharmacologically inactive metabolite carboxylic acid in dogs (excreted 
primarily in urine [53%], followed by bile [18%] then feces [9%]). The major circulating metabolites in both rats 
and dogs were acid metabolite (M1) (due to hydrolysis of niraparib by hepatic carboxylesterase inhibitors) and 
its glucuronide conjugate (M10). Niraparib was not found to be a significant inhibitor of CYP450 enzymes, sparing 
very mild induction of CYP1A2 activity in a dose-dependent fashion. 
 
In studies of oral tolerability of niraparib in rats and dogs, niraparib was evaluated for 8 days, 10 days, 30 days, 
and 90 days of use. In the 8 day evaluation, rats were provided with 10, 100, or 750 mg/kg daily dosing.  In the 
750 mg/kg group, mortality due to bone marrow toxicity was seen in all rats by day 6, and evidence of decreased 
food consumption was seen by day 2-4, though no weight loss was observed. In the 100mg/kg daily group, 
evidence of decreased food consumption was seen by day 6, mild to moderate bone marrow toxicity by day 8, 
with no other major side effects observed. In the 10mg/kg daily group, no significant side effects were observed. 
In the 10 day analysis in dogs, niraparib was given at 4.5, 13.5, and 40.5 mg/kg daily for consecutive 3-day 
intervals. Emesis, mild body weight loss and mild anemia were seen in the 40.5mg/kg daily group. In the 30 day 
evaluations, rats received 5, 10, and 50mg/kg daily dosing with a 2-week recovery period and dogs received 3 
to 15mg/kg daily dosing with a 15-day recovery period. Treatment-related mortality was seen in 5/30 rats in week 
3 at the highest dose, primarily due to septicemia from marrow toxicity. In rats who survived the highest dose, 
side effects such as marrow toxicity and decreased food consumption reversed during the recovery period. No 
significant toxicities were seen in the lower dose level groups. In dogs, the 15mg/kg dose was associated with 
moderate marrow toxicity that reversed during the recovery period. In the 90 day evaluations with a 28-day 
recovery period, rats received 0-30mg/kg daily of niraparib. In the 30mg/kg daily treatment group, significant 
anemia developed requiring a dose reduction to 20mg/kg daily. Dogs received 0, 1.5, 4.5 or 12mg/kg daily of 
niraparib, and all doses were tolerated without treatment-related deaths, with side effects seen only at the 
12mg/kg dose (decreased blood counts, sperm counts). Toxicokinetic analyses for both the rat and dog studies 
revealed the rate (Cmax) and extent (AUC) of systemic exposure increased proportionately. Taking these results 
together, the no-observed-adverse-effect-level (NOAEL) translated to a human dose of 60mg/kg/day, with a 
proposed maximum tolerated dose (MTD) of 300mg/kg/day.  
 
1.4.5 Human Pharmacokinetics, Metabolism and Efficacy of Niraparib 

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The available clinical form that has been used in different clinical trials is a dry-filled capsule (100mg) provided 
at a MTD of 300mg daily as determined in Phase I protocol PN-001.  
 
1.4.5.1 Phase I Niraparib Data 
Niraparib has been evaluated in 153 humans in seven Phase I clinical studies, two ongoing. Three studies 
suspended enrollment early, but not due to safety concerns.  
 
1.4.5.1.1 Niraparib Monotherapy 
In the Phase I study PN-001, the safety, tolerability, PK, PD, and RP2D of niraparib was studied in patients with 
advanced solid tumors. In the dose-escalation portion, 60 patients received niraparib 30mg to 400mg daily, with 
a MTD determined to be 300mg daily. PARP inhibition exceeded 50% at doses greater than 80mg/day and 
antitumor activity was documented beyond doses of 60 mg/day. Analyses of plasma drug concentration profiles 
indicated the Cmax occurs at approximately 3 hours, an approximately 3-4 fold accumulation of AUC and C24 
occurs from Cycle 1 Day 1 to Cycle 2 Day 1, and the mean terminal half-life ranges from 32.8–46.0 hours, 
supporting once daily dosing. In the dose expansion portion of study, 40 patients with platinum-resistant, 
recurrent, high-grade serous ovarian cancer or prostate cancer were enrolled to receive the MTD to assess 
niraparib’s efficacy. Four additional patients (1 recurrent colorectal cancer with PTEN deficiency, 1 recurrent 
endometrial carcinoma, 1 recurrent breast cancer with unfavorable phenotype, and 1 recurrent BRCA wild-type 
epithelial ovarian cancer) were enrolled to receive 300mg daily of niraparib. In all 104 patients treated with at 
least one dose of niraparib, 74% discontinued due to disease progression and 9.6% due to adverse events. Anti-
tumor activity was observed at levels 60 – 400mg, with 14 of the 104 evaluable patients achieving a PR by 
RECIST v1.1 1. In the 20 included BRCA-mutant patients in the dose escalation cohort, the response rate was 
35%, and in BRCA-mutant and platinum-sensitive cancer patients the response rate was 60%. 
 
In the ongoing Phase I study PR-30-5015-C evaluating the absorption, metabolism, excretion, and absolute 
bioavailability of niraparib, 6 patients were enrolled to receive a single dose of 300mg niraparib by mouth on Day 
1 followed by a 15-minute infusion of 300mg niraparib two hours later. Six additional patients were enrolled to 
receive a single 300mg oral dose of niraparib on Day 1. The absolute bioavailability of niraparib was found to be 
approximately 73%, indicating minimal first-pass effect. In this study, niraparib was shown to be moderately 
protein bound to human plasma (83%) and characterized by extensive tissue distribution with a volume of 
distribution of 1220 L. Clearance of niraparib was estimated to be 16.2L/hr, primarily through hepatobiliary and 
renal routes. Age or race had no significant impact on the pharmacokinetics of niraparib. 
 
1.4.5.1.2 Niraparib Combination Therapy 
Study PN-014 is a Phase I study in which niraparib was combined with temozolomide in 19 of 24 planned adult 
patients with advanced solid tumors (recurrent glioblastoma multiforme [GBM] or melanoma) to define DLTs and 
MTD. Initially a Part A dose escalation and Part B efficacy evaluation were planned, but toxicity was too great in 
Part A to proceed. Significant hematologic toxicity was observed at just 40mg of niraparib when combined with 
150mg/m2 of temozolomide. The protocol was ultimately amended to allow for one less frequent administration 
of niraparib at a 30mg dose, or to allow for a reduction of temozolomide to 125mg/m2. Of the evaluable patients, 
a PR was reported in 1 patient with GBM after 6 treatment cycles at 40mg niraparib, and SD was seen in 2 
patients at a dose of 30mg or 40mg. 
 
In the Phase Ib dose-escalation study PN-008 evaluating the use of niraparib in combination with carboplatin, 
carboplatin/paclitaxel and carboplatin/liposomal doxorubicin in patients with advanced solid tumors, niraparib 
was dosed at 40mg on days 1-4 in combination with carboplatin dosed at an AUC = 5 on Day 3 of an every 21 
day cycle.  This combination was poorly tolerated due to myelosuppression, although there were technically no 
DLTs in the 12 enrolled patients in the first study cohort, and was closed. 
 
In the ongoing Phase 1/2 study PN-162 evaluating the safety and efficacy of combination treatment with niraparib 
and pembrolizumab in patients with advanced or metastatic triple negative breast cancer (TNBC) previously 
treated with chemotherapy and patients with advanced, recurrent epithelial ovarian, fallopian tube, primary 
peritoneal cancer previously treated with chemotherapy who are platinum-resistant, eighteen patients are 
expected to enroll. At this time, safety and efficacy data is immature. 
 

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1.4.5.2 Phase II Niraparib Data 
Niraparib has been evaluated in 311 humans in one Phase II clinical study, which is ongoing. 
 
1.4.5.2.1 Niraparib Monotherapy 
PR-30-5020-C (QUADRA) is an open-label, single-arm study evaluating the safety and efficacy of niraparib 
300mg monotherapy daily in patients with advanced, relapsed, high-grade serous epithelial ovarian, fallopian 
tube, or primary peritoneal cancer, to assess the ORR, duration of response, PFS, and DCR. Subset analyses 
will be performed for BRCA mutant and HRDpos tumors. An anticipated 400 patients are expected to enroll, with 
311 enrolled and treated as of 5/20/2016. Efficacy data is immature. 
 
1.4.5.3 Phase III Niraparib Data 
Niraparib (or placebo) has been evaluated in 720 human patients in four Phase III clinical studies, all ongoing, 
based on the results of Phase I/II data and from other trials of PARP inhibitors. 
 
1.4.5.3.1 Niraparib Monotherapy 
PR-30-5011-C (NOVA) is a double-blinded, 2:1 randomized, placebo controlled study in platinum-sensitive 
ovarian cancer patients who have received at least 2 platinum-based regimens with effect and germline mutated 
BRCA1/BRCA2 or a tumor with high-grade serous histology to assess whether maintenance niraparib extends 
progression-free survival (PFS). Patients randomized to receive niraparib maintenance were given 300mg on 
Day 1 of each 28 day cycle, ongoing until treatment discontinuation. PR-30-5011-C also contains a 14-day, 
open-label, 2-treatment crossover sub-study to evaluate the effect of a high fat meal on niraparib exposure. After 
completion of the 14-day food effect portion of study, patients were continued on maintenance niraparib 300mg 
on Day 1 of each 28-day cycle. Eighteen patients were enrolled in the food effect cohort, with blood samples 
collected pre-dose, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 192 hours post-dose on Days 1 and 8.  
The mean ratios of Cmax and AUC0∞ in the fed versus fasted state were 0.83 and 1.08, respectively. Plasma 
concentrations of niraparib declined in a similar manner under fed and fasted conditions with a mean half-life of 
57 hours in fed and 59 hours in fasted. These results overall suggest the administration of niraparib with food is 
expected to have a negligible effect on PK. 
 
Patients with germline BRCA mutations experienced improved PFS as compared with placebo (21 versus 5.5 
months), as did non-germline BRCA mutants (9.3 versus 3.9 months) and HRDpos (12.9 versus 3.8 months) in 
subset analyses. There are no treatment-related deaths reported to date. The incidence of MDS/AML was similar 
for the niraparib and placebo arms (1.4% versus 1.1%, respectively).  
 
In the randomized, open-label Phase III study PR-30-5010-C (BRAVO) comparing niraparib versus physician’s 
choice single-agent chemotherapies (eribulin, vinorelbine, gemcitabine, or capecitabine) in patients with HER2-
negative BRCA1/BRCA2 germline mutated breast cancer, patients are being randomized 2:1 to receive niraparib 
300mg daily by mouth on a continuous dosing regimen or chemotherapy to assess for differences in PFS. 
Efficacy data is unavailable at this time. 
 
And finally, PR-30-5017-C is a double-blind, 2:1 randomized trial evaluating patients with refractory HRDpos 
ovarian tumors to assess the safety and efficacy of niraparib monotherapy. Safety and efficacy data is immature 
at this time. 
 
1.4.6 Safety Pharmacology and Toxicity of Niraparib 
In non-clinical models, niraparib inhibited hERG current with an IC50 value of 10µM and an IC20 value of 3.8µM. 
In vivo cardiac safety studies showed niraparib had no effect on the QTc interval in anesthetized dogs (average 
plasma concentration <15.3µM at 10mg/kg). Mean arterial pressure was increased in a dose-dependent fashion 
by 16% with a 1mg/kg dose, 21% with a 3mg/kg dose, and stabilized at 20% at the 10mg/kg dose. Heart rate 
was also increased dose-dependently (5%, 9%, and 17% with increasing doses). The QRS cardiac interval was 
slightly prolonged at dose 10mg/kg only (6%), though 1-month and 3-month ECGs showed no drug-related ECG 
changes. Niraparib had no effect on neurological function in conscious mice at a single oral dose of 100mg/kg, 
including evaluations for general behavior, neural reflexes, spontaneous activity, and thermoregulation during a 
24 hour post-dose observation period.  
 

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In human clinical studies, the safety of niraparib as monotherapy or in combination with chemotherapy has been 
evaluated in 144 patients in Phase I clinical studies and 427 patients (niraparib or placebo) in Phase III clinical 
studies. All 144 Phase I patients reported at least 1 adverse event (AE), 89.6% of which were likely in part related 
to niraparib. Forty-eight percent reported severe adverse events (SAEs), and 7 (4.9%) patients died – five due 
to disease progression, 1 due to sepsis, and 1 due to cerebral infarction. None of these deaths were considered 
secondary to niraparib. Thirteen patients discontinued study drug for AEs. One patient experienced Grade 3 
pneumonitis, with a possibility for PARP inhibitor induced recall radiation pneumonitis. Most commonly reported 
treatment-related AEs were fatigue (45.1%), nausea (42.4%), anemia (41%), thrombocytopenia (32.6%), 
decreased appetite (23.6%), vomiting (22.2%), neutropenia (22.2%), constipation (19.4%), leukopenia (18.1%), 
and diarrhea (10.4%). In the 60 patients treated at the MTD in monotherapy Phase I evaluations, 21 experienced 
thrombocytopenia (nine Grade 1, five Grade 2, four Grade 3, and three Grade 4), 34 experienced anemia (five 
Grade 1, twenty-one Grade 2, and eight Grade 3), and 16 experienced neutropenia (seven Grade 1, five Grade 
2, and four Grade 3). In combination with temozolomide, 20% of patients experienced dose-limiting 
thrombocytopenia at the 40mg dose versus 100% of patients at the 70mg dose. In PN-001, 12 patients reported 
AEs of prolonged QTc; eight exceeding a 30msec change from baseline. 
 
In the Phase II study PR-30-5020-C, preliminary safety data suggests 90.7% have experienced 1 or more 
treatment-related adverse events, predominately nausea (51.5%), anemia (35.7%), thrombocytopenia (32.6%) 
and fatigue (31.6%). Two patients experienced treatment-related adverse events leading to death (gastric 
hemorrhage, acute respiratory failure). 
 
In the Phase III study PR-30-5011-C, 538 of 546 evaluable patients (niraparib or placebo) experienced AEs, with 
the most common treatment-related AEs being nausea (73.6%), thrombocytopenia (61.3%), and anemia (50.1%). 
Treatment-related Grade 3-5 events that occurred in more than 5% of patients was anemia (23.2%) alone at the 
300mg daily dose. In the substudy PR-30-5011-C1, 26 patients who met the same inclusion criteria as PR-30-
5011-C were treated with niraparib 300mg daily with intensive electrocardiogram (ECG) monitoring to assess for 
cardiac toxicity. There were no reports of clinically significant abnormal ECG changes or QTc prolongation. 
 
1.5 Carboplatin106 
Platinum agents, which have been shown to have broad antitumor activity in solid tumors, are alkylating agents 
which bind to and crosslink DNA. The platinum-DNA adducts then impedes cellular processes including 
replication and transcription, preventing DNA-strand separation. Cisplatin was the first member of the platinum 
family to be discovered to carry antitumor effects and was FDA-approved for that purpose in 1978. Cisplatin use, 
however, has been limited by its toxicity profile, namely nephrotoxicity and gastrointestinal toxicity, and therefore 
safer platinum salts were sought. Carboplatin is a more stable and safer analog of cisplatin and has been shown 
to have similar antitumor activity and efficacy in a variety of different cancer subtypes with essentially no 
nephrotoxic and less gastrointestinal and neurotoxicity. Tumors containing deleterious DNA repair mutations, 
such as BRCA1 or BRCA2 mutations, have been shown to be more sensitive to DNA-damaging agents, including 
platinums107. 
 
Figure 6. Chemical structure of carboplatin 
 
 
1.5.1 Carboplatin Pharmacokinetics 
In patients with creatinine clearances of 60 mL/min or greater, plasma levels of intact carboplatin decay in a 
biphasic manner after a 30-minute intravenous infusion of 300 mg/m2 to 500 mg/m2. The initial plasma half-life 
was found to be 1.1 to 2 hours, and the post-distribution plasma half-life was found to be 2.6 to 5.9 hours. The 
total body clearance, apparent volume of distribution and mean residence time for carboplatin are 4.4 L/hour, 

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16L and 3.5 hours, respectively. The Cmax values and areas under the plasma concentration versus time curves 
from 0 to infinity (AUCinf) increase linearly with dose, although the increase was slightly more than dose 
proportional. Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied (300 mg/m- 
500 mg/m).  
 
Carboplatin is not bound to plasma proteins. No significant quantities of protein-free, ultrafilterable platinum-
containing species other than carboplatin are present in plasma. However, platinum from carboplatin becomes 
irreversibly bound to plasma proteins and is slowly eliminated with a minimum half-life of 5 days. The major route 
of elimination of carboplatin is renal excretion. Patients with creatinine clearances of approximately 60 mL/min 
or greater excrete 65% of the dose in the urine within 12 hours and 71% of the dose within 24 hours. All of the 
platinum in the 24-hour urine is present as carboplatin. Only 3% to 5% of the administered platinum is excreted 
in the urine between 24 and 96 hours. In patients with creatinine clearances below 60 mL/min the total body and 
renal clearances of carboplatin decrease as the creatinine clearance decreases. Carboplatin dosages should be 
reduced in these patients. 
 
1.5.2 Human Efficacy and Safety of Carboplatin 
The efficacy and safety of carboplatin has been studied in a variety of different cancer subtypes. Carboplatin is 
currently FDA-approved in both the first and second-line setting for advanced ovarian carcinoma (in combination 
with cyclophosphamide in first-line), with evidence of improved overall survival. Treatment in studied patients 
was complicated by emesis, hypersensitivity reactions, dose-dependent bone marrow suppression, and 
peripheral neuropathy – particularly in patients over 65 years. Because carboplatin clearance is dependent on 
creatinine clearance, carboplatin doses were reduced to 250mg/m2 (from 300mg/m2) for a creatinine clearance 
of 41-59 mL/min and 200mg/m2 for a creatinine clearance of 16-40 mL/min. In single-agent use in the second-
line setting, carboplatin is administered with a target AUC of 4-6. Carboplatin is also used off-label in combination 
with other chemotherapy agents in breast, bladder, cervical, endometrial, esophageal, head and neck, 
melanoma, lymphoma, non-small cell lung, sarcoma, small-cell lung, testicular, and thymic cancers with similar 
side effect profiles and AUC goals, adjusted for creatinine clearance.  
 
1.6 Rationale for Current Study 
Patients with deleterious DNA repair mutations have been shown to be more sensitive to DNA-damaging agents 
including platinums, and the addition of PARP inhibition in these patients is thought to further sensitize cancer 
cells to the effects of DNA-damaging chemotherapeutic agents. Niraparib is one such PARP inhibitor that is both 
safe and efficacious in patients with advanced solid tumors with HRD and/or BRCA-1/2 mutations. The effects 
of niraparib in combination with platinum-based chemotherapy have not yet been studied in depth, though we 
know from previous evaluations of PARP inhibition with platinum chemotherapy that the combination is safe and 
more efficacious than chemotherapy alone, particularly in HRD tumors70. We therefore hypothesize that using a 
combination of niraparib and carboplatin with close assessment of toxicity and tolerability will lead to better anti-
tumor effect than either agent alone in patients with advanced solid tumor malignancies with evidence of HRD, 
as demonstrated by germline or somatic deleterious mutations in the homologous recombination DNA repair 
pathway. Efficacy of PARP inhibition may negatively correlate with the development of resistance mechanisms, 
and as such we plan to serially assess for the development of resistance in tumor biopsy samples over the 
course of study treatment. 
 

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2.0 STUDY OBJECTIVES 
2.1 Primary Objectives: 
2.1.1 Phase Ia (dose-escalation phase): To identify the RP2D and schedule of niraparib plus carboplatin for 
patients with homologous recombination deficient advanced solid tumor malignancies 
 
2.1.2 Phase Ib (dose-expansion phase): To determine the anti-tumor efficacy of niraparib plus carboplatin in a 
non-disease specific cohort of patients with homologous recombination deficient advanced solid tumor 
malignancies, as determined by RECIST v1.1 
 
2.2 Secondary Objectives: 
Clinical: 
a. To evaluate the safety and tolerability of niraparib plus carboplatin 
b. To determine evidence of any disease specificity with this combination 
c. To assess the anti-tumor efficacy of combined therapy as determined by RECIST v1.1 
d. To assess the anti-tumor efficacy of combined therapy as determined by measurement of overall survival 
(OS) and progression free survival (PFS) 
Scientific: 
a. To assess the effects of niraparib alone, and niraparib plus carboplatin on pharmacodynamic markers 
of DNA damage and repair, including γH2AX/RAD51 foci formation, and as measured by the PARP 
trapping assay 
b. To explore predictive markers of response and/or resistance to therapy in serial tumor biopsy samples  
2.3 Indication: 
Patients with advanced solid tumor malignancies harboring a germline or somatic deleterious mutation in genes 
involved in DNA damage repair through homologous recombination (including but not limited to RAD50/51/51B, 
BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, or BAP1 that may benefit from 
molecularly targeted therapy with the PARP inhibitor, niraparib, in addition to chemotherapy with carboplatin. 

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3.0 SUBJECT POPULATION 
3.1 Subject Population, Number of Subjects and Feasibility 
(See Appendix A for Study Eligibility Checklist) 
 
3.1.1 Subject Population 
Patients will have advanced solid tumor malignancies harboring a germline or somatic deleterious mutation in 
genes involved in DNA damage repair through homologous recombination including but not limited to 
RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, or BAP1 and will have 
biopsiable disease and measurable disease by RECIST v1.1 criteria, and will have an adequate PS, bone 
marrow, hepatic, and renal function. In the Phase Ib portion of study, there will be one expansion cohort of 20 
patients with a patient population identical to Phase Ia.   
 
3.1.2 Number of Subjects 
A minimum of 18 and a maximum of 126 evaluable patients for Phase Ia, and 20 evaluable patients for Phase 
Ib. 
 
3.1.3 Feasibility 
At the multiple sites participating in this study, we anticipate being able to screen as many as 1,000 patients per 
year. Assuming a qualifying mutation rate of 5-10%, and 25% of screened patients being otherwise trial eligible, 
we anticipate enrolling 30 patients per year across multiple medical institutions within the United States. Only 
patients with advanced solid tumor malignancies will be eligible for enrollment. The expected accrual duration 
will be approximately 48 - 60 months. 
 
3.2 Inclusion Criteria 
3.2.1 Patients PRE-identified as having either a germline deleterious mutation or tumor expression of a 
deleterious mutation) as determined by Next-generation DNA sequencing only, in at least one gene involved in 
DNA damage repair through homologous recombination including but not limited to: RAD50/51/51B, BARD1, 
BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, or BAP1. 
 
3.2.1.1 Patients with somatic mutations will be PRE-identified as having a homologous recombination 
mutation based on NGS done in a CLIA certified, CAP tested and bioinformatics-validated testing lab PRIOR 
to enrollment in this current protocol.  The testing may have been done at any time prior to enrollment.   
3.2.1.1.a The determination of a deleterious mutation must be supported in the documentation included 
in the testing, and should include clinical, or pre-clinical literature to support the finding that a specific 
mutation results in impaired function of the gene, and thus impaired DNA repair through homologous 
recombination. Variants of unknown significance will not be eligible. 
3.2.1.1.b For the Phase Ib portion of the study, if any patient has had NGS testing more than 12 months 
prior to enrollment, then a repeat NGS test must be done and the deleterious somatic mutation must be 
re-identified for inclusion. 
 
3.2.1.2 Patients with germline deleterious mutations may have been identified at any time point prior to 
inclusion in the protocol and do NOT need to have this genetic testing repeated regardless of time frame and 
intervening therapy. 
 
3.2.2 Advanced, solid tumor malignancy (other than prostate cancer, see Section 3.3.11).  
3.2.2.1 The tumor must be amenable to biopsy.  
3.2.2.2 For the Phase Ib portion, the patient must consent to 4 mandatory biopsies during study. 
 
Note: If there are any issues with obtaining the study required pre-treatment biopsy (ie. it is deemed unsafe 
to obtain the biopsy or it is determined that the initial biopsy sample obtained did not contain tumor tissue), 
the subject may only be allowed to enroll after receiving permission from the Study Chair(s). Additionally, 
they will be exempt from being required to obtain additional on study biopsies. 
 
3.2.3 Life expectancy of more than 3 months 
 

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3.2.4 Age ≥ 18 years 
 
3.2.5 Measurable disease by RECIST v1.1 criteria (tumor ≥ 1 cm in longest diameter on axial image on computed 
tomography (CT) or magnetic resonance imaging (MRI) and/or lymph node(s) ≥ 1.5 cm in short axis on CT or 
MRI) on baseline imaging 
 
3.2.6 ECOG performance status (PS) of 0 to 1 (Table 11, Appendix A) 
 
3.2.7 Patients who have received and experienced disease progression on, or have been intolerant to, standard 
first line therapies known to confer clinical benefit. Patients who refuse standard therapy would also be eligible, 
as long as their refusal is documented. 
 
3.2.8 Adequate hepatic, bone marrow, and renal function at the time of enrollment: 
3.2.8.1 Bone Marrow: Absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100,000/mm3; Hemoglobin 
≥ 9.0 g/dL.  Patients must be able to meet the criteria without transfusion within 4 weeks or receipt of colony 
stimulating factors, filgrastim (eg neupogen or biosimilar) within 14 days, or peg-filgrastim (eg, neulasta) or 
recombinant erythropoietin within 4 weeks before obtaining sample  
 
3.2.8.2 Renal function: Serum creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min/1.73 m2 
 
3.2.8.3 Hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × the 
upper normal limit of institution's normal range. Total bilirubin ≤ 1.5 × the upper normal limit of institution's 
normal range. For subjects with liver metastases, AST and ALT < 5 × the upper normal limit of institution's 
normal range, and total bilirubin >1.5 - 3.0 x the upper normal limit of institution's normal range are acceptable 
as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia 
 
3.2.8.4 Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) must be ≤ 2 X the upper limit of the 
institution's normal range and International Normalized Ratio (INR) < 2. Subjects on anticoagulation (such 
as coumadin) will be permitted to enroll as long as the INR is in the acceptable therapeutic range as 
determined by the investigator 
 
3.2.9 Patients may have received an unlimited number of prior therapies.  Prior anti-cancer therapies must be 
given ≥ 2 weeks prior to Cycle 1, Day 1 on trial (and the patient must have recovered from all side effects of prior 
therapies that are exclusionary, as per Section 3.3 below) 
 
3.2.10 Patients must have fully recovered from all effects of surgery.  Patients must have had at least two weeks 
after minor surgery and four weeks after major surgery before starting therapy.  Minor procedures requiring 
conscious sedation such as endoscopies or mediport placement may only require a 24-hour waiting period, but 
this must be discussed with an investigator 
 
3.2.11 Female patient has a negative serum or urine pregnancy test within 72 hours prior to taking study 
treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from 
screening through 180 days after the last dose of study treatment, or is of non-childbearing potential. Non-
childbearing potential is defined as follows (by other than medical reasons): 
• ≥45 years of age and has not had menses for >1 year 
• Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy 
must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation 
• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or 
oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. 
Tubal ligation must be confirmed with medical records of the actual procedure 
 
Otherwise the patient must be willing to employ methods to avoid pregnancy. Abstinence is an acceptable 
method to avoid pregnancy if this is the established and preferred method for the patient.  Alternatively, the 
patient and partner must use 2 adequate barrier methods throughout the study, starting with the screening visit 

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35
through 180 days after the last dose of study treatment. Information must be captured appropriately within the 
site’s source documents.  
 
Male patients must also agree to use an adequate method to avoid pregnancy, which may include abstinence, 
if this is the established and preferred method for the patient starting with the first dose of study treatment through 
180 days after the last dose of study treatment.  
 
Additionally, the participants must agree to not breastfeed during the study or for 180 days after the last dose of 
study treatment. 
 
3.2.12 Patient is capable of swallowing pills whole 
 
3.2.13 Subject is capable of understanding and complying with parameters as outlined in the protocol and able 
to sign and date the informed consent, approved by the IRB, prior to the initiation of any screening or study-
specific procedures 
 
3.3 Exclusion Criteria 
3.3.1 Prior disease progression while receiving platinum chemotherapy; or any platinum chemotherapy within 
the last 6 months 
3.3.1.1 For all patients (except breast cancer patients) who received platinum-based adjuvant or neo-
adjuvant chemotherapy, at least 6 months must have passed between the last dose of platinum-based 
therapy and the development of metastatic disease.  
3.3.1.2 For breast cancer patients, at least 12 months must have passed between the last dose of platinum-
based adjuvant or neo-adjuvant therapy and the development of metastatic disease 
 
3.3.2 Patients must not require “support” to maintain adequate blood counts, as defined by: 
3.3.2.1 Patients must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior to initiating 
protocol therapy. 
3.3.1.2 Patient must not have received colony stimulating factors, filgrastim (eg neupogen or biosimilar) within 
14 days, or peg-filgrastim (eg, neulasta) or recombinant erythropoietin within 4 weeks prior initiating protocol 
therapy. 
3.3.2.1 Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior 
chemotherapy that persisted > 4 weeks and was related to the most recent treatment. 
 
3.3.3 Prior PARP inhibitor-based therapy 
 
3.3.4 Known or suspected CNS metastases, unless at least one month has passed since last local CNS therapy 
and there is no evidence for recurrent or progressive CNS disease on follow up imaging. Participants may remain 
on steroids for CNS disease if they are taking a stable dose 
 
3.3.5 Active severe infection, or known chronic infection with HIV or hepatitis B virus (testing not required prior 
to enrollment) 
 
3.3.5.1 Patients with chronic Hepatitis C virus may be enrolled if there is no clinical/laboratory evidence of 
cirrhosis AND the patient’s liver function tests fall within the parameters set in Section 3.2.8.3, Inclusion 
Criteria, Hepatic function 
 
3.3.6 Cardiovascular disease problems including unstable angina, therapy for life-threatening ventricular 
arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months.   
 
3.3.7 Life-threatening visceral disease or other severe concurrent disease that would, in the investigator’s 
judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or 
compromise compliance with the protocol (e.g. chronic active hepatitis, active untreated or uncontrolled fungal, 
bacterial or viral infections, etc.) 
 

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3.3.8 Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome, or small bowel resection) 
 
3.3.9 Presence of a psychiatric illness or social situation that would limit compliance with study requirements 
 
3.3.10 Women who are pregnant or breastfeeding 
 
3.3.11 The subject must not have had diagnosis, detection, or treatment of another type of cancer ≤2 years prior 
to randomization (except basal or squamous cell carcinoma of the skin that has been definitively treated). 
Questions regarding the inclusion of individual subjects should be directed to the Principal Investigator, Dr. 
Isaacs. 
 
3.3.12 Due to licensing agreements for Niraparib, patients with a current diagnosis of prostate cancer will be 
excluded. 
 
3.3.13 Clinically significant peripheral neuropathy at the time of enrollment (defined in the NCI CTCAE v4.0) as 
grade 2 or greater neurosensory or neuromotor toxicity) 
 
3.3.14 Patients must not have had investigational therapy administered ≤4 weeks, or within a time interval less 
than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing 
in this study 
 
3.3.15 Patients must not have had radiotherapy encompassing >20% of the bone marrow within 2 weeks; or any 
radiation therapy within 1 week prior to Day 1 of protocol therapy 
 
3.3.16 Patients must not have a known hypersensitivity to the components of niraparib or the excipients 
 
3.3.17 Patients must not have current evidence of any condition, therapy, or laboratory abnormality (including 
active or uncontrolled myelosuppression [ie, anemia, leukopenia, neutropenia, thrombocytopenia]) that might 
confound the results of the study or interfere with the patient's participation for the full duration of the study 
treatment or that makes it not in the best interest of the patient to participate 
 
3.3.18 Patients must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, 
nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, 
uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure 
disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that 
prohibits obtaining informed consent 
 
3.3.19 Patient must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia 
(AML) 
 
3.4 Additional Study Restrictions 
3.4.1 Granulocyte Colony-Stimulating Factor (GCSF) 
Prophylactic cytokine (Granulocyte Colony-Stimulating Factor [GCSF]) administration should not be given in the 
first cycle of the study, but may be administered in subsequent cycles according to local guidelines and Section. 
 
3.4.2 Substrates of P-glycoprotein 
Niraparib weakly induces Cytochrome P450 (CYP)1A2 in vitro and is a relatively poor substrate for P-
glycoprotein (P-gp); therefore, investigators are advised to use caution with the substrates for CYP1A2 with a 
narrow therapeutic range, i.e. theophylline and tizanidine. The niraparib safety profile includes risk for 
thrombocytopenia; therefore, patients should be advised to use caution with anticoagulation and antiplatelet 
drugs. 

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3.4.3 Other Anticancer Therapy 
For purposes of this protocol, anti-tumor treatment may be defined as, but is not limited to, anti-cancer agents 
(cytotoxic chemotherapy, immunotherapy, endocrine therapy, or biologic therapy), radiotherapy, and 
investigational agents. An investigational agent is any drug or therapy not currently approved for use in humans. 
No other anticancer therapy is permitted during the course of the study treatment for any patient (the patient can 
receive a stable dose of corticosteroids during the study as long as these were started at least 4 weeks prior to 
enrollment, per exclusion criteria above). If the patient discontinues study treatment, this restriction no longer 
applies, however the patient will remain enrolled in the study for the purpose of collecting subsequent outcomes. 
Palliative radiotherapy (excluding the pelvic region and/or palliative radiotherapy encompassing >20% 
of the bone marrow within 2 weeks of the first dose of study treatment) is allowed for pre-existing small 
areas of painful metastases that cannot be managed with local or systemic analgesics as long as no 
evidence of disease progression is present >1 week prior to first dose of study treatment. 
 
3.4.4 Vaccines 
Live vaccines within 7 days prior to the first dose of study treatment. Seasonal flu vaccines that do not contain 
live viruses are allowed. Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, bacille Calmette Guerin, and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed. Intranasal influenza vaccines (eg, Flu-
Mist®) are live attenuated vaccines and are not allowed 
 
3.4.5 Birth Control 
An adequate method of birth control should be used from the time the participant signs the consent form, the 
duration of protocol therapy, and for 180 days following the last dose of niraparib.  Acceptable methods of birth 
control include:  
 
Total sexual abstinence  
 
Two highly effective forms of contraception, defined as: diaphragm, condom (male or female), sponge, 
and/or spermicide per local regulations or guidelines. Appropriate hormonal contraceptives will include 
any registered and marketed contraceptive agent that contains an estrogen and/or a progestational agent 
(including oral, subcutaneous, intrauterine, or intramuscular agents).  
 
Permanent sterilization, defined as hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or 
bilateral orchiectomy.  Participants and their sexual partners who’ve undergone vasectomy or tubal 
occlusion must also use a male condom with spermicide.   
 
Postmenopausal, defined as a female participant or sexual partner >45 years of age who has not 
menstruated for at least 12 consecutive months 
In addition, men must not donate sperm during niraparib therapy and for 180 days after receiving the last dose 
of niraparib. 
 
3.4.6 Breast Feeding 
Patients must not breast-feed from the first dose of niraparib and for 180 days following the final dose of niraparib. 
 
3.4.7 Blood Donation 
Patients must not donate blood during the study or for 90 days after the last dose of study treatment. 
 
3.5 Other Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or herbal 
supplements) that the subject is receiving at Screening up to the Final Visit must be recorded in source 
documents and the case report forms (CRFs). The reason for use, date(s) of administration (including start and 
end dates), and dosage information (including dose and frequency) must be recorded. Any change in 
concomitant therapy during the study period must be similarly recorded. Questions regarding prior or 
concomitant therapy should be directed to one of the investigators. 
 
3.5.1 Prior Surgery 
Patients must have fully recovered from all effects of surgery.  Patients must have had at least two weeks after 
minor surgery and four weeks after major surgery before starting therapy.  Minor procedures requiring conscious 
sedation such as endoscopies or mediport placement only require a 24 hour waiting period. 

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3.5.2 Supportive Care 
Subjects should receive best supportive care and treatment of symptoms during the study as appropriate, 
including transfusion of blood and blood products, oxygen therapy, nutritional support, intravenous fluids, and 
treatment with appropriate medications (antibiotics, antiemetics, antidiarrheals, and analgesics, etc.).  
Medications, including steroids, which are given for supportive care, such as appetite stimulation, may be given 
concurrently. 
 
3.5.2.1 Bisphosphonates and denosumab 
Bisphosphonates and denosumab are permitted for the treatment of osteoporosis and prevention of skeletal 
related events for patients with bone metastases. 
 
3.5.2.2 Hematopoietic growth factors 
Hematopoietic growth factors may be used according to the American Society of Clinical Oncology (ASCO) 
guidelines, but not during the first three cycles of the Phase Ia portion of the study (Section 6.9, Table 8). The 
patient must be referred to a hematologist for further evaluation (1) if frequent transfusions are required or (2) if 
the treatment-related hematologic toxicities have not recovered to CTCAE Grade 1 or less after 4 weeks. 
 
3.5.3 Permitted Concomitant Therapy Requiring Caution 
Medications to be used with caution during niraparib and carboplatin treatment in this study are listed below. 
This list is not comprehensive and is only meant to be used as a guide. These medications should be excluded 
from patient use if possible. If they must be given, then use with caution. There are no known absolutely 
contraindicated medications in combination with niraparib and carboplatin. 
• Inducers of CYP1A2: 
o Moderate inducers: montelukast, phenytoin, theophylline, tizanidine, warfarin 
o Weak inducers: alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, tizanidine, moricizine, 
omeprazole, phenobarbital  
• Antiplatelet and Anticoagulation agents (combined bleeding risk if thrombocytopenia develops): 
o Antiplatelet: aspirin, triflusal, clopidogrel, prasugrel, ticagrelor, ticlopidine, cilostazol, vorapaxar, 
abciximab, eptifibatide, tirofiban, dipyridamole, thromboxane inhibitors 
o Anticoagulation: coumadin, dabigatran, rivaroxaban, apixaban, edoxaban, heparin, fondaparinux, 
bivalirudin, argatroban 
• Aminoglycosides (increased risk of ototoxicity with carboplatin): tobramycin, gentamicin, streptomycin, 
neomycin, kanamycin 
Additionally, patients must not donate blood during the study or for 90 days after the last dose of study treatment. 
 
3.6 Removal/Replacement of Subjects from Therapy or Assessment 
An evaluable patient must meet all inclusion/exclusion criteria, have adequate tissue for initial molecular 
assessment as well as repeat biopsies per protocol, and be evaluable for the primary study endpoints of safety 
and tolerability of niraparib with carboplatin as measured by NCI CTCAE 5.0 as well as anti-tumor efficacy as 
determined by RECIST v1.1.   
 
3.6.1 Screen Failures 
Patients will be identified and enrolled when treatment modification required (initial therapy or change in therapy 
for progressive disease).  All patients must continue to meet the inclusion and exclusion criteria up to and 
including the first day of treatment. Reasons for patients who have enrolled, but become ineligible could include 
(but are not limited to): 
- The patient is no longer eligible based on laboratory parameters 
- The patient’s performance status has declined 
- The patient does not have adequate tissue for molecular assessment  
- The patient no longer has measurable disease 
Patients who become ineligible prior to initiation of therapy per protocol will be considered screen failures.  
Screen failures must be replaced until: 1) enough patients are enrolled to determine the RP2D and schedule in 
the Phase Ia portion of study; and 2) 20 patients are enrolled in the Phase Ib portion of study. 
 
 

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3.6.2 Evaluable Patients 
3.6.2.1 Safety and Tolerability Evaluable 
For the Phase Ia portion, for a patient to be evaluable for safety, tolerability, and assessment of dose-limiting 
toxicities, the patient must complete the first two cycles. Any patient who is taken off study for any reason other 
than toxicity (or death related to toxicity) will not be considered evaluable for assessment of safety, tolerability, 
and assessment of dose-limiting toxicity, and must be replaced. 
 
3.6.2.2 Response Evaluable 
A patient who initiates therapy per protocol, and is taken off study for disease progression or clinical progression, 
including death related to the underlying solid tumor malignancy (as determined by the treating oncologist) will 
be considered evaluable for response assessment.  However, patients who have initiated therapy and who 
withdraw from the study for any reason other than clinical or radiographic progression, or death believed 
unrelated to their underlying solid tumor malignancy will not be considered evaluable for response.  Reasons 
for patients who have initiated therapy, but are no longer evaluable for response could include (but are not limited 
to): 
 
The patient cannot tolerate therapy despite dose modifications, and there is no evidence of 
clinical/radiographic disease progression at the time of stopping therapy 
 
An unexpected and/or unrelated medical illness, such as a stroke or myocardial infarction that is 
considered unrelated to the underlying solid tumor malignancy 
 
An unexpected trauma or death that is considered unrelated to the underlying solid tumor malignancy 
3.7 Multi-Institutional Trial Coordination 
(See Appendix B for the Patient Registration Form) 
 
3.7.1 Personnel 
Georgetown University’s LCCC Consortium IIT Office will play the primary role in coordinating the trial between 
Lombardi-Georgetown and additional sites.  Georgetown University’s LCCC Consortium IIT Office will be the 
main point of contact for Dr. Isaacs and the other site PIs for any study related concerns, including data 
management and regulatory.  
 
3.7.2 Patient Enrollment 
Enrollment at the sites will be competitive.  If a patient is being screened for enrollment, the local research 
coordinator must send an email within 24 hours containing the patient’s initials to the local PI, to Dr. Isaacs, and 
to Georgetown University’s LCCC Consortium IIT Office.  If a patient is successfully screened, the local research 
coordinator must send all supporting documentation to Georgetown University’s LCCC Consortium IIT Office by 
secure email to confirm eligibility. Patients should not start therapy until Dr. Isaacs and Georgetown University’s 
LCCC Consortium IIT Office have reviewed the patient’s records and confirmed that the patient is indeed eligible 
for enrollment. 
 
3.7.3 Data Collection and Management  
Patient data will be entered into the on-line accessible database.  This database is housed at Lombardi-
Georgetown, but is accessible anywhere there is internet access.  The data manager and research coordinator 
at each site will attend an on-line training session so that they may learn how to enroll data into the data base.  
All screening data should be entered prior to starting therapy, and all ongoing patient data should be entered 
within 10 business days of each patient visit.   
 
3.7.4 Conference Calls 
A monthly conference call will be held between Lombardi-Georgetown and the other sites to review patient 
enrollment, toxicity, and response assessment.   
 
In addition, a separate conference call will be held between OHSU and the other sites to review sample collection, 
tissue coordination, and tissue analysis.  This will include an ongoing review of the success rate of the tumor 
biopsies, and of the ex-vivo tumor samples.  
 
 

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3.7.5 Trial Auditing 
Georgetown University’s LCCC Consortium IIT Office will arrange all primary source documents for the patients 
to be audited.  This will include collecting copies of the primary source data for any patients treated at other sites. 
 
4.0 STUDY PROCEDURES: MOLECULAR ASSESSMENT AND TREATMENT 
ASSIGNMENT 
4.1 Study Overview 
This is a multi-institutional Phase I dose-escalation and dose-expansion trial for patients with advanced solid 
tumor malignancies and pre-identified germline or somatic deleterious mutations in the homologous 
recombination DNA repair pathway (HR deficient). The trial is designed to assess the efficacy and safety of 
niraparib plus carboplatin in patients with evidence of HRD. The primary endpoint will be identifying the RP2D 
and schedule of niraparib plus carboplatin, as well as establishing the anti-tumor efficacy of niraparib plus 
carboplatin as determined by RECIST v1.1 criterion.  
 
Potential trial patients will be pre-identified at participating centers as having either a germline or somatic  
deleterious mutation involving genes critical to DNA repair through homologous recombination, as demonstrated 
by Next-generation DNA sequencing in a CLIA certified, CAP tested and bioinformatics-validated testing lab prior 
to enrollment. This could include, but not be limited to one of the following genes – RAD50/51/51B, BARD1, 
BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, or BAP1.  The determination of a deleterious 
mutation must be supported in the documentation included in the testing, and should include clinical, or pre-
clinical literature to support the finding that a specific mutation results in impaired function of the gene, and thus 
impaired DNA repair through homologous recombination. Mutations and deletions will be evaluated against the 
Human Gene Mutation database and other online databases (ClinVar, Breast Cancer Information Core, PubMed) 
to evaluate the functional relevance, and to make a determination on the likelihood of the mutation resulting in 
defective homologous recombination-dependent DNA repair. Variants of unknown significance will not be eligible. 
 
Examples of evaluable mutations by commercially available somatic and germline genetic testing include: 
 
Somatic 
RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, or 
BAP1 
Germline RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, or 
BAP1 
 
If a pathogenic mutation in the HR pathway is confirmed and not listed above, the study PI will determine if the 
patient is eligible based on available clinical or pre-clinical literature. 
 
Patients with advanced solid tumor malignancies with documented germline or somatic deleterious mutations 
involving genes critical to DNA repair through homologous recombination, and who have an adequate 
performance status (PS), bone marrow, hepatic, and renal function will be screened for enrollment.  If a patient 
is eligible because they have a known deleterious germline mutation, testing must have been performed in a 
clinical laboratory improvement amendments (CLIA) certified laboratory prior to study entry. Patients who 
ultimately meet the inclusion and exclusion criteria as detailed in Section 3, and desire participation, will be 
enrolled. Accrual will rely on physician referral of patients identified as having tumor expression of a deleterious 
HR mutation who are thought likely to benefit from trial therapy over standard therapies. Similarly, we will rely 
on physician referrals of patients identified as having a germline deleterious HR mutation. Patients can enroll in 
the first-line treatment setting, or following any previous non-PARP inhibitor-based therapy(ies) or any previous 
platinum-based therapy(ies) assuming the last platinum dose was greater than 6 months prior to enrolment (or 
12 months for breast cancer patients, see Section 3.3.1) and there was no disease progression while on platinum 
chemotherapy. Eligible patients who desire enrollment in the first-line setting will require documentation of 
standard of care therapy refusal.  
 
Patients will be PRE-identified as having the homologous recombination mutations based on NGS done PRIOR 
to enrollment in this current protocol.  The testing may have been done at any time prior to enrollment.   
 

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In the Phase Ib portion of study, there will be an expansion cohort of 20 additional patients with similar 
documented germline or somatic deleterious mutations critical to DNA repair through homologous recombination 
– and who have biopsiable and measurable disease, and an adequate performance status (PS), bone marrow, 
hepatic, and renal function.  These patients will be treated at the recommended Phase II dose and schedule 
determine in the Phase Ia portion of the trial.   
- 
For the Phase Ib portion of the trial, if any patient has had NGS testing more than 12 months prior to 
enrollment then a repeat NGS test must be done and the deleterious mutation identified for inclusion. (Note 
that this stipulation does not include patients who have confirmation of a deleterious germline mutation. 
These patients may have been identified at any time point prior to inclusion in the protocol and do NOT need 
to have this genetic testing repeated regardless of time frame and intervening therapy).      
 
4.1.1 Phase Ia Portion (Dose Escalation Procedures) 
During the Phase I Portion of the study, patients will be enrolled in a 3+3 alternating dose escalating fashion to 
determine the RP2D and schedule of niraparib plus carboplatin, to a maximum dose of niraparib of 300mg daily 
and a maximum dose of carboplatin AUC of 4. To start, 3 patients will be enrolled at dose level 1, niraparib 
100mg daily on days 1-14 of a 21 day cycle (Table 1, Schedule #1). This starting dose is selected to be above 
the dose level previously identified as leading to significant PARP inhibition (80mg daily dose), but below the 
current recommended dose of 300mg due to concerns for combined toxicity with platinum therapy. Given 
concern for adverse events with this combination, particularly myelosuppression, patients will receive the first 
cycle with niraparib alone, to enable the evaluation of PARP inhibitor therapy alone in each individual patient. 
Because these patients’ tumors harbor defects in homologous recombination, we would anticipate these patients 
will gain some anti-tumor benefit from the PARP inhibitor therapy alone – alleviating any concerns over 
compromising efficacy in this niraparib alone run-in cycle.  
 
Then, starting cycle 2, carboplatin will be added. To maximize PARP inhibition prior to dosing with carboplatin, 
carboplatin will be given on Day 2 of a given cycle. The starting dose of carboplatin in dose level 1 will be AUC 
= 2 on day 2 of each 21 day cycle. This starting dose is well below the AUC=5 dose at which significant 
myelosuppression has previously been observed.  
 
 
 
 
Figure 1: Treatment and Biopsy Schedule: Niraparib (Days 1-14) 
 
The 3+3 schema will be employed to ensure safety and tolerability. With this design, if there are less than 2 
dose-limiting toxicities (DLTs) in the first 3 patients, then 3 additional patients will be enrolled to the current dose 
level cohort. If there are less than 2 dose-limiting toxicities (DLTs) in these 6 patients, then 3 additional patients 
will be enrolled in the next dose level (Table 1), and so on. If there are greater than or equal to 2 DLTs in a given 
6 patient cohort, then the dose level below will be considered the maximum tolerated dose (MTD) and will be 
employed as the RP2D and schedule. If dose level 1 is not tolerated, then an alternative schedule will be pursued 

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(Section 4.1.1.1). The RP2D and schedule will be used for the Phase Ib portion of the study.  While 9 dose levels 
are depicted in Table 1, it is very possible that dose escalation will stop at a dose level <9.  
 
Dose 
Cohort 
Niraparib 
(mg Daily) 
Carboplatin 
(AUC) 
1 
100 
2 
2 
100 
3 
3 
100 
4 
4 
200 
2 
5 
200 
3 
6 
200 
4 
7 
300 
2 
8 
300 
3 
9 
300 
4 
Table 1: Dose Escalation for Carboplatin and Niraparib 
(Niraparib Dosing Days 1-14) 
 
Patients will be monitored for safety with blood tests, clinic visits, and physical exams weekly for the first 3 cycles, 
on the first day of the week (e.g. Days 1, 8, and 15). Patients will return for carboplatin dosing on Day 2 beginning 
with the second cycle, but labs from the previous day will not need to be redrawn. Restaging exams will occur 
every 9 weeks, as determined by the cycle number and not the calendar. However, if there are any significant 
delays, restaging exams must not occur more than 12 weeks apart.  Patients who have SD at restaging, and 
who are adequately tolerating therapy will remain on study.  For cycles 4 and beyond, patients will have clinic 
visits, physical exams and lab work on Day 1 only, assuming no toxicities of grade 2 or greater. They will have 
to return for carboplatin infusion (either Day 2, or days 2 and 9 according to the alternative treatment schedules 
below). If a dose change occurs (i.e. alternative schedule pursued), patients will undergo weekly blood 
tests, clinic visits, and physical exams for 1 cycle, then will undergo evaluations on Day 1 only of each 
subsequent cycle. Interim analyses to assess secondary endpoints of OS and PFS will be scheduled to occur 
at 12 months and 24 months. 
 
In addition to dose-escalation evaluation, pharmacodynamic studies will be evaluated on participant’s biopsy 
samples and serial serum samples, directed towards an assessment of DNA damage including ᵞH2AX and 
RAD51 foci formation, as well as an assessment of PARP inhibitory activity, as measured by a PARP-trapping 
assay.   We will also undertake NGS analysis of DNA repair enzymes at the time of progression (off study) to 
evaluate markers that predict response and resistance to therapy.  In addition, a portion of all pre-treatment 
tumor samples will be used in ex vivo models (e.g. organoids) for further analysis of mechanism of resistance 
and to identify combinatorial therapies that can overcome resistance. 
 
4.1.1.1 Alternative Schedules 
Given concerns over the potential for combinatorial toxicity, especially on myelosuppression, two alternative 
dosing schedules will be considered. The decision to pursue one or both of these alternative schedules will be 
determined by the PIs and will take into account toxicities observed to date, as well as the pharmacodynamic 
effects observed on serial tumor biopsies.  
 
Thus, for example, if dose level 1 is too toxic in Schedule #1 (i.e. with 2 or more DLTs), then patients will be 
enrolled according to Schedule #2. If Schedule #2 remains too toxic, then Schedule #3 will be employed.   
 
However, the investigators will also be reviewing the pharmacodynamic assessments of DNA damage, and will 
have the opportunity to compare these results to the clinical efficacy.  If these pharmacodynamics assessments 
suggest that an alternative schedule may be more efficacious, or that an alternative schedule merits scientific 
exploration, then the investigators may choose as a group to pursue one or both of the alternative schedules.  
Ultimately, the schedule and the dose must be selected by the investigators prior to enrollment of the Phase Ib 
expansion cohort – as patients in the Phase Ib expansion cohort will be enrolled in only one RP2D and schedule. 

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In the first alternative schedule (Schedule #2), niraparib will only be dosed on Days 1-7 of an every 21 day cycle 
(Figure 2).  The dose escalation will be otherwise similar (Table 2). Pre-treatment biopsies will again be obtained, 
as depicted in Figure 2.  
 
 
Figure 2: Treatment and Biopsy Schedule: Niraparib (Days 1-7) 
 
Dose 
Cohort 
Niraparib 
(mg Daily) 
Carboplatin 
(AUC) 
1 
100 
2 
2 
100 
3 
3 
100 
4 
4 
200 
2 
5 
200 
3 
6 
200 
4 
7 
300 
2 
8 
300 
3 
9 
300 
4 
Table 2: Dose Escalation for Carboplatin and Niraparib 
(Niraparib Dosing Days 1-7) 
 
The second alternative schedule (Schedule #3) will not include dose-escalation of carboplatin, and as such 
patients will receive carboplatin AUC of 2 weekly for 2 weeks on, 1 week off of every q3week cycle (Table 3). In 
addition, niraparib will only be given for 4 days, each of the first two weeks (Days 1-4, and 8-11).  Carboplatin 
will be given on Days 2 and 9 (Figure 3). Pre-treatment biopsies will again be obtained, as depicted in Figure 3.  
 

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Figure 3: Treatment and Biopsy Schedule: Weekly Carboplatin 
 
Dose        
Cohort 
Niraparib       
(mg Daily) 
1 
100 
2 
200 
3 
300 
Table 3: Dose Escalation - Weekly Carboplatin 
 
4.1.2 Phase Ib Portion (Dose Expansion Procedures) 
Once the recommended dose and schedule–as determined by safety and pharmacodynamic assessment–has 
been established, an expansion cohort will be planned for 20 patients total. Twenty patients will be enrolled with 
deleterious DNA repair mutations (as in Phase Ia) to accelerate our understanding of the efficacy of this 
combination, in preparation for Phase II or III study. We anticipate identifying a higher number of breast cancer 
patients with HR deficient tumors due to frequent utilization of germline genetic testing. In order to obtain 
information about this combination in a variety of tumor types, we will cap the number of breast cancer patients 
at 10 total. Similarly, in order to obtain information in patients with a variety of defects in HR, the total number of 
patients with BRCA1/2 mutations (any disease type) will also be capped at 10 total.  
 
Patients will be evaluated with clinic visits, physical exams, and blood tests weekly for the first cycle, then on 
Day 1 of subsequent cycles only, unless clinically indicated sooner.  Restaging images will occur every 9 weeks. 
If at first restaging there is no evidence of PD, as determined by RECIST v1.1 criteria, and the patient is tolerating 
therapy, then the patient will continue on study therapy. Patients will continue to remain on study as long as there 
is no evidence of PD (according to RECIST v1.1 criteria) and the therapy is adequately tolerated. Patients will 
have a tumor biopsy prior to treatment, a second and third biopsy on treatment based on the schedule chosen 
in Phase Ia (outlined in Sections 4.1.1 and 4.1.1.1), and a final biopsy at the time of PD for correlative study. 
 
After all 20 patients have undergone their initial response assessment at week 9, an interim analysis will be 
conducted to determine how many had a PR, CR, SD, or PD. The study will be stopped early if 4 or fewer patients 
obtain a PR, CR, or SD at 9 weeks. If the study progresses, patients will continue on study therapy with follow 
up evaluations as previously delineated, assuming no significant associated toxicities, with restaging scans to 
assess response every 9 weeks. Interim analyses to assess secondary endpoints of OS and PFS will be 
scheduled to occur at 12 months and 24 months. If patients develop progressive disease, they will be followed 
from progression until death to assess overall survival.  
 
All patients in the Phase 1b portion will undergo three serial tumor biopsies to assess the pharmacodynamic 
effects of niraparib, and then niraparib plus carboplatin on DNA repair.  An off study/at progression tumor biopsy 
will also be required. Correlative studies for the serial tumor biopsies will be the same as for the Phase Ia. 

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Therefore, patients will be required to undergo serial tumor biopsies to assess the effect of niraparib alone, and 
of niraparib plus carboplatin (Figure 1). Specifically, patients will be required to undergo a second tumor biopsy 
(niraparib therapy alone) on Cycle 1, Day 14 (range C1D10-14) and a third tumor biopsy (niraparib plus 
carboplatin) on Cycle 2, Day 14 (range C2D10-14). There can be some flexibility with the timing of the 
biopsies, but it is important that the second and third biopsies take place on a day that the patient 
received a dose of niraparib. 
 
All patients whose disease has NOT rapidly progressed on trial will undergo a biopsy upon disease progression 
for ongoing correlative studies.  Specifically, patients who meet the following conditions will have a biopsy upon 
progression: 
The patient experiences a RECIST 1.1 confirmed partial or complete response at any point, and then 
subsequently experiences disease progression 
Or 
The patient experiences stable disease of ≥27 weeks (to comport with the timing of restaging imaging), 
and then subsequently experiences disease progression. 
 
 
 
4.2 Patient Screening and Enrollment 
Study activities are detailed in Table 4, and a study activity checklist in Table 5. Screening will occur within 14 
days prior to administration of the first dose of niraparib. Assessments performed exclusively to determine 
eligibility for this study will be done only after obtaining informed consent. Assessments performed for clinical 
indications (not exclusively to determine study eligibility) may be used for baseline values even if the studies 
were done before informed consent was obtained.   
 
Signed informed consent will be obtained from the subject or the subject's legally acceptable representative 
before any study-specific procedures are undertaken.  For procedures performed at screening and repeated, the 
later procedure performed prior to dosing, will serve as a baseline for clinical assessment.  A complete history 
and physical will be obtained at the screening visit.  Additionally, labs will be reviewed/ordered during the 
screening visit, prior to the initiation of therapy.   
 
Patients who pass screening will again undergo a full evaluation on Cycle 1 Day 1, including a physical 
examination, vital signs, performance status, chemistry, hematology, medication review, and adverse event 
evaluation.  If any abnormality that would be an exclusion is identified at subject assessment at any time prior to 
initiating therapy on Cycle 1, Day 1, the patient will not start treatment until the abnormality is resolved, and the 
patient again meets all inclusion/exclusion criteria.   
 
For patients being considered for enrollment outside of Georgetown-Lombardi, all primary source documentation 
should be sent to Georgetown University’s LCCC Consortium IIT Office and the Principal Investigator, Dr. Isaacs, 
for review and approval.  Patients must be approved for accrual prior to starting study medications.  Records 
should be emailed to Georgetown University’s LCCC Consortium IIT Office and Dr. Isaacs to confirm eligibility. 
 
The screening procedures include the following listed below. 
 
4.2.1 Informed Consent 
Signed informed consent will be obtained from the subject or the subject's legally acceptable representative 
before any study-specific procedures are undertaken.   
 
4.2.2 Medical History 
The following information will be collected during the Screening Period: 
1) Complete medical history, including documentation of any clinically significant medical conditions  
2) History of tobacco and alcohol use 
3) Presence and severity of any symptoms/conditions associated with their advanced solid tumor 
malignancy 

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4) Detailed oncology history, including: 
a. Date of primary cancer diagnosis 
b. Pathology (histology or cytology) of primary tumor 
c. Metastasis information (including the location) 
d. Surgical history 
e. Anti-cancer and radiation treatments administered (including dates and type of modality, and if 
therapy was in the neoadjuvant, adjuvant, or metastatic setting) 
5) At each visit, the subject's medical history will be reviewed and any changes from baseline will be 
recorded in the CRF. On Cycle 1 Day 1 any changes observed from the screening assessments, prior to 
dosing, will be recorded in the subject's medical history. All medications (prescription or over-the-counter, 
including vitamins and/or herbal supplements) will be recorded beginning with the Screening Visit and 
continuing up through the date of the off study visit 
 
4.2.3 Demographics 
Age, gender, race and ethnicity will be recorded. 
 
4.2.4 Review subject eligibility criteria 
 
4.2.5 Review previous and concomitant medications 
 
4.2.6 Physical exam including vital signs, height, and weight 
A complete physical examination will be performed at the Screening Visit.  Body weight will be recorded during 
every physical exam. The subject will wear lightweight clothing and no shoes during weighing.  Height will be 
measured at the Screening Visit only; the subject will not wear shoes. 
 
4.2.7 Vital sign determinations 
Vital sign determinations of heart rate, blood pressure and body temperature will be obtained at the Screening 
Visit. If possible, blood pressure and heart rate measurements should not immediately follow scheduled blood 
collections. 
 
4.2.8 Performance Status (PS) 
PS will be evaluated prior to study entry according to Table 11 in Appendix A. 
 
4.2.9 Hematology 
Hematology samples (complete blood count [CBC]) will be collected and assessed using a certified laboratory.  
The Investigator will review, initial and date all laboratory results. Any laboratory value outside the reference 
range stated in the inclusion criteria will preclude the patient from study participation. 
 
4.2.10 Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline phosphatase (ALP), ALT, AST, blood urea 
nitrogen (BUN), creatinine, electrolytes (sodium, potassium, calcium, chloride, bicarbonate), glucose, and total 
bilirubin. Any laboratory value outside the reference range stated in the inclusion criteria will preclude the patient 
from study participation. 
 
4.2.11 Pregnancy Test 
For female subjects of childbearing potential, a serum or urine pregnancy test will be performed at the Screening 
Visit within 14 days of Cycle 1 Day 1 and a urine pregnancy test will be done within 72 hours of C1D1 or at the 
Cycle 1 Day 1 (C1D1) visit prior to the first dose of study drug. Female patients will not be eligible for enrollment 
if she has a positive urine or serum pregnancy test ≤3 days prior to study drug administration, is breast-feeding, 
or is planning to conceive children within the projected duration of the study treatment. Subjects considered not 
of childbearing potential must be documented as being surgically sterile or post-menopausal (for at least 1 year).  
The test results must be reviewed and determined to be negative prior to dosing. If the urine pregnancy test is 
positive at Cycle 1 Day 1, it should be confirmed by a serum pregnancy test. The test may be repeated at the 
discretion of the investigator at any time during the study.  Should a female study subject become pregnant or 
suspect she is pregnant while participating in this study, she should inform the treating Investigator immediately, 

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47
as well as the study PI (Dr. Isaacs) and GSK, as outlined in Section 6.7. If a patient becomes pregnant, or if a 
patient’s spouse becomes pregnant while on trial, he or she will be removed from the study immediately. 
 
4.2.12 Tumor assessment 
Subjects must have measurable disease, defined as at least 1 unidimensionally measurable lesion as defined 
by RECIST v1.1 (tumor ≥ 1 cm in longest diameter on axial image on CT or MRI and/or lymph node(s) ≥ 1.5 cm 
in short axis on CT or MRI). Subjects must also have tumor tissue amenable to serial biopsies.   
 
4.3 Treatment Assignment and Tumor Assessment 
4.3.1 Patient Study Number Assignment and Sample Labeling 
A scientific objective of this Phase I study is to assess the pharmacodynamic effects of niraparib in addition to 
carboplatin on tumor tissue and to correlate those effects with efficacy measures. Thus, for all patients, a pre-
treatment biopsy will be required.  In addition, for all patients in the Phase Ib portion, we will require 4 core 
biopsies of a primary tumor or metastatic lesion: 
 
A fresh core biopsy prior to treatment (within 4 weeks of Cycle 1 Day 1) 
 
A repeat core biopsy on Cycle 1 Day 14 (range C1D10-14), preferably on the same tumor site if possible 
 
A repeat core biopsy on Cycle 2 Day 14 (range C2D10-14), preferably on the same tumor site if possible 
 
A final core biopsy after PD or off study, preferably on the same tumor site if possible, with the same 
specifications as listed above in section 4.1.1. 
This biopsy scheduling schema will differ if alternative schedules pursued, and will be updated as needed by the 
PIs.  
- 
For the Phase Ib portion, NGS does not need to be repeated on the pre-treatment biopsy sample, if a 
patient’s initial NGS was completed within 12 months of enrollment.  HOWEVER, if any patient has had 
NGS testing more than 12 months prior to enrollment then a repeat NGS test must be done and the 
deleterious somatic mutation must be re-identified for inclusion. (Note that this stipulation does not include 
patients who have confirmation of a deleterious germline mutation. These patients may have been 
identified at any time point prior to inclusion in the protocol and do NOT need to have this genetic testing 
repeated regardless of time frame and intervening therapy).   
The specific procedures of biopsy collection are outlined below in Section 4.3.2.  Throughout the study, the 
following labeling procedures will be followed. 
 
4.3.1.1 Patient Sample Labeling 
Patients will be de-identified and labeled with a 12 character study label (XX-X-X-XXXXXX): 
- 
The first two characters will be the patient’s initials 
- 
The third character will be the site number from which the patient was enrolled (single digit) 
o 1 = Georgetown 
o 2 = Yale 
o 3 = Hackensack 
o 4 = Levine 
o 5 = John’s Hopkins 
o 6 = Vanderbilt 
o 7 = Other 
- 
The fourth and fifth characters will be the patient study number (e.g. 01, 02, 03, etc.) 
- 
The sixth character will be the timing of collection 
o 1 = First biopsy/sample 
o 2 = Second biopsy/sample 
o 3 = Third biopsy/sample  
o 4 = Fourth biopsy/sample at Final Off Study Visit or at progression 
o 5 = Serum collection 
- 
The final characters will be the date in MM/DD/YR format 
 
4.3.2 Tumor Biopsy Algorithm (Please See the Corresponding Lab Manual) 

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A rigorous tumor collection algorithm will be instituted for this protocol. Shipping details and addresses are all 
summarized in Appendix D. If alternative treatment schedules pursued, the timing of tissue biopsies will differ 
from what is outlined below, and the schedule will be updated by a PI as needed. 
 
Of note, patients who are on chronic anticoagulation will be required to hold anticoagulation prior to the biopsies 
being performed.  Patients on warfarin must hold treatment for 5 days, but will be on low molecular weight heparin 
(LMWH), 1 mg/kg subcutaneously twice a day. The LMWH will continue until the last biopsy is complete.  Patients 
may then resume warfarin the day after the last biopsy.  Additionally, patients on LMWH will hold (i.e., not receive) 
the dose of LMWH the morning of the procedure, but will resume the LMWH the evening of the day of the biopsy. 
 
4.3.2.1 Timing of the Pre-Treatment Biopsy 
Following successful screening and enrollment of patients with an advanced solid tumor malignancy and known 
deleterious mutations in selected DNA repair genes, a pre-treatment tumor biopsy will be obtained (within 4 
weeks of Day 1 of study treatment).  
- 
For the Phase Ib portion, NGS does not need to be repeated on the pre-treatment biopsy sample, if a 
patient’s initial NGS was completed within 12 months of enrollment.  HOWEVER, if any patient has had 
NGS testing more than 12 months prior to enrollment then a repeat NGS test must be done and the 
deleterious somatic mutation must be re-identified for inclusion. (Note that this stipulation does not 
include patients who have confirmation of a deleterious germline mutation. These patients may have 
been identified at any time point prior to inclusion in the protocol and do NOT need to have this genetic 
testing repeated regardless of time frame and intervening therapy).   
4.3.2.2 Pre-Treatment Biopsy Tissue Utilization and Prioritization 
First Biopsy Tissue Utilization and Prioritization 
For the first biopsy, 5 individual cores will be obtained with an 18-20 gauge needle. Any extra cores that are 
taken, and are not needed will be embedded in paraffin, and the formalin-fixed, paraffin embedded (FFPE) 
block(s) will be kept in the lab of Dr. Brody.  The cores will be prepared as follows: 
- 
The first two cores will be placed in an institution-supplied single formalin vial, and sent to Dr. Brody’s lab 
at OSHU for testing. 
- 
The next two cores (ex vivo samples) will be placed in a pre-provided single Eppendorf tube with 
collection media.  This will be shipped on ice to Dr. Brody’s lab at OSHU. 
- 
The last core will be placed in a pre-supplied single formal vial from the Caris Life Sciences collection kit 
and sent to Caris for NGS testing  
 
4.3.2.3 Second Biopsy – Cycle 1 Day 14 (For patients in the Phase Ib portion) 
A second biopsy will be obtained as outlined in Figures 1-3 following 14 (range 10-14) days of therapy with 
niraparib to assess the tumor effect of therapy with niraparib alone.  The second biopsy will occur on C1D14 
(range C1D10-14). If unable to perform biopsy within this timeframe (weekend, holiday), biopsy planning will 
have to be reviewed on a case-by-case basis with a study PI (Dr. Isaacs). There can be some flexibility with the 
timing of the biopsies, but it is important that the second biopsy takes place on a day that the patient received a 
dose of niraparib.  The second biopsy will be used for serial pharmacodynamic tests identical to those evaluated 
with the first biopsy sample. 
 
4.3.2.4 Second Biopsy Tissue Utilization and Prioritization (For patients in the Phase Ib portion) 
Second Biopsy Tissue Utilization and Prioritization 
For the second biopsy, 5 individual cores will be obtained with an 18-20 gauge needle.  Any extra cores that are 
taken, and are not needed will be embedded in paraffin, and the FFPE block(s) will be kept in the lab of Dr. 
Brody. The cores will be prepared as follows: 
- 
The first three cores will be placed in an institution-supplied single formalin vial, and sent to Dr. Brody’s 
lab at OHSU for testing. 
- 
The last two cores (ex vivo samples) will be placed in a pre-provided single Eppendorf tube with collection 
media.  This will be shipped on ice to Dr. Brody’s lab at OHSU. 
  
4.3.2.5 Third Biopsy – Cycle 2 Day 14 (For patients in the Phase Ib portion) 
A third biopsy will be obtained as outlined in Figures 1-3 following initiation of cycle 2 to assess the tumor effect 
of therapy with carboplatin in addition to niraparib.  The second biopsy will occur on C2D14 (range C2D10-14). 

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If unable to perform biopsy within this timeframe (weekend, holiday), biopsy planning will have to be reviewed 
on a case-by-case basis with a study PI (Dr. Isaacs). There can be some flexibility with the timing of the biopsies, 
but it is important that the third biopsy takes place on a day that the patient received a dose of niraparib.  The 
third biopsy will be used for serial pharmacodynamic tests identical to those evaluated with the first biopsy sample. 
 
4.3.2.6 Third Biopsy Tissue Utilization and Prioritization (For patients in the Phase Ib portion) 
Third Biopsy Tissue Utilization and Prioritization 
For the third biopsy, 5 individual cores will be obtained with an 18-20 gauge needle.  Any extra cores that are 
taken, and are not needed will be embedded in paraffin, and the FFPE block(s) will be kept in the lab of Dr. 
Brody. The cores will be prepared as follows: 
- 
The first three cores will be placed in an institution-supplied single formalin vial, and sent to Dr. Brody’s 
lab at OHSU for testing. 
- 
The last two cores (ex vivo samples) will be placed in a single pre-provided Eppendorf tube with collection 
media.  This will be shipped on ice to Dr. Brody’s lab at OHSU. 
  
4.3.2.7 Biopsy Upon Progression (For patients in the Phase Ib portion) 
All patients whose disease has NOT rapidly progressed on trial will undergo a biopsy upon disease progression 
for ongoing correlative studies.  Specifically, patients who meet the following conditions will have a biopsy upon 
progression: 
- 
The patient experiences a RECIST 1.1 confirmed partial or complete response at any point, and then 
subsequently experiences disease progression 
Or 
- 
The patient experiences stable disease of ≥27 weeks (to comport with the timing of restaging imaging), 
and then subsequently experiences disease progression 
The final biopsy will be used for serial pharmacodynamic tests identical to those evaluated with the first biopsy 
sample, as well as NGS testing. 
 
4.3.2.8 Biopsy Upon Progression Tissue Utilization and Prioritization (For patients in the Phase Ib portion) 
Biopsy Upon Progression Tissue Utilization and Prioritization 
For the fourth biopsy, 5 individual cores will be obtained with an 18-20 gauge needle.  Any extra cores that are 
taken, and are not needed will be embedded in paraffin, and the FFPE block(s) will be kept in the lab of Dr. 
Brody. The cores will be prepared as follows: 
- 
The first two cores will be placed in an institution-supplied single formalin vial, and sent to Dr. Brody’s lab 
at OHSU for testing. 
- 
The second two cores (ex vivo sample) will be placed in a single pre-provided Eppendorf tube with 
collection media.  This will be shipped on ice to Dr. Brody’s lab at OHSU 
- 
The final core will be placed in a pre-supplied single formalin vial, and placed in a shipment kit to be sent 
to Caris Life Sciences. Caris Life Sciences will perform a 600 gene NGS cancer related exome analysis. 
  
4.3.3 Additional Exploratory Correlative Analyses 
During the course therapy, patients will also undergo sample collection for additional correlative analyses: 
- 
Patients will submit a 10mL sample of blood in a red top tube for future research on Cycle 1 Day 1 and 
every 3 weeks until progression.  These samples will be processed to isolate serum and stored frozen 
until shipped. Samples will be batched and shipped frozen to Dr. Brody’s lab at OHSU. 
 
4.4 Detailed Patient Assessments 
4.4.1 Patient Monitoring Until Progression 
Subject assessments (physical examinations, vital signs, performance status, laboratories, medication review, 
and adverse event evaluations) will be conducted at screening, Cycle 1 Day 1, every week for cycles 1-3 (on the 
first day of the week – D8, for example), and then on Day 1 only of subsequent cycles, assuming patient has 
achieved SD, PR, or CR. Study visits may be performed 3 days before or after the scheduled date due to 
unforeseen or unavoidable circumstances, and attempts should be made to schedule visits to line up with the 
start of a new cycle (within the constraints of the above parameters). Study drugs will be dispensed at the last 
visit prior to the start of the next 21 day cycle. The radiologic first response assessment at 9 weeks, and 
subsequent radiologic response assessments every 9 weeks thereafter, may be performed up to 7 days before 

Version 3.0 (Amendment 9), 7/3/2023 
50
or after the scheduled date due to unforeseen or unavoidable circumstances. Details are provided in Table 4, 
and a checklist highlighting the important events for screening through the completion of the trial is provided 
below, as Table 5.   
 
Assessments performed for clinical indications (not exclusively to determine study eligibility) may be used for 
baseline values and for procedures performed at screening and repeated, the later procedure performed prior to 
dosing will serve as a baseline for clinical assessment.  If any abnormality that would be an exclusion is identified 
at subject assessment at any time prior to initiating therapy on Day 1, the patient will not start treatment until the 
abnormality is resolved, and the patient again meets all inclusion/exclusion criteria.  The monitoring procedures 
include the following listed below. 
 
4.4.1.1 Medical History 
At each visit, the subject's medical history will be reviewed and any changes from baseline will be recorded in 
the CRF. On Cycle 1 Day 1 any changes observed from the screening assessments, prior to dosing, will be 
recorded in the subject's medical history. All medications (prescription or over-the-counter, including vitamins 
and/or herbal supplements) will be recorded beginning with the Screening Visit and continuing up through the 
date of the off study visit.   
 
 
4.4.1.2 Physical Examinations 
A physical examination including height, weight, vital signs, and performance status will be performed weekly for 
cycles 1-3. Patients with SD, PR, or CR at restaging after cycle 3 will have clinic visits and physical exams Day 
1 only. Any significant physical examination findings after the administration of the first doses of niraparib and 
carboplatin will be recorded as adverse events. Body weight will be recorded during every physical exam. The 
subject will wear lightweight clothing and no shoes during weighing.  Weight will be measured on the same scale 
at each visit. Height will be measured at the screening visit only; the subject will not wear shoes. 
 
4.4.1.3 Vital Signs 
Vital sign determinations of body temperature (in degrees Celsius), heart rate, respiratory rate, and blood 
pressure will be obtained at the screening visit, on each day the subject is seen by the treating physician, and at 
the final visit. If possible, blood pressure and heart rate measurements should not immediately follow scheduled 
blood collections. 
 
4.4.1.4 Clinical Laboratory Tests 
All subjects will undergo the laboratory assessments outlined in Table 4.  
1. A CBC with differential will be collected at the screening visit, on Cycle 1 Day 1, weekly through the first 
3 cycles, and then on Day 1 only thereafter (unless clinically indicated sooner) for Phase Ia. For Phase 
Ib, a CBC with differential will be collected at the screening visit, on Cycle 1 Day 1, weekly through the 
first cycle, and then on Day 1 only thereafter (unless clinically indicated sooner). 
2. Serum chemistries (total protein, albumin, total bilirubin, AST, ALT, ALP, sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, and calcium) will be collected at the screening visit, on Cycle 1 Day 1, 
weekly through the first 3 cycles, and then on Day 1 only thereafter (unless clinically indicated sooner) 
for Phase Ia. For Phase Ib, serum chemistries (total protein, albumin, total bilirubin, AST, ALT, ALP, 
sodium, potassium, chloride, bicarbonate, BUN, creatinine, and calcium) will be collected at the screening 
visit, on Cycle 1 Day 1, weekly through the first cycle, and then on Day 1 only thereafter (unless clinically 
indicated sooner). 
3. PT/PTT/INR will be collected at the screening visit, on Cycle 1 Day 1, and on Cycle 2, Day 1, and at the 
final visit. 
Laboratory samples for this study will be assessed using the certified laboratory at the investigators’ institutions 
or at a clinical laboratory such as Quest or LabCorp and these data will be used for all data analysis.  The 
Principal Investigator or sub-investigator will review, initial and date all laboratory results. Any laboratory value 
outside the reference range that is considered clinically significant by the investigator will be followed as 
appropriate. Clinically significant laboratory values will be recorded as adverse events if they meet the criteria 
as specified in Section 6.3. 
 

Version 3.0 (Amendment 9), 7/3/2023 
51
4.4.1.5 Tumor Imaging Assessment 
Baseline imaging should be performed within four weeks of initiating therapy. Ideally, this will included a CT scan 
of the chest, abdomen, and pelvis with oral and IV contrast, or can consist of an abdominal MRI and positron 
emission tomography (PET) scan for patients who cannot undergo a contrast-enhanced CT scan.  If a patient 
has an allergy to IV contrast, appropriate pre-medication can be given to prevent a contrast reaction. Patients 
may undergo other modalities such as an MRI instead of a CT scan at the treating physician’s discretion if 
appropriate (such as severe allergy to CT contrast, extremity tumors, bone metastases requiring bone scans, 
etc.).  Patients must have measurable disease as per RECIST v1.1 and the index lesions could not have been 
previously treated with local therapy, such as radiation.  
 
4.4.1.6 Timing of Assessments 
Treatment will be initiated on Cycle 1 Day 1, and patients will be evaluated every week during the first 3 cycles 
for Phase Ia and every week during the first cycle for Phase Ib, and then on Day 1 only of subsequent cycles, 
as outlined above. To be clear, for the purposes of standardizing data collection, patient data (blood test results, 
H&P results, etc) will be collected at “protocol defined visits.” These visits may or may not coincide with the 
regular visits that a physician may wish to have with the patient, but these will be required visits used for data 
collection. Restaging exams will occur every 9 weeks, as determined by the cycle and not the calendar in both 
the Phase Ia and Phase Ib portion of study. If there are any significant delays, restaging exams must not occur 
more than 12 weeks apart. During the treatment period, a visit window of +/- 2 days will be allowed.  
4.4.1.7 Adverse event assessment 
Baseline symptoms at Cycle 1 Day 1 (prior to initiating therapy) should be detailed and graded.  Once treatment 
has started, adverse events will be assessed weekly through the end of cycle 3 at the protocol defined visits. 
Beginning with cycle 4, adverse events will be assessed every three weeks on Day 1 of each subsequent cycle. 
The individual investigator should record any adverse event in detail including the date of onset, event diagnosis 
(if known) or sign/symptom, severity, time course, duration and outcome, relationship of the adverse event to 
study drug, and any action(s) taken. For serious adverse events not considered "probably related" to study drug, 
the investigator will provide an "Other" cause of the event. For adverse events to be considered intermittent, the 
events must be of similar nature and severity. See Section 6.5 for Adverse Event monitoring and reporting. The 
Principal Investigator or sub-investigators will assess adverse events, laboratory data and vital signs throughout 
the study.  Adverse events will be assessed by NCI CTCAE Version 5.0. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x
11.pdf   
Adverse events, whether in response to a query, observed by site personnel, or reported spontaneously by the 
subject will be recorded. All adverse events will be followed to a satisfactory conclusion. 
 
4.4.1.8 Correlative Blood Samples and Patient-Reported Outcomes 
Correlative blood samples and patient-related outcomes surveys will be obtained at time frames detailed below 
in Section 9.   
 
4.4.1.9 Unscheduled Assessments 
For any suspected myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) case reported while a 
patient is receiving treatment or followed for post-treatment assessments, bone marrow aspirate and biopsy 
testing must be completed by a local hematologist. Testing completed as part of standard of care is sufficient as 
long as the study site receives a copy of the hematologist’s report, which must include a classification according 
to World Health Organization (WHO) criteria108. The site must keep a copy of the report with the patient’s study 
file. 
 
4.4.2 Response Assessment 
Patients will receive therapy until disease progression, as per RECIST v1.1, or therapy intolerance.  Dose and 
schedule modifications will depend upon the specific regimen selected.  Response assessment will occur every 
9 weeks (+/- 7 days), based on the cycle. If there are any significant delays, restaging exams must not occur 
more than 12 weeks apart.  Only patients with SD, PD, or CR, as demonstrated by RECIST v1.1 will continue 
on treatment per protocol.   
 

Version 3.0 (Amendment 9), 7/3/2023 
52
Response assessment will continue every 9 weeks, and patients will continue to receive therapy, with dose 
adjustments if necessary, as detailed below until disease progression per RECIST v1.1 or treatment intolerability.  
 
4.4.3 Removal of Subjects from Study 
Each subject has the right to withdraw from study treatment at any time. In addition, the investigator may 
discontinue a subject from the study treatment at any time for any reason if the investigator considers it necessary, 
including the occurrence of an adverse event or noncompliance with the protocol. Each subject will be withdrawn 
from the study if any of the following occur: 
1) The subject experiences either clinical or radiographic progressive disease.  
2) The subject requires radiotherapy or alternate antineoplastic agents during the study period. 
3) The investigator believes it is in the best interest of the subject. 
4) Clinically significant deterioration of the subject's medical status as determined by the investigator. 
5) The subject requires alternative anti-cancer agents or non-palliative radiation therapy for primary or 
metastatic disease during the treatment portion of the study. 
6) Subject becomes pregnant or begins breastfeeding during the treatment portion of the study. 
7) The subject or subject's legally acceptable representative decides to withdraw consent for any reason.  
8) Any other medical reason that the study investigator deems appropriate. 
 
 
 
4.4.3.1 Discontinuation of Individual Subjects 
When a subject discontinues from the study (without reaching a protocol-defined endpoint), the investigator will 
notify the principal investigator as soon as possible (provided, in each case, subject care and safety are not 
compromised).  When a subject discontinues the study, a final visit will be conducted, preferably prior to the 
initiation of another anticancer therapy. However, these procedures should not interfere with the initiation of any 
new treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's condition. 
Following discontinuation of the study drug, the subject will be treated in accordance with the investigator's best 
clinical judgment.  At the final visit, the reason(s) for the discontinuation from the study will be recorded and a 
physical examination, body weight, vital signs measurement, laboratory analyses, performance status, tumor 
assessment, collection of unused study drug and an assessment of adverse events will be performed as soon 
as possible after discontinuation from the study.  If a subject is discontinued from the study with an ongoing 
adverse event or an unresolved clinically significant laboratory result, the site will attempt to provide follow up 
until a satisfactory clinical resolution of the laboratory result or adverse event is achieved.  In the event that a 
positive result is obtained on a pregnancy test for a subject during the study, the administration of study drug to 
that subject must be discontinued immediately.  Response assessment must be done at the end of treatment 
visit, if not done within 30 days prior.   
 
4.4.3.2 Patient Replacement Criteria 
In the event a patient is removed from the study due to reasons other than disease progression, severe adverse 
side effects related to the study drug, or patient death (situations in which outcomes will be considered evaluable), 
then an additional patient will be enrolled as needed to meet protocol accruement goals. For patients who are 
removed from the study prior to completion of greater than or equal to 14 days of niraparib, additional patients 
will be enrolled as needed to meet protocol accruement goals. 
 
4.4.3.3 Discontinuation of Entire Study 
The investigators may terminate this study provided that written notice is submitted at a reasonable time in 
advance of the intended termination.  The following procedures for discontinuation will be followed:  
1) If the investigators have decided to prematurely discontinue the study, the investigators will promptly 
notify in writing the IRB of the decision and give detailed reasons for the discontinuation. 
2) The principal investigator must promptly notify the enrolled subjects of the premature discontinuation and 
administer appropriate treatments such as replacement of protocol therapy, if applicable, by other 
appropriate regimens. 
 
4.4.4 Longitudinal Outcomes Assessment 

Version 3.0 (Amendment 9), 7/3/2023 
53
Patients will be followed after progression until death (or up to 24 months) to assess overall survival, and to 
monitor for the development of secondary malignancies.  Information pertaining to survival and post-treatment 
therapy will be collected approximately every 12 weeks (Month 3, 6, 9, 12, 15 and 18) beginning after the final 
visit, for a period up to 24 months. 
 
4.4.5 Protocol Deviations 
The investigator should not implement any deviation from the protocol without prior review and agreement by 
the Sponsor and in accordance with the IRB and local regulations, except when necessary to eliminate an 
immediate hazard to study subjects.  
 

Version 3.0 (Amendment 9), 7/3/2023 
54 
Table 4a: Study Activities for Phase Ia, Schedule #1 
ASSESSMENT/EVENT 
Screening 
≤28 Days 
prior to 
C1D1 
≤14 
Days 
prior to 
C1D117 
Treatment Period16 
EOT 
Follow 
Up 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 > 
Every 9 
weeks 
C1D1 
C1D8 
C1D15 
C2D1 
C2D2 
C2D8 
C2D15 
C3D1 
C3D2 
C3D8 
C3D15 
D1 
D2 
Administrative procedures and forms 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed consent  
X18 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History & 
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility Criteria 
Inclusion/Exclusion        
Patient Registration1 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECOG PS 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
  
X 
  
Concomitant 
Medications Collection 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Adverse Events 
Assessments2 
  
  
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Long-term follow up 
including survival and 
secondary malignancy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X14 
Procedures and tests 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Examination  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Vital Signs, Height3, 
Weight (temperature, 
pulse, respiratory rate, 
and blood pressure) 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Tumor Biopsy8 
X 
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
Imaging Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
RECIST Criteria - 
Tumor evaluation and 
assessment 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
CT Scan 
X4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
MRI Scan 
X4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
Laboratory 
Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hematology (CBC w/ 
diff and platelets) 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  

Version 3.0 (Amendment 9), 7/3/2023 
55 
Coagulation: 
Prothrombin Time (PT) 
and INR; Activated 
Partial Thromboplastin 
Time (aPTT)5 
X 
  
  
  
 
 
  
  
 
  
  
  
  
  
  
  
 
  
Serum Chemistries6 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Pregnancy test7 
 
 X 
X 
  
  
 X 
  
  
  
X  
  
  
  
 X 
  
  
  
  
Research Serum 
Samples9 
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
X 
  
Caris NGS testing 
X10 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X11 
Drug Administration 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Carboplatin 
Administration 
  
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
Niraparib Dispensing 
for Oral Administration   
Schedule Days 1-1412 
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
Study Drug 
Accountability13  
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
 
1. 
Patient registration form will be provided. Please ensure all reports required for registration including Pathology Report, Physicians Note validating Previous treatments, Imaging showing RECIST 
criteria, Laboratory Results and, Past Medical History are de-identified.  
2. 
Adverse Events must be monitored for 30 days post EOT and until resolution to baseline. 
3. 
Height only needs to be captured in Screening. 
4. 
Screening scans are to be performed within 28 days of Cycle 1 Day 1. Tumor measurements evaluated by RECIST 1.1.  CTs or MRIs are acceptable.  
5. 
PT/PTT as required for biopsy will be performed at screening. 
6. 
Serum Chemistries include: albumin, ALP, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium total protein, AST, ALT, and sodium. 
7. 
Serum or Urine pregnancy test for women of child-bearing potential, within 14 days of first dose for screening, and repeated within 72 hours of first dose. 
8. 
Tumor biopsy to be performed prior to Cycle 1, Day 1. 
9. 
Research Serum Samples are to be performed at Day 1 of every cycle and at the time of the first radiologic response assessment. 
10. NGS does not need to be repeated on the pre-treatment biopsy sample  
11. NGS at End of Treatment upon progression is not mandatory. 
12. Niraparib will be dispensed on Day 1 of every cycle. 
13. Study drug accountability will be performed at Day 1 of every cycle. 
14. Patients will be contacted every three months (for 24 months post End of Treatment visit) to collect overall survival and development of secondary malignancy. 
15. Imaging must be done at End of Treatment, if not done within 30 days prior. 
16. Visit Window during the Treatment period will be +/- 2 days. 
17. Assessments done outside of 14 days prior to C1D1 must be repeated within 14 days through prior to treatment on Day 1 to confirm the subject is still eligible.  
18. Re-consent is not required if the subject requires re-screening after 28 days, unless there is an updated consent form that requires the subject be re-consented.  
 
 
 
 
 
 
 

Version 3.0 (Amendment 9), 7/3/2023 
56 
Table 4b: Study Activities for Phase Ia, Schedule #2 
ASSESSMENT/EVENT 
Screening 
≤28 Days 
prior to 
C1D1 
≤14 
Days 
prior 
to 
C1D117 
Treatment Period16 
EOT 
Follow 
Up 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 > 
Every 
9 
weeks 
C1D1 
C1D8 
C1D15 
C2D1 
C2D2 
C2D8 
C2D15 
C3D1 
C3D2 
C3D8 
C3D15 
D1 
D2 
Administrative procedures and forms 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed consent  
X18 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility Criteria 
Inclusion/Exclusion             
Patient Registration1 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECOG PS 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Concomitant Medications 
Collection 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Adverse Events 
Assessments2 
  
  
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Long-term follow up 
including survival and 
secondary malignancy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X14 
Procedures and tests 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Examination  
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Vital Signs, Height3, Weight 
(temperature, pulse, 
respiratory rate, and blood 
pressure) 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Tumor Biopsy8 
X 
  
  
 
 
  
  
  
 
  
  
  
  
  
  
  
 
  
Imaging Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
RECIST Criteria - Tumor 
evaluation and assessment 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
CT Scan 
X4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
MRI Scan 
X4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
Laboratory Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hematology (CBC w/ diff 
and platelets) 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  

Version 3.0 (Amendment 9), 7/3/2023 
57 
Coagulation: 
Prothrombin Time (PT) and 
INR; Activated Partial 
Thromboplastin Time 
(aPTT)5 
X 
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
 
  
Serum Chemistries6 
X 
X 
X 
X 
X 
X 
  
X 
X 
X 
  
X 
X 
X 
  
X 
X 
  
Pregnancy test7 
 
X  
X 
  
  
X  
  
  
  
 X 
  
  
  
 X 
  
  
  
  
Research Serum Samples9 
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
X 
  
Caris NGS testing 
X10 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X11 
Drug Administration 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Carboplatin  Administration 
  
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
Niraparib Dispensing for 
Oral Administration 
Schedule Days  1-712 
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
Study Drug Accountability13 
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
 
1. 
Patient registration form will be provided. Please ensure all reports required for registration including Pathology Report, Physicians Note validating Previous treatments, CT showing RECIST criteria, 
Laboratory Results and, Past Medical History are de-identified.  
2. 
Adverse Events must be monitored for 30 days post EOT and until resolution to baseline. 
3. 
Height only needs to be captured in Screening. 
4. 
Screening scans are to be performed within 28 days of Cycle 1 Day 1. Tumor measurements evaluated by RECIST 1.1 CTs or MRIs are acceptable. 
5. 
PT/PTT as required for biopsy will be performed at screening. 
6. 
Serum Chemistries include: albumin, ALP, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium total protein, AST, ALT, and sodium. 
7. 
Serum or Urine pregnancy test for women of child-bearing potential, within 14 days of first dose for screening, and repeated within 72 hours of first dose. 
8. 
Tumor biopsy to be performed prior to Cycle 1, Day 1. 
9. 
Research Serum Samples are to be performed at Day 1 of every cycle and at the time of the first radiologic response assessment.  
10. NGS does not need to be repeated on the pre-treatment biopsy sample 
11. NGS at End of Treatment upon progression is not mandatory. 
12. Niraparib will be dispensed on Day 1 of every cycle. 
13. Study drug accountability will be performed at Day 1 of every cycle. 
14. Patients will be contacted every three months (for 24 months post End of Treatment visit) to collect overall survival and development of secondary malignancy. 
15. Imaging must be done at End of Treatment, if not done within 30 days prior. 
16. Visit Window during the Treatment period will be +/- 2 days. 
17. Assessments done outside of 14 days prior to C1D1 must be repeated within 14 days through prior to treatment on Day 1 to confirm the subject is still eligible.  
18. Re-consent is not required if the subject requires re-screening after 28 days, unless there is an updated consent form that requires the subject be re-consented.  
 
 
 
 

Version 3.0 (Amendment 9), 7/3/2023 
58 
Table 4c: Study Activities for Phase Ia, Schedule #3 
ASSESSMENT/ 
EVENT 
Screening 
≤28 Days 
prior to 
C1D1 
≤14 
Days 
prior to 
C1D117 
Treatment Period16 
EOT 
Follow 
Up 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 > 
Every 9 
weeks 
C1
D1 
C1
D8 
C1
D15 
C2
D1 
C2
D2 
C2
D8 
C2
D9 
C2D
15 
C3
D1 
C3
D2 
C3
D8 
C3
D9 
C2D
15 
D1 
D2 
D9 
Administrative procedures and forms 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed consent  
X18 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility Criteria 
Inclusion/Exclusion        
Patient Registration1 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECOG PS 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
X 
  
X 
  
X 
X 
  
  
X 
X 
  
Concomitant 
Medications Collection 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
X 
  
X 
  
X 
X 
  
  
X 
X 
  
Adverse Events 
Assessments2 
  
  
X 
X 
X 
X 
  
X 
  
X 
X 
  
X 
  
X 
X 
  
  
X 
X 
  
Long-term follow up 
including survival and 
secondary malignancy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X14 
Procedures and tests 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Examination  
X 
X 
X 
X 
X 
X 
  
X 
  
X 
X 
  
X 
  
X 
X 
  
  
X 
X 
  
Vital Signs, Height3, 
Weight (temperature, 
pulse, respiratory rate, 
and blood pressure) 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
X 
  
X 
  
X 
X 
  
  
X 
X 
  
Tumor Biopsy8 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Imaging Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
RECIST Criteria - 
Tumor evaluation and 
assessment 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
CT Scan 
X4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
MRI Scan 
X4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
Laboratory 
Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hematology (CBC w/ 
diff and 
platelets)(Central Lab) 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
X 
  
X 
  
X 
X 
  
  
X 
X 
  

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59 
Coagulation: 
Prothrombin Time (PT) 
and INR; Activated 
Partial Thromboplastin 
Time (aPTT)5 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
Serum Chemistries6 
X 
X 
X 
X 
X 
X 
  
X 
  
X 
X 
  
X 
  
X 
X 
  
  
X 
X 
  
Pregnancy test7 
 
X  
X 
  
  
 X 
  
  
  
  
 X 
  
  
  
  
X  
  
  
  
  
  
Research Serum 
Samples9 
  
  
X 
  
  
X 
  
  
  
  
X 
  
  
  
  
X 
  
  
  
X 
  
Caris NGS testing 
X10 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X11 
Drug Administration 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Carboplatin 
Administration 
  
  
  
  
  
  
X 
  
X 
  
  
X 
  
X 
  
  
X 
X 
  
  
  
Niraparib Dispensing 
for Oral 
Administration 
Schedule               
Days 1-4, 8-1112 
  
  
X 
  
  
X 
  
  
  
  
X 
  
  
  
  
X 
  
  
  
  
  
Study Drug 
Accountability13 
  
  
X 
  
  
X 
  
  
  
  
X 
  
  
  
  
X 
  
  
  
  
  
 
1. 
Patient registration form will be provided. Please ensure all reports required for registration including Pathology Report, Physicians Note validating Previous treatments,  CT showing RECIST criteria, 
Laboratory Results and, Past Medical History are de-identified.  
2. 
Adverse Events must be monitored for 30 days post EOT and until resolution to baseline. 
3. 
Height only needs to be captured in Screening. 
4. 
Screening scans are to be performed within 28 days of Cycle 1 Day 1. Tumor measurements evaluated by RECIST 1.1.  CTs or MRIs are acceptable.  
5. 
PT/PTT as required for biopsy will be performed at screening. 
6. 
Serum Chemistries include: albumin, ALP, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium total protein, AST, ALT, and sodium. 
7. 
Serum or Urine pregnancy test for women of child-bearing potential, within 14 days of first dose for screening, and repeated within 72 hours of first dose. 
8. 
Tumor biopsy to be performed prior to Cycle 1, Day 1. 
9. 
Research Serum Samples are to be performed at Day 1 of every cycle and at the time of the first radiologic response assessment.  
10. NGS does not need to be repeated on the pre-treatment biopsy sample. 
11. NGS at End of Treatment upon progression is not mandatory. 
12. Niraparib will be dispensed on Day 1 of every cycle. 
13. Study drug accountability will be performed at Day 1 of every cycle. 
14. Patients will be contacted every three months (for 24 months post End of Treatment visit) to collect overall survival and development of secondary malignancy. 
15. Imaging must be done at End of Treatment, if not done within 30 days prior. 
16. Visit Window during the Treatment period will be +/- 2 days. 
17. Assessments done outside of 14 days prior to C1D1 must be repeated within 14 days through prior to treatment on Day 1 to confirm the subject is still eligible.  
18. Re-consent is not required if the subject requires re-screening after 28 days, unless there is an updated consent form that requires the subject be re-consented.  
 
 
 
 
 

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Table 4d: Study Activities for Phase Ib 
ASSESSMENT/EVENT 
Screening 
≤28 Days 
prior to 
C1D1 
≤14 Days 
prior to 
C1D117 
Treatment Period16 
EOT 
Follow 
Up 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 > 
Every 
9 
weeks 
C1D1 
C1D8 
C1D15 
C2D1 
C2D2 
C2D8 
C2D15 
C3D1 
C3D2 
C3D8 
C3D15 
D1 
D2 
Administrative procedures and forms 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Informed consent  
X18 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History & 
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility Criteria 
Inclusion/Exclusion          
Patient Registration1 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ECOG PS 
X 
X 
X 
X 
X 
X 
  
 
 
X 
  
 
 
X 
  
  
X 
  
Concomitant Medications 
Collection 
X 
X 
X 
X 
X 
X 
  
 
 
X 
  
 
 
X 
  
X 
X 
  
Adverse Events 
Assessments2 
  
  
X 
X 
X 
X 
  
 
 
X 
  
 
 
X 
  
X 
X 
  
Long-term follow up 
including survival and 
secondary malignancy 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X14 
Procedures and tests 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Examination  
X 
X 
X 
X 
X 
X 
  
 
 
X 
  
 
 
X 
  
X 
X 
  
Vital Signs, Height3, Weight 
(temperature, pulse, 
respiratory rate, and blood 
pressure) 
X 
X 
X 
X 
X 
X 
  
 
 
X 
  
 
 
X 
  
X 
X 
  
Tumor Biopsy8 
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
  
  
  
X 
  
Imaging Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
RECIST Criteria - Tumor 
evaluation and assessment 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
CT Scan 
X4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
MRI Scan 
X4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X15 
  
Laboratory Assessments 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hematology (CBC w/ diff 
and platelets) 
X 
X 
X 
X 
X 
X 
  
 
 
X 
  
 
 
X 
  
X 
X 
  

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Coagulation: 
Prothrombin Time (PT) and 
INR; Activated Partial 
Thromboplastin Time 
(aPTT)5 
X 
  
 X 
  
 
 X 
  
  
 
  
  
  
  
  
  
  
X 
  
Serum Chemistries6 
X 
X 
X 
X 
X 
X 
  
 
 
X 
  
 
 
X 
  
X 
X 
  
Pregnancy test7 
 
X 
X 
  
  
X  
  
  
  
X  
  
  
  
X  
  
  
  
  
Research Serum Samples9 
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
X 
  
Caris NGS testing 
X10 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X11 
Drug Administration 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Carboplatin Administration 
  
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
Niraparib Dispensing for 
Oral Administration                 
Schedule Days 1-1412 
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
Study Drug Accountability13  
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
 
1. 
Patient registration form will be provided. Please ensure all reports required for registration including Pathology Report, Physicians Note validating Previous treatments,  CT showing RECIST criteria, 
Laboratory Results and, Past Medical History are de-identified.  
2. 
Adverse Events must be monitored for 30 days post EOT and until resolution to baseline. 
3. 
Height only needs to be captured in Screening. 
4. 
Screening scans are to be performed within 28 days of Cycle 1 Day 1. Tumor measurements evaluated by RECIST 1.1.  CTs or MRIs are acceptable.  
5. 
PT/PTT as required for biopsy will be performed at screening, on Cycle 1, Day 1, Cycle 2, Day 1, and at the EOT visit. 
6. 
Serum Chemistries include: albumin, ALP, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium total protein, AST, ALT, and sodium. 
7. 
Serum or Urine pregnancy test for women of child-bearing potential, within 14 days of first dose for screening, and repeated within 72 hours of first dose. 
8. 
Tumor biopsy scheduled is dependent upon the final schedule chosen before moving on to Phase Ib.  For example, the biopsies may be performed prior to Cycle 1, Day 1; on Cycle 1, Day 14 
(range C1D10-14); and on Cycle 2, Day 14 (range C2D10-14), and upon progression (if appropriate, as per Section 4.1.1). 
9. 
Research Serum Samples are to be performed at Day 1 of every cycle and at the time of the first radiologic response assessment.  
10. NGS does not need to be repeated on the pre-treatment biopsy sample, if a patient’s initial NGS was completed within 12 months of enrollment. 
11. NGS at End of Treatment is upon progression. 
12. Niraparib will be dispensed on Day 1 of every cycle. 
13. Study drug accountability will be performed at Day 1 of every cycle. 
14. Patients will be contacted every three months (for 24 months post End of Treatment visit) to collect overall survival and development of secondary malignancy. 
15. Imaging must be done at End of Treatment, if not done within 30 days prior. 
16. Visit Window during the Treatment period will be +/- 2 days. 
17. Assessments done outside of 14 days prior to C1D1 must be repeated within 14 days through prior to treatment on Day 1 to confirm the subject is still eligible.  
18. Re-consent is not required if the subject requires re-screening after 28 days, unless there is an updated consent form that requires the subject be re-consented.  
 

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Table 5a: Study Activities Checklist for Phase Ia, Schedule #1 
Screening (within 4 weeks of Cycle 1, Day 1) 
Subject Assessment  
 
 
 
 
 
_______ 
Eligibility Criteria 
 
 
 
 
 
 
_______ 
Informed Consent 
 
 
 
 
 
 
_______ 
Demographics 
 
 
 
 
 
 
_______ 
Medical History 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Height  
 
 
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
PT/INR, PTT  
 
 
 
 
 
 
_______ 
Caris Molecular Profile with DNA Repair Gene Mutation 
 
_______ 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
Tumor Amenable to Biopsy  
 
 
 
 
_______ 
Pre-Treatment Biopsy (1) Scheduled/Complete 
 
 
_______ 
 
Within 2 Weeks of Cycle 1, Day 1 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
______________ 
Weight  
 
 
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Pregnancy Test (within 14 days) 
 
 
 
 
_______ 
 
Cycle 1, Day 1  
Subject Assessment  
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
Pregnancy Test (within 72 hours) 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-14)  
 
 
 
 
_______ 
 
Every Week Until First Response Assessment 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 

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63
Cycle 2, Day 1 (In addition to the above)  
Research Serum Sample 
 
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-14)  
 
 
 
 
_______ 
Pregnancy Test 
 
 
 
 
 
 
_______ 
 
 
Day 2 of Cycles 2 and 3 
Carboplatin treatment  
 
 
 
 
 
_______ 
 
Cycle 3, Day 1 (In addition to the above) 
Research Serum Sample 
 
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-14)  
 
 
 
 
_______ 
Pregnancy Test 
 
 
 
 
 
 
_______ 
 
First Response Assessment (at 9 weeks on treatment) 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
 
Day 1 of Each Cycle After First Response Assessment 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-14)  
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
Pregnancy Test 
 
 
 
 
 
 
_______ 
 
Every 9 Weeks After First Response Assessment 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
 
Off Study 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Events Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
 
Follow-up Assessments 
Subject Assessment (may be done via phone)  
 
 
_______ 
Vital Status Data Collection  
 
 
 
 
_______ 
Development of a Secondary Malignancy  
 
 
 
_______     
 

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64
Table 5b: Study Activities Checklist for Phase Ia, Schedule #2 
Screening (within 4 weeks of Cycle 1, Day 1) 
Subject Assessment  
 
 
 
 
 
_______ 
Eligibility Criteria 
 
 
 
 
 
 
_______ 
Informed Consent 
 
 
 
 
 
 
_______ 
Demographics 
 
 
 
 
 
 
_______ 
Medical History 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Height  
 
 
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
PT/INR, PTT  
 
 
 
 
 
 
_______ 
Caris Molecular Profile with DNA Repair Gene Mutation 
 
_______ 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
Tumor Amenable to Biopsy  
 
 
 
 
_______ 
Pre-Treatment Biopsy (1) Scheduled/Complete 
 
 
_______ 
 
Within 2 Weeks of Cycle 1, Day 1 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Pregnancy Test (within 14 days) 
 
 
 
 
_______ 
 
Cycle 1, Day 1  
Subject Assessment  
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
Pregnancy Test (within 72 hours) 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-7) 
 
 
 
 
 
_______ 
 
Every Week Until First Response Assessment 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 

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65
Cycle 2, Day 1 (In addition to the above) 
Research Serum Sample 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-7) 
 
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
Pregnancy Test 
 
 
 
 
 
 
_______ 
 
Day 2 of Cycles 2 and 3 
Carboplatin treatment  
 
 
 
 
 
_______ 
 
Cycle 3, Day 1 (In addition to the above) 
Research Serum Sample 
 
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-7) 
 
 
 
 
 
_______ 
Pregnancy Test 
 
 
 
 
 
 
_______ 
 
First Response Assessment (at 9 weeks on treatment) 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
 
Day 1 of Each Cycle After First Response Assessment 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-7) 
 
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
Pregnancy Test 
 
 
 
 
 
 
_______ 
 
Every 9 Weeks After First Response Assessment 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
 
Off Study 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Events Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
 
Follow-up Assessments 
Subject Assessment (may be done via phone)  
 
 
_______ 
Vital Status Data Collection  
 
 
 
 
_______ 
Development of a Secondary Malignancy  
 
 
 
_______    
 
 

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Table 5c: Study Activities Checklist for Phase Ia, Schedule #3 
Screening 
Subject Assessment  
 
 
 
 
 
_______ 
Eligibility Criteria 
 
 
 
 
 
 
_______ 
Informed Consent 
 
 
 
 
 
 
_______ 
Demographics 
 
 
 
 
 
 
_______ 
Medical History 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Height  
 
 
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
PT/INR, PTT  
 
 
 
 
 
 
_______ 
Caris Molecular Profile with DNA Repair 
 
 
 
_______ 
Gene Mutation 
 
 
 
 
 
 
_______ 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
Tumor Amenable to Biopsy  
 
 
 
 
_______ 
Pre-Treatment Biopsy (1) Scheduled/Complete 
 
 
_______ 
 
Within 2 Weeks of Week 1, Day 1 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Pregnancy Test (within 14 days) 
 
 
 
 
_______ 
 
Cycle 1, Day 1  
Subject Assessment  
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
Pregnancy Test (within 72 hours) 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-4, D8-11) 
 
 
 
 
_______ 
 
Every Week Until First Response Assessment 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 

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67
Serum Chemistries 
 
 
 
 
 
 
_______ 
 
Cycle 2, Day 1 (In addition to the above) 
Research Serum Sample 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-4, D8-11) 
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
Pregnancy Test 
 
 
 
 
 
 
_______ 
 
Day 2 of Cycles 2 and 3 
Carboplatin treatment  
 
 
 
 
 
_______ 
 
Cycle 3, Day 1 (In addition to the above) 
Research Serum Sample 
 
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-4, D8-11) 
 
 
 
 
_______ 
Pregnancy Test 
 
 
 
 
 
 
_______ 
 
First Response Assessment (at 9 weeks on treatment) 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
 
Day 1 of Each Cycle After First Response Assessment 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Dispense Niraparib (D1-4, D8-11) 
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
Pregnancy Test 
 
 
 
 
 
 
_______ 
 
Every 9 Weeks After First Response Assessment 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
 
Off Study 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Events Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
 
Follow-up Assessments 
Subject Assessment (may be done via phone)  
 
 
_______ 
Vital Status Data Collection  
 
 
 
 
_______ 
Development of a Secondary Malignancy  
 
 
 
_______    

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68
 
Table 5d: Study Activities Checklist for Phase Ib 
Screening 
Subject Assessment  
 
 
 
 
 
_______ 
Eligibility Criteria 
 
 
 
 
 
 
_______ 
Informed Consent 
 
 
 
 
 
 
_______ 
Demographics 
 
 
 
 
 
 
_______ 
Medical History 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Height  
 
 
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
PT/INR, PTT  
 
 
 
 
 
 
_______ 
Caris Molecular Profile with DNA Repair Gene Mutation 
 
_______ 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
Tumor Amenable to Biopsy  
 
 
 
 
_______ 
Pre-Treatment Biopsy (1) Scheduled/Complete 
 
 
_______ 
 
Within 2 Weeks of Week 1, Day 1 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Pregnancy Test (within 14 days) 
 
 
 
 
_______ 
 
Cycle 1, Day 1  
Subject Assessment  
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
Pregnancy Test (within 72 hours) 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
PT/INR, PTT  
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Dispense Niraparib 
 
 
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
 
Every Week of First Cycle 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 

Version 3.0 (Amendment 9), 7/3/2023 
69
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
 
Cycle 1, Day 14 (Range Days 10-14)***Subject to change*** 
On-Treatment Biopsy (2) Scheduled/Complete 
 
 
_______ 
 
Cycle 2 Day 1 
PT/INR, PTT  
 
 
 
 
 
 
_______ 
 
Day 1 of Every Cycle Starting Cycle 2 
Subject Assessment  
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Event Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Dispense Niraparib 
 
 
 
 
 
 
_______ 
Study Drug Accountability 
 
 
 
 
 
_______ 
Pregnancy Test 
 
 
 
 
 
 
_______ 
 
Day 2 of Every Cycle Starting Cycle 2 
Carboplatin treatment  
 
 
 
 
 
_______ 
 
Cycle 2, Day 14 (Range Days 10-14)***Subject to change*** 
On-Treatment Biopsy (2) Scheduled/Complete 
 
 
_______ 
 
Every 9 Weeks  
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
 
Off Study 
Subject Assessment  
 
 
 
 
 
_______ 
Weight  
 
 
 
 
 
 
 
_______ 
Vital Signs 
 
 
 
 
 
 
 
_______ 
Concurrent Medications 
 
 
 
 
 
_______ 
History and Physical  
 
 
 
 
 
_______ 
Performance Status  
 
 
 
 
 
_______ 
Adverse Events Evaluation 
 
 
 
 
 
_______ 
CBC with Differential  
 
 
 
 
 
_______ 
Serum Chemistries 
 
 
 
 
 
 
_______ 
PT/INR, PTT  
 
 
 
 
 
 
_______ 
Research Serum Sample 
 
 
 
 
 
_______ 
Radiology Evaluation and Tumor Measurements 
 
 
_______ 
Off-Treatment Biopsy (4) Scheduled/Complete 
 
 
_______ 
 
Follow-up Assessments 
Subject Assessment (may be done via phone)  
 
 
_______ 
Vital Status Data Collection  
 
 
 
 
_______ 
Development of a Secondary Malignancy  
 
 
 
_______  
 
 
 

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5.0 DOSAGES AND DISPENSATION OF DRUGS  
 
5.1 Dispensation of Study Drug and Treatments Administered 
The study drugs are defined as niraparib and carboplatin.  Niraparib will be supplied by GSK.  Carboplatin will 
be supplied by the institution.  Patients will receive niraparib by mouth and carboplatin intravenously.  Patients 
will receive sufficient quantities of niraparib for 1 cycle of administration on Day 1 of each cycle.  Patients will 
receive bottles of niraparib from the on-site study coordinator and will be provided with drug diaries (see Appendix 
E) to record the date and time they took the drugs. Niraparib should specifically be taken with a large glass of 
water (~250 mL) at the same time each day (including on the days that carboplatin is administered) and should 
be swallowed whole without crushing, chewing, or opening the pills.  If vomiting occurs, no re-dosing of the 
patient is allowed prior to the next scheduled dose.  If doses are not taken within 6 hours of the intended time, 
the dose should be skipped and not replaced or made up on a subsequent day. Patients should be instructed to 
store niraparib at room temperature. Subjects should return bottles of niraparib (empty, partially filled, or full) and 
their diaries (See Appendix E) to the study site prior to start of next cycle and at the final visit. Carboplatin will 
be administered IV on day 2 of each cycle (or other variation as outlined above in Section 4.1.1) at each patient’s 
respective on-site infusion center. Patients should receive a minimum of ondansetron 8mg IV and 
dexamethasone 8mg IV prior to carboplatin, and the infusion should be given over 60 minutes. The carboplatin 
infusion should be prepared by each treating institution the day of infusion and refrigerated prior to drug delivery. 
Concurrent intravenous fluids with 0.9% normal saline is recommended for a total of 1000 mL, though not 
required. Orders for carboplatin will be written on the day of treatment at each participating institution for a target 
AUC of 2-4, as defined in Dose Escalation Table 1(or per the alternative schedule if employed).  
 
5.2 Packaging and Labeling of Niraparib 
Niraparib will be packaged in bottles containing 100 mg tablets or capsules with a sufficient quantity in the bottle 
for one cycle, plus enough for one extra day (see Table 6). 
 
Table 6. Dispensation of Niraparib by Dose Level 
Dose Level  
Dose 
100 mg Tablets Dispensed 
1 
100 mg 
14 + 1 
2 
100 mg 
14 + 1 
3 
100 mg 
14 + 1 
4 
200 mg 
28 + 2 
5 
200 mg 
28 + 2 
6 
200 mg 
28 + 2 
7 
300 mg 
42 + 3 
8 
300 mg 
42 + 3 
9 
300 mg 
42 + 3 
 
Each bottle will be labeled with an open-label white single panel or booklet label that will include, but is not limited 
to, the following information: 
1. Protocol number 
2. Drug identification 
3. Number of capsules 
4. Storage conditions 
5. Dosing instructions 
6. Blank spaces to write the subject's identification number, initials and date dispensed 
Each bottle label must remain affixed to the bottle.   
 
5.3 Storage and Disposition of Niraparib and Carboplatin 
Niraparib should be stored at room temperature and should be protected from light and moisture. Carboplatin 
should be refrigerated at the participating treatment center following preparation on day of treatment (prior to 
preparation vials can be stored at room temperature, protected from light). Niraparib will be packaged in high-
density polyethylene bottles with child-resistant plastic closures. All clinical supplies must be stored in a secure 
place until they are dispensed for subject use or are returned to the participating center’s pharmacy.  
Investigational products are for investigational use only, and are to be used only within the context of this study. 

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The clinical supplies supplied for this study must be maintained under adequate security and stored under 
conditions specified on the label. Destruction of used and unused study drug will be performed at the site. 
 
5.4 Treatment Compliance 
Subjects will be instructed to return all bottles of niraparib to the study site personnel prior to each cycle and at 
the final visit.  The study site personnel will document the bottles of study drug returned and the number of 
capsules per bottle, according to institutional policy.  If the number of capsules taken and the number of capsules 
returned do not add up to the number of capsules dispensed, an explanation will be provided.  Unless otherwise 
directed by the principal investigator, a subject will be considered compliant with study drug if 85% of the 
assigned dose is taken during a cycle. Doses of carboplatin will be recorded per treatment institution and tracked 
by the on-site study coordinator. Patients may not miss a dose of carboplatin, but are allowed to receive dose 
modifications as outlined in Section 4.1.1. 
 
5.5 Drug Accountability 
The investigator or designee will verify that niraparib supplies are received intact and in the correct amounts. A 
signed and dated Proof of Receipt (POR) or similar document will support documentation of the receipt of 
supplies.  An accurate running inventory of niraparib will be maintained by the site, and will include the lot number, 
POR number(s), the bottle numbers, and the date study drug was dispensed for each subject. Upon completion 
or termination of the study, all original containers (empty or containing unused study drug) will be returned to the 
manufacturer or destruction of used and unused study drug will be performed at the site. Labels must remain 
attached to the containers. The investigator or his/her designated representative agrees not to supply study 
medication to any persons not enrolled in the study or not named as a sub-investigator.  The site will record the 
lot number(s) and doses of niraparib and carboplatin given to each subject. 
 
5.6 Selection of Doses in the Study (Niraparib Investigator’s Brochure90) 
Initial doses of niraparib in this study are based on data from other PARP inhibitors in combination with 
chemotherapy including carboplatin, and on Phase I data of niraparib alone and in combination with other 
chemotherapy regimens (temozolomide and carboplatin). The Phase I dose escalation trial of single agent 
niraparib demonstrated a trend towards greater PARP inhibition at doses ≥80mg daily. The dose limiting 
toxicities were related to myelosuppression, and the RP2D as a single agent was 300mg daily. In the open-label 
Phase I study PN-014 evaluating the use of niraparib in combination with temozolomide in patients with advanced 
cancer (enrolled 19 patients with glioblastoma multiforme or melanoma), Niraparib was dosed at 40mg daily, 
days 1-8 in combination with temozolomide dosed at 150mg/m2 days 5-8 of an every 28 day cycle.  A DLT of 
thrombocytopenia was observed in heavily pretreated patients receiving the 40mg dose of niraparib, limiting 
feasibility of dosing. Investigators ultimately concluded that a dose of niraparib 30mg with a dose of 
temozolomide 150mg/m2 was well tolerated, though this dose was well below the established RP2D and as such 
the study was closed before assessing planned efficacy measures. In another Phase Ib dose-escalation study 
PN-008 evaluating the use of  niraparib  in combination with carboplatin, carboplatin/paclitaxel and 
carboplatin/liposomal doxorubicin in patients with advanced solid tumors, niraparib was dosed at 40mg on days 
1-4 in combination with carboplatin dosed at an AUC = 5 on Day 3 of an every 21 day cycle.  This combination 
was also poorly tolerated due to myelosuppression, although there were technically no DLTs in the 12 enrolled 
patients in the first study cohort. We therefore have selected an initial dose of niraparib of 100mg daily, a dose 
that allows for appropriate PARP inhibition, with carboplatin AUC of 2, a lower dose than previously studied in a 
niraparib combination regimen. We believe this starting dose will provide appropriate efficacy with a low 
likelihood for significant DLTs.  
 
5.7 Carboplatin Dosing 
Carboplatin dosing to a goal AUC of 2 – 4 (as per the Dose escalation Tables) will be based off of creatinine 
clearance per the Cockroft-Gault formula. Dose capping of carboplatin may be carried out according to local 
institutional protocols. 
 
 

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6.0 SAFETY VARIABLES AND TOXICITY ASSESSMENT 
 
The Principal Investigator or Sub-investigators will assess adverse events, laboratory data and vital signs 
throughout the study.  Adverse events will be assessed by NCI CTCAE Version 5.0. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x
11.pdf   
 
6.1 Adverse Events Assessment 
The investigators will monitor each subject for clinical and laboratory evidence of adverse events on a routine 
basis throughout the study. The investigator will assess and record any adverse event in detail including the date 
of onset, event diagnosis (if known) or sign/symptom, severity, time course, duration and outcome, relationship 
of the adverse event to study drug, and any action(s) taken. For serious adverse events not considered "probably 
related" to study drug, the investigator will provide an "Other" cause of the event. For adverse events to be 
considered intermittent, the events must be of similar nature and severity. Adverse events, whether in response 
to a query, observed by site personnel, or reported spontaneously by the subject will be recorded. All adverse 
events will be followed to a satisfactory conclusion. 
 
6.2 Study Monitoring 
6.2.1 Data Safety Monitoring Committee at Georgetown 
The Georgetown Lombardi Comprehensive Cancer Center (LCCC) will be responsible for the data and safety 
monitoring of this trial.  As this study is an investigator initiated Phase I study utilizing FDA-approved on label, 
and off label therapies, it is considered a high risk study which requires real-time monitoring by the PI and study 
team and quarterly reviews by the LCCC Data and Safety Monitoring Committee (DSMC). 
 
The Principal Investigator, Dr. Isaacs, and the Study Chairs will review the data including safety monitoring at 
their monthly teleconferences with participating sites.   
 
SAEs are required to be reported to the local and/or to the Georgetown IRB, per IRB reporting guidelines.  Based 
on SAEs, the IRB retains the authority to suspend further accrual pending more detailed reporting and/or 
modifications to further reduce risk and maximize the safety of participating patients. 
 
Progress on the trial and the toxicities experienced will be reviewed by the LCCC Data and Safety Monitoring 
Committee every 3 months from the time the first patient is enrolled on the study. Results of the DSMC meetings 
will be forwarded to the IRB with recommendations regarding need for study closure. 
 
DSMC recommendations should be based not only on results for the trial being monitored as well as on data 
available to the DSMC from other studies.  It is the responsibility of the PI to ensure that the DSMC is kept 
apprised of non-confidential results from related studies that become available.  It is the responsibility of the 
DSMC to determine the extent to which this information is relevant to its decisions related to the specific trial 
being monitored. 
 
A written copy of the DSMC recommendations will be given to the trial PI and the IRB.  If the DSMC recommends 
a study change for patient safety or efficacy reasons the trial PI must act to implement the change as 
expeditiously as possible.  In the unlikely event that the trial PI does not concur with the DSMC recommendations, 
then the LCCC Associate Director of Clinical Research must be informed of the reason for the disagreement.  
The trial PI, DSMC Chair, and the LCCC Associate Director for Clinical Research will be responsible for reaching 
a mutually acceptable decision about the study and providing details of that decision to the IRB.  Confidentiality 
must be preserved during these discussions.  However, in some cases, relevant data may be shared with other 
selected trial investigators and staff to seek advice to assist in reaching a mutually acceptable decision. 
 
If a recommendation is made to change a trial for reasons other than patient safety or efficacy the DSMC will 
provide an adequate rationale for its decision. If the DSMC recommends that the trial be closed for any reason, 
the recommendation will be reviewed by the Associate Director for Clinical Research at LCCC.  Authority to close 
a trial for safety reasons lies with the IRB, with the above described input from DSMC and the Associate Director 
for Clinical Research.   

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Of note, the DSMC will also review the safety data of the patients enrolled outside of Georgetown University.  
Georgetown University’s LCCC Consortium IIT Office will be tasked with the job of collecting all primary source 
documentation for patients enrolled outside of Georgetown University.  In addition, the data managers at each 
site will be entering data into the Georgetown database, so that all data will be available for the DSMC at 
Georgetown to review.  Records should be sent via email to the Georgetown University’s LCCC Consortium IIT 
Office, and Dr. Isaacs. 
 
6.3 Adverse Event and Toxicity Definitions 
6.3.1 Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.  Such an event can 
result from use of the drug as stipulated in the protocol or labeling, as well as from accidental or intentional 
overdose, drug abuse, or drug withdrawal. Any worsening of a pre-existing condition or illness is considered an 
adverse event.  Laboratory abnormalities and changes in vital signs are considered to be adverse events only if 
they result in discontinuation from the study, necessitate therapeutic medical intervention, and/or if the 
investigator considers them to be adverse events.  
 
An elective surgery/procedure scheduled to occur during a study will not be considered an adverse event if the 
surgery/procedure is being performed for a pre-existing condition and the surgery/procedure has been pre 
planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly during the study 
(e.g., surgery performed earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event. 
 
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored until the AE has 
resolved, any abnormal laboratory values have returned to baseline or stabilized at a level acceptable to the 
Investigator, until there is a satisfactory explanation for the changes observed, until the patient is lost to follow-
up, or until the patient has died. 
 
AEs may also include signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae. 
 
A treatment-emergent adverse event will be defined as any new AE that begins, or any preexisting condition 
that worsens in severity during the Treatment Period after at least 1 dose of study medication and throughout 
the treatment period until 30 days after cessation of study treatment for non-serious AEs or until 90 days after 
cessation of study treatment for SAEs and AESIs (or to a minimum of 30 days post-treatment if the patient starts 
alternate anticancer therapy). 
 
6.3.2 Serious Adverse Events 
If an adverse event meets any of the following criteria, it is to be reported to the DSMC as a SAE within 24 hours 
of the site being made aware of the serious adverse event. 
1) Death of Subject An event that results in the death of a subject. 
2) Life-Threatening An event that, in the opinion of the investigator, would have resulted in immediate 
fatality if medical intervention had not been taken. This does not include an event that would have been 
fatal if it had occurred in a more severe form. 
3) Hospitalization (unless planned for observation, protocol compliance, elective procedures, social 
reasons) or 
4) Prolongation of Hospitalization An event that results in an admission to the hospital for any length of 
time or prolongs the subject's hospital stay. This does not include an emergency room visit or admission 
to an outpatient facility. 
5) Congenital Anomaly An anomaly detected at or after birth, or any anomaly that results in fetal loss.  

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6) Persistent or Significant Disability/Incapacity An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject. Disability is not intended to include 
experiences of relatively minor medical significance such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle). 
7) Important Medical Event Requiring Medical or Surgical Intervention to Prevent Serious Outcome 
An important medical event that may not be immediately life-threatening or result in death or 
hospitalization, but based on medical judgment may jeopardize the subject and may require medical or 
surgical intervention to prevent any of the outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
8) Spontaneous Abortion Miscarriage experienced by study subject.  
 
Disease progression is an efficacy criterion and is therefore not considered an AE or SAE (even if fatal). Disease 
progression should be documented. If AEs/SAEs occur in relation to disease progression that are not consistent 
with the natural progression of the patient’s disease, these AEs/SAEs must be reported per AE/SAE reporting 
requirements 
 
6.3.3 Adverse Events of Special Interest 
Selected non-serious AEs and SAEs are also known as Adverse Events of Special Interest (AESI) and must be 
reported within 24 hours of awareness of the event to the Sponsor Institution and to GSK regardless of causality 
assessment to study drug.   
AESIs for this trial are defined as:  
 
Myelodysplastic Syndromes (MDS) 
 
Acute Myeloid Leukemia (AML) 
 
Secondary cancers (new malignancies [other than MDS or AML]) 
 
AESI should be collected and reported as follows: 
 
MDS and AML along with other secondary cancers should be reported to the Sponsor throughout the 
Follow-up Assessment Period 
 
6.3.5 Adverse Event Severity 
The study investigator will rate the severity of each adverse event according to the NCI CTCAE Version 5.0.  For 
adverse events not captured by the NCI CTCAE Version 5.0, the following should be used: 
1) Grade 1 (Mild) The adverse event is transient and easily tolerated by the subject. 
2) Grade 2 (Moderate) The adverse event causes the subject discomfort and interrupts the subject's usual 
activities.  
3) Grade 3/4 (Severe or Life Threatening) The adverse event causes considerable interference with the 
subject's usual activities and may be incapacitating or life-threatening. 
4) Grade 5 (Severe, Resulting in Death) The adverse event resulted in death of the subject. 
 
6.3.6 Relationship to Study Drug 
6.3.6.1 Assessment of Toxicity Relatedness to Study Medications  
The investigator will use the following definitions to assess the relationship of the adverse event to the use of 
study drug(s). 
 
Related: A causal relationship between the medicinal product (and/or study procedures) and AE is a 
reasonable possibility. For example, the occurrence of the AE cannot be explained by other causative 
factors. The AE, however, can be explained by pharmacological effect of the medicinal product such as 
a similar event having been reported previously, alteration of the dose effect, or the timing or seriousness 
of the AE, etc. Positive re-challenge/de-challenge is supportive.  
 

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 
Not Related: A causal relationship between the medicinal product (and/or study procedures) and AE is 
not a reasonable possibility: there is no temporal relationship between the medicinal product and event, 
or an alternative etiology is more reasonable. 
 
6.3.6.2 Attribution of Relationship to Study Medications 
For every adverse event, the investigator must also attribute whether the adverse event was due to (A) 
carboplatin, (B) niraparib, (C) both study medications, or (D) other causes. 
 
If an investigator's opinion of probably not or not related to study drug(s) is given, an Other cause of event must 
be provided by the investigator for the adverse event.   
 
6.3.6.3 Assessment of Expectedness 
For every adverse event, the investigator must also attribute whether the adverse event is ‘expected’ or 
‘unexpected’.   
 
An AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information provided in the Reference Safety Information of the effective Investigator 
Brochure (IB). 
 
For Niraparib: 
o While events of MDS/AML are considered expected, fatal MDS/AML is considered unexpected 
for the purposes of reporting to regulatory authorities, investigators and ethics committees/review 
boards, as applicable.  
o Similarly, while events of neutropenic sepsis and hypertension are considered expected, life-
threatening neutropenic sepsis and life-threatening hypertension are considered unexpected 
for the purposes of reporting to regulatory authorities, investigators and ethics committees/review 
boards, as applicable.  
o All fatal Adverse Drug Reactions (ADRs) are considered unexpected.  
o The following life threatening ADRs are considered expected: thrombocytopenia, anemia, 
neutropenia, pancytopenia, leukopenia, and myelodysplastic syndrome/ acute myeloid leukemia 
6.3.7 Suspected Unexpected Serious Adverse Reactions (SUSARs) 
For any AE that is serious, associated with the use of the study treatment, and unexpected (defined as any term 
not listed in the expectedness section of the current Investigator’s Brochure) additional reporting requirements 
are described below. These types of reports are referred to as (SUSARs). 
a. If the SUSAR is fatal or life-threatening, associated with the use of the study treatment, and unexpected, 
Regulatory Authorities and IECs will be notified within 7 calendar days after the Investigator learns of the 
event. Additional follow-up (cause of death, autopsy report, and hospital report) information should be 
reported within an additional 8 days (15 days total). 
b. If the SUSAR is not fatal or life-threatening but is otherwise serious, associated with the use of the study 
treatment, and unexpected, Regulatory Authorities and IECs will be notified within 15 calendar days after 
the Investigator learns of the event. 
 
The Institution will also provide annual safety updates to the Regulatory Authorities and IECs responsible for the 
study. These updates will include information on SUSARs and other relevant safety findings. 
 
6.4 Adverse Event Collection Period 
All adverse events reported from the time of the administration of study drug until 30 days following 
discontinuation of therapy has elapsed will be collected, whether elicited or spontaneously reported by the 
subject.  All serious adverse events and adverse events of special interest will be collected from the time the 
subject signed the study-specific informed consent until at least 90 days after cessation of study treatment for 
(or to a minimum of 30 days post-treatment if the patient starts alternate anticancer therapy). 
 
 
 
 
 

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6.5 Adverse Event Reporting 
In the event of a serious adverse event, whether related to study drugs, study procedures such as a biopsy, or 
even if not directly related to any study intervention, the investigator will notify the IRB if required by local 
institutional IRB reporting guidelines. Furthermore, the investigator will forward all treatment emergent SAE 
reports regardless of causality, to GSK within 24 hours of becoming aware of the event, by email to 
OAX37649@gsk.com or by facsimile to GSK at +44(0) 2081814780. The institution will forward initial and any 
follow-up reports. 
 
The SAE report should comprise a full written summary, detailing relevant aspects of the adverse events in 
question.  Where applicable, information from relevant hospital case records and autopsy reports should be 
included.  Follow-up information should be forwarded to GSK within 24 hours. SAEs brought to the attention of 
the investigator at any time after cessation of the study drugs and considered by the investigator to be related or 
possibly related to the study drugs must be reported to the IRB if and when they occur. Additionally, in order to 
fulfill international reporting obligations, SAEs that are related to study participation (e.g., procedures, invasive 
tests, change from existing therapy) or are related to a concurrent medication will be collected and recorded from 
the time the subject consents to participate in the study until he/she is discharged. 
 
For patients enrolled outside of Georgetown University, serious adverse events will also be reported, and all 
supporting documentation sent (faxed or emailed) to Georgetown University’s LCCC Consortium IIT Office and 
to the study PI, Dr. Isaacs within 24 hours.  Records should be sent by secure email to the LCCC Consortium 
IIT Office and to Dr. Isaacs (isaacsc@georgetown.edu) to confirm receipt of those records. 
 
6.6 Reporting Product Quality Complaints for Niraparib 
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 GSK QA at  gsk-rd.complaints@gsk.com. 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. 
 
6.7 Pregnancy 
Pregnancies (and pregnancy outcomes) occurring in a female patient or a female partner of a male patient must 
be reported to the Institution within 24 hours. Elective abortions without complications should not be considered 
AEs unless they were therapeutic abortions. Hospitalization for normal delivery of a healthy newborn should not 
be considered an SAE. Spontaneous abortions should always be reported as SAEs. The Investigator should 
follow-up with the study patient or the female partner of the study patient until delivery or termination of 
pregnancy, even if the patient was withdrawn from the clinical study or the clinical study was completed. GSK 
will be informed of all pregnancy outcomes.   
 
In the event of a positive pregnancy test result, study drugs will be immediately discontinued. The investigator 
must report the positive pregnancy test within 24 hours of the site becoming aware of the pregnancy to the IRB 
and to OAX37649@gsk.com. 
 
Reporting pregnancy to GSK should occur on an Initial Pregnancy Report Form. The Investigator must follow-
up all pregnancies, document the course and the outcome, and report this information to the Sponsor Institution 
and to GSK on a Pregnancy Outcome Report Form within 24 hours of becoming aware of the outcome- even if 
the patient was withdrawn from the study or the study has finished. 
 
Any SAE that occurs during pregnancy must be recorded on the Pregnancy Outcome Report Form, reported as 
an SAE on the SAE Report Form (e.g., maternal serious complications, therapeutic abortion, ectopic pregnancy, 
stillbirth, neonatal death, congenital anomaly, birth defect) and reported to the Sponsor Institution and GSK within 
24 hours. Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. 

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For patients enrolled outside of Georgetown University, documentation should be emailed to Georgetown 
University’s LCCC Consortium IIT Office and to the study PI, Dr. Isaacs, within 24 hours.   
 
Patients should also notify the investigator if it is determined after completion of the study that they become 
pregnant either during the treatment phase of the study or within 180 days after the treatment period. Male 
participants should notify the investigator if their partner becomes pregnant during the treatment phase or within 
90 days after treatment.  Information regarding a pregnancy occurrence in a study subject and the outcome of 
the pregnancy will be collected, and the status of the mother and child should be reported to the IRB and GSK 
after delivery.   
 
6.8 Potential Risks of Niraparib 
The following adverse reactions (all CTCAE grades) have been reported in ≥20% of patients who received 
niraparib: anemia, thrombocytopenia, nausea, constipation, vomiting, fatigue, platelet count decreased, 
decreased appetite, headache, and insomnia. The median exposure to niraparib in these patients was 250 days. 
 
The following adverse reactions and laboratory abnormalities have been identified in ≥10 to <20% of the 367 
patients receiving niraparib: neutropenia, palpitations, asthenia, dizziness, dysgeusia, dyspnea, cough and 
hypertension.  
 
The following adverse reactions and laboratory abnormalities have been identified in ≥1 to <10% of the 367 
patients receiving niraparib: tachycardia, dry mouth, mucosal inflammation, aspartate aminotransferase 
increased, alanine aminotransferase increased, and photosensitivity reaction. 
 
Posterior reversible encephalopathy syndrome (PRES) has been observed in 0.1% of patients treated with 
Niraparib. If PRES is suspected, promptly discontinue Niraparib. 
 
Hypertension, Including Hypertensive Crisis  
Hypertension, including hypertensive crisis, has been reported with the use of niraparib. Pre-existing 
hypertension should be adequately controlled before starting niraparib treatment. Blood pressure and heart rate 
should be monitored at least weekly for the first two months, then monthly for the first year and periodically 
thereafter during treatment with niraparib. 
 
Hypertension should be medically managed with antihypertensive medicinal products as well as adjustment of 
the niraparib dose, if necessary.  In the clinical development program, most cases of hypertension were 
controlled adequately using standard antihypertensive treatment with or without niraparib dose adjustment. 
Niraparib should be discontinued in case of hypertensive crisis or if medically significant hypertension cannot be 
adequately controlled with antihypertensive therapy. 
 
Posterior Reversible Encephalopathy Syndrome (PRES)  
There have been rare reports of niraparib-treated patients developing signs and symptoms that are consistent 
with Posterior Reversible Encephalopathy Syndrome (PRES). PRES is a rare neurologic disorder that can 
present with the following signs and symptoms including seizures, headache, altered mental status, visual 
disturbance, or cortical blindness, with or without associated hypertension. A diagnosis of PRES requires 
confirmation by brain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, 
treatment of specific symptoms including control of hypertension is recommended, along with discontinuation of 
niraparib. The safety of reinitiating niraparib therapy in patients previously experiencing PRES is not known. 
 
6.8.1 Description of selected adverse reactions 
Hematologic adverse reactions (thrombocytopenia, anemia, neutropenia) including clinical diagnoses and/or 
laboratory findings generally occurred early during niraparib treatment with the incidence decreasing over time. 
The median time to onset of thrombocytopenia regardless of grade was 22 days. Most events were transient 
with thrombocytopenia resolving within 10 days. In the clinical program, thrombocytopenia was managed with 
laboratory monitoring and dose modification (see Section 6.9). Discontinuation due to thrombocytopenia 
occurred in 3% of patients. The median time to onset of anemia of any grade was 42 days, and for Grade 3/4 

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events was 85 days. The median duration of anemia of any grade was 63 days and was considerably shorter for 
Grade 3/4 anemia at 8 days. Discontinuation due to anemia occurred in 1% of patients. Most patients did not 
receive treatment for neutropenia events.  Discontinuation due to neutropenia events occurred in 2% of patients. 
 
Hypertension, including hypertensive crisis, has been reported with niraparib therapy.  In the clinical program, 
hypertension was readily managed with anti-hypertensive medication. Discontinuation due to hypertension 
occurred in <1% of patients. 
 
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including cases with fatal outcome, have been 
reported in a small number of patients who received niraparib or placebo. In the Phase 3 international trial 
ENGOTOV16 / NOVA, the incidence of MDS/AML in patients who received niraparib (1.4%) was similar to that 
in patients who received placebo (1.1%). The duration of niraparib treatment in patients prior to developing 
MDS/AML varied from 1 month to >2 years. The cases were typical of secondary, cancer therapy-related 
MDS/AML. All patients had received multiple platinum-containing chemotherapy regimens and many had also 
received other DNA damaging agents and radiotherapy. Some of the patients had a history of bone marrow 
dysplasia. If MDS and/or AML are confirmed while on treatment with niraparib, niraparib should be discontinued 
and the patient treated appropriately. 
 
6.9 Toxicity Management and Dose Adjustments 
6.9.1 Dose Limiting Toxicity (DLT) Definitions 
Toxicities will be defined in the Phase Ia portion of the study as DLTs if they are included below (as defined 
by NCI CTCAE v.5.0) and they occur during the first two cycles of therapy and are deemed related to the 
study regimen as assessed by the investigator. In addition, any toxicity which results in withholding of therapy 
for > 4 weeks will be treated as a DLT. 
 
Table 8. Criteria for Defining DLTs in the Phase Ia Portion of Study Related to Niraparib or Carboplatin 
Toxicity 
DLT (per CTCAE v. 5.0) 
Hematology 
≥ Grade 4 neutropenia (ANC < 500/µL) lasting ≥ 7 consecutive days 
Grade 3 or 4 febrile neutropenia  
≥ Grade 4 thrombocytopenia 
Grade 3 thrombocytopenia with clinically significant bleeding 
Grade 4 anemia or Grade 3 anemia requiring blood transfusion 
Cardiac 
≥ Grade 3 cardiac toxicity, clinical signs of cardiac disease such as unstable 
angina, myocardial infarction, or troponin ≥ Grade 3 
Gastrointestinal 
≥ Grade 3 vomiting ≥ 48 hours despite optimal anti-emetic therapy 
≥ Grade 3 diarrhea ≥ 48 hours despite optimal anti-diarrheal therapy 
(Optimal therapy for vomiting and diarrhea should be based on institutional 
guidelines with consideration of the prohibited medications listed in these 
protocol guidelines). 
Hepatobiliary 
≥ Grade 2 total bilirubin > 7 consecutive days 
≥ Grade 3 total bilirubin 
≥ Grade 2 AST/ALT AND ≥ Grade 2 bilirubin elevation of any duration in the 
absence of liver metastases 
≥ Grade 3 AST/ALT for > 4 consecutive days 
Grade 4 ALT or AST 
Renal 
≥ Grade 3 serum creatinine 
Non-hematologic, non-
hepatic adverse events 
≥ Grade 3 except for the following exceptions: 
Exceptions to DLT 
criteria 
Grade 3 alopecia 
< 7 days of Grade 3 fatigue 
Grade 3 fever or infection without neutropenia < 5 days duration 
Grade 3 laboratory abnormalities that are responsive to oral supplementation or 
deemed by the investigator to be clinically insignificant 
Other 
Any toxicity which results in withholding of therapy for > 4 weeks  
 

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If a DLT is experienced, patients should be monitored as follows: 
 
Hematologic: daily blood counts with CBC until toxicity is Grade 3 or less, then weekly blood counts for 
CBC until Grade 1 or less with the following exceptions: 
o If febrile Grade 3 or 4 neutropenia, patient should be hospitalized for antibiotics and clinical 
monitoring (including daily blood counts for CBC) 
o If Grade 3 thrombocytopenia with bleeding, daily blood counts with CBC until bleeding ceases, 
then weekly blood counts for CBC until Grade 1 or less 
 
Cardiac Disease: prompt cardiac consultation and management per recommendations 
 
Gastrointestinal: daily symptom evaluation (clinic or telephone) until toxicity is < Grade 2, and then 
weekly evaluation until Grade 1 or less (clinic or telephone) 
 
Hepatobiliary: daily serum liver function tests until toxicity is: 
o Grade 3 or less for isolated Grade 4 AST/ALT elevation or isolated Grade 4 alkaline phosphatase 
elevation, then weekly serum liver function tests until Grade 1 or less 
o Grade 2 or less for isolated Grade 3 or 4 total bilirubin elevation, then weekly serum liver function 
tests until Grade 1 or less 
For combined > Grade 2 AST/ALT elevation AND > Grade 2 bilirubin elevation in the absence of liver 
metastases, daily serum liver function tests until toxicity is Grade 2 or less, then weekly serum liver 
function tests until Grade 1 or less. If initial toxicity is Grade 2, proceed with weekly serum liver function 
tests until Grade 1 or less only 
 
Renal: daily serum creatinine measurement until toxicity is < Grade 2, and then weekly serum creatinine 
measurement until Grade 1 or less 
 
Other: daily evaluation by labwork or symptom evaluation (clinic or telephone) based on toxicity until < 
Grade 2, and then weekly evaluation by labwork or symptom evaluation (clinic or telephone) based on 
toxicity until Grade 1 or less 
 
6.9.2 Therapeutic Dosing in Response to DLTs 
6.9.2.1 Schedule #1 
According to Schedule #1, niraparib will be given on D1-14 of each cycle, and carboplatin is given on D2 
beginning with Cycle 2. If a DLT is experienced, guidelines should be followed as listed in Table 8 and 9. When 
toxicity resolves to Grade 1 or less (within 28 days), the patient may resume treatment at the dose level below 
the previous dose level.  
 
If the DLT is experienced during Cycle 1 and resolves to Grade 1 or less (within 28 days), the patient 
may resume at the dose level below beginning at Cycle 1 
 
If the DLT is experienced during Cycle 2 PRIOR to carboplatin dose and resolves to Grade 1 or less 
(within 28 days), the patient may resume the dose level below beginning at Cycle 1  
 
If the DLT is experienced during Cycle 2 AFTER carboplatin dose and resolves to Grade 1 or less (within 
28 days), the patient may resume the dose level below beginning at Cycle 2, and so on  
For the Phase Ib portion, if toxicity hinders biopsy accession, a biopsy should be attempted at the appropriate 
time within the next dose level treatment schedule. 
 
6.9.2.2 Schedule #2 
According to Schedule #2, niraparib will be given on D1-7 of each cycle, and carboplatin is given on D2 beginning 
with Cycle 2. If a DLT is experienced, guidelines should be followed as listed in Table 8 and 9. When toxicity 
resolves to Grade 1 or less (within 28 days), patient may resume treatment at the dose level below the previous 
dose level.  
 
If the DLT is experienced during Cycle 1 and resolves to Grade 1 or less (within 28 days), the patient 
may resume the dose level below beginning at Cycle 1 
 
If the DLT is experienced during Cycle 2 PRIOR to carboplatin dose and resolves to Grade 1 or less 
(within 28 days), the patient may resume the dose level below beginning at Cycle 1 
 
If the DLT is experienced during Cycle 2 AFTER carboplatin dose and resolves to Grade 1 or less (within 
28 days), patient may resume the dose level below beginning at Cycle 2, and so on 
For the Phase Ib portion, if toxicity hinders biopsy accession, a biopsy should be attempted at the appropriate 
time within the next dose level treatment schedule. 
 

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6.9.2.3 Schedule #3 
According to Schedule #3, niraparib will be given on D1-4 and D8-11 of each cycle, and carboplatin is given on 
D2 and D9 beginning with Cycle 2. If a DLT is experienced, guidelines should be followed as listed in Table 8 
and 9. When toxicity resolves to Grade 1 or less (within 28 days), patient may resume treatment at the dose 
level below the previous dose level.  
 
If the DLT experienced during Cycle 1 and resolves to Grade 1 or less (within 28 days), the patient may 
resume the dose level below beginning at Cycle 1 
 
If the DLT is experienced during Cycle 2 PRIOR to D2 carboplatin dose and resolves to Grade 1 or less 
(within 28 days), the patient may resume the dose level below beginning at Cycle 1 
 
If the DLT is experienced during Cycle 2 AFTER D2 or D9 carboplatin dose and resolves to Grade 1 or 
less (within 28 days), the patient may resume the dose level below beginning at Cycle 2, and so on 
For the Phase Ib portion, if toxicity hinders biopsy accession, a biopsy should be attempted at the appropriate 
time within the next dose level treatment schedule. 
 
6.10 General Management of Significant Toxicities 
6.10.1 Significant Toxicities Management 
The following are general guidelines for dose reduction, delay and discontinuation of the study drugs if a subject 
experiences a DLT, as per Table 8, or an adverse event that is specifically outlined in Table 9 and is deemed 
possibly, probably, or definitely related to study therapy: 
 
All treatment should be discontinued/delayed until the toxicity resolves to Grade 1 or lower or to baseline 
if Grade 2 at the time of study entry 
 
Subjects may delay retreatment for up to 4 weeks to allow the toxicity to resolve. If the toxicity requiring 
dose interruption has not resolved completely or to CTCAE Grade 1 (or to baseline if Grade 2 at time of 
study entry) during the maximum 4-week dose interruption period, the patient must permanently 
discontinue treatment on study 
 
Patients may restart therapy if toxicity(ies) resolve to Grade 1 or lower (or to baseline if Grade 2 at time 
of study entry), but at a lower dose level as per Table 1 for both Phase Ia and Phase Ib. 
 
No more than two dose level reductions are allowed. 
 
If patients are at the lowest dose level and a dose reduction is required, then that patient will be taken off 
study. 
 
If a dose interruption or modification is required at any point on study because of hematologic toxicity, 
weekly blood draws for CBC will be monitored until the AE resolves, and to ensure safety of the new 
dose, weekly blood draws for CBC also will be required for an additional 4 weeks after the AE has been 
resolved to the specified levels, after which monitoring every 4 weeks may resume. 
 
Any patient requiring transfusion of platelets or red blood cells (1 or more units) or hematopoietic growth 
factor support must undergo a dose reduction upon recovery if study treatment is resumed. 
 
The patient must be referred to a hematologist for further evaluation (1) if frequent transfusions are required 
or (2) if the treatment-related hematologic toxicities have not recovered to CTCAE Grade 1 or less after 4 
weeks.  
 
For major surgery while on treatment, up to 28 days of study treatment interruption is allowed.  
 
Once the dose of study treatment has been reduced, any re-escalation must be discussed with the 
medical monitor. 
 
All dose interruptions and reductions (including any missed doses), and the reasons for the 
reductions/interruptions, are to be recorded. 
 
Table 9. Dose Modifications for Toxicities Related to Niraparib or Carboplatin 
The following table defines the therapeutic management of patients in the trial.   
Please note that these rules cover BOTH toxicities that meet the definition of a DLT, and NON-DLT-defining 
toxicities for both the Phase Ia and Phase Ib portions of the trial. The following are general guidelines for dose 
reduction, delay and discontinuation of the study drugs if a subject experiences an adverse event that is 
specifically outlined in Table 9 and is deemed possibly, probably, or definitely related to study therapy: 
 
Hematologic 
Thrombocytopenia1 

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Platelet count > 100 x 109/L 
No dose adjustment required 
Grade 1 (75 x 109/L – 99 x 109/L) 
Hold niraparib and carboplatin until platelet counts are > 100 x 
109/L with weekly blood counts for CBC monitored until 
recovery. Study drugs may then be resumed at the same dose 
if resolved in < 7 days. If requires > 7 days to resolve, resume 
at a reduced dose (the previous dose level as outlined in Phase 
Ia). 
Grade 2 & 3 ( < 74 x 109/L) 
Hold niraparib and carboplatin until platelet counts are > 100 x 
109/L with weekly blood counts for CBC monitored until 
recovery. Study drugs may then be resumed at a reduced dose 
(the previous dose level as outlined in Phase Ia). Discontinue 
study drugs if the platelet count has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the 
patient was already receiving the lowest dose. 
Second occurrence of platelet count <100 x 
109/L (any grade) 
Hold niraparib and carboplatin until platelet counts are > 100 x 
109/L with weekly blood counts for CBC monitored until 
recovery. Study drugs may then be resumed at a reduced dose 
(the previous dose level as outlined in Phase Ia). Discontinue 
study drugs if the platelet count has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the 
patient was already receiving the lowest dose. 
Grade 4 ( < 25 x 109/L) 
Hold niraparib and carboplatin until platelet counts are > 100 x 
109/L with daily blood counts for CBC monitored until platelet 
count > 25 x 109/L, and then weekly blood counts for CBC until 
recovery. Study drugs may then be resumed at a reduced dose 
(the previous dose level as outlined in Phase Ia) if resolved 
within 28 days. Discontinue study drugs if the platelet count has 
not returned to acceptable levels within 28 days of the dose 
interruption period, or if the patient was already receiving the 
lowest dose. 
Neutropenia (ANC) 
Grade 1 (≥ 1.5 x 109/L) 
No dose adjustment required 
Grade 2 (≥ 1.0 – < 1.5 x 109/L) 
Hold niraparib and carboplatin until recovery ≥ 1.5 x 109/L with 
weekly blood counts for CBC. Study drugs may then be 
resumed at a reduced dose (the previous dose level as outlined 
in Phase Ia). Discontinue study drugs if the neutrophil count has 
not returned to acceptable levels within 28 days of the dose 
interruption period, or if the patient was already receiving the 
lowest dose. 
Grade 3 (≥ 0.5 – < 1.0 x 109/L) 
Hold niraparib and carboplatin until recovery ≥ 1.5 x 109/L with 
weekly blood counts for CBC. Study drugs may then be 
resumed at a reduced dose (the previous dose level as outlined 
in Phase Ia). Discontinue study drugs if the neutrophil count has 
not returned to acceptable levels within 28 days of the dose 
interruption period, or if the patient was already receiving the 
lowest dose. 
Grade 4 (< 5 x 109/L) 
Hold niraparib and carboplatin until recovery ≥ 1.5 x 109/L with 
daily blood counts for CBC monitored until ANC ≥ 0.5 – < 1.0 x 
109/L, and then weekly blood counts for CBC until recovery. 
Study drugs may then be resumed at a reduced dose (the 
previous dose level as outlined in Phase Ia). Discontinue study 
drugs if the neutrophil count has not returned to acceptable 

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levels within 28 days of the dose interruption period, or if the 
patient was already receiving the lowest dose. 
If recurs at Grade 4: 
Discontinue all therapy (off study) 
Febrile neutropenia 
Grade 3 (ANC < 1.0 x 109/L with a single 
temperature > 38.3 °C (101 °F) or a 
sustained temperature of ≥ 38.3 °C (101 °F) 
for more than 1 hour 
Hold niraparib and carboplatin until recovery ≥ 1.5 x 109/L with 
weekly blood counts for CBC and afebrile. Study drugs may 
then be resumed at a reduced dose (the previous dose level as 
outlined in Phase Ia). 
If recurs: 
Discontinue all therapy (off study) 
Grade 4 (life-threatening consequences, 
urgent intervention indicated) 
Discontinue all therapy (off study) 
Anemia (hemoglobin) 
Grade 1 (≥ 10.0 – LLN g/dL) 
No dose adjustment required 
Grade 2 (≥ 8.0 – < 10.0 g/dL) 
No dose adjustment required 
Grade 3 (< 8.0 g/dL) 
Hold niraparib and carboplatin until recovery to > 9.0 g/dL with 
weekly blood counts for CBC. Packed red blood cell 
transfusions allowed to achieve a hemoglobin of ≥ 9.0g/dL. 
Study drugs may then be resumed at a reduced dose (the 
previous dose level as outlined in Phase Ia). Discontinue study 
drugs if the hemoglobin count has not returned to acceptable 
levels within 28 days of the dose interruption period, or if the 
patient was already receiving the lowest dose. 
Grade 4 (life-threatening consequences, 
urgent intervention indicated) 
Hold niraparib and carboplatin until recovery ≥ 9.0g/dL with daily 
blood counts for CBC until Grade 3 anemia, and then weekly 
blood counts for CBC monitored until recovery. Study drugs 
may then be resumed at a reduced dose (the previous dose 
level as outlined in Phase Ia). Discontinue study drugs if the 
hemoglobin count has not returned to acceptable levels within 
28 days of the dose interruption period, or if the patient was 
already receiving the lowest dose. 
If recurs: 
Discontinue all therapy (off study) 
Confirmed diagnosis of MDS or AML 
Discontinue all therapy (off study) 

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Hepatotoxicity 
Total bilirubin elevation without AST/ALT increase above baseline value2 
Grade 1 (> ULN – 1.5 x ULN) confirmed on 
repeat 48-72 hours later 
ONLY IF GRADE 0 AT BASELINE 
Maintain dose level with liver enzymes and bilirubin tests 
monitored weekly until normalizes 
Grade 2 (> 1.5 – 3.0 x ULN) 
Hold niraparib and carboplatin until < 1.5 x ULN monitored with 
weekly blood tests for liver enzymes and bilirubin tests. Study 
drugs may then be resumed at the same dose if resolved to ≤ 
Grade 1 in ≤ 14 days. If it requires > 14 days or toxicity recurs, 
re-initiate niraparib and carboplatin at a reduced dose (the 
previous dose level as outlined in Phase Ia). 
Repeat liver enzymes and bilirubin tests twice weekly for 2 
weeks following re-initiation 
If recurs at reduced dose level, discontinue all therapy (off 
study) 
Grade 3 (> 3.0 – 10.0 x ULN) 
Hold niraparib and carboplatin until < 1.5 x ULN monitored with 
weekly blood tests for liver enzymes and bilirubin tests. Study 
drugs may then be resumed at a reduced dose (the previous 
dose level as outlined in Phase Ia) if resolved to ≤ Grade 1 in ≤ 
21 days. If resolved to ≤ Grade 1 in > 21 days or toxicity recurs, 
discontinue all therapy (off study) 
Repeat liver enzymes and bilirubin tests twice weekly for 2 
weeks following re-initiation 
Grade 4 (> 10.0 x ULN) 
Discontinue all therapy (off study) 
 
 
 
 
 
AST or ALT elevation without bilirubin elevation > 2 x ULN 

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Same grade as baseline or increase from 
baseline Grade 0 to Grade 1 confirmed 48-72 
hours later 
No dose adjustment required with LFTs monitored per protocol 
if same grade as baseline or bi-weekly in case of increase from 
baseline grade 0 to 1 
Increase from baseline Grade 0 or 1 to Grade 
2 (> 3.0 – 5.0 x ULN) 
Hold niraparib and carboplatin until LFTs resolve to ≤ baseline 
value with weekly blood tests for liver enzymes. Study drugs 
may then be resumed at the same dose if resolved to baseline 
value in ≤ 14 days. If resolved to ≤ baseline value in > 14 days 
or toxicity recurs, re-initiate niraparib and carboplatin at a 
reduced dose (the previous dose level as outlined in Phase Ia). 
Repeat liver enzymes and bilirubin tests twice weekly for 2 
weeks following re-initiation 
If recurs at reduced dose level or recovery to ≤ baseline value 
in > 14 days, discontinue all therapy (off study) 
Increase from baseline Grade 0 or 1 to Grade 
3 (> 5.0 – 20.0 x ULN) 
Hold niraparib and carboplatin until LFTs resolve to ≤ baseline 
value with weekly blood tests for liver enzymes. Study drugs 
may then be resumed at a reduced dose (the previous dose 
level as outlined in Phase Ia) if resolved to baseline value in ≤ 
21 days. 
Repeat liver enzymes and bilirubin tests twice weekly for 2 
weeks following re-initiation 
If recurs at reduced dose level or recovery to ≤ baseline value 
in > 21 days, discontinue all therapy (off study) 
Increase from baseline Grade 2 (i.e., in a 
patient with liver metastases) to Grade 3 (> 5.0 
– 20.0 x ULN) 
Hold niraparib and carboplatin until LFTs resolve to ≤ baseline 
value with weekly blood tests for liver enzymes. Study drugs 
may then be resumed at a reduced dose (the previous dose 
level as outlined in Phase Ia) if resolved to baseline value in ≤ 
21 days. 
Repeat liver enzymes and bilirubin tests twice weekly for 2 
weeks following re-initiation 
If recurs at reduced dose level or recovery to ≤ baseline value 
in > 21 days, discontinue all therapy (off study) 
Grade 4 (> 20.0 x ULN) 
Discontinue all therapy (off study) 
AST or ALT and concurrent bilirubin elevation 
Normal ALT or AST or total bilirubin at 
baseline:  
AST or ALT ≥ Grade 2 with total bilirubin > 2 
x ULN without evidence of cholestasis 
OR 
Elevated AST or ALT or total bilirubin at 
baseline: baseline: [AST or ALT >2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT 
8.0 x ULN]- whichever is lower-combined 
with [total bilirubin 2x baseline AND > 2.0 x 
ULN]  
Discontinue all therapy (off study) 
 
 
All Other Adverse Reactions 

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Grade 1 
No dose adjustment recommended, initiate appropriate medical 
therapy and monitor 
Grade 2 (unless Grade 2 at baseline) 
Hold niraparib and carboplatin until ≤ Grade 1, treat with 
appropriate medical therapy and monitor, re-initiate at same 
dose 
If recurs at Grade 2, hold niraparib and carboplatin until ≤ Grade 
1, re-initiate niraparib and carboplatin at a reduced dose 
(previous dose level as outlined in Phase Ia). 
Grade 3 
Hold niraparib and carboplatin until ≤ Grade 1, treat with 
appropriate medical therapy and monitor, re-initiate niraparib 
and carboplatin at a reduced dose (previous dose level as 
outlined in Phase Ia).  
If recurs at Grade 3, discontinue all therapy (off study) 
Grade 4 
Discontinue all therapy (off study), treat with appropriate 
medical therapy 
1   For patients with platelet count ≤ 10,000/μL, prophylactic platelet transfusion per guidelines may be considered.{Schiffer, 
2001 #154}{Slichter, 2007 #155}. For patients taking anticoagulation or antiplatelet drugs, consider the risk/benefit of 
interrupting these drugs and/or prophylactic transfusion at an alternate threshold, such as ≤ 20,000/μL. 
2 Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before dose 
interruption/reduction. They include but are not limited to: evidence of obstruction, such as elevated ALP and GGT typical 
of gall bladder or bile duct disease, hyperbilirubinemia due to the indirect component only (i.e. direct bilirubin component ≤1 
x ULN) due to hemolysis or Gilbert Syndrome, pharmacologic treatment, viral hepatitis, alcoholic or autoimmune hepatitis, 
other hepatotoxic drugs. For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin 
only. Bilirubin will be fractionated if elevated.  
 
6.10.2 Management of Phase Ib Toxicities in Alternative Schedules 
6.10.2.1 Schedule #1 
According to Schedule #1, niraparib will be given on D1-14 of each cycle, and carboplatin is given on D2 
beginning with Cycle 2. If a toxicity is experienced that requires treatment hold, guidelines should be followed as 
listed in Table 9. Treatment should resume at the same Cycle from whence the toxicity was noted, but perhaps 
at a reduced dose (per Table 9). If toxicity hinders biopsy accession, a biopsy should be attempted at the 
appropriate time when treatment is resumed. 
 
6.10.2.2 Schedule #2 
According to Schedule #2, niraparib will be given on D1-7 of each cycle, and carboplatin is given on D2 beginning 
with Cycle 2. If a toxicity is experienced that requires treatment hold, guidelines should be followed as listed in 
Table 9. Treatment should resume at the same Cycle from whence the toxicity was noted, but perhaps at a 
reduced dose (per Table 9). If toxicity hinders biopsy accession, a biopsy should be attempted at the appropriate 
time when treatment is resumed. 
 
6.10.2.3 Schedule #3 
According to Schedule #3, niraparib will be given on D1-4 and D8-11 of each cycle, and carboplatin is given on 
D2 and D9 beginning with Cycle 2. If a toxicity is experienced that requires treatment hold, guidelines should be 
followed as listed in Table 9. Treatment should resume at the same Cycle from whence the toxicity was noted, 
but perhaps at a reduced dose (per Table 9). If toxicity is noted on D8 limiting the second treatment with niraparib 
and/or carboplatin, then the Cycle should be resumed at D1 once the toxicity resolves, perhaps at a reduced 
dose (per Table 9). If toxicity hinders biopsy accession, a biopsy should be attempted at the appropriate time 
when treatment is resumed. 

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7.0 MEASUREMENT OF EFFECT 
7.1 Definitions 
Tumor response and/or disease progression will be assessed by a CT scan (or other appropriate modalities such 
as MRI consistent with the modality used prior to treatment) utilizing RECIST v1.1 criteria. Changes in only the 
largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST v1.1 criteria. 
Assessments will be performed within 4 weeks before screening every 9 weeks thereafter, and at the final visit, 
if not performed within the last four weeks.  
 
7.1.1 Safety and Tolerability Evaluable 
For the Phase Ia portion, for a patient to be evaluable for safety, tolerability, and assessment of dose-limiting 
toxicities, the patient must complete the first two cycles. Any patient who is taken off study for any reason other 
than toxicity (or death related to toxicity) will not be considered evaluable for assessment of safety, tolerability, 
and assessment of dose-limiting toxicity, and must be replaced. 
 
7.1.2 Response Evaluable 
A patient who initiates therapy per protocol, and is taken off study for disease progression or clinical progression, 
including death related to the underlying solid tumor malignancy (as determined by the treating oncologist) will 
be considered evaluable for response assessment.  However, patients who have initiated therapy and who 
withdraw from the study for any reason other than clinical or radiographic progression, or death believed 
unrelated to their underlying solid tumor malignancy will not be considered evaluable for response.  Reasons 
for patients who have initiated therapy, but are no longer evaluable for response could include (but are not limited 
to): 
- The patient cannot tolerate therapy despite dose modifications, and there is no evidence of 
clinical/radiographic disease progression at the time of stopping therapy 
-  An unexpected and/or unrelated medical illness, such as a stroke or myocardial infarction that is 
considered unrelated to the underlying solid tumor malignancy 
- An unexpected trauma or death that is considered unrelated to the underlying solid tumor malignancy 
 
7.1.3 Disease Parameters 
7.1.3.1 Measurable Disease  
The presence of at least one measurable lesion. If the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should be confirmed by cytology/histology. 
 
7.1.3.2 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, x-ray) or as >10 mm with spiral CT 
scan. Previously irradiated lesions are non-measurable except in cases of documented progression of the lesion 
since the completion of radiation therapy. 
 
7.1.3.3 Non-measurable disease 
All other lesions, including small lesions (longest diameter <20 mm with conventional techniques or <10 mm 
using spiral CT scan), bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory 
breast disease, lymphangitis cutis/pulmonis and cystic lesions are considered non-measurable disease.   
 
All measurements should be taken and recorded in metric notation, using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 
weeks before the beginning of the treatment.  The same method of assessment and the same technique should 
be used to characterize each identified and reported lesion at baseline and during follow-up.  Clinical lesions will 
only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For the 
case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is 
required. 
 
7.2 Methods of Measurement 
CT and MRI are the best currently available and reproducible methods to measure target lesions selected for 
response assessment. Conventional CT and MRI should be performed with cuts of 10 mm or less in slice 

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thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. This 
applies to tumors of the chest, abdomen and pelvis. For accurate objective response evaluation, ultrasound 
should not be used to measure tumor lesions. However, ultrasound is a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions and thyroid nodules. Ultrasound might 
also be useful to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination.  The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to 
evaluation by clinical examination when both methods have been used to assess the antitumor effect of a 
treatment. 
 
7.2.1 Baseline Documentation of "Target" and "Non-Target" Lesions 
7.2.1.1 Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all 
involved organs, should be identified as target lesions and recorded and measured at baseline.  Target lesions 
should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).  A sum of the longest diameter (LD) for all 
target lesions will be calculated and reported as the baseline sum LD.  The baseline sum LD will be used as 
reference by which to characterize the objective tumor response. 
 
7.2.1.2 Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should 
be identified as non-target lesions and should also be recorded at baseline.  Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up. 
 
7.3 Response Criteria 
7.3.1 Evaluation of Tumor Response-Measurable Disease 
7.3.1.1 Complete Response (CR) 
The disappearance of all known disease, determined by two observations not less than 4 weeks apart. There 
can be no appearance of new lesions. 
 
7.3.2.2 Partial Response (PR) 
A 30% or more decrease in the sum of the LD of target lesions that have been measured to determine the effect 
of therapy by two observations not less than 4 weeks apart. There can be no appearance of new lesions. 
 
7.3.2.3 Progressive Disease (PD) 
At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded 
since the treatment started, or the appearance of one or more new lesions resulting in at least a 20% increase 
in the sum of the LD of target lesions, and/or an unequivocal progression of non-target lesions resulting in at 
least a 20% increase in the sum of the LD of target lesions. 
 
7.3.2.4 Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the 
smallest sum LD since the treatment started. 
 
7.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since 
the treatment started).  The patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
 
 
 
 
 
 

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    Table 10:  Response Evaluation 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall 
Response 
Best Response for this 
Category Also Requires: 
CR 
CR 
No 
CR 
>4 wks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
Documented at least once >4 
wks from baseline 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration”.  Every effort should 
be made to document the objective progression even after discontinuation of treatment. 
Note: If subjects respond to treatment and are able to have their disease resected, the patient’s response will be 
assessed prior to the surgery. 
 
7.5 Definition of Disease Progression 
Disease progression will be defined as: 
1) Radiologic progression of disease by RECIST v1.1 criteria. 
2) Clinical progression as determined by the investigator, which may be characterized as, but is not limited 
to: 
a. Increase of at least 2 points in ECOG performance status attributable to cancer progression. 
b. Requirement for palliative chemotherapy or surgery. 
3) Death from disease progression 

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8.0 STATISTICAL CONSIDERATIONS 
8.1 Objectives 
8.1.1 Primary Objective of the Phase Ia Portion: 
To identify the RP2D and schedule of niraparib plus carboplatin for patients with homologous recombination 
deficient advanced solid tumor malignancies  
 
8.1.2 Primary Objective of the Phase Ib Portion: 
To determine the anti-tumor efficacy of niraparib plus carboplatin in a non-disease specific cohort of patients with 
homologous recombination deficient advanced solid tumor malignancies, as determined by RECIST v1.1 
 
8.1.3 Secondary Objectives: 
Clinical: 
a. To evaluate the safety and tolerability of niraparib plus carboplatin 
b. To determine evidence of any disease specificity with this combination 
c. To assess the anti-tumor efficacy of combined therapy as determined by RECIST v1.1 
d. To assess the anti-tumor efficacy of combined therapy as determined by measurement of OS and PFS 
 
Scientific: 
a. To assess the effects of niraparib alone, and niraparib plus carboplatin on pharmacodynamic markers 
of DNA damage and repair, including γH2AX/RAD51 foci formation, and as measured by the PARP 
trapping assay 
b. To explore predictive markers of response and/or resistance to therapy in serial tumor biopsy samples 
8.2 Study Design 
This study is a single-arm, open-label, multi-institutional Phase I dose-escalation and dose-expansion trial of the 
combination of niraparib and carboplatin in patients with advanced solid tumor malignancies with deleterious 
mutation(s) in DNA damage repair genes. The Phase Ia portion of the trial will be conducted in a 3+3 design, 
enrolling patients in cohorts of 3 patients each, to ensure safety and tolerability. With this design, if there are less 
than 2 dose-limiting toxicities (DLTs) in the first 3 patients, then 3 additional patients will be enrolled to the current 
dose level cohort. If there are less than 2 dose-limiting toxicities (DLTs) in these 6 patients, then 3 additional 
patients will be enrolled in the next dose level (Table 1), and so on. If there are greater than or equal to 2 DLTs 
in a given 6 patient cohort, then the dose level below will be considered the maximum tolerated dose (MTD) and 
will be employed as the RP2D and schedule.  
 
Once the RP2D and schedule are identified, a Phase Ib expansion cohort of 20 additional patients will be enrolled 
as a pilot subgroup to determine efficacy.  Of the 20 patients in this Phase Ib cohort, no more than 10 patients 
will have underlying breast cancer; and additionally no more than 10 patients may harbor BRCA1 or BRCA2 
mutations.  
 
Efficacy for both Phase Ia and Phase Ib will be assessed by radiologic assessment every 9 weeks for objective 
response, as well as measurement of PFS and OS. All patients meeting the eligibility criteria and who have 
signed a consent form, have begun treatment for at least 1 cycle of therapy, are not lost to follow-up, and are 
not taken off study for reasons other than progression or death will be considered evaluable for the assessment.  
Interim analyses to assess secondary endpoints of OS and PFS will be scheduled to occur at 12 months and 24 
months. 
 
Pharmacodynamic studies will be evaluated on participant’s serial biopsy samples and serum in both portions of 
study, directed towards an assessment of DNA damage including ᵞH2AX and RAD51 foci formation, as well as 
an assessment of PARP inhibitory activity, as measured by a PARP-trapping assay.  We will also undertake a 
next-generation sequencing analysis of DNA repair enzymes to evaluate markers that predict response and 
resistance to therapy.  In addition, a portion of all pre-treatment tumor samples will be used in ex vivo models 
(e.g. organoids) for further analysis of mechanism of resistance and to identify combinatorial therapies that can 
overcome resistance. 
 
 

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8.3 Sample Size Considerations 
At the sites participating in this study, we anticipate being able to screen as many as 1,000 patients per year. 
Assuming a qualifying mutation rate of 5-10%, and 25% of screened patients being otherwise trial eligible, we 
anticipate enrolling 30 patients per year across multiple medical institutions within the United States. Only 
patients with advanced solid tumor malignancies will be eligible for enrollment. For the Phase Ia portion, there 
may be as few as 18 patients (6 patients at dose level 1, which proves to be too toxic, with three different 
schedules). The maximum number of patients (126) would occur if each schedule is employed and 6 patients 
are enrolled at each dose level. In the Phase Ib portion, we plan to enroll 20 patients to accelerate our 
understanding of the efficacy of the combination of niraparib with carboplatin, in preparation for Phase II or III 
study. With 20 evaluable patients in the Phase Ib portion, combined with a minimum of 18 to a maximum of 126 
patients enrolled in the Phase Ia portion of the trial, there will be up to 146 patients enrolled total. At an expected 
accrual rate of 2-3 patients per month (roughly 30 patients per year), and an anticipated total patient population 
to meet study goals of 80 patients, the expected accrual duration will be approximately 34-38 months. 
 
Once the RP2D and schedule are identified, a Phase Ib expansion cohort of 20 additional patients will be enrolled 
as a pilot subgroup to determine efficacy.  Of the 20 patients in this Phase Ib cohort, no more than 10 patients 
will have underlying breast cancer; and additionally no more than 10 patients may harbor BRCA1 or BRCA2 
mutations.  
 
For the first expansion cohort, we anticipate identifying a higher number of breast cancer patients with HR 
deficient tumors due to frequent utilization of germline genetic testing. In order to obtain information about this 
combination in a variety of tumor types, we will cap the number of breast cancer patients at 10 total. Similarly, in 
order to obtain information in patients with a variety of defects in HR, the total number of patients with BRCA1/2 
mutations (any disease type) will also be capped at 10 total.  
 
Enrolled patients in the Phase Ib expansion cohorts will be screened for enrollment similar to patients enrolled 
in the Phase Ia portion of study, and must meet the same inclusion and exclusion criteria (Appendix A). Phase 
Ia enrollment requirements, such as baseline imaging and consent for serial biopsies, will be upheld. Patients 
will then be started on treatment at the RP2D and schedule as determined during Phase Ia. 
 
8.4 Endpoints 
8.4.1 Primary Endpoints 
8.4.1.1 Phase Ia Primary Endpoint 
The number of grade 3 and 4 toxicities according to NCI CTCAE; Version 5.0 that occur after Cycle 1, Day 1 will 
be recorded at each study visit. 
 
8.4.1.2 Phase Ib Primary Endpoint 
Anti-tumor efficacy by ORR. ORR is defined as the proportion of patients whose best overall response recorded 
during the treatment is either CR or PR according to the RECIST v1.1. 
 
8.4.2 Secondary Endpoints:  
Clinical: 
a. Median overall survival. OS is defined by time from study enrollment till death from any cause 
b. Median progression free survival. PFS is defined as the time from study enrollment to determination of 
tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first 
c. Disease control rate (DCR). DCR is defined as the proportion of patients with a documented CR, PR, or 
SD at 4 months according to the RECIST version 1.1 
Scientific: 
a. Quantification of DNA damage and repair, as measured by γH2AX/RAD51 foci formation 
b. Quantification of PARP inhibition, as measured by PARP trapping assays 
c. Changes in predictive markers of response and/or resistance to therapy in serial tumor biopsy samples 
and in ex vivo samples  
 
 

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8.5 Analysis Plan 
8.5.1 Analysis for the Primary Endpoint 
As a Phase I trial, statistics will be primarily descriptive. Descriptive statistics will be used to summarize patients’ 
characteristics as well as those parameters measured in the laboratory tests. Patients’ adverse events and 
toxicities will be tabulated according to their grades and attributions. The ORR will be estimated with its 95% 
exact confidence interval. In both the Phase Ia and Phase Ib portion of study, ORR will be assessed overall and 
by tumor subtype (breast/gynecologic, gastrointestinal [esophageal, gastric, colorectal, anal], pancreatobiliary, 
GU, other). The main purpose of Phase Ib is not hypothesis testing but rather observing the efficacy. However, 
if we observe at least 5 or more out of the 20 patients who obtain a PR, CR or SD at 9 weeks, this would 
be equivalent to a one-stage Phase II testing of the response rate of 0.1 vs. at least 0.3 at a 0.05 one-sided 
alpha level. The sample size of 20 patients would give 76% power to reject the null hypothesis of the response 
rate at 0.1. If, in this study, 6, 7 or 8 patients obtain a PR, CR or SD at 9 weeks, then the 80% confidence intervals 
for the response rates would be 16.6%-46.6%, 21.2%-51.2%, and 24.8%-56.8%, respectively.   
‘ 
8.5.2 Analysis for the Secondary Endpoints 
PFS and OS will be estimated using the Kaplan-Meier method. The median PFS and OS will be presented with 
their 95% confidence intervals if estimable. The DCR will be calculated according to RECIST v1.1 criteria, and 
will be compared descriptively to historical outcomes. If non-inferiority of combined therapy is observed in both 
portions of study as compared to historical outcomes, and combined therapy is well-tolerated, then further Phase 
II and/or III study will be pursued. 
 
8.5.4 Safety Assessments 
8.5.4.1 Safety Assessments 
The safety of niraparib and carboplatin will be assessed by evaluating study drug exposure, adverse events, 
serious adverse events, oncology-related events, all deaths, as well as changes in laboratory determinations 
and vital sign parameters.   
 
8.5.4.2 Duration of Study Drug 
A summarization of the number of days and/or cycles subjects were exposed to study drug will be provided. 
 
8.5.4.3 Adverse Events   
Analyses of adverse events (and serious adverse events) will include only "treatment-emergent" events, i.e., 
those that have an onset on or after the day of the first dose of study drug. Analyses will not include those that 
have an onset greater than 30 days after the last dose of study drug. Treatment emergent adverse events will 
be summarized by system organ class and preferred term according to the MedDRA adverse event coding 
dictionary. The percentage of subjects experiencing an adverse event at a given severity, NCI CTCAE toxicity 
grade, and relationship to study drug will be provided.  
 
8.5.4.4 Deaths 
The number of subject deaths will be summarized (1) for deaths occurring while the subject was still receiving 
study drug in this study, (2) for deaths occurring off treatment within 30 days after the last dose of study drug, 
and (3) for all deaths in this study regardless of the number of days after the last dose of study drug.  The 
relatedness of the deaths to the study drugs will also be provided. 
 
 

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9.0 CORRELATIVE RESEARCH AND TUMOR SAMPLE MANAGEMENT 
The premise that underlies the use of this combination is that niraparib plus carboplatin will induce significant 
DNA damage, and that tumors with evidence of HRD will be particularly dependent upon PARP activity to recover 
from the carboplatin-induced DNA damage.  Thus, concurrent inhibition of PARP will result in overwhelming DNA 
damage in cancer cells, ultimately leading to increased cancer cell death. It is therefore possible that tumors that 
exhibit these deficiencies will be particularly sensitive to DNA damage and PARP inhibition, which may predict 
an increased ORR with therapy. To assess this hypothesis – that increased DNA damage due to anti-cancer 
therapy may lead to increased ORR – we will perform correlative analyses to quantify DNA damage by 
measurement of ᵞH2AX and RAD51 foci formation in patient tumor samples. All patients will undergo serial, fresh 
tumor biopsies to carry out these assessments, as outlined in Figures 1-3. 
 
Furthermore, we would presume that tumors that are resistant to this combination would have lower PARP or 
DNA repair gene expression levels, and/or no induction of gene expression upon treatment. To monitor for the 
development of resistance to therapy, a portion of all pre-treatment tumor samples will be used in ex vivo models 
(e.g. organoids) for further analysis of mechanism of resistance and to identify combinatorial therapies that can 
overcome resistance. Additionally, we will assess ongoing PARP inhibitor activity as measured by a PARP-
trapping assay on each tumor biopsy sample.  
 
Finally, serial blood samples for patients will be collected prior to treatment on D1 of each cycle for additional 
correlative study by Caris Life Sciences and Dr. Brody’s lab. 
 
9.1 Sample Labeling Overview  
Patients will be de-identified and labeled with a 12 character study label (XX-X-X-XXXXXX): 
- 
The first two characters will be the patient’s initials 
- 
The third character will be the site number from which the patient was enrolled (single digit) 
o 1 = Georgetown 
o 2 = Yale 
o 3 = Hackensack 
o 4 =Levine 
o 5 = John’s Hopkins 
o 6 = Vanderbilt 
o 7 = Other 
- 
The fourth and fifth characters will be the patient study number (e.g. 01, 02, 03, etc.) 
- 
The sixth character will be the timing of collection 
o 1 = First biopsy/sample 
o 2 = Second biopsy/sample 
o 3 = Third biopsy/sample  
o 4 = Fourth biopsy/sample at Final Off Study Visit or at progression 
o 5 = Serum collection 
- 
The final characters will be the date in MM/DD/YR format 
 
9.2 Timing and Utilization of Tumor Biopsies 
For each biopsy, 5 individual cores will be obtained with an 18-20 gauge needle.  The utilization of the cores 
differs depending upon which biopsy is being obtained. Please refer to Section 4.3.2 and the Lab Manual for 
details 
 
Shipping details and addresses are all summarized in Appendix D. 
 
Pre-Treatment Biopsy 
Following successful screening and enrollment of patients with advanced solid tumor malignancy and known 
deleterious mutations in selected DNA repair genes, a pre-treatment tumor biopsy will be obtained (within 4 
weeks of Day 1 of study treatment).   
 
 
 

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Second & Third Biopsies (For patients in the Phase Ib portion) 
Second and third biopsies will be obtained as outlined in Figures 1-3. The second biopsy will occur on C1D14 
(range C1D10-14) in schedule #1 (timing of biopsy in alternative schedules will differ), on niraparib therapy alone. 
The third biopsy will occur on C2D14 (rabge C2D10-14), on niraparib and carboplatin therapy. There can be 
some flexibility with the timing of the biopsies, but it is important that the second and third biopsies take 
place on a day that the patient received a dose of niraparib. 
 
Biopsy Upon Progression  (For patients in the Phase Ib portion) 
All patients whose disease has NOT rapidly progressed on trial will undergo a biopsy upon disease progression 
for ongoing correlative studies.  Specifically, patients who meet the following conditions will have a biopsy upon 
progression: 
- 
The patient experiences a RECIST 1.1 confirmed partial or complete response at any point, and then 
subsequently experiences disease progression 
Or 
The patient experiences stable disease of  27 weeks (to comport with the timing of restaging imaging), 
and then subsequently experiences disease progression 
9.3 Correlates 
9.3.1 RAD51 Foci Formation 
9.3.1.1 Background 
RAD51 is a protein that assists in repair of DNA DSBs, particularly in homologous recombination of DNA during 
DSB repair. Further, RAD51 allows for DNA strand transfer between a damaged sequence and its undamaged 
homologue. RAD51 is particularly important in HRD tumors, as tumors with previously defined HRD status are 
unable to induce RAD51 foci on DNA damage109-110. As such, HRD tumors tend to have low levels of quantifiable 
RAD51 foci formation. In this portion of correlative study, we will measure RAD51 foci formation by 
immunofluorescence to not only attempt to quantify DNA damage following combined treatment with niraparib 
plus carboplatin, but also to determine if lower levels of RAD51 foci formation are seen in a variety of subtypes 
of HRD tumors. 
 
9.3.1.2 Methodology for RAD51 Foci Formation Immunofluorescence 
Tumor samples will be tested in Dr. Brody’s lab at OHSU, who will perform RAD51 foci formation 
immunofluorescence as outlined below: 
Growing and fixing the cells: 
1. Plating: Prior to plating cells, cover slips are sterilized by soaking in methanol or 70% ethanol for 10-15 
minutes, washed at least 2X with sterile PBS and treated with histogrip. Plate 5x104 cells (or fewer depending 
on cell type and length of culture time). overnight on three sterile cover slips per condition in 12-well dishes 
(Fisher 12-546 18CIR-2). Cells should be in log phase growth and not likely to be confluent by the end of 
treatment as confluency can affect the DNA damage repair response. 
2. Treat cells as desired. 
3. PBS Wash: At the appropriate endpoint, place cells on ice, aspirate media, and wash with 2ml cold PBS 
twice with 10m incubation in between. 
4. Fixing: Add 1.0 ml cold paraformaldehyde solution for 15m (keep cells on ice and protected from light) 
5. Remove paraformaldehyde solution and wash with 2 ml PBS for 10m. Aspirate PBS. 
6. Add 1.5 ml cold PBS, cover, and store at 4°C. (up to a month). 
7. Permeabilization: Aspirate PBS and add 1mL of 0.5% triton into each well for 10 minutes.  
8. After a PBS wash, incubate with 1mL BSA blocking buffer for 30 minutes at RT on a shaker. After the 30 min 
blocking buffer step, rinse with 1mL PBS per well. 
9. Staining: Prepare the 1° antibody in BSA blocking buffer (GeneTex at 1:500 dilution). After blocking rinse 
well with PBS and incubate with 1° antibody dilution on shaker for 1 hour. Protect from light. 
10. Wash twice with PBS for 10 minutes each.  
11. Prepare the LIGHT SENSITIVE 2° antibody dilution (Red anti mouse 594; Alexa Fluor A11005 antibody at 
1:2000 dilution in BSA blocking buffer.  
12. After two PBS washes, add 0.4mL of prepared 2° antibody on each cover slip and incubate in dark for 30 
minutes. 
13. Aspirate 2° antibody dilution and wash cover slips twice with 1 mL PBS, 10 minutes each. 

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14. Mount coverslips on slides with mounting media ProlongGold containing DAPI . Let dry overnight at room 
temperature and protected from light.  
15. Store in slide box at 4°C until imaging. 
 
9.3.1.3 Data Collection  
Testing will be done in a patient DE-IDENTIFIED manner. The de-identified data report, linked with a patient 
study number, will be entered into the study database in a CRF designed to capture the results.  
 
9.3.1.4 Statistical Analyses 
Fisher’s exact tests will be used to compare the level of pharmacodynamic activity among cohorts and treatment 
schedules, as well as to compare any differences in the anti-tumor efficacy among cohorts, treatment schedules 
and pharmacodynamic activity profiles.  
 
9.3.2 ᵞH2AX Foci Formation 
9.3.2.1 Background 
H2AX is a member of the histone H2A family, and is involved in organizing DNA into chromatin. H2AX 
phosphorylation at serine-139 (ᵞH2AX) is an established, sensitive marker of DSBs111. More specifically, H2AX 
is a key component in DNA repair, becoming rapidly phosphorylated from the carboxyl terminus to form ᵞH2AX 
at DSB sites, and generating a focus at the DSB where other proteins involved in DNA repair and chromatin 
remodeling accumulate112-113. Because many cancer treatments induce DSBs, ᵞH2AX quantification serves as a 
measure of treatment effect. As such, measurement of ᵞH2AX foci formation by immunofluorescence foci 
imaging and counting will be used in this study to quantify DNA damage following combined treatment with 
niraparib plus carboplatin, and to determine if higher levels of ᵞH2AX are associated with improved treatment 
efficacy. 
 
9.3.2.2 Methodology for ᵞH2AX Foci Formation Immunofluorescence 
Tumor samples will be tested in Dr. Brody’s lab at OHSU, who will perform ᵞH2AX foci formation 
immunofluorescence as outlined below: 
1. Seed cells in 6-well dishes on cover slips for treatments. 
2. After treatment, remove culture media and gently wash cells twice with 1x PBS. 
3. Fix cells with 3.7% Formaldehyde in 1X PBS at room-temp for 10 minutes. 
4. Rinse cells twice with 1X PBS (can be stored in 1X PBS @ 4°C for several weeks). 
5. Permeabilize cells with 0.3% TritonX (diluted in 1X PBS) for 30 min at 37C.  
6. Incubate cells with primary antibody (Millipore mouse monoclonal (Ser139) (Cat# 05-636), typically 1:500) in 
5% BSA blocking buffer for 1 hour at room temp (or overnight at 4°C). 
7. Wash cells twice with 1X PBS, 10minutes each. 
8. Incubate cells with secondary antibody (Alexafluor 488 anti-mouse, typically 1:1000) in 5% BSA blocking 
buffer for 1 hour at RT. 
9. Wash twice with 1X PBS. 
10. Mount coverslips on slides with mounting media ProlongGold containing DAPI. Let dry overnight at RT and 
protected from light.  
11. Store in slide box at 4°C until imaging. 
 
9.3.2.3 Data Collection  
Testing will be done in a patient DE-IDENTIFIED manner. The de-identified data report, linked with a patient 
study number, will be entered into the study database in a CRF designed to capture the results.  
 
9.3.2.4 Statistical Analyses 
Fisher’s exact tests will be used to compare the level of pharmacodynamic activity among cohorts and treatment 
schedules, as well as to compare any differences in the anti-tumor efficacy among cohorts, treatment schedules 
and pharmacodynamic activity profiles.  
 
 
 
 

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9.3.3 PARP Trapping Assay 
9.3.3.1 Background 
Critical in determining the anti-tumor efficacy of PARP-inhibitor therapy is applying a validated method to 
measure PARP activity within a tumor sample. For this portion of correlative study, PARP-inhibitor activity will 
be measured by cellular fractionation and PARP trapping in chromatin bound fraction (immunoblots), as well as 
assessing PARP inhibitor efficacy by PARP assays quantifying Relative PARylation through ELISA and 
immunoblots. 
 
9.3.3.2 Preliminary Methodology for PARP Trapping Assay 
Tumor samples will be assayed using an enzyme-linked immunosorbent assay (ELISA, Trevigen, as per 
manufacturer’s instructions) to evaluate potency of PARP inhibition.  
Tumor samples will be tested for PARP inhibitor activity by Dr. Brody’s lab at OHSU by PARP trapping assay as 
outlined below: 
1. Cells are harvested and washed three times with ice-cold PBS, and pelleted by quick spinning at 1,000 rpm 
for 1 to 2 min. 
2. Soluble proteins are then extracted with ice-cold 0.1% Triton X-100 in CSK buffer for 20 min at 4°C.  
3. The insoluble, chromatin-bound fraction was then pelleted by low-speed centrifugation at 3,000 rpm for 5 
min at 4°C. 
4. These pellets are then re-extracted by incubating in CSK buffer and collected by centrifugation at 3,000 rpm 
for 10 min at 4°C. 
5. The final pellet fraction (containing chromatin-bound proteins) or total cell pellets are solubilized in 
radioimmunoprecipitation assay (RIPA) buffer and equal protein is resolved by sodium dodecyl sulfate (SDS)-
polyacrylamide gel electrophoresis (PAGE). Histone H3 and GAPDH will be used as positive controls for 
validating chromatin- bound and soluble protein fractions respectively. Trapped PARP1 will be normalized 
and quantified by Licor densitometry.  
6. Additional updates to PARP Assay methodology section to come as lab performing this portion of correlative 
study finalizes protocol(s). 
 
9.3.3.3 Data Collection  
Testing will be done in a patient DE-IDENTIFIED manner. The de-identified data report, linked with a patient 
study number, will be entered into the study database in a CRF designed to capture the results.  
 
9.3.3.4 Statistical Analyses 
Fisher’s exact tests will be used to compare the level of pharmacodynamic activity among cohorts and treatment 
schedules, as well as to compare any differences in the anti-tumor efficacy among cohorts, treatment schedules 
and pharmacodynamic activity profiles.  
 
9.3.4 Resistance Mechanisms 
Serial tumor biopsies will be prepared for ex vivo analyses to monitor the development of mechanisms of 
resistance to either PARP-inhibitor or carboplatin therapies. Tumor samples will be placed in a pre-provided 
Eppendorf tube with collection media and shipped on ice to Dr. Brody’s lab at OHSU. Cancer-derived organoids 
have been shown in vitro to retain the same complex, heterogeneity of genetic alterations present in vivo in a 
given patient’s tumor. As such, organoids are an ideal medium for exploration of the development of resistance 
mechanisms in cancer tissues following the initiation of anti-cancer therapy, with new mutations identified likely 
playing a role in the development of resistance to therapy. The specific genetic alterations leading to PARP-
inhibitor resistance are unknown, and we hope to add significant framework to this discussion with our correlative 
analysis as outlined.  
 
9.3.5 Additional Correlates 
During the course therapy, patients will also undergo blood sample collection for additional correlative analyses: 
- 
Patients will submit a 10mL sample of blood in a red top heparinized tube for future research at the time 
of first biopsy, Cycle 1 Day 1, and every 3 weeks until progression.  These samples will be processed to 
isolate serum, which will be batched and shipped to Dr. Brody’s lab at OHSU. 
 
 

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10.0 ETHICAL CONSIDERATIONS 
10.1 Institutional Review Board (IRB) 
GCP requires that the clinical protocol, any protocol amendments, the Investigator's Brochure, the informed 
consent and all other forms of subject information related to the study (e.g., advertisements used to recruit 
subjects) and any other necessary documents be reviewed by an IRB. IRB approval of the protocol, informed 
consent and subject information and/or advertising, as relevant, will be obtained prior to the authorization of drug 
shipment to a study site.  Any amendments to the protocol will require IRB approval prior to implementation of 
any changes made to the study design.  Any serious adverse events that meet the reporting criteria, as dictated 
by local regulations, will be reported to the IRB. During the conduct of the study, the investigator should promptly 
provide written reports to the IRB of any changes that affect the conduct of the study and/or increase the risk to 
subjects.  
 
10.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable regulations and 
guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  
 
10.3 Subject Information and Consent 
Prior to the initiation of any screening or study-specific procedures, the investigator or his/her representative will 
explain the nature of the study to the subject and answer all questions regarding this study. Each informed 
consent will be reviewed, signed and dated by the subject and the person who administered the informed consent. 
A copy of each informed consent will be given to the subject and each original will be placed in the subject's 
medical record. An entry must also be made in the subject's dated source documents to confirm that informed 
consent was obtained prior to any study-related procedures and that the subject received a signed copy.  Tissue 
sample collection for analysis will only be performed if the subject has voluntarily consented to participate after 
the nature of the testing has been explained and the subject has had the opportunity to ask questions. If the 
subject does not consent to the tissue sample collection, it will not impact the subject's participation in the study. 
 
10.4 Ethical Consideration for Enrollment 
Only patients with advanced cancer, for whom no curative therapy exists, will be considered for enrollment.  The 
only treatment options for these patients are conventional chemotherapy, radiation, or participation in a clinical 
trial. As described above, the combination of niraparib and carboplatin is a rational and promising combination 
for such patients. 
 
10.5 Protection of Patient Confidentiality 
All patient records, questionnaires, and tissue specimens will be de-identified using a letter and number assigned 
to their case at the time of enrollment on study.  No record or specimen will contain information which could 
identify the patient.  The key which connects patient identifiable information with this assigned number will be 
held by the Principal investigator.  For computer records, the key will be protected by a double password 
protection system.  Any paper records will be contained in a locked cabinet within a locked office to ensure 
patient’s privacy is protected.  
 
 
 
 
 
 
 

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97
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APPENDIX A: STUDY ELIGIBILITY CHECKLIST 
Niraparib Plus Carboplatin in Patients with Homologous Recombination Deficient 
Advanced Solid Tumor Malignancies  
Study ID: _________ 
 
Instructions: This form should be completed by the research staff before registering the patient into the trial. 
Completed form should be scanned/emailed to LCCC-Multicenter-IITs@georgetown.edu with cc: isaacsc@georgetown.edu. 
□ Georgetown University Medical Center 
 
   
□ Other Institution ____________________________ 
   
 
Inclusion Criteria 
Yes 
No 
NA 
3.2.1 Patients PRE-identified as having either a germline deleterious mutation or tumor 
expression of a deleterious mutation) as determined by Next-generation DNA sequencing 
only, in at least one gene involved in DNA damage repair through homologous 
recombination including but not limited to: RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, 
BRIP1, FANCA/C/D2/E/F/G/L, PALB2, or BAP1. 
 
3.2.1.1 Patients with somatic mutations will be PRE-identified as having a homologous 
recombination mutation based on NGS done in a CLIA certified, CAP tested and bioinformatics-
validated testing lab PRIOR to enrollment in this current protocol.  The testing may have been done 
at any time prior to enrollment.   
 
3.2.1.1.a The determination of a deleterious mutation must be supported in the 
documentation included in the testing, and should include clinical, or pre-clinical literature to 
support the finding that a specific mutation results in impaired function of the gene, and thus 
impaired DNA repair through homologous recombination. Variants of unknown significance will not 
be eligible. 
 
3.2.1.1.b For the Phase Ib portion of the study, if any patient has had NGS testing more 
than 12 months prior to enrollment, then a repeat NGS test must be done and the deleterious 
somatic mutation must be re-identified for inclusion. 
 
3.2.1.2 Patients with germline deleterious mutations may have been identified at any time point 
prior to inclusion in the protocol and do NOT need to have this genetic testing repeated regardless 
of time frame and intervening therapy. 
 
 
 
 
Advanced, solid tumor malignancy (other than prostate cancer, see Section 3.3.11).  
3.2.2.1 The tumor must be amenable to biopsy.  
3.2.2.2 For the Phase Ib portion, the patient must consent to 4 mandatory biopsies during study. 
 
Note: If there are any issues with obtaining the study required pre-treatment biopsy (ie. it is 
deemed unsafe to obtain the biopsy or it is determined that the initial biopsy sample obtained did 
not contain tumor tissue), the subject may only be allowed to enroll after receiving permission from 
the Study Chair(s). Additionally, they will be exempt from being required to obtain additional on 
study biopsies. 
 
 
 
 
3.2.3 Life expectancy of more than 3 months 
 
 
 
 
3.2.4 Age ≥ 18 years 
 
 
 
 
3.2.5 Measurable disease by RECIST v1.1 criteria (tumor ≥ 1 cm in longest diameter on axial 
image on computed tomography (CT) or magnetic resonance imaging (MRI) and/or lymph 
node(s) ≥ 1.5 cm in short axis on CT or MRI) on baseline imaging 
 
 
 
 
3.2.6 ECOG performance status (PS) of 0 to 1 (Table 11, Appendix A) 
 
 
 
 
3.2.7 Patients who have received and experienced disease progression on, or have been 
intolerant to, standard first line therapies known to confer clinical benefit. Patients who 
refuse standard therapy would also be eligible, as long as their refusal is documented. 
 
 
 
 
 
 

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103
Inclusion Criteria 
Yes 
No 
NA 
3.2.8 Adequate hepatic, bone marrow, and renal function at the time of enrollment: 
 
3.2.8.1 Bone Marrow: Absolute neutrophil count (ANC) ≥ 1,500/mm3; Platelets ≥ 100,000/mm3; 
Hemoglobin ≥ 9.0 g/dL.  Patients must be able to meet the criteria without transfusion within 4 
weeks or receipt of colony stimulating factors, filgrastim (eg neupogen or biosimilar) within 14 days, 
or peg-filgrastim (eg, neulasta) or recombinant erythropoietin within 4 weeks before obtaining 
sample  
 
3.2.8.2 Renal function: Serum creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min/1.73 
m2 
 
3.2.8.3 Hepatic function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤ 2.5 × the upper normal limit of institution's normal range. Total bilirubin ≤ 1.5 × the upper normal 
limit of institution's normal range. For subjects with liver metastases, AST and ALT < 5 × the upper 
normal limit of institution's normal range, and total bilirubin >1.5 - 3.0 x the upper normal limit of 
institution's normal range are acceptable as long as there is no persistent nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia 
 
3.2.8.4 Prothrombin Time (PT) and Partial Thromboplastin Time (PTT) must be ≤ 2 X the 
upper limit of the institution's normal range and International Normalized Ratio (INR) < 2. Subjects 
on anticoagulation (such as coumadin) will be permitted to enroll as long as the INR is in the 
acceptable therapeutic range as determined by the investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.2.9 Patients may have received an unlimited number of prior therapies.  Prior anti-cancer 
therapies must be given ≥ 2 weeks prior to Cycle 1, Day 1 on trial (and the patient must have 
recovered from all side effects of prior therapies that are exclusionary, as per Section 3.3 
below) 
 
 
 
 
3.2.10 Patients must have fully recovered from all effects of surgery.  Patients must have 
had at least two weeks after minor surgery and four weeks after major surgery before 
starting therapy.  Minor procedures requiring conscious sedation such as endoscopies or 
mediport placement may only require a 24-hour waiting period, but this must be discussed 
with an investigator 
 
 
 
 
3.2.11 Female patient has a negative serum or urine pregnancy test within 72 hours prior to 
taking study treatment if of childbearing potential and agrees to abstain from activities that 
could result in pregnancy from screening through 180 days after the last dose of study 
treatment, or is of non-childbearing potential.  
 
Non-childbearing potential is defined as follows (by other than medical reasons): 
• ≥45 years of age and has not had menses for >1 year 
• Patients who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy 
must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation 
• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or 
oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. 
Tubal ligation must be confirmed with medical records of the actual procedure 
Otherwise the patient must be willing to employ methods to avoid pregnancy. Abstinence is an acceptable 
method to avoid pregnancy if this is the established and preferred method for the patient.  Alternatively, the 
patient and partner must use 2 adequate barrier methods throughout the study, starting with the screening 
visit through 180 days after the last dose of study treatment. Information must be captured appropriately within 
the site’s source documents.  
 
Male patients must also agree to use an adequate method to avoid pregnancy, which may include 
abstinence, if this is the established and preferred method for the patient starting with the first dose of study 
treatment through 180 days after the last dose of study treatment. 
 
Additionally, the participants must agree to not breastfeed during the study or for 180 days after the 
last dose of study treatment. 
 
 
 
 
 
 
 
 
 
 
 
 

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104
Inclusion Criteria 
Yes 
No 
NA 
3.2.12 Patient is capable of swallowing pills whole 
 
 
 
 
3.2.13 Subject is capable of understanding and complying with parameters as outlined in 
the protocol and able to sign and date the informed consent, approved by the IRB, prior to 
the initiation of any screening or study-specific procedures 
 
 
 
 
Exclusion Criteria 
Yes 
No 
NA 
3.3.1 Prior disease progression while receiving platinum chemotherapy; or any platinum 
chemotherapy within the last 6 months 
3.3.1.1 For all patients (except breast cancer patients) who received platinum-based adjuvant or 
neo-adjuvant chemotherapy, at least 6 months must have passed between the last dose of 
platinum-based therapy and the development of metastatic disease.  
3.3.1.2 For breast cancer patients, at least 12 months must have passed between the last dose of 
platinum-based adjuvant or neo-adjuvant therapy and the development of metastatic disease 
 
 
 
 
3.3.2 Patients must not require “support” to maintain adequate blood counts, as defined by: 
3.3.2.1 Patients must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks prior 
to initiating protocol therapy. 
3.3.1.2 Patient must not have received colony stimulating factors, filgrastim (eg neupogen or 
biosimilar) within 14 days, or peg-filgrastim (eg, neulasta) or recombinant erythropoietin within 4 
weeks prior initiating protocol therapy. 
3.3.2.1 Participant has had any known Grade 3 or 4 anemia, neutropenia or thrombocytopenia due 
to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment. 
 
 
 
3.3.4 Known or suspected CNS metastases, unless at least one month has passed since last 
local CNS therapy and there is no evidence for recurrent or progressive CNS disease on 
follow up imaging. Participants may remain on steroids for CNS disease if they are taking a 
stable dose 
 
 
 
 
3.3.5 Active severe infection, or known chronic infection with HIV or hepatitis B virus 
(testing not required prior to enrollment) 
 
3.3.5.1 Patients with chronic Hepatitis C virus may be enrolled if there is no clinical/laboratory 
evidence of cirrhosis AND the patient’s liver function tests fall within the parameters set in Section 
3.2.8.3, Inclusion Criteria, Hepatic function 
 
 
 
 
3.3.6 Cardiovascular disease problems including unstable angina, therapy for life-
threatening ventricular arrhythmia, or myocardial infarction, stroke, or congestive heart 
failure within the last 6 months.   
 
 
 
 
3.3.7 Life-threatening visceral disease or other severe concurrent disease that would, in the 
investigator’s judgment, cause unacceptable safety risks, contraindicate patient 
participation in the clinical study or compromise compliance with the protocol (e.g. chronic 
active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.) 
 
 
 
 
3.3.8 Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) 
 
 
 
 
3.3.9 Presence of a psychiatric illness or social situation that would limit compliance with 
study requirements 
 
 
 
 
3.3.10 Women who are pregnant or breastfeeding 
 
 
 
 
3.3.11 The subject must not have had diagnosis, detection, or treatment of another type of 
cancer ≤2 years prior to randomization (except basal or squamous cell carcinoma of the 
skin that has been definitively treated). Questions regarding the inclusion of individual 
subjects should be directed to the Principal Investigator, Dr. Isaacs. 
 
 
 
 

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105
Exclusion Criteria 
Yes 
No 
NA 
3.3.12 Due to licensing agreements for Niraparib, patients with a current diagnosis of 
prostate cancer will be excluded. 
 
 
 
 
3.3.13 Clinically significant peripheral neuropathy at the time of enrollment (defined in the 
NCI CTCAE v4.0) as grade 2 or greater neurosensory or neuromotor toxicity) 
 
 
 
 
3.3.14 Patients must not have had investigational therapy administered ≤4 weeks, or within 
a time interval less than at least 5 half-lives of the investigational agent, whichever is 
longer, prior to the first scheduled day of dosing in this study 
 
 
 
 
3.3.15 Patients must not have had radiotherapy encompassing >20% of the bone marrow 
within 2 weeks; or any radiation therapy within 1 week prior to Day 1 of protocol therapy 
 
 
 
 
3.3.16 Patients must not have a known hypersensitivity to the components of niraparib or 
the excipients 
 
 
 
 
3.3.17 Patients must not have current evidence of any condition, therapy, or laboratory 
abnormality (including active or uncontrolled myelosuppression [ie, anemia, leukopenia, 
neutropenia, thrombocytopenia]) that might confound the results of the study or interfere 
with the patient's participation for the full duration of the study treatment or that makes it 
not in the best interest of the patient to participate 
 
 
 
 
3.3.18 Patients must not be considered a poor medical risk due to a serious, uncontrolled 
medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. 
Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 
90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord 
compression, superior vena cava syndrome, or any psychiatric disorder that prohibits 
obtaining informed consent 
 
 
 
 
3.3.19 Patient must not have any known history of myelodysplastic syndrome (MDS) or 
acute myeloid leukemia (AML) 
 
 
 
 
 
 
INVESTIGATOR SIGNATURE:_____________________________________________________Date:__________________ 
 
 
 
STUDY COORDINATOR SIGNATURE:_______________________________________________Date:__________________ 

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106
Table 11: ECOG Performance Status Scale 
 
 
 
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
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
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade
Completely disabled. Cannot carry on any self-care. Totally confined
to bed or chair.
4
Capable of only limited self care, confined to bed or chair more than
50% of waking hours.
3
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
Restricted in physically strenuous activity but ambulatory and able to  carry 
out work of a light or sedentary nature, e.g., light housework, office work.
1
Fully Active, able to carry on all pre-disease performance without 
restriction.
0
ECOG
Grade

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107
APPENDIX B: PATIENT REGISTRATION FORM 
Niraparib Plus Carboplatin in Patients with Homologous Recombination Deficient 
Advanced Solid Tumor Malignancies  
 
Study ID: _________ 
Instructions: This form should be completed by the research staff before registering the patient into the trial. 
Completed form can be  scanned/emailed to  LCCC-Multicenter-IITs@georgetown.edu with cc: isaacsc@georgetown.edu. 
□ Georgetown University Medical Center 
 
   
  
□ Other Institution __________________________________________ 
 
□ Treating Physician ____________ ____________________________ 
 
 
1.  Date Informed Consent signed: ____/____/___ 
 
2.  Screening Date: ____/____/___ 
 
3.  Start date for treatment: ____/____/_______ 
 
4.  Prior therapies (date initiated/type): 
 
 
 
 
 
5.  Please fax the following documentation: 
□ 
Pathology Report 
□ 
Physicians Note validating: 
□ 
Previous treatments 
□ 
CT showing RECIST criteria 
□ 
Laboratory Results 
□ 
Past Medical History 
 
 
 

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108
APPENDIX C: Data Sharing Plan 
 
Data sharing for this study will be conducted in compliance with the February 26, 2003 NIH Statement on Data 
Sharing (NOTICE: NOT-OD-03-032). The collaborating sites for this study generate a wide variety of scientific 
and clinical data and Data Sharing and Archiving will be handled by in accordance with NIH Statement on Data 
sharing, institutional internal document retention policies and all application rules, regulations and statutes.  
Subject to institutional policies, local IRB guidelines, and local, state and Federal laws and regulations including 
the Privacy Rule and the Bayh-Dole Act, we will make finished research data available through scientific 
presentations, publications (paper, web and other), depositing gene sequence, gene expression and other data 
in searchable electronic repositories, attendance at scientific meetings and extending invitations to scientists 
from other institutions for discussion. In accordance with the NIH policy, such data shall be made widely and 
freely available while safeguarding the privacy of participants and protecting Lombardi’s confidential and 
proprietary data.  
 
The participating sites will maintain awareness, and may participate in, discussions between members of multiple 
scientific and technical disciplines and their professional societies concerning data sharing, standards and best 
practices, and to create an environment that supports and develops data sharing tools. We will participate in or 
make ourselves aware of the outcome of any workshops the NIH or AACR will convene to address data sharing 
and which may address areas such as cleaning and formatting data, writing documentation, redacting data to 
protect subjects' identities and proprietary information, and estimating costs to prepare documentation and data 
for sharing.  
 
The NIH has recognized the need to protect patentable and other proprietary data and notes the restrictions on 
the sharing of data that may be imposed by agreements with third parties. Under the Bayh-Dole Act, grantees 
have the right to elect and retain title to subject inventions developed with Federal funding, and further, to 
commercialize any invention to which they retain title. Since its is not the stated intent of the NIH statement on 
Data Sharing to discourage, impede or prohibit the development of commercial products from federally funded 
research, our collaborating sites will continue to perform inventive activities, to seek patent protection for 
inventions that relate to data generated and may choose to defer publication or enter into agreements with third 
parties that may result in certain restrictions on data sharing. We note that seeking patent protection results in 
publication of the patent application into the public domain and, thus, may result in the data being broadly 
disseminated.  
 
All specimens submitted to any of the shared resource laboratories will be bar-coded upon receipt and assigned 
a unique identifier using a common software program. Tracking of specimens and their utilization will be carried 
out using a web-based system  that will represent a modification of the systems presently in place at Georgetown 
(including but not limited to G-DOC, Georgetown Database of Cancer, Medidata Rave, REDCap), which will also 
give us the ability to track sample utilization. These systems have an “honest broker” interface which ensures 
HIPPA compliance and protection of any human subjects. As the same sample may well be used for genomic, 
proteomic, histopathological and clinical interrogation, assignment of a unique identifier as well as a common 
administrative structure ensures efficient cross-database interrogation.  
 
Data security 
The rights and privacy of people who participate in sponsored clinical research will be protected at all times. In 
the event that data is intended for broader use, it will be de-identified and would not permit linkages to individual 
research participants and variables that could lead to deductive disclosure of the identity of individual subjects. 
No efforts will be made to identify individual cases, and any shared archive data will not be linked to other 
identifiable data. The following de-identification and security procedures will be followed to share information 
with collaborators part of the study: 
 
1) Deletion of 18 HIPAA identifiers 
a. Non-identifiable unique patient ID will be generated in G-DOC 
2) Secure netID-based single sign-on (netID is Georgetown’s LDAP based secure login system) 
3) Users will have to authenticate themselves prior to accessing controlled data 
4) Furthermore, based on their roles, users will require authorization to see specific studies 

Version 3.0 (Amendment 9), 7/3/2023 
109
5) Auditing and security assessments will be performed on a quarterly basis to ensure appropriate de-
identification procedures and use of data. 
For future studies involving new data types that are not covered in the descriptions above, NIH policy on data 
sharing will be followed where applicable. For example, Genome Wide Association Studies, if conducted, will 
comply with NIH Guidelines NOT-OD-07-088 (http://grants.nih.gov/grants/gwas/) for data release. Following 
these guidelines, GWAS data will be submitted to NCBI’s dbGAP 
(http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap) or other tools as the NIH’s policy on GWAS evolves. 
 
Data Disclosure 
GUMC (Georgetown University Medical Center) has a Confidentiality and Non-Disclosure policy that pertains 
only to proprietary information belonging to GUMC. The disclosure of research information such as microarray 
analysis results is at the discretion of the faculty and staff. Notably, investigators with NIH funding are expected 
to make their data and results public in a reasonable time frame (Please see the University plan for sharing 
and distributing biomedical research resources at 
http://otc.georgetown.edu/documents/inventors/NIHGrantLetter_ModelOrganismsUpdate_6-27-05.doc . To 
protect institutional intellectual property, the institution does have an internal review process prior to 
submission of journal manuscripts. This process will be propagated to other study sites as well. 
 

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110
APPENDIX D: Sample Shipment Addresses 
 
Please refer to the Lab manual for current Shipment Addresses 
 
Formalin-Fixed Tumor Biopsies 
- 
Samples will be placed in an institution-supplied formalin vial, and shipped to: 
- 
Dr. Jonathan Brody (Clinical trial samples, Immediate attention) 
 
Ex vivo model Tumor Biopsy Sample(s) 
- 
Biopsy samples collected for Ex vivo models will be collected in pre-supplied Eppendorf tubes containing 
collection media and will be shipped overnight on ice to: 
- 
Dr. Jonathan Brody (Clinical trial samples, Immediate attention) 
 
Brody Lab Blood Collection for Correlative Study 
- 
Samples will be collected in institution-supplied red top tubes, serum isolated, and sent frozen in batches 
to: 
- 
Dr. Jonathan Brody (Clinical trial samples, Immediate attention) 
 
Extra Cores 
- 
Core biopsy sample(s) that are collected to be held in reserve should be placed in a standard formalin 
vial and submitted to surgical pathology for paraffin embedding.  The sample(s) from this(these) FFPE 
block should not be cut for an H&E analysis.  Rather, the block(s) will be requested from surgical 
pathology, and sent to: 
- 
Dr. Jonathan Brody (Clinical trial samples, Immediate attention) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX E – PATIENT DRUG DIARY  
 
PATIENT INITIALS AND STUDY NUMBER   ___________________ 
 
Cycle Number: ________  Day 1 Date: ___/____/_____ 
 
 
 
Day 1 
Niraparib 
time: 
____:____ 
Day 2* 
Niraparib 
time: 
____:____ 
Day 3 
Niraparib 
time: 
____:____ 
Day 4 
Niraparib 
time: 
____:____ 
Day 5 
Niraparib 
time: 
____:____ 
Day 6 
Niraparib 
time: 
____:____ 
Day 7 
Niraparib 
time: 
____:____ 
Day 8 
Niraparib 
time: 
____:____ 
Day 9 
Niraparib 
time: 
____:____ 
Day 10 
Niraparib 
time: 
____:____ 
Day 11 
Niraparib 
time: 
____:____ 
Day 12 
Niraparib 
time: 
____:____ 
Day 13 
Niraparib 
time: 
____:____ 
Day 14 
Niraparib 
time: 
____:____ 
 
Day 15 
 
No drug 
Day 16 
 
No drug 
 
Day 17 
 
No drug 
Day 18 
 
No drug 
Day 19 
 
No drug 
Day 20 
 
No drug 
Day 21 
 
No drug 
* Treatment with Carboplatin, starting Cycle 2 
 
 
 
 
 
 
 
 
 
 
Instructions: 
 
Record the date and time that you took your Niraparib dose 
 
Take with a large glass of water (~250 mL) at the same time each day, with or without food 
 
Swallow whole without crushing, chewing, or opening the pills   
 
If vomiting occurs, do not take another dose.   
 
If dose is not taken within 6 hours of the intended time, the dose should be skipped and not replaced or made up 
on a subsequent day.  
 
Store niraparib at room temperature.  
 
Bring your bottles of niraparib (empty, partially filled, or full) and this diary to your next appointment. 
 
 
 
 
 
 
 
 
 
 
 
 

Version 3.0 (Amendment 9), 7/3/2023 
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Alternative Dose Schedule (Schedule #2) 
 
PATIENT INITIALS AND STUDY NUMBER   ___________________ 
 
Cycle Number: ________  Day 1 Date: ___/____/_____ 
 
 
Day 1 
Niraparib 
time: 
____:____ 
Day 2* 
Niraparib 
time: 
____:____ 
Day 3 
Niraparib 
time: 
____:____ 
Day 4 
Niraparib 
time: 
____:____ 
Day 5 
Niraparib 
time: 
____:____ 
Day 6 
Niraparib 
time: 
____:____ 
Day 7 
Niraparib 
time: 
____:____ 
 
Day 8 
 
No drug 
 
Day 9 
 
No drug 
 
Day 10 
 
No drug 
 
Day 11 
 
No drug 
 
Day 12 
 
No drug 
 
Day 13 
 
No drug 
 
Day 14 
 
No drug 
 
Day 15 
 
No drug 
Day 16 
 
No drug 
 
Day 17 
 
No drug 
Day 18 
 
No drug 
Day 19 
 
No drug 
Day 20 
 
No drug 
Day 21 
 
No drug 
* Treatment with Carboplatin, starting Cycle 2 
 
 
 
 
 
 
Instructions: 
 
Record the date and time that you took your Niraparib dose 
 
Take with a large glass of water (~250 mL) at the same time each day, with or without food 
 
Swallow whole without crushing, chewing, or opening the pills   
 
If vomiting occurs, do not take another dose.   
 
If dose is not taken within 6 hours of the intended time, the dose should be skipped and not replaced or made up 
on a subsequent day.  
 
Store niraparib at room temperature.  
 
Bring your bottles of niraparib (empty, partially filled, or full) and this diary to your next appointment. 
 
 

Version 3.0 (Amendment 9), 7/3/2023 
113
Alternative Dose Schedule (Schedule #3) 
 
PATIENT INITIALS AND STUDY NUMBER   ___________________ 
 
Cycle Number: ________  Day 1 Date: ___/____/_____ 
 
 
Day 1 
Niraparib 
time: 
____:____ 
Day 2* 
Niraparib 
time: 
____:____ 
Day 3 
Niraparib 
time: 
____:____ 
Day 4 
Niraparib 
time: 
____:____ 
 
Day 5 
 
No drug 
 
Day 6 
 
No drug 
 
Day 7 
 
No drug 
Day 8 
Niraparib 
time: 
____:____ 
Day 9* 
Niraparib 
time: 
____:____ 
Day 10 
Niraparib 
time: 
____:____ 
Day 11 
Niraparib 
time: 
____:____ 
 
Day 12 
 
No drug 
 
Day 13 
 
No drug 
 
Day 14 
 
No drug 
 
Day 15 
 
No drug 
Day 16 
 
No drug 
 
Day 17 
 
No drug 
Day 18 
 
No drug 
Day 19 
 
No drug 
Day 20 
 
No drug 
Day 21 
 
No drug 
* Treatment with Carboplatin, starting Cycle  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Instructions: 
 
Record the date and time that you took your Niraparib dose 
 
Take with a large glass of water (~250 mL) at the same time each day, with or without food 
 
Swallow whole without crushing, chewing, or opening the pills   
 
If vomiting occurs, do not take another dose.   
 
If dose is not taken within 6 hours of the intended time, the dose should be skipped and not replaced or made up 
on a subsequent day.  
 
Store niraparib at room temperature.  
 
Bring your bottles of niraparib (empty, partially filled, or full) and this diary to your next appointment. 
 
 
 
 
 

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Appendix F– Safety Reporting Information 
Reporting Product Quality Complaints for Niraparib 
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 GSK QA at gsk-rd.complaints@gsk.commailto:. 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. 
 
Reporting Adverse Events 
Recording of Adverse Events 
Adverse events (AEs) will be collected from the first dose of drug name to 30 days after last study drug 
administration.  Each AE will be assessed by the investigator for seriousness, causality, and severity.  
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  For the purposes of safety reporting, “reasonable possibility” means there is evidence 
to suggest a causal relationship between the drug and the adverse event.  Suspected adverse reaction implies 
a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by 
a drug. For the purposes of this study, causality should be assessed for each study drug as Yes/No. 
 Severity should be assessed in accordance with the Common Terminology Criteria for Adverse Events (CTCAE 
v.5) 
 
Serious Adverse Events (SAEs) 
A serious AE (SAE) is defined as any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening - This means that the patient is at immediate risk of death at the time of the event; it 
does not mean that the event hypothetically might have caused death if it were more severe 
 
Requires inpatient hospitalization or prolongation of existing hospitalization - Planned hospitalization (eg, 
for observation, protocol compliance, elective procedures, social reasons, etc.) will not be considered an 
SAE; however, any AE that prolongs hospitalization will be considered an SAE.  Planned hospitalizations 
should be captured in medical history. 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event(s) - An important medical event may not be immediately life-threatening or 
result in death or hospitalization but that may jeopardize the patient or require intervention to prevent one 
of the above outcomes. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
For any AE that is serious, associated with the use of the study treatment, and unexpected (defined as any term 
not listed in the expectedness section of the current Investigator’s Brochure or current prescribing information) 
additional reporting requirements are described below. These types of reports are referred to as (SUSARs). 
 
For interventional clinical trials, if the SUSAR is fatal or life-threatening, associated with the use of the 
study treatment, and unexpected, the Sponsor will report to Regulatory Authorities and Independent 
Ethics Committees (IECs) within 7 calendar days after the Investigator learns of the event. Additional 
follow-up (cause of death, autopsy report, and hospital report) information should be reported within an 
additional 8 days (15 days total).  
 
For all other SUSARs, the Sponsor will report to Regulatory Authorities and IECs within 15 calendar days 
after the Sponsor learns of the event.  
The Sponsor will also provide annual safety updates to the Regulatory Authorities and IECs responsible for the 
study. These updates will include information on SUSARs and other relevant safety findings. 
 

Version 3.0 (Amendment 9), 7/3/2023 
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Adverse Events of Special Interest 
The Adverse Events of Special Interest (AESIs) for this study are myelodysplastic syndrome (MDS) and acute 
myeloid leukemia (AML). AESIs must be reported to the Institution as soon as the Investigator becomes aware 
of them. 
 
Pregnancy 
Pregnancies (and pregnancy outcomes) occurring in a female patient or a female partner of a male patient must 
be reported to the Institution.  
Elective abortions without complications should not be considered AEs unless they were therapeutic abortions. 
Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. Spontaneous 
abortions should always be reported as SAEs. 
The Investigator should follow-up with the study patient or the female partner of the study patient until delivery 
or termination of pregnancy, even if the patient was withdrawn from the clinical study or the clinical study was 
completed. GSK will be informed of all pregnancy outcomes.   
 
Reporting to Sponsor 
Investigators must report to the Institution any SAE, AESI or pregnancy occurring from the first dose of drug 
name to 30 days after last study drug administration.  Serious adverse events occurring after this 30 day period 
and coming to the attention of the Investigator must be reported only if they are considered causally-related to 
the study drug.  All events should be reported within 24 hours of becoming aware of the event. 
 
Institution AE and Pregnancy Reporting Information 
Email to the LCCC Consortium IIT Office and to Dr. Isaacs (isaacsc@georgetown.edu) to confirm 
receipt of those records. 
 
Reporting to GSK 
Sponsor will forward any SAE, AESI, or pregnancy to GSK within 24 hours of becoming aware of the event.  The 
institution will forward both initial and follow-up versions of each report.   
 
GSK SAE, AESI, and Pregnancy Reporting Information 
Email: OAX37649@gsk.com 
Fax: +44(0) 208754 7822 
 
 
On a monthly basis, Sponsor will forward a line listing of all events that have been reported to date.  On at least 
an annual basis, Sponsor will provide a copy of the safety reports submitted to applicable Regulatory Authorities 
or IECs.  Annual reports should be provided to GSK within 3 business days of submission to the applicable 
regulatory body. GSK’s practice is to acknowledge receipt of all safety information with 72 hours.  Institution 
should resend any materials that are not acknowledged within this time period. 
 
Follow-up of Adverse Events 
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored until the AE has 
resolved, any abnormal laboratory values have returned to baseline or stabilized at a level acceptable to the 
Investigator, until there is a satisfactory explanation for the changes observed, until the patient is lost to follow-
up, or until the patient has died. 
 
SUSAR Distribution 
A central contact at the Sponsor will forward any SUSARs which have occurred on other trials that involve the 
use of GSK’s Investigational Product for the duration of this study. 
 
Investigational Product 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure 
appropriate supply, handling, storage, distribution, and usage of these materials in accordance with the protocol 
and any applicable laws and regulations. 

Version 3.0 (Amendment 9), 7/3/2023 
116
 
Dispensing 
The investigator agrees that study drug(s) will be dispensed by the investigator or sub-investigator(s) named on 
the Investigator Agreement or their qualified designees.  The investigator, sub-investigators, or qualified 
designees also agree that the study drug(s) will be dispensed only to study subjects who have provided written 
informed consent and have met all entry criteria and in accordance with the instructions provided in the pharmacy 
manual.  
 
Drug Accountability 
The Investigator or designee is responsible for maintaining accurate dispensing records of the study treatment 
throughout the clinical study. The study treatment accountability log includes information including the enrollment 
number, amount and date dispensed, and amount and date returned to the pharmacy, if applicable. Product 
returned to the pharmacy will be stored under the same conditions as products not yet dispensed but will be 
marked as 'returned' and kept separate from the products not yet dispensed. 
 
All dispensing and accountability records should be stored in accordance to the Sponsor-Investigator’s 
directions. The pharmacist will dispense study treatment for each patient according to the protocol and Pharmacy 
Manual, if applicable.