Conditions: Pancreatic Adenocarcinoma
Keywords: Platinum chemotherapy Niraparib Ipilimumab Nivolumab Pancreatic adenocarcinoma PARP inhibitor Pancreatic ductal adenocarcinoma DDR PDAC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 104
Healthy volunteers: no

Brief summary:
The main purpose of this study is to look at the effectiveness, safety, and anti-tumor activity (preventing growth of the tumor) of the drugs Niraparib with either Ipilimumab or Nivolumab on patients and their pancreatic cancer.

Detailed description:

Arms:
arm 1: Niraparib + Nivolumab arm 2: Niraparib + Ipilimumab

Interventions: intervention 1: Niraparib + Nivolumab intervention 2: Niraparib + Ipilimumab
Intervention descriptions: intervention 1: Niraparib 200mg PO daily on days 1-28 of each 28-day cycle. Nivolumab 480mg IV day 1 of each cycle. intervention 2: Niraparib 200mg PO daily on days 1-21 of each 21-day cycle. Ipilimumab 3mg/kg IV day 1 of each cycle, for the first 4 cycles only.

Protocol document:
ICF_005.pdf: 
PARPVAX 
 UPCC 35217 (Penn IRB # 828516) 
Version: 10; July 8, 2024 
1 of 29 
 
PENN MEDICINE RESEARCH SUBJECT  
COMBINED INFORMED CONSENT FORM AND HIPAA AUTHORIZATION 
Protocol Title: 
Funding Supporters: 
PARPVAX: A Phase 1B/2, open label study of Niraparib plus either 
Ipilimumab or Nivolumab in patients with advanced Pancreatic Cancer 
whose disease has not progressed on platinum- based therapy 
Bristol-Myers Squibb and TESARO, Inc. a GlaxoSmithKline (GSK) 
Company 
Regulatory Sponsor 
University of Pennsylvania 
Principal Investigator: 
Kim Reiss Binder, MD 
Abramson Cancer Center of the University of Pennsylvania 
Philadelphia, PA 19104 
215-360-0735
Sub-investigators: 
 
 
Emergency Contact: 
24 Hour Emergency – Call 215-662-4000 
Ask for Oncologist On-Call 
Summary 
You are being invited to participate in a research study.  Your participation is voluntary and you should 
only participate if you completely understand what the study requires and what the risks of participation 
are.  You should ask the study team any questions you have before agreeing to join the study.  If you have 
any questions about your rights as a human research participant at any time before, during or after 
participation, please contact the Institutional Review Board (IRB) at (215) 898-2614 for assistance. 
You are being invited to participate in a research study because you have pancreatic cancer. This 
research study is designed to learn more about the safety and effectiveness of drugs niraparib with either 
ipilimumab or nivolumab given to individuals who have been diagnosed with pancreatic cancer.  You may 
or may not receive direct medical benefit from participating in this study. The hope is that this study 
treatment may provide a new treatment option for patients with pancreatic cancer, however, such a benefit 
cannot be guaranteed. 
If you agree to join the study, you will be asked to complete the following research procedures: research 
blood tests and tumor biopsy. Additional procedures that are consistent with your standard of care 
treatment will also be performed. 
Your participation will last up to until your disease progresses or you experience side effects that require 
treatment be stopped.  Even after you discontinue study treatment, you will be contacted 30 days, 90 or 
100 days and then annually by a study team representative who will ask questions about your health. 
The following are some of the most commonly observed side effects: with Niraparib decreased blood cells 
such as white blood cells, red blood cells, and platelets; with Nivolumab fatigue, rash, diarrhea, and with 
Ipilimumab increased liver enzymes. . There is always the possibility that unknown risks and side effects 
may occur. These may be mild or very serious, and in some cases, may be very serious, long-lasting, or 
may never go away. There may also be a risk of death.   
Other treatment options may be available to you.  These could include treatment of your symptoms, 
without any effect on your disease, and/or treatment with currently approved drugs for pancreatic cancer . 
IRB Approval From: 07-12-2024 To: 07-13-2025
NCT03404960

Prot_SAP_004.pdf: 
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PARPVAX: A PHASE IB/2, OPEN LABEL STUDY OF NIRAPARIB PLUS 
EITHER IPILIMUMAB OR NIVOLUMAB IN PATIENTS WITH ADVANCED 
PANCREATIC CANCER WHOSE DISEASE HAS NOT PROGRESSED 
ON PLATINUM-BASED THERAPY 
 
 
Principal Investigator: 
Kim A. Reiss Binder, MD 
University of Pennsylvania, Department of Internal Medicine 
Division of Hematology/Oncology 
Perelman Center for Advanced Medicine 
South Tower, 10th Floor, Room 107 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
(215) 360-0735 (phone); (215) 662-4646 (fax) 
Email: kim.reissbinder@pennmedicine.upenn.edu 
Regulatory Sponsor: 
University of Pennsylvania 
8046 Maloney Building 
3400 Spruce Street 
Philadelphia, PA 19104 
(215) 349-8627 (phone) 
Sponsor Representative: 
 
 
Medical Monitor: 
 
Statistician: 
 
Investigational Products: 
Niraparib 
Nivolumab 
Ipilimumab 
UPCC Number: 
UPCC 35217 
UPenn IRB Number: 
828516 
IND/ IDE Number: 
 
ClinicalTrials.gov Number: NCT03404960 
 
 
Initial version 
v.1 28 Jul 2017 


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Amendments 
v. 1.1, 14 Aug 2017 
v. 2, 22 Sept 2017 
v. 3, 23 Nov 2017 
v. 4, 13 Apr 2018 
v. 5, 29 Sept 2020 
v. 6, 10 Aug 2021 
v. 7, 7 Oct 2021 
v. 8, 2 Dec 2021 
v. 9, 6 Jun 2024 
 
 
 


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TABLE OF CONTENTS 
Summary of Changes from Protocol v8 to v9 ............................................................................. 8 
1 
STUDY SUMMARY .............................................................................................................. 8 
2 
BACKGROUND AND STUDY RATIONALE ................................................................. 14 
2.1 
Introduction ..................................................................................................................... 14 
2.2 
Background and Relevant Literature ........................................................................... 14 
2.3 
Name and Description of the Investigational Products ............................................... 16 
2.3.1 
Niraparib .................................................................................................................... 16 
2.3.2 
Nivolumab .................................................................................................................. 16 
2.3.3 
Ipilimumab ................................................................................................................. 17 
2.4 
Niraparib Background and Data ................................................................................... 17 
2.4.1 
Niraparib Pharmacology .......................................................................................... 17 
2.4.2 
Niraparib Pharmacokinetics, Metabolism and Drug-Drug Interaction 
Potential ...................................................................................................................... 17 
2.4.3 
Niraparib Toxicology ................................................................................................ 18 
2.4.4 
Niraparib Clinical Studies ........................................................................................ 19 
2.4.5 
Baseline Platelet Count and Weight as Predictors of Thrombocytopenia ........... 19 
2.5 
Ipilimumab ....................................................................................................................... 20 
2.5.1 
Clinical Pharmacodynamics ..................................................................................... 20 
2.5.2 
Pharmacokinetics ...................................................................................................... 20 
2.5.3 
Clinical Studies .......................................................................................................... 21 
2.6 
Nivolumab ........................................................................................................................ 22 
2.6.1 
Nivolumab Clinical Pharmacodynamics ................................................................. 22 
2.6.2 
Nivolumab Pharmacokinetics .................................................................................. 23 
2.6.3 
Nivolumab Drug-Drug Interactions ........................................................................ 24 
2.6.4 
Nivolumab Clinical Studies ...................................................................................... 24 
2.7 
Niraparib Plus Immune Checkpoint Blockade ............................................................ 25 
3 
STUDY OBJECTIVES ........................................................................................................ 26 
3.1 
Primary Objective ........................................................................................................... 26 
3.2 
Secondary Objectives ...................................................................................................... 26 
4 
INVESTIGATIONAL PLAN .............................................................................................. 26 
4.1 
General Design ................................................................................................................. 26 
4.1.1 
Screening Phase ......................................................................................................... 26 
4.1.2 
Study Intervention Phase .......................................................................................... 27 
4.1.3 
Treatment Discontinuation ....................................................................................... 27 
4.1.4 
Follow Up Phase ........................................................................................................ 27 
4.1.5 
Study Schema ............................................................................................................. 28 
4.2 
Study Endpoints .............................................................................................................. 28 
4.2.1 
Primary Study Endpoints ......................................................................................... 28 
4.2.2 
Secondary Study Endpoints ..................................................................................... 29 
5 
STUDY POPULATION AND DURATION OF PARTICIPATION .............................. 29 
5.1 
Inclusion Criteria ............................................................................................................ 29 
5.2 
Exclusion Criteria ........................................................................................................... 30 
5.3 
Patients or Partners of Patients with Reproductive Potential .................................... 32 
5.4 
Total Number of Subjects and Sites .............................................................................. 33 
5.5 
Vulnerable Populations ................................................................................................... 33 
6 
STUDY INTERVENTION .................................................................................................. 33 
6.1 
Description ....................................................................................................................... 33 


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6.1.1 
Niraparib .................................................................................................................... 33 
6.1.2 
Nivolumab .................................................................................................................. 34 
6.1.3 
Ipilimumab ................................................................................................................. 34 
6.1.4 
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab ............... 35 
6.2 
Intervention Regimen ..................................................................................................... 36 
6.2.1 
Niraparib + Nivolumab (Arm A) ............................................................................. 36 
6.2.2 
Niraparib + Ipilimumab (Arm B) ............................................................................ 36 
6.2.3 
DLT Definition and De-Escalation Decision Process (for Phase I Portion) ......... 36 
6.2.4 
Starting Dose and Dose Modifications of Protocol-Specified Treatment ............. 37 
6.2.5 
Dose Modification Criteria and Criteria for Stopping Treatment ....................... 37 
6.2.6 
Treatment Beyond Progression ................................................................................ 45 
6.3 
Prior and Concomitant Therapies ................................................................................. 46 
6.3.1 
Anticancer or Experimental Therapy ..................................................................... 46 
6.3.2 
Hematopoietic Growth Factors and Blood Products ............................................. 46 
6.3.3 
Bisphosphanates ........................................................................................................ 46 
6.3.4 
Anticoagulants ........................................................................................................... 46 
6.3.5 
Other Concomitant Medications .............................................................................. 47 
6.3.6 
Substrates of P-glycoprotein .................................................................................... 47 
6.3.7 
Vaccines ...................................................................................................................... 47 
6.3.8 
Blood Donation .......................................................................................................... 47 
6.4 
Warnings and Precautions ............................................................................................. 47 
6.4.1 
Niraparib .................................................................................................................... 47 
6.4.2 
Nivolumab .................................................................................................................. 49 
6.4.3 
Ipilimumab ................................................................................................................. 53 
6.5 
Receipt .............................................................................................................................. 55 
6.6 
Storage .............................................................................................................................. 56 
6.6.1 
Niraparib .................................................................................................................... 56 
6.6.2 
Nivolumab .................................................................................................................. 56 
6.6.3 
Ipilimumab ................................................................................................................. 56 
6.7 
Administration and Accountability ............................................................................... 56 
6.8 
Subject Compliance Monitoring .................................................................................... 57 
6.9 
Return or Destruction of Investigational Product ....................................................... 57 
7 
STUDY PROCEDURES ...................................................................................................... 58 
7.1 
Schedule of Assessments- ARM A (Niraparib + Nivolumab) ..................................... 58 
7.2 
Schedule of Assessments- ARM B (Niraparib + Ipilimumab) .................................... 61 
7.3 
Screening Phase ............................................................................................................... 64 
7.4 
Treatment Phase .............................................................................................................. 65 
7.4.1 
Day 1 of Cycles 1-4 .................................................................................................... 65 
7.4.2 
Day 1 of Cycles 5 and Beyond, Both Arms ............................................................. 66 
7.4.3 
Tumor Assessments ................................................................................................... 67 
7.4.4 
End of Treatment Visit ............................................................................................. 67 
7.5 
30-day Follow-up Visit .................................................................................................... 68 
7.6 
90 or 100 Day Follow-up Visit for MDS/AML ............................................................. 68 
7.7 
Long-term Follow-Up ..................................................................................................... 68 
7.8 
Subject Withdrawal ........................................................................................................ 69 
7.8.1 
Data Collection and Follow-up for Withdrawn Subjects ...................................... 69 
8 
STUDY EVALUATIONS AND MEASUREMENTS ....................................................... 69 
8.1 
Medical Record Review .................................................................................................. 69 
8.2 
Physical Examination ...................................................................................................... 69 


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8.3 
Body Weight and Height ................................................................................................. 69 
8.4 
Vital Signs ........................................................................................................................ 69 
8.5 
ECOG Performance Status ............................................................................................ 69 
8.6 
Clinical Laboratory Evaluations .................................................................................... 70 
8.7 
Efficacy Evaluations ........................................................................................................ 70 
8.7.1 
Tumor Assessments ................................................................................................... 70 
8.7.2 
Tumor Markers ......................................................................................................... 71 
8.8 
Genetic Testing and Correlative Science ....................................................................... 71 
8.9 
Immune Endpoints .......................................................................................................... 71 
8.9.1 
Specimen Collection .................................................................................................. 71 
8.9.2 
Immune Correlative Science .................................................................................... 71 
8.9.3 
Immune Biomarkers ................................................................................................. 72 
9 
STATISTICAL PLAN ......................................................................................................... 73 
9.1 
Primary Endpoints .......................................................................................................... 73 
9.2 
Secondary Endpoints ...................................................................................................... 73 
9.3 
Sample Size and Power Determination ......................................................................... 74 
9.3.1 
Statistical Methods .................................................................................................... 74 
9.3.2 
Baseline Data ............................................................................................................. 74 
9.3.3 
Efficacy Analysis ....................................................................................................... 74 
9.3.4 
Safety Analysis ........................................................................................................... 74 
9.4 
Subject Population(s) for Analysis ................................................................................. 75 
10 SAFETY AND ADVERSE EVENTS ................................................................................. 75 
10.1 
Definitions ........................................................................................................................ 75 
10.1.1 
Unanticipated Problems Involving Risk to Subjects or others ............................. 75 
10.1.2 
Adverse Event ............................................................................................................ 75 
10.1.3 
Serious Adverse Event .............................................................................................. 75 
10.1.4 
Adverse Events of Special Interest (AESIs) for Niraparib .................................... 76 
10.2 
Recording of Adverse Events ......................................................................................... 77 
10.3 
Intensity of Adverse Events ............................................................................................ 77 
10.4 
Causal Relationship of Adverse Events to Study Drugs .............................................. 77 
10.5 
Outcome and Action Taken ............................................................................................ 78 
10.6 
Adverse Event Reporting Period ................................................................................... 79 
10.7 
Preexisting Condition ...................................................................................................... 79 
10.8 
General Physical Examination Finding ......................................................................... 79 
10.9 
Post-Study Adverse Event .............................................................................................. 79 
10.10 Abnormal Laboratory Values ........................................................................................ 79 
10.11 Pregnancy or Drug Exposure ......................................................................................... 80 
10.12 Hospitalization, Prolonged Hospitalization or Surgery ............................................... 80 
10.13 Reporting to the UPenn Sponsor ................................................................................... 81 
10.13.1 
Adverse Events .......................................................................................................... 81 
10.13.2 
Reporting Product Quality Complaints for Niraparib .......................................... 81 
10.14 Investigator Reporting: Local Reporting Requirements ............................................. 82 
10.15 Protocol Exceptions ......................................................................................................... 82 
10.16 Protocol Deviations ......................................................................................................... 82 
10.17 Investigator Reporting to Sponsor of Exceptions and Deviations .............................. 83 
10.18 Medical Monitor .............................................................................................................. 83 
10.19 Confidentiality ................................................................................................................. 83 
10.20 Data Collection and Management ................................................................................. 84 
10.21 Records Retention ........................................................................................................... 84 


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11 STUDY MONITORING, AUDITING, AND INSPECTING ........................................... 84 
11.1 
Study Monitoring Plan .................................................................................................... 84 
11.2 
Auditing and Inspecting .................................................................................................. 84 
12 ETHICAL CONSIDERATIONS ........................................................................................ 85 
13 STUDY FINANCES ............................................................................................................. 85 
13.1 
Funding Source ................................................................................................................ 85 
13.2 
Conflict of Interest .......................................................................................................... 85 
14 PUBLICATION PLAN ........................................................................................................ 85 
15 REFERENCES ..................................................................................................................... 86 
16 APPENDIX ........................................................................................................................... 88 
16.1 
Appendix A: ECOG ........................................................................................................ 88 
16.3 
Appendix C: COVID-19 Study Implication Memo ...................................................... 92 
 
 


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Table of Tables 
Table 1. 
Phase IB Portion: Niraparib Criteria for Dose De-Escalation and Cohort 
Size .......................................................................................................................... 36 
Table 2. 
Recommended Niraparib Dose Reductions for Adverse Reactions .................. 37 
Table 3. 
Niraparib Dose Modification for Non-hematologic Adverse Reactions ........... 37 
Table 4. 
Niraparib Dose Modifications for Hematologic Adverse Reactions ................. 38 
Table 5. 
GI Adverse Event Management Algorithm for Nivolumab and Ipilimumab .. 39 
Table 6. 
Renal Adverse Event Management Algorithm for Nivolumab and 
Ipilimumab ............................................................................................................. 40 
Table 7. 
Pulmonary Adverse Event Management Algorithm for Nivolumab and 
Ipilimumab ............................................................................................................. 41 
Table 8. 
Hepatic Adverse Event Management Algorithm for Nivolumab and 
Ipilimumab ............................................................................................................. 42 
Table 9. 
Endocrinopathy Management Algorithm for Nivolumab and Ipilimumab ..... 43 
Table 10. 
Skin Adverse Event Management Algorithm for Nivolumab and 
Ipilimumab ............................................................................................................. 44 
Table 11. 
Neurological Adverse Event Management Algorithm for Nivolumab and 
Ipilimumab ............................................................................................................. 45 
Table 12. 
Schedule of Assessments – Arm A ........................................................................ 58 
Table 13. 
Schedule of Assessments – Arm B ........................................................................ 61 
Table 14. 
Causal Relationship of Adverse Events to Study Drugs .................................... 78 
Table 15. 
Eastern Cooperative Oncology Group (ECOG) Performance Status Scale .... 88 
Table 16. 
Evaluation of Target Lesions ................................................................................ 90 
Table 17. 
Evaluation of Nontarget Lesions .......................................................................... 90 
Table 18. 
Evaluation of Best Overall Response ................................................................... 90 
 




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Section(s) Affected 
Changes (Listed by Initial Order of 
Appearance) 
Rationale 
End of Study 
Section 4.1.3 
The section was redefined 
To reflect the purpose of this 
amendment 
Secondary Study 
Endpoints. 
Section 4.2.2 
Removed Identification of HRDs and allele 
specific LOH in patients who have achieved 
stability on platinum-based therapy via whole 
exome sequencing. 
To align with Secondary Objectives 
Secondary Study 
Endpoints. 
Section 4.2.2 
Removed Correlation of HRDs with response to 
treatment with niraparib plus immune 
checkpoint blockade. 
To align with Secondary Objectives 
Secondary Study 
Endpoints. 
Section 4.2.2 
Removed Correlation of immune activity prior 
to and during therapy with response to treatment 
with niraparib and immune checkpoint blockade 
therapy. 
To align with Secondary Objectives 
Secondary Study 
Endpoints. 
Section 4.2.2 
Removed Duration of response (DOR) as 
defined by the time from first documentation of 
complete or partial response by RECIST v.1.1 to 
date of disease progression or death due to any 
cause. Responders who have not progressed will 
be censored on the most recent date that 
documents progression-free status 
To align with Secondary Objectives 
 
 


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1 STUDY SUMMARY 
 
Title 
PARPVAX: A PHASE 1B/2, OPEN LABEL STUDY OF NIRAPARIB 
PLUS EITHER IPILIMUMAB OR NIVOLUMAB IN PATIENTS 
WITH ADVANCED PANCREATIC CANCER WHOSE DISEASE 
HAS NOT PROGRESSED ON PLATINUM-BASED THERAPY 
Short Title 
Niraparib Plus Ipilimumab or Nivolumab in Patients with Advanced 
Pancreatic Adenocarcinoma Whose Disease Has Not Progressed on 
Platinum-Based Chemotherapy 
UPENN IRB 
Number 
828516 
Protocol Number 
UPCC 35217 
Phase 
Clinical Phase Ib/II 
Methodology 
Randomized, Two Arm, Open Label 
Study Duration 
3.5 years 
Study Center 
Abramson Cancer Center at University of Pennsylvania 
 
 
 


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Objectives 
Primary: 
• Determine the clinical impact of combining PARP inhibition with 
immune checkpoint blockade in patients with advanced PDAC 
and durable platinum stability. 
1. Establish the safety of this combination (phase I portion) 
2. Determine clinical efficacy as measured by PFS rate at 6 
months (phase II portion) 
Secondary: 
• To evaluate efficacy by assessment of objective response 
(RECIST v.1.1) in those with measurable disease and objective 
response rate (ORR). 
• To evaluate overall survival (OS) 
Number of 
Subjects 
84 (42 patients per arm) 
 
 


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Main Inclusion 
and Exclusion 
Criteria 
KEY INCLUSIONS: 
1. Histologically or cytologically confirmed diagnosis of pancreatic 
adenocarcinoma with locally advanced or metastatic disease 
2. Patients must have received treatment with platinum-based 
(cisplatin, oxaliplatin or carboplatin) treatment for locally 
advanced or metastatic pancreatic cancer and have received a 
minimum of 16 weeks of therapy without evidence of disease 
progression based on the investigator’s opinion 
Note: this requires at least stable imaging and a stable or 
decreasing tumor marker as applicable and as determined by 
the investigator. 
If a patient has demonstrated a biochemical and imaging 
response to platinum therapy and has not progressed within 16 
weeks of starting this therapy but had to discontinue platinum 
prior to 16 weeks for a legitimate medical reason (as 
determined by the investigator), the patient may still be 
considered for the trial 
3. Patients may have previously failed non-platinum containing 
therapy or may never have previously progressed on treatment. 
-Discontinuation of the platinum component of the regimen for 
chemotherapy-related toxicity is permissible provided the 
patient has previously received at least 16 weeks of platinum- 
based therapy without evidence of disease progression ≤8 
weeks after treatment with the platinum agent 
4. Measurable disease is not required for study entry 
5. Adequate organ function 
6. ECOG performance status of 0-1 
KEY EXCLUSIONS: 
1. Prior treatment with a PARP inhibitor, ipilimumab, nivolumab or 
other cytotoxic T-lymphocyte-associated protein (CTLA-4), PD-1 or 
PD-L1 inhibitor. 
2. Patients who have demonstrated resistance to platinum agents 
(e.g. oxaliplatin, cisplatin) are not eligible to participate in this 
study 
3. Clinical evidence of uncontrolled malabsorption and/or any other 
gastrointestinal disorder or defect that would, in the opinion of 
the investigator, interfere with the absorption of niraparib. 


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4. Received any systemic treatment for pancreatic cancer during the 
14 days prior to first dose of treatment 
 
5. Acute infection requiring intravenous antibiotics, antiviral or 
antifungal agents during the 14 days prior to first dose of study 
therapy. 
6. Patients will be excluded if they have an active, known or 
suspected autoimmune disease, defined as: patients with a history 
of inflammatory bowel disease are excluded from this study, as 
are patients with a history of symptomatic autoimmune disease 
(e.g. rheumatoid arthritis, systemic progressive sclerosis 
(scleroderma), systemic lupus erythematosus, autoimmune 
vasculitis e.g. Wegener’s Granulomatosis); motor neuropathy 
considered of autoimmune origin (e.g. Guillain-Barre Syndrome). 
NOTE: Patients are permitted to enroll if they have vitiligo, 
type I diabetes mellitus, residual hypothyroidism due to 
autoimmune condition only requiring hormone replacement, 
psoriasis not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger. 
7. Has a history of interstitial lung disease or active, non-infectious 
pneumonitis 
8. Has received a live vaccine within 4 weeks prior to the first dose 
of trial therapy (Note: seasonal influenza vaccines for injection 
are generally inactivated and are allowed; however intranasal 
influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines 
and are not allowed). 
Statistical 
Methodology 
We will enroll 84 patients in a two-arm phase II design. Progression-free 
survival rate at 6 months (PFS6) from the start of study therapy will be 
the primary clinical outcome in each arm. A one sample test of the null 
hypothesis of a PFS6 rate equal to 44% versus the alternative hypothesis 
of a PFS6 rate equal to 60% will be conducted. Per each arm: with 42 
patients enrolled over 36 months and with 6 months of additional follow- 
up, there is 81% power for the test assuming exponential survival and 5% 
2-sided type I error rate. 
 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures. 


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2 BACKGROUND AND STUDY RATIONALE 
2.1 Introduction 
A subset of pancreatic cancers (PDAC) are characterized by a deficiency in DNA repair (DDR) 
and respond exceptionally well to platinum agents and PARP inhibitors. Mutations in BRCA1, 
BRCA2 and PALB2 are the most well-defined causes of DDR. Mutations in ATM, CHEK2 and 
other DDR genes have been identified in pancreatic cancer, but their relationship to 
chemotherapy response is not defined. In addition, somatic alterations such as methylation may 
also lead to homologous recombination deficiency (HRD). Targeting platinum-stable tumors 
with a durable response to therapy may enrich for a DDR population. PARP inhibition should 
increase tumor apoptosis and may release endogenous tumor-associated neo-antigens. However, 
effector T-cells are actively suppressed by the PDAC microenvironment, limiting the immune 
response. In vivo data show that combining PARP inhibition with immune checkpoint blockade 
in DDR tumors can lead to a powerful T-cell mediated anti-tumor effect. 
Hypothesis: Combining PARP inhibition with immune checkpoint blockade in a population 
enriched for DDR PDAC will unleash an immune response against large numbers of neo- 
antigens, creating an anti-tumor in situ vaccine. 
 
2.2 Background and Relevant Literature 
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy. In metastatic disease, 
even the most commonly used first-line regimens (FOLFIRINOX and gemcitabine/abraxane) are 
associated with a median overall survival of <1 year [1, 2]. There is, however, a subgroup of 
patients who respond exceptionally well to cytotoxic therapy and maintain a durable response. 
For such patients, there does not exist a less toxic maintenance option and they inevitably 
develop cumulative and eventually prohibitive toxicities such as neuropathy, myelosuppression 
and fatigue. There is, therefore, a great need to (1) develop tolerable maintenance strategies for 
appropriately selected patients by (2) identifying biomarkers that will predict response to these 
specific treatments. 
It is well known that a meaningful subset of PDAC is characterized by a homologous 
recombination deficiency (HRD)[3-5].  3-10% of these cases are caused by an inherited germ 
line mutation in key genes involved in the repair of damaged DNA[6]. An additional 5% may be 
caused by de novo germ line mutations in the same genes [4, 5, 7, 8]. Beyond this, HR genes 
may also be somatically mutated resulting in a genomically unstable phenotype. Finally, there is 
an overlap between defects in the BRCA pathway genes, the genomically unstable phenotype 
and a previously described BRCA-associated mutational signature [9]. Patients of all three 
groups appear to have a similar phenotype, with exceptional and durable responses to platinum- 
based chemotherapy and to PARP inhibitors[3,10], meaning that their identification has 
therapeutic implications. 
The identification of this likely substantial and heterogeneous sub-population is a clinical 
challenge for several reasons. First, the use of clinical factors such as a positive family history, 
multiple cancers in a single host or young age of disease onset can be helpful in identifying germ 
line mutations, but miss somatic ones. Additionally, recent data in prostate cancer suggest that 
even these clinical surrogates may be inadequate to identify patients with germline mutations 
[11]. Second, tumor testing with next generation sequencing (NGS) panels and germ line panels 


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are limited to a list of known cancer drivers, but would miss any yet-identified mutations. 
Finally, there is a lag time of approximately 3-4 weeks for either of these methods, while patients 
can often not wait on the results to start therapy. 
As an alternative strategy, using the clinical surrogate marker of durable platinum stability in an 
otherwise unselected group of PDAC patients who are stable on treatment will presumably 
enrich for both germline and somatically mutated tumors. Performing broad sequencing and 
LOH testing of blood and tumor tissue will allow the opportunity both to prove this hypothesis 
and to further characterize DDR tumors. 
The rationale for identifying this subgroup of patients during a period of prolonged platinum 
stability is twofold: First, patients who have prolonged exposure to platinum suffer cumulative 
toxicities of cytotoxic chemotherapy and are desperately in need of alternative maintenance 
strategies. Second, platinum sensitivity, at least in part, coincides with PARP inhibitor 
sensitivity, meaning that sensitivity to platinum agents confers sensitivity to PARP inhibitors. 
Likewise, resistance to platinum agents confers a resistance to PARP inhibitors [12]. Therefore, 
waiting for these tumors to become platinum resistant prior to initiating PARP inhibitor-based 
treatment is not appropriate. 
In the setting of ongoing platinum stability, the treatment of DDR tumors with PARP inhibition 
should increase tumor cell apoptosis, resulting in a concomitant rise in endogenous tumor- 
associated or –specific antigens (TAA, TSA) that may prime for a subsequent immune response. 
However, a major barrier to immune activation is the highly immunosuppressive PDAC 
microenvironment. PDAC tumors are infiltrated with regulatory T-cells (Tregs) and have a 
paucity of immune effector cells. The tumor, therefore, actively suppresses the adaptive immune 
response [13]. The addition of immune checkpoint blockade should off-set this suppression and 
allow for a rise in immune activity. 
Preclinical in vivo data by Adams et al demonstrates that in an HRD model of ovarian cancer, the 
combination of CTLA-4 antibodies plus PARP inhibition resulted in a T-cell mediated tumor 
clearance.  This effect led to a significant survival benefit for the animals and was dependent on 
a rise in local levels of IFN-gamma[14]. The clinical combination of PARP inhibition and 
immune checkpoint blockade in an ovarian cancer model is currently in phase II testing (NCT 
02657889). In a second preclinical model, breast cancer cell lines and xenograft tumors were 
treated with PARP inhibition followed by an assessment of PD-L1 expression. PARP inhibition 
was found to up-regulate PD-L1 expression, and blockade of PD-L1 of these cells resulted in T- 
cell killing. 
We hypothesize, therefore that combining PARP inhibition with either CTLA4 or PD1 blockade 
in a population of PDAC patients enriched for those with an HRD will result in a powerful anti- 
tumor effect by unleashing an immune response against large numbers of neo-antigens. Our 
mission is to further characterize and identify HRD PDAC patients and to identify a low-toxicity 
maintenance strategy for these people following successful induction chemotherapy. 
Our specific aims are: 
• Determine the clinical impact of combining PARP inhibition with immune checkpoint 
blockade in patients with advanced PDAC and durable platinum stability. 
• Establish the safety of this combination 


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• Determine clinical efficacy as measured by PFS at 6 months, ORR, DOR and OS. 
• Determine the immune pharmacodynamics of combining PARP inhibition with immune 
checkpoint blockade by analyzing the tumor microenvironment and peripheral blood for 
evidence of an increased immune response and reduction in immunosuppression 
• Identify and further characterize deficits in DNA repair in patients with advanced PDAC 
and sustained platinum stability by performing broad sequencing of ctDNA and tumor 
tissue. 
 
Clinical impact: It has become increasingly evident that a substantial subpopulation of PDAC is 
driven by germline or somatic deficits in DNA repair. These tumors classically respond 
exceptionally well to platinum-based therapies with durable responses to treatment. However, 
prolonged exposure to platinum-based chemotherapies leads to cumulative toxicities that 
eventually become prohibitive. The characterization of this subpopulation of patients coupled 
with the development of tailored, less toxic maintenance treatment strategies represents an 
important step forward in pancreatic cancer care. 
 
2.3 Name and Description of the Investigational Products 
 
2.3.1 
Niraparib 
Niraparib is an orally available, selective PARP1 and -2 inhibitor. 
The chemical name for niraparib is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7- 
carboxamide 4-methylbenzenesulfonate hydrate (1:1:1). The empirical molecular formula for 
niraparib is C26H30N4O5S and its molecular weight is 510.61. 
Niraparib tosylate monohydrate drug substance is a white to off-white, non-hygroscopic 
crystalline solid. Niraparib solubility is pH independent below the pKa of 9.95, with an aqueous 
free base solubility of 0.7 mg/mL to 1.1 mg/mL across the physiological pH range. 
Niraparib is supplied in HDPE bottles with child resistant closures. 
Niraparib does not contain gluten. 
2.3.2 
Nivolumab 
Nivolumab, also referred to as BMS-936558-01 or BMS-936558, is a soluble protein consisting 
of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical light chains. The 
physical and chemical properties of nivolumab are provided below. 
 
BMS Number 
BMS-936558-01 
Other Names 
Nivolumab, BMS-936558, MDX1106, ONO-4538, anti-PD-1 
Molecular Weight 
146,221 daltons (143,619.17 daltons, protein portion) 
Appearance 
Clear to opalescent, colorless to pale yellow liquid, light (few) particulates may be 
present 
Solution pH 
5.5 to 6.5 
 


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Nivolumab Injection, 100 mg/10 mL (10 mg/mL), 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is a clear to opalescent, colorless to pale 
yellow liquid, which may contain light (few) particulates. The drug product is a sterile, non- 
pyrogenic, single-use, isotonic aqueous solution formulated at 10 mg/mL in sodium citrate, 
sodium chloride, mannitol, diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 
(Tween™ 80), pH 6.0 and includes an overfill to account for vial, needle, and syringe holdup. It 
is supplied in 10-cc Type I flint glass vials, stoppered with butyl rubber stoppers and sealed with 
aluminum seals. The only difference between the two drug final products is the vial fill volume. 
 
2.3.3 
Ipilimumab 
Ipilimumab (BMS-734016, MDX-010) is a fully human IgG1κ consisting of 4 polypeptide 
chains; 2 identical heavy chains primarily consisting of 447 amino acids each with 2 identical 
kappa light chains consisting of 215 amino acids each linked through inter-chain disulfide bonds. 
The physical and chemical properties of ipilimumab drug substance are provided in the table 
below. 
 
BMS Number 
734016 
Molecular Weight 
147,991 Daltons 
Appearance 
Clear to slightly opalescent, colorless to pale yellow liquid, may contain particles 
Solution pH 
7.0 
pI 
The isoelectric focusing analysis generates a banding pattern in the pI range of 8.5 to 
8.8, with the major isoform at an approximate pI of 8.7. 
 
Ipilimumab injection, 200 mg/40 mL (5 mg/mL), is formulated as a clear to slightly opalescent, 
colorless to pale yellow, sterile, nonpyrogenic, single-use, isotonic aqueous solution that may 
contain particles. Ipilimumab injection, 50 mg/10 mL and 200 mg/40 mL, is supplied in 10-cc or 
50-cc Type I flint glass vials, respectively, stoppered with gray butyl stoppers and sealed with 
aluminum seals. The drug product is formulated at a concentration of 5 mg/mL at a pH of 7.0. 
 
2.4 Niraparib Background and Data 
2.4.1 
Niraparib Pharmacology 
Niraparib is a selective PARP-1 and -2 inhibitor that selectively kills tumor cells in vitro and in 
mouse xenograft models. PARP inhibition leads to irreparable DSBs, use of the error-prone 
DNA repair pathway, resultant genomic instability and ultimately cell-death. Additionally, 
PARP trapping at genetic lesions as a result of the suppression of auto-parlyation can contribute 
to cytotoxicity. 
2.4.2 
Niraparib Pharmacokinetics, Metabolism and Drug-Drug Interaction 
Potential 
Absorption: Following a single-dose administration of 300 mg niraparib under fasting 
conditions, niraparib was measurable in plasma within 30 minutes and the mean peak plasma 
concentration (Cmax) for niraparib was reached in about 3 hours [804 ng/mL (%CV:50.2%)]. 
Following multiple oral doses of niraparib from 30 mg to 400 mg once daily, accumulation of 


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niraparib was approximately 2 fold. The systemic exposures (Cmax and AUC) to niraparib 
increased in a dose proportional manner when the dose of niraparib increased from 30 mg to 400 
mg. The absolute bioavailability of niraparib is approximately 73%, indicating minimal first-pass 
effect. Concomitant administration of a high fat meal did not significantly affect the PK of 
niraparib after administration of 300 mg of niraparib. 
Distribution: Niraparib was moderately protein bound to human plasma (83.0%). The apparent 
Vd/F was 1220 L, indicating extensive tissue distribution of niraparib. In a population PK 
analysis, the Vd/F of niraparib was 1074 L in cancer patients. 
Metabolism: Niraparib is metabolized primarily by CEs to form a major inactive metabolite, 
M1. In a mass balance study, M1 and M10 (the subsequently formed M1 glucuronides) were the 
major circulating metabolites. The mean half-life of M1 was 88 hours. The exposure ratio of M1 
to niraparib was approximately 1.3-2.2 fold in plasma. 
Elimination: Following a single oral 300-mg dose of niraparib, the mean terminal half-life of 
niraparib ranged from 48 to 51 hours (approximately 2 days). In a population PK analysis, the 
apparent total clearance of niraparib was 16.2 L/h in cancer patients. Niraparib is eliminated 
primarily through the hepatobiliary and renal routes. Following administration of a single oral 
300 mg dose of [14C]-niraparib, on average 86.2% (range 71% to 91%) of the dose was 
recovered in urine and feces over 21 days. Radioactive recovery in the urine accounted for 
47.5% (range 33.4% to 60.2%) and the feces for 38.8% (range 28.3% to 47.0%) of the dose. In 
pooled samples collected over 6 days, 36.7% of the dose was recovered in the urine primarily as 
metabolites and 21.1% of the dose was recovered in the feces primarily as unchanged niraparib. 
Specific Populations: 
Geriatric Patients: Population PK analyses indicated that age had no significant impact on the PK 
of niraparib. 
Racial or Ethnic Groups: Population PK analyses indicated that race had no significant impact on 
the PK of niraparib. 
 
2.4.3 
Niraparib Toxicology 
Carcinogenesis: No carcinogenicity studies have been conducted with niraparib. 
Mutagenesis: Niraparib was clastogenic in an in vitro mammalian chromosomal aberration 
assay and in an in vivo rat bone marrow micronucleus assay. This clastogenicity is consistent 
with genomic instability resulting from the primary pharmacology of niraparib and indicates 
potential for genotoxicity in humans. Niraparib was not mutagenic in a bacterial reverse mutation 
assay (Ames) test. 
Impairment of Fertility: No nonclinical reproductive studies have been conducted with 
niraparib, but a reversible decrease in spermatogenesis was observed in rats and dogs. It is not 
known whether niraparib or its metabolites are excreted in milk. 
Animal Toxicology: In repeat-dose oral toxicity studies, niraparib was administered daily for up 
to 3 months duration in rats and dogs. The major primary target organ for toxicity in both species 
was the bone marrow, with associated changes in peripheral hematology parameters. 
Additionally, decreased spermatogenesis was seen in both species. These findings occurred at 


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exposures below those seen clinically. All findings showed reversibility within 4 weeks of 
cessation of dosing. 
Phototoxicity: Niraparib did not exhibit cutaneous or ocular phototoxicity in a 3-day repeat-dose 
study in pigmented rats. 
 
2.4.4 
Niraparib Clinical Studies 
Kindly refer to the niraparib IB for clinical study updates. 
The safety and efficacy of niraparib as maintenance therapy was studied in a Phase 3 
randomized, double-blind, placebo-controlled trial (NOVA) in patients with platinum-sensitive 
recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. All patients had 
received at least two prior platinum-containing regimens and were in response (complete or 
partial) to their most recent platinum-based regimen. 
Eligible patients were assigned to one of 2 cohorts based on the results of a germline BRCA 
mutation test. Women who were hereditary germline BRCA mutation carriers were assigned to 
the gBRCAmut cohort (n = 203) and women who did not carry a hereditary germline BRCA 
mutation were assigned to the non-gBRCAmut cohort (n = 350). Within each cohort, patients 
were randomized using a 2:1 allocation of niraparib to placebo. Randomization occurred within 8 
weeks of the last dose of the most recent platinum-containing regimen. 
The primary endpoint, PFS, was determined by central independent assessment per RECIST 
(version 1.1) or clinical signs and symptoms and increased CA-125. PFS as defined in the 
NOVA study was measured from the time of randomization (which occurred up to 2 months 
after completion of the most recent chemotherapy regimen) to disease progression or death. 
Prior to unblinding of the study, tumors from patients randomized to the non-gBRCAmut cohort 
were tested for the presence of HRD using the Myriad myChoice® HRD test, which evaluates 
three independent biomarkers of tumor genome instability: loss of heterozygosity, telomeric 
allelic imbalance, and large-scale state transitions. Tumors with homologous recombination 
deficiencies and those with somatic BRCA mutations were defined as HRDpos. 
PFS was significantly longer for patients who received niraparib compared to those who received 
placebo for all three primary efficacy populations. Within the gBRCAmut cohort, the median 
PFS from time of randomization was 21.0 months with niraparib versus 5.5 months with 
placebo. In the overall non-gBRCAmut cohort, the median PFS from time of randomization was 
9.3 months with niraparib versus 3.9 months with placebo. PFS was also significantly longer 
with niraparib than with placebo in the HRDpos group of the non-gBRCAmut cohort: 12.9 
months versus 3.8 months. 
 
2.4.5 
Baseline Platelet Count and Weight as Predictors of Thrombocytopenia 
An analysis was conducted using the data collected in ENGOT-OV16/NOVA and the initial 
phase I study, PN001. This analysis determined that only baseline platelets had an impact on 
platelet nadir; lower baseline platelets (<180 109/L) were associated with an increased frequency 
of thrombocytopenia Grade ≥1 (76%) or Grade ≥ 3 (45%) compared to patients with higher 
baseline platelet counts. Further, an exploratory analysis of clinical data versus baseline body 
weight from ENGOT-OV16/NOVA was conducted. For this analysis, the weight categories 
were based on quartiles with the lowest quartile (patients with a body weight less than 58 kg at 


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baseline) compared to the highest quartile (patients with a body weight greater than or equal to 
77 kg at baseline). While TEAEs occurred in most patients regardless of body weight, Grade ≥3 
TEAEs, SAEs, and TEAEs leading to dose modification or treatment discontinuation occurred 
more commonly in the weight <58 kg cohort than in the ≥77 kg cohort. In the cohort of patients 
with a body weight <58 kg, approximately 80% of patients had a dose reduction compared to 
59% of patients with a weight greater than or equal to 77 kg. Treatment discontinuations were 
increased in the subjects with lower body weight (24%) compared to patients in the highest 
quartile (10%). 
The potential relationship between body weight and TEAEs was further explored in an analysis 
to evaluate the correlation of grade 3 or 4 thrombocytopenia and baseline body weight. The 
lowest platelet count in the first 30 days was plotted versus baseline body weight to determine if 
low body weight identified a subgroup of patients with higher levels of thrombocytopenia during 
Cycle 1. In the first 30 days of treatment, a baseline body weight >77 kg is associated with a 
lower incidence of grade 3 or 4 thrombocytopenia (14%) relative to the group with body weight 
<58 kg (43%). 
Finally, a classification tree approach was used to refine the best cut-off points for predicting the 
likelihood of a patient developing ≥Grade 3 thrombocytopenia within 30 days after the first dose 
of niraparib. The results of the model show that the subgroup of patients with a baseline body 
weight <77 kg or baseline platelet count <150,000 µL had a grade 3/4 thrombocytopenia rate in 
the first 30 days of 35.4% compared to 11.5% in the group of patients with a body weight >77 kg 
and a platelet count >150,000 µL. Further, the average daily dose was 258 mg through the first 
two cycles for patients with a body weight >77 kg and platelet count >150,000 µL, and was only 
206 mg for patients with body weight < 77 kg or platelet count <150,000 µL. Thus, the actual 
delivered dose approximated a starting dose of 200 mg despite the intended delivery of a starting 
dose of 300 mg. These observations are to be confirmed in the present study with the inclusion of 
study treatment dosed at 200 mg (2 capsules of niraparib or placebo) in patients whose baseline 
weight is <77 kg or baseline platelet count is <150,000 µL. 
 
2.5 Ipilimumab 
2.5.1 
Clinical Pharmacodynamics 
CTLA-4 is a key regulator of T-cell activity. Ipilimumab is a CTLA-4 immune checkpoint 
inhibitor that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, increasing the 
number of tumor reactive T-effector cells that mobilize to mount a direct T-cell immune attack 
against tumor cells. Preclinical data indicate that CTLA-4 blockade can also reduce Treg 
function, which may lead to an increase in anti-tumor immune response. Ipilimumab may 
selectively deplete Tregs at the tumor site, leading to an increase in the intratumoral T- 
effector/Treg cell ratio which drives tumor response leading to cell death.[21] 
 
2.5.2 
Pharmacokinetics 
The PPK of ipilimumab was studied in 785 subjects (3200 serum concentrations) with advanced 
melanoma in 4 Phase 2 studies (CA184004, CA184007, CA184008, and CA184022), 1 Phase 3 
study (CA184024), and 1 Phase 1 study (CA184078). The PPK analysis demonstrated that the 
PK of ipilimumab is linear, the exposures are dose proportional across the tested dose range of 


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0.3 to 10 mg/kg, and the model parameters are time-invariant, similar to that determined by non- 
compartmental analyses. 
Upon repeated dosing of ipilimumab, administered q3w, minimal systemic accumulation was 
observed by an accumulation index of 1.5-fold or less, and ipilimumab steady-state 
concentrations were achieved by the third dose. The ipilimumab CL of 16.8 mL/h from PPK 
analysis is consistent with that determined by non-compartmental PK analysis. The terminal T- 
HALF and Vss of ipilimumab calculated from the model were 15.4 days and 7.47 L, 
respectively, which are consistent with that determined by noncompartmental analysis. Volume 
of central compartment (Vc) and peripheral compartment were found to be 4.35 and 3.28 L, 
respectively, suggesting that ipilimumab first distributes into plasma volume and, subsequently, 
into extracellular fluid space. CL of ipilimumab and Vc were found to increase with increase in 
BW. However, there was no significant increase in exposure with increase in BW when dosed on 
a milligram/kilogram basis, supporting dosing of ipilimumab based on a weight normalized 
regimen. The PK of ipilimumab is not affected by age, gender, race, and immunogenicity (anti- 
drug antibody [ADA] status); concomitant use of chemotherapy; prior therapy; BW; 
performance status; or tumor type. Other covariates had effects that were either not statistically 
significant or were of minimal clinical relevance. 
 
2.5.3 
Clinical Studies 
Kindly refer to the ipilimumab IB for clinical study updates. 
BMS and Medarex (acquired by BMS in Sep-2009) have co-sponsored an extensive clinical 
development program for ipilimumab, encompassing more than 19,500 subjects (total number of 
subjects enrolled in ipilimumab studies) in several cancer types in completed and ongoing 
studies, including a compassionate use. The focus of the clinical program is in melanoma, 
prostate cancer, and lung cancer, with advanced melanoma being the most comprehensively 
studied indication. Ipilimumab is being investigated both as monotherapy and in combination 
with other modalities such as chemotherapy, radiation therapy, and other immunotherapies. 
Phase 3 programs are ongoing in melanoma, prostate cancer, and lung cancer. In melanoma, 
completed Phase 3 studies (MDX010-20 and CA184024) have demonstrated a clinically 
meaningful and statistically significant survival benefit in pretreated advanced melanoma and 
previously untreated advanced melanoma with a manageable safety profile, respectively. An 
ongoing Phase 3 study (CA184029) in melanoma is investigating ipilimumab as adjuvant 
monotherapy for high-risk Stage III melanoma. In addition, a Phase 3 study (CA184169) 
comparing the safety and efficacy of 3 versus 10 mg/kg ipilimumab monotherapy in pretreated or 
treatment-naïve subjects with unresectable or metastatic melanoma is ongoing. 
The completed Phase 3 study (CA184043) evaluated ipilimumab in subjects with mCRPC who 
had progressed during or following treatment with docetaxel. Eligible subjects were randomized 
to a single dose of bone-directed RT, followed by either ipilimumab 10 mg/kg or placebo (799 
randomized: 399 ipilimumab and 400 placebo). This study did not meet its primary endpoint of 
OS. The HR of 0.85 (95% CI: 0.72, 1.00) for survival favored ipilimumab but did not reach 
statistical significance with a P value of 0.053. Planned sensitivity analyses favored ipilimumab, 
where the greatest benefit appeared to be in subgroups defined by good prognostic features and 
low burden of disease. Additional evidence of ipilimumab activity observed in the study included 
a reduced risk of disease progression relative to placebo (HR = 0.70), superior clinical outcomes 


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compared to placebo in tumor regression, and declines in PSA. The safety profile in this study 
was consistent with the previously defined AE profile at the same dose. 
A second Phase 3 study (CA184095) evaluated ipilimumab 10 mg/kg versus placebo in subjects 
with asymptomatic or minimally symptomatic, chemotherapy-naïve mCRPC with no visceral 
metastases. 
Activity was also observed in a large Phase 2 study in lung cancer (NSCLC and SCLC; 
CA184041) in combination with chemotherapy. Two ongoing Phase 3 studies are evaluating 
ipilimumab in combination with chemotherapy in squamous NSCLC (CA184104) and SCLC 
(CA184156). In Study CA184104, the last patient, last visit was achieved in June-2015, and 
database lock occurred on 01-Sep-2015. No final data are currently available, but preliminary 
data indicate that no new safety concerns were identified in the course of standard clinical safety 
monitoring of the study. In Study CA184156, preliminary data indicate the primary endpoint of 
prolonging survival was not achieved, but no new safety signals were identified. 
While the types of safety events observed in subjects receiving ipilimumab do not appear to 
change, even in combination with other anti-cancer agents, the proportion of subjects 
experiencing 1 type or another irAE may be impacted by the choice of combination partner. Skin 
and GI irAEs predominate in monotherapy studies. In combination with DTIC (melanoma), the 
incidence of skin and GI irAEs was lower than expected, and the incidence of hepatic irAEs was 
higher. In combination with paclitaxel and carboplatin (NSCLC), the incidence of all types of 
irAEs appeared to be numerically lower compared to the incidence observed for ipilimumab 
monotherapy in the Phase 2 program. In a Phase 1 study (CA184161), the concomitant 
administration of vemurafenib and ipilimumab in subjects with BRAF-mutated metastatic 
melanoma resulted in asymptomatic and reversible increases in aspartate aminotransferase (AST) 
and alanine aminotransferase (ALT), exceeding the incidence to be expected when either agent is 
administered as a single agent therapy, leading to discontinuation of this treatment. In a Phase 2 
study (CA184240), sequential treatment with vemurafenib followed by 10 mg/kg ipilimumab in 
subjects with BRAF-mutated metastatic melanoma was tolerable with a manageable safety 
profile. No significant signals of hepatobiliary toxicity were reported. The benefit/risk of this 
sequence needs to be evaluated further based on individual subject characteristics and new 
treatment options. 
Ipilimumab is also being evaluated in clinical studies conducted independently by the Cancer 
Therapy Evaluation Program of the US NCI, as well as in several additional externally- 
sponsored studies. 
 
2.6 Nivolumab 
2.6.1 
Nivolumab Clinical Pharmacodynamics 
The clinical pharmacodynamics (PD) were assessed for nivolumab monotherapy and for 
nivolumab in combination with ipilimumab. 
The PD effects of nivolumab were studied by assessing receptor occupancy (RO), peripheral 
immune cell population modulation, systemic cytokine modulation, and change in absolute 
lymphocyte count (ALC) in studies MDX1106-03 and/or CA209009. Results were as follows: 
• Peripheral RO of PD-1 is saturated at doses ≥0.3 mg/kg dose levels as measured on 
CD3+ cells from frozen and fresh PBMCs. 


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• Nivolumab treatment had no clinically meaningful changes in activated T-cells in 
peripheral blood; no dose response was evident. 
• Mean ALC measured over time did not change at any nivolumab dose nor was it 
associated with response to nivolumab. 
• Baseline measurements of select immune cell subsets were not associated with response 
to nivolumab. 
• Median percent increase from baseline to post-dose for CXCL9 and CXCL10 were 
consistent with demonstration of immunomodulatory activity of nivolumab on these 
chemokines. 
 
To understand if the effect of nivolumab in combination with ipilimumab was distinct from that 
of either nivolumab or ipilimumab monotherapy, changes in immunomodulatory PD biomarkers 
with combination nivolumab and ipilimumab treatment was assessed in study CA209004. ALC, 
activated CD4+ and CD8+ T cells in the periphery, and levels of inflammatory cytokines were 
measured in blood and serum in CA209004. Results were as follows: 
• No consistent rise in ALC was observed with combination nivolumab and ipilimumab 
therapy, similar to nivolumab monotherapy. 
• Increases in activated CD4+ and CD8+ T cells were observed with the combination 
regimen, consistent with the pharmacodynamic effects of ipilimumab alone and distinct 
from the effects of nivolumab alone. 
• Combination therapy resulted in increases in interferon-γ induced serum cytokines, such 
as MIG (CXCL9) and IP-10 (CXCL10), which are also increased with single agent 
nivolumab. 
 
2.6.2 
Nivolumab Pharmacokinetics 
Single Dose Pharmacokinetics: Single-dose PK of nivolumab was studied in 39 subjects with 
cancer. The single-dose PK of nivolumab was linear and dose-proportional in the range of 0.3 
mg/kg to 10 mg/kg. The mean terminal T-HALF of nivolumab ranged between 17 and 25 days 
across the dose range of 0.3 mg/kg to 10 mg/kg. Geometric mean total clearance varied from 
0.13 mL/h/kg to 0.19 mL/h/kg, while mean volume of distribution varied between 83 mL/kg and 
113 mL/kg across doses. The clearance and half-life of nivolumab are consistent with that of 
IgG4. 
Multiple-dose Pharmacokinetics: The pharmacokinetics (PK) of nivolumab was studied in 
subjects over a dose range of 0.1 to 20 mg/kg administered as a single dose or as multiple doses 
of nivolumab every 2 or 3 weeks. Based on a population pharmacokinetic (PPK) analysis using 
data from patients with various tumor types, including melanoma, NSCLC, and RCC and a time 
varying CL model, nivolumab clearance was shown to decrease over time, with a median 
maximal reduction from baseline values of approximately 25% resulting in a geometric mean 
steady state clearance (CLss) (% coefficient of variation [CV%]) of 8.2 mL/h [53.9%]. The 
decrease in CLss is not considered to be clinically relevant. The geometric mean [CV%] volume 


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of distribution at steady state (Vss) is 6.8 L (27.3%), and elimination half-life (t1/2) is 25 days 
(77.5%). Steady-state concentrations of nivolumab were reached by approximately 12 weeks 
when administered at 3 mg/kg every 2 weeks, and systemic accumulation was approximately 
3.7-fold. The exposure to nivolumab increased dose proportionally over the dose range of 0.1 to 
10 mg/kg administered every 2 weeks. The clearance of nivolumab increased with increasing 
body weight. The PPK analysis suggested that the following factors had no clinically important 
effect on the clearance of nivolumab: age (29 to 87 years), gender, race, baseline LDH, PD-L1, 
solid tumor type, baseline tumor size, and hepatic impairment. Although ECOG status, baseline 
glomerular filtration rate (GFR), albumin, and body weight had an effect on nivolumab CL, the 
effect was not clinically meaningful. PPK analysis suggested that nivolumab CL in subjects with 
cHL was approximately 32% lower relative to subjects with NSCLC; however, the lower CL in 
cHL subjects was not considered to be clinically relevant as nivolumab exposure was not a 
significant predictor for safety risks for these patients. 
 
2.6.3 
Nivolumab Drug-Drug Interactions 
Although monoclonal antibodies are not direct inhibitors/inducers of metabolizing enzymes, 
recent literature reports suggest that therapeutic proteins that are modulators of cytokines may 
indirectly affect expression of cytochrome (CYP) enzymes. The indirect drug-drug interaction 
potential of nivolumab was assessed using systemic cytokine modulation data for cytokines 
known to modulate CYP enzymes, at single and multiple doses of 0.3 to 10 mg/kg Q3W from 
CA209009. 
There were no meaningful changes in cytokines known to have indirect effects on CYP enzymes 
across all dose levels of nivolumab (0.3, 2 and 10 mg/kg) during the course of treatment. This 
lack of cytokine modulation suggests that nivolumab has no or low potential for modulating CYP 
enzymes, thereby indicating a low risk of therapeutic protein-drug interaction. 
Nivolumab is an IgG4 monoclonal antibody, which is eliminated by mechanisms similar to that 
of other antibodies, namely by non-specific catabolism (mainly by enzymes in the 
reticuloendothelial system). These enzymes are not known to be inhibited or induced by drugs, 
and therefore it is unlikely that other drugs will have an impact on the PK of nivolumab. 
 
2.6.4 
Nivolumab Clinical Studies 
Nivolumab has demonstrated clinical activity in subjects with a variety of malignancies. Kindly 
refer to the nivolumab IB for clinical trial updates. 
Nivolumab monotherapy (OPDIVO™) was first approved on 04-Jul-2014 in Japan for 
unresectable melanoma and has since been approved in multiple countries, including the US and 
EU, and has been approved for several other indications (e.g., metastatic NSCLC, advanced 
RCC, cHL). Nivolumab is also approved in combination with ipilimumab (YERVOY™) for 
unresectable or metastatic melanoma in multiple countries, including the US and EU. 
In addition to the current approvals, nivolumab is currently being tested in the following clinical 
studies: 


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NSCLC: 
• CA209012: ongoing Phase 1 study with nivolumab in combination with ipilimumab, 
platinum-based chemotherapy or erlotinib in subjects with treatment-naive Stage IIIB/IV 
NSCLC 
• ONO-4538-04: completed Phase 1, open-label study of nivolumab in combination with 
chemotherapy in Japanese subjects with Stage IIIB/IV or recurrent NSCLC. 
RCC: 
• CA209016: ongoing Phase 1 dose-escalation study of nivolumab in combination with 
VEGFR-TKIs or ipilimumab in subjects with metastatic RCC 
cHL: 
• ONO-4538-15: completed, Phase 2 open-label study of nivolumab in Japanese subjects 
with relapsed or refractory cHL 
SCCHN: 
• CA209141: completed Phase 3, randomized, open-label study of nivolumab vs 
investigator’s choice therapy in recurrent or metastatic platinum-refractory SCCHN 
SCLC: 
• CA209032: ongoing Phase 1/2, open-label study of nivolumab monotherapy or 
nivolumab combined with ipilimumab in subjects with advanced or metastatic solid 
tumors, including SCLC 
Gastric Cancer: 
• ONO 12: Nivolumab (ONO-4538/BMS-936558) as Salvage Treatment After Second- or 
Later-Line Chemotherapy for Advanced Gastric or Gastroesophageal Junction Cancer 
(AGC): A Double-Blinded, Randomized, Phase 3 Trial 
Colorectal Cancer: 
• CA209142: ongoing Phase 2, open-label study of nivolumab monotherapy or nivolumab 
combined with ipilimumab in subjects with recurrent or metastatic microsatellite 
instability high (MSI-H) colorectal cancer 
 
 
2.7 Niraparib Plus Immune Checkpoint Blockade 
Niraparib has recently been combined with pembrolizumab in the phase I/II TOPACIO study 
(NCT02657889). Although this study is currently recruiting participants, the phase I portion is 
complete and the recommended Phase 2 dose of niraparib was established as 200 mg oral 
niraparib once daily. The most common treatment related grade ≥ 3 adverse events occurring in 
≥ 2 patients included anemia (35.7%), thrombocytopenia (35.7%), neutropenia (14.3%) and 
decreased platelet counts (14.3%). Data from the phase 2 is going and less than 7% of Phase 2 
patients had experienced grade ≥3 thrombocytopenia during the first treatment cycle. Thirty 
patients (36.1%) enrolled in Phase 2 reported treatment-related grade ≥3 adverse events 


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including anemia (8.4%), fatigue (6.0%), platelet count decrease (6.0%) and thrombocytopenia 
(6.0%)[15]. 
The final starting dose of 200 mg has been established. The starting dose could be reduced if 
additional data indicates that reduction of the starting dose may be warranted. 
We do not expect any overlapping toxicity between the combination of niraparib and nivolumab 
or niraparib and ipilimumab, given the known toxicities of these agents. Therefore, we chose 
full dose of checkpoint inhibition plus niraparib based on the available clinical data with PD-1. 
However, we have added a safety hold after 3 patients have enrolled for each arm to ensure that 
dose modifications do not need to be made. 
 
3 STUDY OBJECTIVES 
3.1 Primary Objective 
• Determine the clinical impact of combining PARP inhibition with immune checkpoint 
blockade in patients with advanced PDAC and durable platinum stability. 
• Establish the safety of this combination 
• Determine clinical efficacy as measured by the PFS rate at 6 months 
 
3.2 Secondary Objectives 
• To evaluate the efficacy by assessment of objective response (RECIST v.1.1) in those 
with measurable disease and objective response rate (ORR). 
• To evaluate overall survival (OS) 
 
4 INVESTIGATIONAL PLAN 
4.1 General Design 
This is a two arm, open-label randomized study of niraparib plus either ipilimumab or nivolumab 
in patients with locally advanced or metastatic pancreatic adenocarcinoma who have achieved 
stability on platinum-based therapy. 
Patients will be randomized to either Arm A (niraparib + nivolumab) or Arm B (niraparib + 
ipilimumab). No more than 6 patients will be treated over a 2-week period without approval of the 
Penn PI and Sponsor. During the DLT period after the third patient in each Arm is enrolled, 
enrollment will be suspended until the third patient has received the second dose of either 
nivolumab in Arm A or ipilimumab in Arm B on Cycle 2 Day 1. The first 3 weeks are considered 
the “DLT evaluation period”. 
 
4.1.1 
Screening Phase 
All patients will undergo screening assessments within 28 days prior to the first dose of therapy. 
AEs that occur after signing of the informed consent form and before administration of the first 
treatment dose will also be collected during this period. 


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Screening assessments will include demographics and medical history, family history, prior 
treatments for pancreatic cancer (and other malignancies if applicable), prior and current 
medications and procedures, ECOG performance status, hematology, whole blood sample for 
cytogenetic analysis, serum chemistry, serum pregnancy for women of childbearing potential, 
urinalysis, physical examination, vital signs, weight and height measurements, adverse events, 
and radiological assessment by CT or magnetic resonance imaging (MRI). For patients who pass 
the screening phase, a tumor biopsy prior to first dose of treatment will be collected from 
patients for whom this is deemed safe and feasible. Archival tumor tissue samples, if available, 
will also be collected and stored. 
All patients will have blood collected prior to treatment for correlative analyses and storage. 
 
4.1.2 
Study Intervention Phase 
During the treatment phase (continuous 28 day cycles (Arm A) or continuous 21 day cycles 
(Arm B)), patients will be monitored for safety and efficacy. Assessments during the treatment 
phase will include AEs, ECOG performance status, concomitant medications and procedures, 
physical examination, vital signs and weight measurements, hematology and serum chemistry, 
serum or urine pregnancy (per investigator discretion) for women of childbearing potential, CA 
19-9 measurement, blood samples for research analyses and study drug administration and 
accountability. An on-treatment tumor biopsy will be obtained if considered safe and feasible. A 
biopsy is not required if there appears to be no evidence of disease (complete remission). 
Patients will be assessed for disease status per RECIST v1.1 after every 2nd cycle of treatment 
(Arm A) or every 3rd cycle of treatment (Arm B). Patients will continue to receive treatment 
until disease progression or other reason for treatment discontinuation. 
Patients will be monitored continuously for safety. 
 
4.1.3 
Treatment Discontinuation 
Upon treatment discontinuation, all patients will return to the clinic for an End of Treatment 
(EOT) visit if they are able to. 
Assessments at this visit will include AEs, ECOG performance status, concomitant medications 
and procedures, physical examination, vital signs and weight measurements, hematology and 
serum chemistry, serum pregnancy for women of childbearing potential, CA 19-9 measurement, 
research blood sample for research analyses, whole blood sample for cytogenetic analysis, 
disease status assessment and study drug accountability. 
 
4.1.4 
Follow Up Phase 
Patients who received nivolumab (Arm A) will have a 100 day follow-up period for AEs 
following the last dose of study treatment. Patients who received ipilimumab (Arm B) will have 
a 90-day follow-up period for AEs following the last dose of study treatment. Please refer to the 
study calendar for details. 
CT scans at 30-day follow-up should also be performed for patients who discontinued treatment 
for reason other than disease progression and did not have a radiologic assessment at the End of 
Treatment visit. After the 30-day follow-up visit, patients will be followed for until 90, or 100 
days post treatment depending on drugs administered and then for adverse events of special 


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interests and survival annually until death, loss to follow-up, withdrawal of consent or until 5 
years have passed, whichever occurs first. 
 
Once the Primary Study Endpoints are met, there will be no follow-up for the subjects receiving 
study treatment under compassionate use.  For subjects in long-term follow-up, the follow-up 
period will end once the study is complete. 
 
4.1.5 
Study Schema 
 
 
4.1.6 
End of Study 
The study will be complete when the Primary Study Endpoints are met and the active subjects 
transition to receiving therapy under compassionate use in a clinical setting. 
 
4.2 Study Endpoints 
4.2.1 
Primary Study Endpoints 
The primary study endpoint will be progression-free survival at 6 months (PFS6) defined as the 
time from randomization to the occurrence of disease progression according to RECIST v1.1, as 
assessed by the investigator, or death from any cause. Patients who are alive and progression-free 


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will be censored on the most recent date that documents progression-free status (i.e. scan date or 
clinic visit date). The PFS6 will be determined from the Kaplan-Meier curve. 
Evaluation of safety and tolerability of this combination as determined by CTCAE v5.0. 
 
4.2.2 
Secondary Study Endpoints 
The secondary endpoints include: 
• Evaluation of safety and tolerability of this combination as determined by CTCAE v5.0. 
• Overall response rate (ORR) by RECIST v.1.1 in those with measurable disease. 
• Overall survival (OS) as defined by the time from start of study therapy to death due to 
any cause. Patients who are alive will be censored on the most recent date of patient 
contact. 
• The incidence of adverse events (AEs), clinical laboratory abnormalities and dose 
modifications. 
 
 
5 STUDY POPULATION AND DURATION OF PARTICIPATION 
5.1 Inclusion Criteria 
Eligible patients must meet the following inclusion criteria: 
• Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma with 
locally advanced or metastatic disease 
• ≥18 years of age. 
• Patients must be able to understand the study procedures and agree to participate in the 
study by providing written informed consent 
• Patients must have received treatment with platinum-based (cisplatin, oxaliplatin or 
carboplatin) treatment for locally advanced or metastatic pancreatic cancer and have 
received a minimum of 16 weeks of therapy without evidence of disease progression 
based on the investigator’s opinion. This does not have to be the patient’s current 
treatment. 


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− Note: This requires at least stable imaging and a stable or decreasing tumor marker as 
applicable and as determined by the investigator. 
− If a patient has demonstrated a biochemical and imaging response to platinum therapy 
and has not progressed within 16 weeks of starting this therapy but had to discontinue 
platinum prior to 16 weeks for a legitimate medical reason (as determined by the 
investigator), the patient may still be considered for the trial 
• Patients may have previously failed non-platinum containing therapy or may never have 
previously progressed on treatment. 
− Discontinuation of the platinum component of the regimen for chemotherapy-related 
toxicity is permissible provided the patient has previously received at least 16 weeks of 
platinum-based therapy without evidence of disease progression ≤8 weeks after treatment 
with the platinum agent 
• Measurable disease is not a requirement for study entry. 
• Female participant has a negative serum pregnancy test within 24 hours prior to taking 
study treatment if of childbearing potential and agrees to abstain from activities that 
could result in pregnancy from screening through 6 months after the last dose of study 
treatment, or is of nonchildbearing potential (see Section 5.3). 
• Male patient agrees to use an adequate method of contraception starting with the first 
dose through 90 days after the last dose of study treatment (see Section 5.3). 
• Adequate organ function confirmed by the following laboratory values obtained ≤7 days 
prior to the first day of study therapy: 
− Absolute neutrophil count (ANC) ≥1.5 x 109/L 
− Platelets>100 x 109/L 
− Hemoglobin ≥9g/dL 
− Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 x upper 
limit of normal (ULN); if liver metastases, then ≤5 x ULN 
− Total bilirubin ≤1.5 x ULN; if liver metastases or metabolic disorder such as Gilbert’s 
syndrome, then ≤2.5 x ULN. 
− Serum creatinine ≤1.5 x ULN or estimated glomerular filtration rate (GFR) ≥45 
mL/min using Cockcroft Gault formula. 
• Eastern Cooperative Oncology (ECOG) performance status of 0 to 1. 
 
 
5.2 Exclusion Criteria 
Patients will be excluded from participation if any of the following criteria apply: 
• Prior treatment with a PARP inhibitor, ipilimumab, nivolumab or other cytotoxic T- 
lymphocyte-associated protein (CTLA-4), PD-1 or PD-L1 inhibitor. 


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• Patients who have demonstrated resistance to platinum agents (e.g. oxaliplatin, cisplatin) 
are not eligible to participate in this study 
• Clinical evidence of uncontrolled malabsorption and/or any other gastrointestinal 
disorder or defect that would, in the opinion of the investigator, interfere with the 
absorption of niraparib 
• Acute infection requiring intravenous antibiotics, antiviral or antifungal agents during the 
14 days prior to first dose of study therapy 
• Patients will be excluded if they have an active, known or suspected autoimmune disease, 
defined as: patients with a history of inflammatory bowel disease are excluded from this 
study, as are patients with a history of symptomatic autoimmune disease (e.g. rheumatoid 
arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, 
autoimmune vasculitis e.g. Wegener’s Granulomatosis); motor neuropathy considered of 
autoimmune origin (e.g. Guillain-Barre Syndrome). 
NOTE: Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, 
residual hypothyroidism due to autoimmune condition only requiring hormone 
replacement, psoriasis not requiring systemic treatment, or conditions not expected to 
recur in the absence of an external trigger. 
• Has a history of interstitial lung disease or active, non-infectious pneumonitis 
• Has received a live vaccine within 4 weeks prior to the first dose of trial therapy 
(Note: seasonal influenza vaccines for injection are generally inactivated and are allowed; 
however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and 
are not allowed). 
• For fertile patient (female able to become pregnant or male able to father a child), refusal 
to use effective contraception during the period of the trial and: 
− Female patients refusing to use effective contraception for 6 months after the last 
dose of study drug. 
− Male patients refusing to use effective contraception for 90 days after the last dose of 
study drug. 
• Received any systemic treatment for pancreatic cancer ≤14 days prior to first dose of 
therapy. 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 
• Patients will be excluded if they have a condition requiring systemic treatment with either 
corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days of study drug administration. Inhaled or topical steroids and 
adrenal replacement doses >10mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease. 
• Patient 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. 


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• Non-study related minor surgical procedure ≤5 days, or major surgical procedure ≤21 
days, prior to the first dose of therapy; in all cases, patients must be sufficiently recovered 
and stable before treatment administration. 
• Active drug or alcohol use or dependence that would interfere with study compliance. 
• Presence of any other condition that may increase the risk associated with study 
participation or may interfere with the interpretation of study results, and, in the opinion 
of the investigator, would make the patient inappropriate for entry into the study. 
• Patient must not have any known history of myelodysplastic syndrome (MDS) or acute 
myeloid leukemia (AML) 
• Patients must not be simultaneously enrolled in any therapeutic clinical trial 
• Patients must not have had radiotherapy within 4 weeks of the first dose of study 
treatment 
• Patients must not have a known hypersensitivity to the components of niraparib or the 
excipients 
• Patients must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks of 
the first dose of study treatment 
• Patients must not be undergoing treatment for an active cancer at the time of 
randomization. Exceptions include: local therapies for skin cancers and hormonal 
therapies for breast or prostate cancer who have no evidence of active disease. 
• Patients must not have a history of positive test for human immunodeficiency virus (HIV) 
or known acquired immunodeficiency syndrome (AIDS), and must not test positive for 
HIV during study screening. 
• Patients must not have known, symptomatic brain or leptomeningeal metastases 
 
 
5.3 Patients or Partners of Patients with Reproductive Potential 
Niraparib, nivolumab and ipilimumab should not be used during pregnancy or in women of 
childbearing potential not using reliable contraception. 
Women of childbearing potential (WOCBP) should not become pregnant while on niraparib, 
nivolumab or ipilimumab and may not be pregnant at the beginning of treatment. 
Pregnancy Testing: A pregnancy test should be performed on all WOCBP within 3 days prior to 
treatment. 
Contraception: WOCBP must use effective contraception during niraparib, nivolumab and 
ipilimumab therapy and for 6 months after receiving the last dose of study treatment. 
Acceptable methods of birth control include: 
• Two highly effective forms of contraception, defined as contraceptive methods with a 
failure rate of less than 1% per year when used consistently and correctly. Patients and 


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their sexual partners who’ve undergone vasectomy or tubal occlusion must also use a 
male condom with spermicide. 
• Permanent sterilization, defined as hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy, or bilateral orchidectomy 
• Postmenopausal, defined as a female patient or sexual partner >45 years of age who has 
not menstruated for at least 12 consecutive months 
• Total sexual abstinence 
 
Males who are sexually active with WOCBP must agree to follow instructions for method(s) of 
contraception for the duration of study treatment and 90 days after the last dose of study 
treatment. 
Patients must not breast-feed from the first dose of study drug and for 30 days following the final 
dose of niraparib or 3 months following the final dose of ipilimumab. 
 
5.4 Total Number of Subjects and Sites 
A total of 84 evaluable subjects will be enrolled at the University of Pennsylvania. 
 
5.5 Vulnerable Populations 
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study. 
 
6 STUDY INTERVENTION 
Oral niraparib plus either intravenous ipilimumab or intravenous nivolumab 
 
6.1 Description 
6.1.1 
Niraparib 
For complete details regarding Niraparib, please refer to the Investigator’s Brochure. 
Niraparib starting dose will be 200mg PO daily. 
Niraparib is an orally available, selective PARP1 and -2 inhibitor. 
The chemical name for niraparib is 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7- 
carboxamide 4-methylbenzenesulfonate hydrate (1:1:1). The empirical molecular formula for 
niraparib is C26H30N4O5S and its molecular weight is 510.61. 
Niraparib tosylate monohydrate drug substance is a white to off-white, non-hygroscopic 
crystalline solid. Niraparib solubility is pH independent below the pKa of 9.95, with an aqueous 
free base solubility of 0.7 mg/mL to 1.1 mg/mL across the physiological pH range. 
Niraparib is supplied in HDPE bottles with child resistant closures. 
Niraparib does not contain gluten. 


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6.1.2 
Nivolumab 
For complete details regarding nivolumab, please refer to the Investigator’s Brochure and FDA 
approved label. 
Nivolumab dose will be 480mg IV every four weeks over a 30 minute period. Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible. However, given 
the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (ie, 
infusion time is 30 minutes: -5mn/+10min). 
Nivolumab, also referred to as BMS-936558-01 or BMS-936558, is a soluble protein consisting 
of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical light chains. The 
physical and chemical properties of nivolumab are provided below. 
 
BMS Number 
BMS-936558-01 
Other Names 
Nivolumab, BMS-936558, MDX1106, ONO-4538, anti-PD-1 
Molecular Weight 
146,221 daltons (143,619.17 daltons, protein portion) 
Appearance 
Clear to opalescent, colorless to pale yellow liquid, light (few) particulates may be 
present 
Solution pH 
5.5 to 6.5 
 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) 
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is a clear to opalescent, colorless to pale 
yellow liquid, which may contain light (few) particulates. The drug product is a sterile, non- 
pyrogenic, single-use, isotonic aqueous solution formulated at 10 mg/mL in sodium citrate, 
sodium chloride, mannitol, diethylenetriaminepentacetic acid (pentetic acid), and polysorbate 80 
(Tween© 80), pH 6.0 and includes an overfill to account for vial, needle, and syringe holdup. It 
is supplied in 10-cc Type I flint glass vials, stoppered with butyl rubber stoppers and sealed with 
aluminum seals. The only difference between the two drug product presentations is the vial fill 
volume. 
Drug Product Preparation: Nivolumab Injection, 100 mg/10 mL (10 mg/mL). Nivolumab 
injection is to be administered as an IV infusion through a 0.2-micron to 1.2-micron pore size, 
low-protein binding (polyethersulfone membrane) in-line filter at the protocol specified doses 
and infusion times. It is not to be administered as an IV push or bolus injection. Nivolumab 
injection can be infused undiluted (10 mg/mL) or diluted with 0.9% Sodium Chloride Injection, 
USP or 5% Dextrose Injection, USP to protein concentrations as low as 0.35 mg/mL. During 
drug product preparation and handling, vigorous mixing or shaking is to be avoided. Instructions 
for dilution and infusion of nivolumab injection may be provided in the clinical protocol, 
pharmacy binder, pharmacy manual, or pharmacy reference sheet. Care must be taken to assure 
sterility of the prepared solution as the product does not contain any antimicrobial preservative or 
bacteriostatic agent. Nivolumab infusions are compatible with polyvinyl chloride (PVC) or 
polyolefin containers and infusion sets, and glass bottles. 
 
6.1.3 
Ipilimumab 
For complete details regarding ipilimumab, please refer to the Investigator’s Brochure and FDA 
approved label. 


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Ipilimumab dose will be 3mg/kg IV every 3 weeks over a 30-minute period. Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible. However, given 
the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5mn/+10min). 
Ipilimumab (BMS-734016, MDX-010) is a fully human IgG1κ consisting of 4 polypeptide 
chains; 2 identical heavy chains primarily consisting of 447 amino acids each with 2 identical 
kappa light chains consisting of 215 amino acids each linked through inter-chain disulfide bonds. 
The physical and chemical properties of ipilimumab drug substance are provided in the table 
below. 
 
BMS Number 
734016 
Molecular Weight 
147,991 Daltons 
Appearance 
Clear to slightly opalescent, colorless to pale yellow liquid, may contain particles 
Solution pH 
7.0 
pI 
The isoelectric focusing analysis generates a banding pattern in the pI range of 8.5 to 
8.8, with the major isoform at an approximate pI of 8.7. 
 
Ipilimumab injection, 200 mg/40 mL (5 mg/mL), is formulated as a clear to slightly opalescent, 
colorless to pale yellow, sterile, non-pyrogenic, single-use, isotonic aqueous solution that may 
contain particles. Ipilimumab injection, 50 mg/10 mL or 200 mg/40 mL, is supplied in 10-cc or 
50-cc Type I flint glass vials, respectively, stoppered with gray butyl stoppers and sealed with 
aluminum seals. The drug product is formulated at a concentration of 5 mg/mL at a pH of 7.0. 
 
6.1.4 
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab 
Long infusion times place a burden on patients and treatment centers. It is now established that 
nivolumab and ipilimumab can be safely administered using shorter infusion times of 
30 minutes’ duration. This will limit the burden to patients. 
Previous clinical studies of nivolumab and ipilimumab monotherapies and the combination of 
nivolumab and ipilimumab have used a 60-minute infusion duration for nivolumab and a 
90-minute infusion duration for ipilimumab (1 - 3 mg/kg dosing for both). However, both 
nivolumab and ipilimumab have been administered at up to 10 mg/kg with the same infusion 
duration (i.e., 60 minutes). However, recent data has shown that ipilimumab can be safely 
administered over a 30 minute period with acceptably low incidence of infusion related reactions 
[16]. 
Nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg over a 
long treatment duration. In subjects with advanced/metastatic clear cell RCC, a dose association 
was observed for infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% 
at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1/2 and were manageable. An 
infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) 
is not expected to present any safety concerns compared to the prior experience at 10 mg/kg 
nivolumab dose infused over a 60-minute duration. 
Overall, a change in safety profile is not anticipated with 30-minute infusions of nivolumab, or 
ipilimumab. 


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6.2 Intervention Regimen 
6.2.1 
Niraparib + Nivolumab (Arm A) 
Niraparib 200mg PO daily on days 1-28 of each 28-day cycle. 
Nivolumab 480mg IV day 1 of each cycle 
6.2.2 
Niraparib + Ipilimumab (Arm B) 
Niraparib 200mg PO daily on days 1-21 of each 21-day cycle. 
Ipilimumab 3mg/kg IV day 1 of each cycle, for the first 4 cycles only. 
6.2.3 
DLT Definition and De-Escalation Decision Process (for Phase I Portion) 
For Arm A and Arm B, dose limiting toxicities (DLTs) will be defined by toxicity occurring 
during the first 3 weeks of the study. A DLT will be considered as any non-hematologic AE of 
Grade 3 or higher that is at least possibly treatment-related with the exception of Grade 3 or 
higher nausea and vomiting which have not been treated with optimal anti-emetic therapy or 
Grade 3 or higher hypertension that has not been treated with optimal anti-hypertensive therapy. 
The following hematologic DLT will be considered if any occurs in the first cycle: 
• A grade 4 neutropenia lasting >7 days 
• Febrile neutropenia 
• Platelet count of <10,000/mm3 
 
Any DLT that causes a patient to miss >28 consecutive days of niraparib therapy will result in 
the patient being taken off treatment. 
Cohort Expansion and Dose Reduction For Arm A or Arm B: If a DLT is observed in 1 or 
fewer patients in the first cohort of 3 patients, an additional 3 patients will be enrolled on that 
arm. If a DLT occurs in 2 or more patients within that cohort, then the dose of niraparib will be 
lowered as according to the table below. If <2/6 subjects experience a DLT, then this dose will 
then be declared as the MTD. No dose escalations are planned. Patients will be evaluable for 
toxicity if they have taken at least one dose of niraparib. 
Table 1. 
Phase IB Portion: Niraparib Criteria for Dose De-Escalation and Cohort 
Size 
 
Number of patients with DLT 
Rule 
0-1/3 DLT 
Increase cohort to 6 patients 
≥2/3 DLT 
De-escalate dose, enroll 6 patients 
If the cohort size is increased to 6 patients, the following rules apply 
Number of patients with DLT 
Rule 
<1/6 DLT 
Current dose is the MTD 
≥2/6 DLT 
De-escalate dose, enroll 6 patients 
 


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6.2.4 
Starting Dose and Dose Modifications of Protocol-Specified Treatment 
6.2.4.1 
Niraparib 
The starting dose of niraparib will be 200mg PO daily on days 1-28 of each 28-day cycle (Arm 
A) and 200mg PO daily on days 1-21 of each 21-day cycle (Arm B). 
Table 2. 
Recommended Niraparib Dose Reductions for Adverse Reactions 
 
Dose Level 
Dose 
Starting Dose 
200mg/day 
First (and only) Dose Reduction 
100mg/day 
 
Refer to Section 6.2.5.1 for specific instructions regarding Niraparib dose modifications. 
Patients may not re-escalate once they have been dose reduced. 
 
6.2.4.2 
Nivolumab 
The starting dose of nivolumab will be 480mg IV on day 1 of each 28 day cycle 
There are no recommended dose reductions for nivolumab. Refer to Section 6.2.5.2 for specific 
instructions regarding when to hold and restart therapy for adverse reactions. 
 
6.2.4.3 
Ipilimumab 
The starting dose of ipilimumab will be 3mg/kg IV on days 1 of each 21-day cycle. 
There are no recommended dose reductions for ipilimumab. Refer to Section 6.2.5.2 for specific 
instructions regarding when to hold and restart therapy for adverse reactions. 
 
6.2.5 
Dose Modification Criteria and Criteria for Stopping Treatment 
Dose adjustments are for AEs deemed related to the study medications. If, in the opinion of the 
treating Investigator, a toxicity is thought to be unrelated to study medications and resolves to a 
“Continue” or below lowest grade, no dose adjustments for the study medications are necessary. 
For any toxicity leading to discontinuation of Niraparib, Nivolumab or Ipilimumab as described 
below, subjects may continue on the other study agent with approval of the PI. 
For any toxicity (regardless of grade) that, despite optimal supportive care, is felt by the treating 
Investigator to present a risk to the patient safety, additional dose reduction, treatment delay, or 
treatment discontinuation is permitted at the discretion of the treating Investigator. 
6.2.5.1 
Niraparib Dose Modifications 
Table 3. 
Niraparib Dose Modification for Non-hematologic Adverse Reactions 
 
Non-hematologic CTCAE* ≥ Grade 3 treatment- 
related adverse reaction where prophylaxis is not 
considered feasible or adverse reaction event 
persists despite treatment 
Withhold niraparib for a maximum of 28 days or until 
resolution of adverse reaction. 
Resume niraparib at a reduced dose as per Section 6.2.4.1. 
One dose reduction is permitted. 
CTCAE ≥ Grade 3 treatment-related adverse 
reaction event lasting more than 28 days while 
patient is administered niraparib 100 mg/day 
Discontinue medication. 
*CTCAE = Common Terminology Criteria for Adverse Events 


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Table 4. 
Niraparib Dose Modifications for Hematologic Adverse Reactions 
 
Test complete blood counts weekly for the first month, monthly for the next 11 months of treatment and 
periodically after this time. Medical and supportive therapy should be optimized for management of toxicities. 
Platelet count <100,000/µL 
First occurrence: 
Withhold niraparib for a maximum of 28 days and monitor blood counts 
weekly until platelet counts return to ≥100,000/µL. 
Resume niraparib at same or reduced dose per Section 6.2.4.1. 
If platelet count is <75,000/µL, resume at a reduced dose. 
Second occurrence: 
Withhold niraparib for a maximum of 28 days and monitor blood counts 
weekly until platelet counts return to ≥100,000/µL. 
Resume niraparib at a reduced dose. 
Discontinue niraparib if the platelet count has not returned to acceptable levels 
within 28 days of the dose interruption period, or if the patient has already 
undergone dose reduction to 100 mg QD. 
Neutrophil <1,000/µL 
Withhold niraparib for a maximum of 28 days and monitor blood counts 
weekly until neutrophil counts return to ≥1,500/µL. 
Resume niraparib at a reduced dose. 
Discontinue niraparib if neutrophil level has not returned to acceptable levels 
within 28 days of the dose interruption period, or if the patient has already 
undergone dose reduction to 100 mg QD. 
Hemoglobin <8 g/dL 
Withhold niraparib for a maximum of 28 days and monitor blood counts 
weekly until hemoglobin returns to ≥9 g/dL. 
Resume niraparib at a reduced dose. 
Discontinue niraparib if hemoglobin has not returned to acceptable levels 
within 28 days of the dose interruption period, or if the patient has already 
undergone dose reduction to 100 mg QD. 
Hematologic adverse reaction 
requiring transfusion or 
hematopoietic growth factor 
support 
For patients with platelet count ≤10,000/μL, platelet transfusion should be 
considered. If there are other risk factors such as co-administration of 
anticoagulation or antiplatelet drugs, consider interrupting these drugs and/or 
transfusion at a higher platelet count. 
Resume niraparib at a reduced dose. 
Confirmed diagnosis of MDS* 
or AML† 
Permanently discontinue niraparib. 
*MDS = myelodysplastic syndrome 
†AML = acute myeloid leukemia 
 
If dose interruption or modification is required at any point on study because of hematologic 
toxicity, weekly blood draws for CBC will be monitored until the AE resolves, and to ensure 
safety of the new dose, weekly blood draws for CBC also will be required for an additional 4 
weeks after the AE has been resolved to the specified levels, after which monitoring every 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. 


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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. 
6.2.5.2 
Nivolumab and Ipilimumab Dose Modifications 
Table 5. 
GI Adverse Event Management Algorithm for Nivolumab and Ipilimumab 
 
Grade of Diarrhea/Colitis 
(CTCAE v5) 
Management 
Follow-up 
Grade 1 
Diarrhea: <4 stools/day over 
baseline 
Colitis: asymptomatic 
• 
Continue immunotherapy 
(I-O) per protocol 
• Symptomatic treatment 
• Close monitoring for worsening of 
symptoms 
• Educate patient to report worsening 
immediately 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated 
<24 hrs; not interfering with 
ADL 
Colitis: abdominal pain; blood in 
stool 
• Hold I-O therapy 
• Symptomatic treatment 
If improves to grade 1: 
• Resume I-O therapy per protocol 
If persists > 5-7 days or recur: 
• 0.5-1.0 mg/kg/day methylprednisolone 
or oral equivalent 
• When symptoms improve to grade 1, 
taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume I- 
O therapy per protocol. 
If worsens or persists > 3-5 days with oral 
steroids: 
• Treat as Grade 3/4 
Grade 3-4 
Diarrhea (G3): ≥7 stools per day 
over baseline; incontinence; IV 
fluids ≥24 hrs; interfering with 
ADL 
Colitis (G3): severe abdominal 
pain, medical intervention 
indicated, peritoneal signs 
G4: life-threatening, perforation 
• Discontinue I-O therapy per 
protocol 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics 
for opportunistic infections 
• Consider lower endoscopy 
If improves: 
• Continue steroids until grade 1, then 
taper over at least 1 month 
If persists > 3-5 days, or recurs after 
improvement: 
• Add infliximab 5 mg/kg (if no 
contraindication). 
Note: Infliximab should not be used in 
cases of perforation or sepsis 
 


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Table 6. 
Renal Adverse Event Management Algorithm for Nivolumab and 
Ipilimumab 
 
Grade of Creatinine Elevation 
(CTCAE v5) 
Management 
Follow-Up 
Grade 1 
Creatinine >ULN and > than 
baseline but ≤1.5x baseline 
• Continue I-O therapy per 
protocol 
• Monitor creatinine weekly 
If returns to baseline: 
• Resume routine creatinine 
monitoring per protocol 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2-3 
Creatinine > 1.5x baseline to 
≤6x ULN 
• Hold I-O therapy 
• Monitor creatinine every 2-3 
days 
• 0.5-1.0 mg/kg/day 
methylprednisolone IV or oral 
equivalent 
• Consider renal biopsy with 
nephrology consult 
If returns to Grade 1: 
Taper steroids over at least 1 
month, consider prophylactic 
antibiotics for opportunistic 
infections, resume I-O therapy and 
routine creatinine monitoring per 
protocol. 
If elevations persist> 7 days or 
worsen: 
• Treat as Grade 4 
Grade 4 
Creatinine >6x ULN 
• Discontinue I-O therapy per 
protocol 
• Monitor creatinine daily 
• 1.0-2.0mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Consult nephrology 
• Consider renal biopsy 
If returns to Grade 1: 
• Taper steroids over at least 1 
month and add prophylactic 
antibiotics for opportunistic 
infections. 
 


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Table 7. 
Pulmonary Adverse Event Management Algorithm for Nivolumab and 
Ipilimumab 
 
Grade of Pneumonitis 
(CTCAE v5) 
Management 
Follow-Up 
Grade 1 
Radiographic changes only 
• Consider holding I-O therapy 
• Monitor for symptoms every 2-3 
days 
• Consider Pulmonary and ID 
consults 
• Re-image at least every 3 weeks 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
Mild to moderate new symptoms 
• Hold I-O therapy 
• Pulmonary and ID consults 
• Monitor symptoms daily, 
consider hospitalization 
• 1.0mg/kg/day 
methylprednisolone IV or oral 
equivalent 
• Consider bronchoscopy, lung 
biopsy 
• Re-image every 1-3 days 
If improves: 
• When symptoms return to near 
baseline, taper steroids over at 
least 1 month and then resume I- 
O therapy per protocol and 
consider prophylactic antibiotics 
If not improving after 2 weeks or 
worsening: 
• Treat as Grade 3-4 
Grade 3-4 
Severe new symptoms; 
New/worsening hypoxia; Life- 
threatening 
• Discontinue I-O therapy per 
protocol 
• Hospitalize 
• Pulmonary and ID consults 
• 2-4mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider bronchoscopy, lung 
biopsy 
If improves to baseline: 
• Taper steroids over at least 6 
weeks 
If not improving after 48 hours or 
worsening: 
• Add additional 
immunosuppression 
 


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Table 8. 
Hepatic Adverse Event Management Algorithm for Nivolumab and 
Ipilimumab 
 
Grade of Liver Test* Elevation 
(CTCAE v5) 
Management 
Follow-Up 
Grade 1 
AST or ALT >ULN – 3x ULN 
and/or T.bili >ULN – 1.5x ULN 
• Continue I-O therapy per 
protocol 
• Continue LFT monitoring per 
protocol 
If worsens: 
• Treat as Grade 2 or Grade 3-4 
Grade 2 
AST or ALT > 3x to ≤5x ULN 
and/or T.bili >1.5 to ≤ 3x ULN 
• Hold I-O therapy 
• Increase frequency of monitoring 
to every 3 days 
If returns to baseline: 
• Resume routine monitoring, 
resume I-O therapy per protocol 
If elevation persists >5-7 days or 
worsens: 
• 0.5-1mg/kg/day 
methylprednisolone or oral 
equivalent and when LFT returns 
to grade 1 or baseline, taper 
steroids over at least 1 months, 
consider prophylactic antibiotics 
for opportunistic infections, and 
resume I-O therapy per protocol 
Grade 3-4 
AST or ALT > 5x ULN or T.bili 
>3x ULN 
• Discontinue I-O therapy** 
• Increase frequency of monitoring 
to every 1-2 days 
• 1.0-2.0mg/kg/day 
methylprednisolone IV or IV 
equivalent*** 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consult gastroenterologist 
If returns to grade 2: 
• Taper steroids over at least one 
month 
If does not improve in >3-5 days, 
worsens or rebounds: 
• Add mycophenolate mofetil 1g 
BID 
• If no response within an 
additional 3-5 days, consider 
other immunosuppressants per 
local guidelines. 
* Exceptions/Notes: 
• If a subject has a baseline AST or ALT that is within normal limits, delay dosing for drug-related Grade ≥ 2 
toxicity (2 grade shift) 
• If a subject has baseline AST or ALT within the Grade 1 toxicity range, delay dosing for drug-related Grade ≥ 
3 toxicity (2 grade shift) 
• If a subject has baseline AST or ALT within the Grade 2 toxicity range, delay dosing for a two-fold drug- 
related increase in AST or ALT or for AST or ALT values 8x ULN (whichever is lower). 
 
**I-O therapy may be delayed rather than discontinued if AST/ALT ≤8x ULN or T.bili ≤5x ULN 
***The recommended starting dose for grade 4 hepatitis is 2mg/kg/day methylprednisolone IV. 
 


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Table 9. 
Endocrinopathy Management Algorithm for Nivolumab and Ipilimumab 
 
Asymptomatic TSH Elevation 
• Continue I-O therapy per protocol 
• If TSH <0.5x LLN or TSH > 2x ULN, or consistently out of range in 2 
subsequent measurements: include fT4 at subsequent cycles as clinically 
indicated; consider endocrinology consult 
Symptomatic Endocrinopathy 
• Evaluate endocrine function 
• Consider pituitary scan 
Symptomatic with abnormal 
labs/pituitary scan: 
• Hold I-O therapy 
• 1-2mg/kg/day 
methylprednisolone IV or PO 
equivalent 
• Initiate appropriate hormone 
therapy 
No abnormal lab/pituitary MRI scan 
but symptoms persist: 
• Repeat labs in 1-3 weeks/MRI in 
1 month 
If improves (with or without 
hormone replacement): 
• Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
infections 
• Resume I-O therapy per protocol 
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component 
Suspicion of Adrenal Crisis (eg 
severe dehydration, hypotension, 
shock out of proportion to 
current illness) 
• Hold or discontinue I-O therapy per protocol 
• Rule out sepsis 
• Stress dose IV steroids with mineralocorticoid activity 
• IV fluids 
• Consult endocrinologist 
• If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathy 
 


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Table 10. 
Skin Adverse Event Management Algorithm for Nivolumab and 
Ipilimumab 
 
Grade of Rash (CTCAE v5) 
Management 
Follow-Up 
Grade 1-2 
Covering ≤30% BSA* 
• Symptomatic therapy (e.g. 
antihistamines, topical steroids) 
• Continue I-O therapy per 
protocol 
If persists >1-2 weeks or recurs: 
• Consider skin biopsy 
• Delay I-O therapy per protocol 
• Consider 0.5-1.0mg/kg/day 
methylprednisolone IV or oral 
equivalent. Once improved, taper 
steroids over at least 1 months, 
consider prophylactic antibiotics 
for opportunistic infections, and 
resume I-O therapy per protocol. 
If worsens: 
• Treat as Grade 3-4 
Grade 3-4 
Covering >30% BSA; Life 
threatening consequences 
• Hold or discontinue I-O therapy 
per protocol 
• Consider skin biopsy 
• Dermatology consult 
• 1.0-2.0mg/kg/day IV 
methylprednisolone or IV 
equivalent 
If improves to Grade 1: 
• Taper steroids over at least 1 
month and add prophylactic 
antibiotics for opportunistic 
infections 
• Resume I-O therapy per protocol 
*Refer to NCI CTCAE v5 for term-specific grading criteria 
 


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Table 11. 
Neurological Adverse Event Management Algorithm for Nivolumab and 
Ipilimumab 
 
Grade of Neurological Toxicity 
(CTCAE v5) 
Management 
Follow-Up 
Grade 1 
Asymptomatic or mild symptoms; 
intervention not indicated 
• Continue I-O therapy per 
protocol 
• Continue to monitor the patient. 
If worsens: 
• Treat as Grade 2 or 3-4 
Grade 2 
Moderate symptoms; limiting 
instrumental ADLs 
• Hold I-O therapy 
• Treat symptoms per local 
guidelines 
• Consider 0.5-1.0mg/kg/day 
methylprednisolone IV or PO 
equivalent 
If improves to baseline: 
• Resume I-O therapy per protocol 
when improved to baseline 
If worsens: 
• Treat as Grade 3-4 
Grade 3-4 
Severe symptoms; limiting self- 
care ADL; Life-threatening 
• Discontinue I-O therapy per 
protocol 
• Obtain neurology consult 
• Treat symptoms per local 
guidelines 
• 1.0-2.0mg/kg/day IV or IV 
equivalent methylprednisolone 
• Add prophylactic antibiotics or 
opportunistic infections 
If improves to Grade 2: 
• Taper steroids over at least 1 
month 
If worsens of atypical presentation: 
• Consider IVIG or other 
immunosuppressive therapies 
per local guidelines 
 
 
Hepatic Impairment (Ipilimumab): 
Clearance (CL) of ipilimumab in subjects with mild and moderate hepatic impairment was 
similar to that of subjects with normal hepatic function. 
Hepatic Impairment (Nivolumab): 
No clinically important differences in the CL of nivolumab were found between subjects with 
mild hepatic impairment and normal hepatic function. 
Renal Impairment (Nivolumab): 
No clinically important differences in the CL of nivolumab were found between subjects with 
mild or moderate renal impairment and subjects with normal renal function. 
 
6.2.6 
Treatment Beyond Progression 
If the patient has met criteria for radiologic progression by RECIST v1.1, but the patient is still 
receiving benefit from study therapy (e.g., patient has mixed radiologic response or is continuing 


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to have symptomatic benefit without decline in performance status) according to the Investigator, 
then continuation of treatment will be considered. In such cases, the decision to continue will be 
made by the Investigator, and must be documented prior to continuing treatment with study 
treatment. Patients will continue to have all protocol-required assessments specified in the 
Schedule of Assessments Table. Treatment must be discontinued when the patient is no longer 
benefiting from therapy, as per the Investigator. 
 
6.3 Prior and Concomitant Therapies 
Patients who have received prior treatment with PARP inhibitors and/or immune checkpoint 
inhibitors are not eligible to participate in this study. Patients who have demonstrated resistance 
of their pancreatic adenocarcinoma to platinum agents (e.g. oxaliplatin, cisplatin) are not eligible 
to participate in this study. 
During the study, supportive care (e.g., antiemetics; analgesics of pain control) may be used at 
the investigator’s discretion and in accordance with institutional procedures. 
All procedures performed (e.g., thoracentesis, paracentesis etc.) and medications used during the 
study must be documented on the electronic case report form (eCRF). 
 
6.3.1 
Anticancer or Experimental Therapy 
No other concomitant therapies for pancreatic cancer (including chemotherapy, radiation, 
hormonal treatment, antibody or other immunotherapy, gene therapy, vaccine therapy, 
angiogenesis inhibitors, or other experimental drugs) of any kind will be permitted while the 
patient is participating in the study. 
Ongoing therapies for previously treated non-pancreatic cancer (e.g., hormonal treatment for 
prior breast cancer) are permitted. The data on niraparib in combination with cytotoxic medicinal 
products are limited. Therefore, caution should be taken if niraparib is used in combination with 
other cytotoxic medicinal products. 
Palliative radiotherapy (excluding the pelvic region and/or palliative radiotherapy encompassing 
> 20% of the bone marrow within 4 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. 
 
6.3.2 
Hematopoietic Growth Factors and Blood Products 
Hematopoietic colony-stimulating factors for treatment of cytopenias should be administered 
according to institutional guidelines. Transfusion thresholds for blood product support will be in 
accordance with institutional guidelines. 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 6.2.5.1. 
 
6.3.3 
Bisphosphanates 
Bisphosphanates are permitted. 
 
6.3.4 
Anticoagulants 
Anticoagulants are permitted. 


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6.3.5 
Other Concomitant Medications 
Therapies considered necessary for the patient’s well-being may be given at the discretion of the 
investigator. Other concomitant medications, except for analgesics, chronic treatments for 
concomitant medical conditions, or agents required for life-threatening medical problems, should 
be avoided. Herbal and complementary therapies should not be encouraged because of unknown 
side effects and potential drug interactions. 
 
6.3.6 
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. 
 
6.3.7 
Vaccines 
The combination of niraparib with vaccines or immunosuppressant agents has not been studied. 
 
6.3.8 
Blood Donation 
Patients must not donate blood during the study or for 90 days after the last dose of study 
treatment. 
 
6.4 Warnings and Precautions 
6.4.1 
Niraparib 
 
6.4.1.1 
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 NOVA trial, the incidence of 
MDS/AML in patients who received niraparib (1.4%) was similar to that seen 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, then niraparib should be permanently 
discontinued. 
 
6.4.1.2 
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 2 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 program, blood pressure 


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measurements were obtained on Day 1 of each 28-day cycle while the patient remained on 
niraparib. In most cases, hypertension was 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. 
 
6.4.1.3 
Posterior Reversible Encephalopathy Syndrome (PRES) 
There have been rare reports (0.09% of clinical trial patients) 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 reinstating niraparib therapy in patients previously 
experiencing PRES is not known. 
 
6.4.1.4 
Embryo-fetal Toxicity 
No embryo-fetal toxicity study has been performed. Based on its mechanism of action, niraparib 
could cause embryonic or fetal harm when administered to a pregnant woman. Refer to 
Section 5.3. 
 
6.4.1.5 
Pregnancy and Contraception 
Refer to Section 5.3. 
 
6.4.1.6 
Overdosage 
An overdose is defined as the accidental or intentional ingestion or infusing of any dose of study 
treatment that exceeds the dose described in the protocol. Overdoses are not considered AEs; 
however, all overdoses should be recorded on a Special Situations Report Form or its designated 
representative, within 24 hours. An overdose should be reported even if it does not result in an 
AE. 
There is no specific treatment in the event of niraparib overdose, and symptoms of overdose are 
not established. In the event of an overdose, physicians should follow general supportive 
measures and should treat symptomatically. 
 
6.4.1.7 
Other 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, neutrophil 
count decreased, dizziness, dysgeusia, dyspnea, cough and hypertension. The following adverse 
reactions and laboratory abnormalities have been identified in ≥1 to <10% of the 367 patients 


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receiving niraparib: tachycardia, dry mouth, mucosal inflammation, white blood cell count 
decreased, aspartate aminotransferase increased, alanine aminotransferase increased and 
photosensitivity reaction. 
 
6.4.2 
Nivolumab 
 
6.4.2.1 
Overdosage 
There is no available information concerning overdose with nivolumab. Depending on the 
symptoms and/or signs leading to the suspicion of overdose, supportive medical management 
should be provided. There is no specific antidote. 
 
6.4.2.2 
Pulmonary Adverse Events 
Pulmonary AEs have been observed following treatment with nivolumab. The frequency of 
pulmonary AEs may be greater with nivolumab combination therapies than with nivolumab 
monotherapy. The majority of cases reported were Grade 1 or 2, and subjects presented with 
either asymptomatic radiographic changes (e.g., focal ground glass opacities and patchy 
infiltrates) or with symptoms of dyspnea, cough, or fever. Subjects with reported Grade 3 or 4 
pulmonary AEs were noted to have more severe symptoms, more extensive radiographic 
findings, and hypoxia. Pulmonary AEs have been reported in subjects with a variety of tumor 
types; however, there have been numerically more cases in subjects with NSCLC. It is not clear 
whether the underlying NSCLC is a distinct risk factor, or if subjects with NSCLC are more 
likely to develop radiographic changes and symptoms for which it is difficult to distinguish 
between nivolumab-related and unrelated causes. At this time, no other underlying risk factor, 
including prior radiotherapy, presence of lung metastases, or underlying pulmonary medical 
history, has yet to be identified. 
Asymptomatic subjects were typically managed with dose delay. Subjects with Grade 2 
pneumonitis were managed with dose delay, treated with corticosteroids, and had resolution of 
pneumonitis within days to weeks. In cases where nivolumab treatment was restarted, recurrence 
of pneumonitis was infrequently reported across the nivolumab program. Subjects with more 
severe cases of pneumonitis can be difficult to treat. In a few cases, subjects who did not initially 
respond to corticosteroids were administered anti-tumor necrosis factor therapy (infliximab) 
and/or cyclophosphamide. In some of these cases, pneumonitis began to resolve following the 
use of these additional therapies. 
Guidelines on the recommended management of pneumonitis and other pulmonary AEs are 
found in Table 7. Early recognition and treatment of pneumonitis is critical to its management. 
Subjects should be advised to seek medical evaluation promptly if they develop new-onset 
dyspnea, cough, or fever or if they have worsening of these baseline symptoms. As respiratory 
symptoms are common in subjects with cancer (e.g., NSCLC), it is important that an 
evaluation/work-up distinguishes between non-drug-related causes (e.g., infection or progression 
of disease) and a possible drug-related pulmonary toxicity as the management of these events can 
be quite different. For symptomatic nivolumab-related pneumonitis, the principal treatment is 
corticosteroids Table 7. All subjects with Grade 3-4 pneumonitis should discontinue nivolumab 
and initiate treatment with high doses of corticosteroids. 


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6.4.2.3 
Gastrointestinal Adverse Events 
Gastrointestinal AEs have been observed following treatment with nivolumab. Most cases of 
diarrhea were of low grade (Grade 1-2). Colitis occurred less frequently than diarrhea. High- 
grade cases of diarrhea and colitis were managed with corticosteroids and, in all cases, the events 
resolved. 
The recommended management of GI AEs is provided in Table 5. Early recognition and 
treatment of diarrhea and colitis are critical to their management. Subjects should be advised to 
seek medical evaluation if they develop new-onset diarrhea, blood in stool, or severe abdominal 
pain or if they have worsening of baseline diarrhea. As GI symptoms are common in subjects 
with cancer, it is important that an evaluation/work-up distinguishes between non-drug-related 
causes (e.g., infection or progression of disease) and a possible drug-related AE as the 
management can be quite different. The principal treatment for high-grade GI AEs is 
corticosteroids Table 5. Caution should be taken in the use of narcotics in subjects with diarrhea, 
colitis, or abdominal pain as pain medicines may mask the signs of colonic perforation. 
Diverticular Perforation: The prevalence of diverticulosis in the general population is common 
and increases with age from 10% under 40 years of age to approximately 50% over 60 years of 
age. Approximately 10% to 25% of subjects with diverticulosis develop diverticulitis. 
Perforation occurs in 50% to 70% of instances of complicated diverticulitis. Corticosteroids, 
non-steroidal anti-inflammatory drugs (NSAIDs), and opioid analgesics are known risk factors 
for diverticular perforation. Given the high prevalence of diverticulosis and diverticulitis in the 
general population, it is expected that some nivolumab-treated subjects will have these 
conditions concurrently with their malignancy. Cases of diverticular perforation while on 
concomitant corticosteroids (6 cases) or NSAID (1 case) were observed in nivolumab program. 
While there is insufficient evidence to suggest that diverticulosis or diverticulitis is a 
predisposing factor for GI perforation following nivolumab administration, clinical caution 
should be exercised, as appropriate, for subjects on concomitant medications of corticosteroids, 
NSAID, or opioid analgesics. In addition, be vigilant for signs and symptoms of potential 
perforation, especially in subjects with known diverticular disease. 
 
6.4.2.4 
Hepatic Adverse Events 
Hepatic AEs, including elevated liver function tests (LFTs) and, infrequently, DILI, have been 
observed following treatment with nivolumab and nivolumab in combination with ipilimumab. 
Most cases were of low or moderate grade. Higher-grade hepatic AEs, including DILI, were 
managed with corticosteroids (with or without mycophenolate mofetil) and, in almost all cases, 
the events resolved. 
The recommended management of hepatic AEs is provided in Table 8 . Early recognition and 
treatment of elevated LFTs and DILI are critical to their management. Subjects should be 
advised to seek medical evaluation if they notice jaundice (yellow appearance of skin or sclera) 
or if they develop bruising, bleeding, or right-sided abdominal pain. Physicians should monitor 
LFTs prior to each nivolumab treatment. As LFT abnormalities are common in subjects with 
cancer, it is important that an evaluation/work-up distinguishes between non-drug-related causes 
(e.g., infection, progression of disease, concomitant medications, or alcohol) and a possible drug- 
related AE as the management can be quite different. The principal treatment for high-grade 
hepatic AEs is corticosteroids (Table 8). 


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6.4.2.5 
Endocrinopathies 
Endocrinopathies have been observed following treatment with nivolumab. Most cases were of 
low or moderate grade. The events have typically been identified through either routine periodic 
monitoring of specific laboratories (e.g., TSH) or as part of a work-up for associated symptoms 
(e.g., fatigue). Events may occur within weeks of beginning treatment, but also have been noted 
to occur after many months (while still on treatment). More than 1 endocrine organ may be 
involved (e.g., hypophysitis [pituitary inflammation] may need to be evaluated at the time 
adrenal insufficiency or thyroid disorder is suspected). Moderate- to high-grade cases were 
managed with hormone replacement therapy and, in some cases, with the addition of 
corticosteroids. In some cases, nivolumab treatment was held until adequate hormone 
replacement was provided. 
Guidelines on the recommended management of endocrinopathies are provided in Table 9. Early 
recognition and treatment of endocrinopathies are critical to its management. Subjects should be 
advised to seek medical evaluation if they notice new-onset fatigue, lightheadedness, or 
difficulty with vision or if baseline fatigue worsens. As fatigue is common in subjects with 
cancer, it is important that an evaluation/work-up distinguishes between non-drug-related causes 
(e.g., progression of disease, anemia, concomitant medications, or depression) and a possible 
drug-related AE as the management can be quite different. The principal management of 
endocrinopathies is hormone replacement therapy. For subjects with moderate- or high-grade 
events, corticosteroids may also be used. 
 
6.4.2.6 
Skin Adverse Events 
Rash and pruritus were the most common skin AEs observed following treatment with 
nivolumab. The rash was typically focal with a maculopapular appearance occurring on the 
trunk, back, or extremities. Most cases have been of low or moderate grade. In some cases, rash 
and pruritus resolved without intervention. Topical corticosteroids have been used for some 
cases of rash. Anti-histamines have been used for some cases of pruritus. More severe cases 
responded to systemic corticosteroids. 
Subjects should be advised to seek medical evaluation if they notice new-onset rash. Early 
consultation with a dermatology specialist and a biopsy should be considered if there is 
uncertainty as to the cause of the rash, or if there is any unusual appearance or clinical feature 
associated with it. Other drugs that may cause rash should be considered in the differential and, if 
possible, discontinued. In addition, careful evaluation of potential benefit-risk is necessary when 
considering the use of nivolumab or ipilimumab in a patient who has previously experienced a 
severe or life-threatening skin adverse reaction on a prior immune-stimulating therapy. 
Guidelines on the recommended management of skin AEs are provided in Table 10. The 
principal treatment for skin AEs, such as rash and pruritus, consists of symptomatic 
management. Topical corticosteroids can be used for low- to moderate-grade focal rash. 
Systemic corticosteroids should be used for diffuse and high-grade rash. Rare cases of Stevens- 
Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some with fatal outcome, have 
been observed. If symptoms or signs of SJS or TEN appear, nivolumab or nivolumab in 
combination with ipilimumab should be withheld and the patient referred for specialized care for 
assessment and treatment. If the patient has confirmed SJS or TEN, permanent discontinuation of 
nivolumab or nivolumab in combination with ipilimumab is recommended. 


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6.4.2.7 
Renal Adverse Events 
Elevated creatinine and biopsy-confirmed tubulointerstitial nephritis and allergic nephritis have 
been infrequently observed following treatment with nivolumab. The frequency of renal AEs 
may be greater with nivolumab combination therapies than with nivolumab monotherapy. Most 
cases were Grade 2 or 3 and based on creatinine elevation. Subjects with a history of RCC or 
prior nephrectomy did not appear to be at higher risk. Events were managed with corticosteroids 
and, in all cases, renal function partially or fully improved. 
The recommended management of renal AEs is provided in Table 6. Physicians should monitor 
creatinine regularly. As creatinine abnormalities are common in subjects with cancer and other 
comorbidities, it is important that an evaluation/work-up distinguishes between non-drug-related 
causes (e.g., dehydration, concomitant medications, hypotension, or progression of disease) and 
a possible drug-related AE as the management can be quite different. The principal treatment for 
renal AEs is corticosteroids (Table 6). 
 
6.4.2.8 
Neurological Adverse Events 
Neurologic AEs have been uncommonly observed following treatment with nivolumab. The 
frequency of neurologic AEs may be greater with nivolumab + ipilimumab combination 
therapies than with nivolumab monotherapy or other nivolumab combinations. Neurologic AEs 
can manifest as central abnormalities (e.g., aseptic meningitis, encephalopathy, or encephalitis) 
or peripheral sensory/motor neuropathies (e.g., Guillain-Barre Syndrome, myasthenia gravis 
complicated with sepsis and fatality). The onset has been observed as early as after a single 
treatment with the nivolumab + ipilimumab combination. 
The recommended management of neurologic AEs is provided in Table 11. Early recognition 
and treatment of neurologic AEs is critical to its management. Subjects should be advised to seek 
medical evaluation if they notice impairment in motor function (e.g., weakness), changes in 
sensation (e.g., numbness), or symptoms suggestive of possible central nervous system 
abnormalities such as new headache or mental status changes. As neurologic symptoms can be 
common in subjects with cancer, it is important that an evaluation/work-up distinguishes 
between non-drug-related causes (e.g., progression of disease, concomitant medications, or 
infection) and a possible drug-related AE as the management can be quite different. The 
principal treatments for neurologic toxicity are dose delay, corticosteroids, and IV 
immunoglobulin as outlined in the safety algorithm (Table 11). For high-grade related 
neurological AEs, nivolumab should be discontinued. 
 
6.4.2.9 
Infusion Reactions 
Infusion reactions, including high-grade hypersensitivity reactions, following administration of 
nivolumab are uncommon. Investigators are advised to monitor for fever, chills, shakes, itching, 
rash, hypertension or hypotension, or difficulty in breathing during and immediately after 
administration of nivolumab. Study protocols provide explicit guidance on the management of 
infusion-related reactions. 
 
6.4.2.10 
Lipase/Amylase Elevations 
Asymptomatic elevations in lipase and amylase have been reported. In monotherapy studies, 
lipase and amylase levels were not systematically monitored, so an estimate of the frequency of 


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asymptomatic lipase/amylase elevations is unknown. In studies evaluating the safety of the 
nivolumab + ipilimumab combination in multiple tumor types, lipase and amylase levels were 
systematically monitored, and elevations in any grade of lipase/amylase were consistently noted 
in approximately 10% to 30% of subjects. Very few subjects reported associated symptoms (e.g., 
abdominal pain) or radiographic findings (e.g., stranding) consistent with pancreatitis. Thus, 
there does not seem to be clinical significance to the elevated laboratory values. 
As lipase/amylase abnormalities are not uncommon in subjects with cancer, it is important that 
an evaluation/work-up distinguishes between non-drug-related causes (e.g., progression of 
disease, concomitant medications, or alcohol) and a possible drug-related cause as the 
management can be quite different. The recommended management of nivolumab-related 
elevated lipase/amylase values centers around close observation. Physicians should ensure that 
subjects have no associated symptoms consistent with pancreatitis, such as abdominal pain. 
Corticosteroids do not seem to alter the natural history of lipase/amylase elevations. Laboratory 
values tend to fluctuate on a day-to-day basis and eventually return to baseline or low grade over 
the course of weeks, whether or not subjects receive corticosteroids. Asymptomatic elevations 
should be monitored approximately on a weekly basis, and nivolumab should be held per 
protocol instructions. For sustained asymptomatic Grade 4 elevations, nivolumab should be 
discontinued per protocol instructions. For subjects with elevated lipase/amylase and symptoms 
consistent with possible pancreatitis, nivolumab should be discontinued, and consultation with a 
gastroenterologist should be considered. 
 
6.4.2.11 
Uveitis and Visual Complaints 
Immune therapies have been uncommonly associated with visual complaints. Inflammation of 
components within the eye (e.g., uveitis) is an uncommon, but clinically important, event. 
Uveitis may occur more frequently with nivolumab + ipilimumab combination therapy than with 
nivolumab monotherapy or nivolumab in combination with other therapies. An ophthalmologist 
should evaluate visual complaints with examination of the conjunctiva, anterior and posterior 
chambers, and retina. Topical corticosteroids may be used to manage low-grade events. Low- 
grade events that do not resolve and high-grade events should be managed with systemic 
corticosteroids. Complaints of double vision should also prompt medical evaluation. In addition 
to ocular inflammatory events, a work-up should also consider pituitary inflammation as a cause. 
 
6.4.2.12 
Other Immune-mediated Adverse Events 
For suspected immune-related adverse reactions, adequate evaluation should be performed to 
confirm etiology or exclude other causes. Based on the severity of the adverse reaction, 
nivolumab or nivolumab in combination with ipilimumab should be withheld and corticosteroids 
administered. Upon improvement, nivolumab or nivolumab in combination with ipilimumab may 
be resumed after corticosteroid taper. Nivolumab or nivolumab in combination with ipilimumab 
must be permanently discontinued for any severe immune-related adverse reaction that recurs 
and for any life-threatening immune-related adverse reaction. 
 
6.4.3 
Ipilimumab 
Blockade of CTLA-4 by ipilimumab leads to T-cell activation, with the potential for clinical 
inflammatory AEs primarily involving the skin (dermatitis/pruritus), GI tract (diarrhea/colitis), 
liver (hepatitis), endocrine glands (e.g., hypophysitis and adrenal or thyroid abnormalities), and 


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other less frequent organs (e.g., uveitis/episcleritis). The majority of these inflammatory AEs 
initially manifested during treatment; however, a minority occurred weeks to months after 
discontinuation of ipilimumab. The majority of the inflammatory AEs is reversible with the 
guidance issued below. In rare cases, these inflammatory AEs may be fatal. 
Patients should be assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy, and 
endocrinopathy, and clinical chemistries (including liver function, adrenocorticotropic hormone 
[ACTH] level, and thyroid function tests) should be evaluated at baseline and before each dose 
of ipilimumab. 
During evaluation of a suspected inflammatory AE, all efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes. Serological, immunological, 
imaging, and biopsy with histology (e.g., biopsy-proven lymphocytic) data should be used to 
support the diagnosis of an immune-mediated toxicity or support an alternative cause of the AE. 
In general, for severe inflammatory AEs, ipilimumab should be permanently discontinued, and 
systematic high-dose corticosteroid therapy should be initiated. For moderate immune-mediated 
AEs, ipilimumab should be held or delayed, and moderate-dose corticosteroids should be 
considered. 
Based on limited current clinical experience, corticosteroids do not appear to adversely affect the 
anti-tumor response. For example, disease control was maintained in subjects with objective 
responses who received corticosteroid administration for concomitant serious inflammatory AEs. 
The management guidelines for general inflammatory GI, liver, skin, endocrine, and 
neurological toxicities are provided in this Protocol in Section 6.2. 
 
6.4.3.1 
Gastrointestinal Toxicities 
The most common site for ipilimumab-induced GI toxicity was the lower GI tract, and the most 
common presentation was mild to severe diarrhea or colitis with occasional bloody stools. In 
some cases, diarrhea began as mild and then worsened. Constipation was rarely associated with 
ipilimumab administration. Delay in corticosteroid treatment may be associated with a poor 
outcome for patients with high-grade diarrhea. 
 
6.4.3.2 
Liver Toxicities 
Subjects receiving ipilimumab may develop elevations in LFTs in the absence of clinical 
symptoms. Occasionally, patients may present with symptoms, including right upper quadrant 
abdominal pain or unexplained vomiting. Most cases of inflammatory hepatitis responded to 
high-dose corticosteroids (IV route recommended). 
All patients require close medical monitoring of LFTs and immediate intervention to prevent 
serious sequelae. LFTs should be routinely assessed and reviewed prior to administration of each 
dose of ipilimumab. 
 
6.4.3.3 
Endocrine Toxicities 
The most common inflammatory endocrine toxicities occurring in ipilimumab-treated subjects 
are hypophysitis and hypopituitarism. Secondary cortisol deficiency (hypoadrenalism), 
hypothyroidism or thyroiditis, and, less commonly, other endocrinopathies may occur 
concomitantly with hypophysitis; however, these may also present as the only or as primary 


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endocrinopathy. Most patients with hypopituitarism presented with nonspecific complaints such 
as fatigue, visual field defects, confusion, or impotence. Some patients have had headache as the 
predominant presentation. The majority of subjects with hypopituitarism demonstrated enlarged 
pituitary glands based on brain magnetic resonance imaging (MRI). Low ACTH and cortisol 
were the most common biochemical abnormality; abnormal (mostly low) thyroid-stimulating 
hormone (TSH), free thyroxine (fT4), triiodothyronine (T3), testosterone, or prolactin have also 
been reported in some subjects. Symptoms of hypopituitarism and other endocrine toxicities 
were generally controlled with appropriate hormone replacement. 
 
6.4.3.4 
Skin Toxicities 
The most common inflammatory skin toxicities occurring in ipilimumab-treated subjects are rash 
and pruritus, mostly mild to moderate in severity. Two cases of fatal treatment-related toxic 
epidermal necrolysis have been reported in clinical trials. Post-marketing surveillance identified 
a fatal toxic epidermal necrolysis event in one subject who received ipilimumab after 
experiencing a severe or life-threatening skin adverse reaction on a prior cancer immune- 
stimulating therapy. Caution should be used when considering the use of ipilimumab in patients 
who have previously experienced a severe or life-threatening skin adverse reaction on a prior 
cancer immune-stimulating therapy (CARES Database No. 21333844). 
 
6.4.3.5 
Neurological Toxicities 
Neurological manifestations in subjects treated with ipilimumab may include motor and/or 
sensory neuropathy. Given the difficulty in definitely establishing an inflammatory etiology, 
alternative etiologies (e.g., tumor progression) should be excluded. Fatal Guillain-Barre 
syndrome and cases of myasthenia gravis have been reported in clinical trials of ipilimumab. 
Unexplained motor neuropathy, muscle weakness, or sensory neuropathy should be evaluated, 
and non-inflammatory causes such as disease progression, infections, metabolic disorders, and 
medications should be excluded. 
 
6.4.3.6 
Other Toxicities 
Ocular inflammation, manifested as Grade 2 or 3 episcleritis or uveitis, was associated with 
concomitant diarrhea in a few subjects (< 1%) and occasionally occurred in the absence of 
clinically apparent GI symptoms. 
Other presumed inflammatory events reported include, but were not limited to, the following 
(individually reported for < 1% of subjects unless noted otherwise): arthritis/arthralgias, 
pneumonitis, pancreatitis, autoimmune (aseptic) meningitis, autoimmune nephritis, pure red cell 
aplasia, non-infective myocarditis, polymyositis, eosinophilia, pericarditis, urticaria (2%), large 
intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, infusion reactions, 
and MG. 
 
6.5 Receipt 
Niraparib, nivolumab and ipilimumab will be received by the Investigational Drug Pharmacy at 
each clinical site. 


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6.6 Storage 
6.6.1 
Niraparib 
Niraparib is supplied by TESARO in high-density polyethylene (HDPE) bottles with child- 
resistant plastic closures. The study treatment will be open-label and will not be participant- 
specific. Detailed information on the product can be found in the Niraparib Storage and Handling 
Guidelines. 
All study treatment supplies must be stored in accordance with the manufacturer’s instructions 
and package labeling. Until dispensed to the participants, the study treatment will be stored in a 
securely locked area, accessible to authorized personnel only. 
 
6.6.2 
Nivolumab 
Nivolumab Injection, 40mg/Vial (10mg/mL), 100 mg/Vial (10 mg/mL), and 240mg/Vial 
(10mg/mL): Nivolumab Injection Vials of nivolumab injection must be stored at 2°C to 8°C 
(36°F to 46°F) and protected from light and freezing. The unopened vials can be stored at room 
temperature (up to up to 25°C, 77°F) and room light for up to 48 hours. 
Undiluted Nivolumab Injection and Diluted Nivolumab Injection in the IV Container: The 
administration of nivolumab infusion must be completed within 24 hours of preparation. If not 
used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at 
room temperature (up to 25°C, 77°F) and room light. The maximum 8 hours under room 
temperature and room light conditions includes the product administration period. 
 
6.6.3 
Ipilimumab 
Ipilimumab Injection, 50mg/10mL (5 mg/mL) or 200 mg/40 mL (5 mg/mL), must be stored 
refrigerated (2°C to 8°C) and protected from light. Ipilimumab injection must not be frozen. 
Partially used vials or empty vials of ipilimumab injection should be discarded at the site 
according to appropriate drug disposal procedures. 
Ipilimumab injection may be stored undiluted (5 mg/mL) or following dilution in 0.9% Sodium 
Chloride Injection, or 5% Dextrose Injection in PVC, non-PVC/non-DEHP or glass containers 
for up to 24 hours (at 2°C to 8°C) or room temperature/room light. 
Recommended safety measures for preparation and handling include protective clothing, gloves, 
and safety cabinets. 
 
6.7 Administration and Accountability 
Niraparib: An adequate quantity of niraparib will be provided to the patient to last until the next 
scheduled visit. Patients will be instructed to record daily doses taken or not taken in a provided 
institutional dosing diary, and will be instructed to bring their niraparib tablets, all containers 
(empty, partially used and/or unopened) and dosing diary to the next scheduled visit for 
reconciliation by site personnel. Food does not significantly affect the absorption of niraparib; 
therefore, niraparib may be taken without regard to meals. If a patient vomits or misses a dose of 
niraparib, an additional dose should not be taken. The next dose should be taken at the regularly 
scheduled time. 


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Ipilimumab and nivolumab are injectable drugs that will be administered in the clinic by 
research and clinical nursing staff. 
 
6.8 Subject Compliance Monitoring 
Documentation of dosing will be recorded in a study specific institutional dosing diary. Study 
site personnel will review dosing information with the patient (or legally authorized 
representative) on scheduled clinic visit days, providing instructions regarding dose, dose 
frequency and the number of tablets to be taken for each dose. Patients (or legally authorized 
representative) will be instructed to record dosing information for niraparib taken at home in the 
dosing diary and to bring the dosing diary and all unused tablets with them to scheduled clinic 
visits. A compliance check and tablet count will be performed by study personnel during clinic 
visits. Every effort should be made to ensure patients complete the dosing diary and return their 
study drug containers at the end of each cycle of treatment. In the event a patient has unused 
pills from the prior cycle, these may be re-dispensed. The coordinator will keep a record of 
returned pills and re-dispensed pills. 
 
6.9 Return or Destruction of Investigational Product 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed on-site in accordance with standard policies for the destruction of 
investigational agents with prior sponsor approval. 


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7 STUDY PROCEDURES 
7.1 
Schedule of Assessments- ARM A (Niraparib + Nivolumab) 
All procedures and assessments are to be completed within ±3 days of the scheduled time point. 
Table 12. 
Schedule of Assessments – Arm A 
 
Procedurea 
Day -28 to Day -1 (unless 
otherwise specified) 
C1D1b 
D1 of C2 and 
Beyondy 
EOT 
30 Day FU 
100 Day FU 
LTFU 
Informed Consent 
x 
Randomization 
x 
Demographics/ Medical Historyc 
x 
Physical Exam, Heightd, weight 
x 
X 
x 
x 
ECOG PS 
x 
X 
x 
x 
Vital Signse 
x 
X 
x 
x 
Blood Pressure and heart rate 
Monitoringw 
X 
X 
Adverse Eventsf 
x 
X 
x 
x 
x 
x 
Prior/Concomitant Medications 
and Procedures 
x 
X 
x 
x 
Hematologyg 
xh 
X 
x 
x 
Serum Chemistryi 
xh 
X 
x 
x 
Lipase 
x 
X 
x 
x 
Magnesium 
x 
X 
x 
x 
Phosphorus 
x 
X 
x 
x 
TSH (Thyroid Function)j 
x 
X 
x 
x 
HIV AB 
x 
 
 
 


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Procedurea 
Day -28 to Day -1 (unless 
otherwise specified) 
C1D1b 
D1 of C2 and 
Beyondy 
EOT 
30 Day FU 
100 Day FU 
LTFU 
CA 19-9 and/or CEAt 
X 
x 
x 
Serum Pregnancy Test 
(WOCBP only)k 
x 
X 
x 
x 
Disease Assessment/ Tumor Scansl 
x 
Xm 
Xn 
xo 
Archival Tissue (If availablep) 
x 
Tumor Tissue Biopsy (if 
safe/feasible) 
Xq 
Xr 
PBMC/Serum 
Xx 
xv 
Xv 
Blood for WeS 
X 
Blood for CTM 
xv 
xv 
Xv 
Niraparib Dispensation, 
Administration, Accountability 
X 
x 
x 
Nivolumab Infusion 
X 
x 
Survival Status 
Xs 
Follow-Up for MDS/AML 
Xs 
Bone Marrow aspirate and biopsy 
sampleu 
Xu 
ALP = alkaline phosphatase, ALT = alanine transaminase, ANC = absolute neutrophil count, AST = aspartate transaminase, BUN = blood urea nitrogen, CR 
= complete response, CT = computed tomography, hrs = hours, MRI = magnetic resonance imaging, PET = positron emission tomography, PK = 
pharmacokinetics, PR = partial response, SAE = serious adverse event, WBC = white blood cell, WOCBP = women of childbearing potential 
a = Treatment cycles are 28 days. Unless otherwise specified, all assessments are to be completed within ±3 days of scheduled time point. Delay of treatment 
schedule up to 10 days, as allowed by the protocol, is permitted at the discretion of the treating Investigator with approval of the PI (e.g. toxicity, weather, 
vacation). 
b = Any procedures required on Day 1 of Cycle 1 may be omitted if completed ≤3 days earlier during the screening period. 
c = Patient’s medical record must include prior treatments received, date of progression, and radiology and/or medical report(s) to support assessment of disease 
progression, and, if applicable, intolerable toxicity to chemotherapy. 
d = Height at screening only 
e = Vital signs (blood pressure, pulse, and temperature) to be taken pre-dose on clinic visit days. Blood pressure and heart rate should be monitored at least 
weekly for the first 2 months, then monthly for the first year and periodically thereafter during treatment with niraparib. 
 
 


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f = AEs are recorded from the time of signing informed consent through 30 days after last dose of niraparib. Ongoing SAEs will be followed to resolution or 
until SAE stabilizes. 
g = Includes hemoglobin, hematocrit, WBC and differential (with ANC) and platelet count. Blood will be analyzed by a local laboratory. Weekly CBCs should 
be performed during the first four weeks of therapy. 
h = to be performed ≤7 days prior to the first dose of therapy or prior to dosing on day 1 to confirm eligibility 
j = includes total protein, albumin, creatinine or estimated GFR using Cockgroft Gault formula, BUN, total bilirubin, ALP, ALT, AST, glucose, sodium, 
potassium, chloride, CO2, calcium, phosphorous, magnesium and lipase. Blood will be analyzed by a local laboratory. 
j = If TSH is abnormal, fT4 and T3 will be drawn. The patient will be clinically managed for thyroid abnormalities at the discretion of the investigator. 
k = Women of childbearing potential must have a negative serum pregnancy test result within 24 hours prior to the first dose of niraparib. A serum or urine 
pregnancy test (investigator’s discretion) must be performed ≤3 days prior to Day 1 of every cycle during the treatment phase. A serum pregnancy test must be 
performed at the End of Treatment visit. 
l = Disease assessment to include clinical examination, and appropriate imaging techniques, including CT scans of the chest, abdomen and pelvis, with 
appropriate slice thickness per RECIST; other studies (MRI, X-ray, PET, and ultrasound) may be performed if required. The same method used to detect lesions 
at baseline is to be used to follow the same lesions throughout the clinical study. If a patient has known brain metastases, this disease should be evaluated at each 
required assessment. 
m = Tumor scans to be performed within 7 days prior to start of every 2nd cycle (every odd numbered cycle), or approximately every 8 weeks.  Please refer to 
footnote “y” for procedures for stable patients who are stable following 11 cycles of treatment 
n = End of treatment CT scans should be performed if treatment was discontinued for reason other than radiologic disease progression and if previous tumor 
assessment scan was performed ≥8 weeks prior to EOT visit. 
o = If CT scans were not performed at End of Treatment or within 28 days prior to End of Treatment, a CT scan should be performed at the 28-day follow-up 
visit. 
p = Archival tumor tissue, if available, will be collected and stored. (Note: This sample is not required to be submitted on Cycle 1, Day 1, but should be 
submitted as soon as possible after a patient begins treatment). 
q = A screening core tumor biopsy will be collected prior to C1D1 if deemed safe and feasible for those patients who pass the screening evaluation. 
r = A core tumor biopsy will be performed during treatment at cycle 2 day 1 if deemed safe and feasible +/- 7 days 
s = All patients discontinued from treatment, regardless of reason, should be followed annually until death, loss to follow-up, withdrawal of consent from study, 
five years, or closure of the study. Follow-up can be performed via telephone, email and/or office visit. 
t = Whichever is appropriate for the patient.  Patients with a prior history of both markers being elevated will have both drawn serially as per the study calendar. 
u = For any patient diagnosed with MDS/AML while on study, a bone marrow aspirate/biopsy must be completed by a local hematologist. A whole blood sample 
will also be collected for cytogenetic analysis (mutations of select myeloid-associated genes). Testing completed as part of standard of care is sufficient as long 
as the methods are acceptable to the Sponsor's Medical Monitor. The study site must receive a copy of the hematologist's report of aspirate/biopsy findings 
(which must include a classification according to WHO criteria) and other sample testing results related to MDS/AML. 
v = Blood samples for PBMC, Serum, and CTM will be collected according to the site lab manual at Cycle 1 and every other Cycle (every 8 weeks) starting with 
cycle 3 thereafter, and at EOT. For patients coming in every 12 weeks, PBMD, Serum and CTM will be collected at that visit. 
w= blood pressure and heart rate should be monitored weekly for first 2 months, monthly for first year, and periodically thereafter 
x= PBMC research sample at C1D8 may be collected 
y =  Patients on Arm A who are (1) clinically stable (as per the investigator) following 11 full cycles of treatment and (2) are no longer receiving nivolumab may go 
twelve weeks (ie three cycles)  between clinical assessments and disease assessment imaging. For these patients, three cycles of niraparib may be dispensed at one 
time.  However, all safety blood work must still be collected at D1 (+/- 3 days) of each cycle and will be reviewed by the research team.  
  
 
 


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7.2 
Schedule of Assessments- ARM B (Niraparib + Ipilimumab) 
All procedures and assessments are to be completed within ±3 days of the scheduled time point 
Table 13. 
Schedule of Assessments – Arm B 
 
Procedurea 
Day -28 to Day -1 
(unless otherwise 
specified) 
C1D1b 
C2D1 
C3D1 
C4D1 
C5D1 and 
onwardy 
EOT 
30 Day 
FU 
90 Day 
FU 
LTFU 
Informed Consent 
X 
Randomization 
X 
Demographics/ Medical 
Historyc 
X 
Physical Exam, Heightd, weight 
X 
x 
x 
x 
x 
x 
X 
ECOG PS 
X 
x 
x 
x 
x 
x 
X 
Vital Signse 
X 
x 
x 
x 
x 
x 
X 
Blood Pressure and heart rate 
monitoringw 
x 
x 
x 
x 
x 
Adverse Eventsf 
X 
x 
x 
x 
x 
x 
X 
x 
x 
Prior/Concomitant Medications 
and Procedures 
X 
x 
x 
x 
x 
x 
X 
Hematologyg 
xh 
x 
x 
x 
x 
x 
X 
Serum Chemistryi 
xh 
x 
x 
x 
x 
x 
X 
Lipase 
X 
x 
x 
x 
x 
x 
X 
Magnesium 
X 
x 
x 
x 
x 
x 
X 
Phosphorus 
X 
x 
x 
x 
x 
x 
X 
TSH (Thyroid Function)j 
X 
x 
x 
x 
x 
x 
X 
HIV AB 
X 
CA 19-9 and/or CEAt 
x 
x 
x 
x 
X 
 
 
 


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Procedurea 
Day -28 to Day -1 
(unless otherwise 
specified) 
C1D1b 
C2D1 
C3D1 
C4D1 
C5D1 and 
onwardy 
EOT 
30 Day 
FU 
90 Day 
FU 
LTFU 
Serum Pregnancy Test 
(WOCBP only)k 
X 
x 
x 
x 
x 
x 
X 
Disease Assessment/ Tumor 
Scansl 
X 
Xm 
xm 
Xn 
xo 
Archival Tissue (If availablep) 
X 
Tumor Tissue Biopsy 
(if safe/feasible) 
Xq 
xr 
PBMC/Serum 
xx 
xv 
xv 
xv 
Blood for WeS 
x 
Blood for CTM 
xv 
xv 
xv 
Xv 
Niraparib Dispensation, 
Administration, Accountability 
x 
x 
x 
x 
x 
X 
Ipilimumab Infusion 
x 
x 
x 
x 
Survival Status 
Xs 
Follow-Up for MDS/AML 
Xs 
Bone Marrow aspirate and 
biopsy sampleu 
Xu 
ALP = alkaline phosphatase, ALT = alanine transaminase, ANC = absolute neutrophil count, AST = aspartate transaminase, BUN = blood urea nitrogen, CR 
= complete response, CT = computed tomography, hrs = hours, MRI = magnetic resonance imaging, PET = positron emission tomography, PK = 
pharmacokinetics, PR = partial response, SAE = serious adverse event, WBC = white blood cell, WOCBP = women of childbearing potential 
a = Treatment cycles are 21 days. Unless otherwise specified, all assessments are to be completed within ±3 days of scheduled time point. Delay of treatment 
schedule up to 10 days, as allowed by the protocol, is permitted at the discretion of the treating Investigator with approval of the PI (e.g. toxicity, weather, 
vacation). 
b = Any procedures required on Day 1 of Cycle 1 may be omitted if completed ≤3 days earlier during the screening period. 
c = Patient’s medical record must include prior treatments received, date of progression, and radiology and/or medical report(s) to support assessment of disease 
progression, and, if applicable, intolerable toxicity to chemotherapy. 
d = Height at screening only 
e = Vital signs (blood pressure, pulse, and temperature) to be taken pre-dose on clinic visit days. Blood pressure and heart rate should be monitored at least 
weekly for the first 2 months, then monthly for the first year and periodically thereafter during treatment with niraparib. 
 
 


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f = AEs are recorded from the time of signing informed consent through 30 days after last dose of niraparib. Ongoing SAEs will be followed to resolution or 
until SAE stabilizes. 
g = Includes hemoglobin, hematocrit, WBC and differential (with ANC) and platelet count. Blood will be analyzed by a local laboratory. Weekly CBCs should 
be performed during the first four weeks of therapy. 
h = to be performed ≤7 days prior to the first dose of therapy or prior to dosing on day 1 to confirm eligibility 
i = includes total protein, albumin, creatinine or estimated GFR using Cockgroft Gault formula, BUN, total bilirubin, ALP, ALT, AST, glucose, sodium, 
potassium, chloride, CO2, calcium, phosphorous, magnesium and lipase. Blood will be analyzed by a local laboratory. 
j = If TSH is abnormal, fT4 and T3 will be drawn. The patient will be clinically managed for thyroid abnormalities at the discretion of the investigator. 
k = Women of childbearing potential must have a negative serum pregnancy test result within 24 hours prior to the first dose of niraparib. A serum or urine 
pregnancy test (investigator’s discretion) must be performed ≤3 days prior to Day 1 of every cycle during the treatment phase. A serum pregnancy test must be 
performed at the End of Treatment visit. 
l = Disease assessment to include clinical examination, and appropriate imaging techniques, including CT scans of the chest, abdomen and pelvis, with 
appropriate slice thickness per RECIST; other studies (MRI, X-ray, PET, and ultrasound) may be performed if required. The same method used to detect lesions 
at baseline is to be used to follow the same lesions throughout the clinical study if possible. If a patient has known brain metastases, this disease should be 
evaluated at each required assessment. 
m = Tumor scans to be performed within 7 days prior to start of every 3rd cycle or approximately every 9 weeks. Please refer to footnote “y” for procedures for 
stable patients who are stable following 17 cycles of treatment 
n = End of treatment CT scans should be performed if treatment was discontinued for reason other than radiologic disease progression and if previous tumor 
assessment scan was performed ≥8 weeks prior to EOT visit. 
o = If CT scans were not performed at End of Treatment or within 28 days prior to End of Treatment, a CT scan should be performed at the 28-day follow-up 
visit. 
p = Archival tumor tissue, if available, will be collected and stored. (Note: This sample is not required to be submitted on Cycle 1, Day 1, but should be 
submitted as soon as possible after a patient begins treatment). 
q = A screening core tumor biopsy will be collected prior to C1D1 if deemed safe and feasible for those patients who pass the screening evaluation. 
r = A core tumor biopsy will be performed during treatment at cycle 2 day 1 if deemed safe and feasible +/- 7 days 
s = All patients discontinued from treatment, regardless of reason, should be followed annually until death, loss to follow-up, withdrawal of consent from study, 
five years, or closure of the study. Follow-up can be performed via telephone, email and/or office visit. 
t = Whichever is appropriate for the patient. Patients with a prior history of both markers being elevated will have both drawn serially as per the study calendar. 
u = For any patient diagnosed with MDS/AML while on study, a bone marrow aspirate/biopsy must be completed by a local hematologist. A whole blood sample 
will also be collected for cytogenetic analysis (mutations of select myeloid-associated genes). Testing completed as part of standard of care is sufficient as long 
as the methods are acceptable to the Sponsor's Medical Monitor. The study site must receive a copy of the hematologist's report of aspirate/biopsy findings 
(which must include a classification according to WHO criteria) and other sample testing results related to MDS/AML. 
v = Blood samples for PBMC, Serum, and CTM will be collected according to the site lab manual at Cycle 1 and every 3 Cycles (every 9 weeks) thereafter, and 
at EOT. For patients coming in every 12 weeks, PBMD, Serum and CTM will be collected at that visit. 
w= blood pressure and heart rate should be monitored weekly for first 2 months, monthly for first year, and periodically thereafter 
x= PBMC research sample at C1D8 may be collected 
  y =  Patients on Arm B who are stable (as per the investigator) following 17 full cycles of treatment may go twelve weeks (ie four cycles)  between clinical 
assessments and disease assessment imaging. For these patients, four cycles of niraparib may be dispensed at one time.  However, all safety blood work must still be 
collected at D1 (+/- 3 days) of each cycle and will be reviewed by the research team.   
 


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7.3 
Screening Phase 
Following written informed consent, and unless otherwise specified, the following assessments 
will be performed during the 28-day period prior to the first dose of therapy. Assessments 
performed within this window, but prior to patient signing informed consent, are acceptable only 
if confirmed to have been standard of care. 
• Demographic information (birth date, race, gender, etc.), including smoking status. 
• Medical/oncology history, including date of cancer diagnosis, prior treatments and any 
surgical procedures 
• Physical examination of body system, height and weight 
• ECOG performance status (16.1 Appendix A) 
• Vital signs (blood pressure, pulse, and temperature) 
• Prior and concomitant medications and any surgical procedure 
• Hematology (hemoglobin, hematocrit, WBC and differential [with ANC], and platelet 
count) ≤7 days prior to first dose of niraparib. 
• Serum chemistry (total protein, albumin, creatinine or estimated GFR using Cockcroft 
Gault formula, BUN, total bilirubin, ALP, ALT, AST, glucose, sodium, potassium, 
chloride, CO2, calcium, phosphorous, magnesium and lipase) ≤7 days prior to the first 
dose of treatment. 
• Serum pregnancy test for women of childbearing potential (≤3 days prior to the first dose 
of therapy) 
• HIV antibody 
• Tumor assessments should consist of clinical examination, appropriate imaging 
techniques including CT scans of the chest, abdomen and pelvis, with appropriate slice 
thickness per RECIST; other studies (MRI, X-ray, PET, and ultrasound) may be 
performed if required. The same method used to detect lesions at baseline is to be used to 
follow the same lesions throughout the clinical study. If a patient has known brain 
metastases, this disease should be evaluated at each required assessment. 
• FFPE archival tumor tissue sample, if available. Refer to the site Laboratory Manual for 
detailed sample handling instructions. (Note: this sample is not required to be submitted 
on Cycle 1, Day 1, but should be submitted as soon as possible after a patient begins 
treatment) 
• Tumor tissue core biopsy if considered safe and feasible (patients who pass screening 
only). Tumor tissue will be processed locally as formalin-fixed paraffin-embedded 
(FFPE) tissue. Refer to the site Laboratory Manual for detailed sample handling 
instructions. 
• AE monitoring (after signing informed consent) 


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7.4 
Treatment Phase 
The following procedures should be completed before the first dose of study therapy is 
administered, unless otherwise indicated. 
7.4.1 
Day 1 of Cycles 1-4 
• Physical Examination 
• Weight 
• ECOG performance status (16.1 Appendix A) 
• Vital signs 
− blood pressure and heart rate should be monitored weekly for first 2 months, monthly 
for first year, and periodically thereafter 
• Concomitant medications and procedures 
• Hematology 
− Weekly CBCs should be performed during the first four weeks of therapy 
• Serum chemistry including magnesium, phosphate and lipase 
• CA 19-9 and/or CEA measurement 
• TSH measurement 
• Correlative Research Blood samples will be obtained for Serum, PBMC, Whole Exome 
Sequencing (C1 only), and Circulating tumor material 
− ARM A: Blood samples for PBMC, Serum, and CTM will be collected according to 
the site lab manual at Cycle 1 and every other Cycle (every 8 weeks) thereafter; one 
additional PBMC may be drawn on C1D8. For patients coming in every 12 weeks, 
PBMD, Serum and CTM will be collected at that visit. 
− ARM B Blood samples for PBMC, Serum, and CTM will be collected according to 
the site lab manual at Cycle 1 and every 2 Cycles (every 9 weeks) thereafter; one 
additional PBMC may be drawn on C1D8. For patients coming in every 12 weeks, 
PBMD, Serum and CTM will be collected at that visit. 
• Adverse event monitoring 
• The treatment core biopsy will be performed +/- 7 days of cycle 2, if considered feasible 
and safe as by the first reassessment staging scan and evaluation by the clinical 
investigator and the performing department. 
• Study drug accountability (Cycles 2-4) 
• Niraparib dispensation 
• Nivolumab (Arm A) or Ipilimumab (Arm B) administration 
 
Niraparib will be dispensed to the patient in sufficient quantity to last until Day 1 of the next 
treatment cycle. Patients will ingest niraparib once daily at about the same times every day. 
Bedtime dosing may mitigate nausea. Food does not affect the absorption of niraparib, therefore 


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niraparib may be taken without regard to meals. If a patient vomits or misses a dose of niraparib, 
an additional dose should not be taken. The next dose should be taken at a regularly scheduled 
time. 
Patients will keep all unused pills and containers (empty, partially used, and/or unopened) for 
accountability at the next visit. In the event of toxicities, re-treatment or dose modification will 
be according to the criteria described the protocol). Patients will record dosing information in 
their dosing diary. 
 
7.4.2 
Day 1 of Cycles 5 and Beyond, Both Arms 
Patients will be instructed to refrain from taking their first dose of oral niraparib at home on the 
day of their clinic visits because certain assessments must be performed prior to dosing. 
The following procedures will be completed prior to oral niraparib on Day 1 of Cycles 5 and 
beyond: 
• Physical examination 
• Weight 
• ECOG performance status (16.1 Appendix A) 
• Vital signs 
− blood pressure and heart rate should be monitored monthly for first year, and 
periodically thereafter 
• Concomitant medications and procedures 
• Hematology 
• Serum chemistry including magnesium, phosphate and lipase 
• TSH measurement 
• CA 19-9 and/or CEA measurement 
• Correlative Research Blood samples will be obtained for Serum, PBMC, and Circulating 
tumor material 
− ARM A: Blood samples for PBMC, Serum, and CTM will be collected according to 
the site lab manual at Cycle 1 and every other Cycle (every 8 weeks) thereafter 
− ARM B Blood samples for PBMC, Serum, and CTM will be collected according to 
the site lab manual at Cycle 1 and every 2 Cycles (every 9 weeks) thereafter 
• Disease/ tumor assessment (using the same methodology as was used at screening [e.g., 
CT scan]) prior to the start of every 2 cycles (Arm A) or every 3 cycles (Arm B) (within 
7 days before is permitted) relative to start of treatment on Day 1 of Cycle 1 through to 
18 months on study, then every 16 calendar weeks (within 5 days before is permitted) 
relative to the start of treatment on Day 1 of Cycle 1. Timing of disease/tumor 
assessments is relative to Day 1 of Cycle 1 after enrollment. Blood sample for circulating 
tumor material 
• AE monitoring 


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• Study drug accountability 
• Niraparib dispensation 
• Nivolumab administration (Arm A only) 
 
Niraparib will be dispensed to the patient in sufficient quantity to last until Day 1 of the next 
treatment cycle. Patients will ingest niraparib once daily at about the same times every day. 
Bedtime dosing may mitigate nausea. Food does not affect the absorption of niraparib, therefore 
niraparib may be taken without regard to meals. If a patient vomits or misses a dose of niraparib, 
an additional dose should not be taken. The next dose should be taken at a regularly scheduled 
time. 
Patients will keep all unused niraparib and containers (empty, partially used, and/or unopened) 
for accountability at the next visit. In the event of toxicities, re-treatment or dose modification 
will be according to the criteria described the protocol). Patients will record dosing information 
in their dosing diary. 
 
7.4.3 
Tumor Assessments 
Tumor assessments will be performed every 2nd cycles or every 8 weeks (+/- 7 days) for Arm A 
and every 3rd cycle, or every 9 weeks (+/- 7 days) for Arm B, always prior to the first day of the 
next cycle of therapy. 
 
7.4.4 
End of Treatment Visit 
The following procedures will be performed for all patients as soon as possible after the last dose 
of study therapy: 
• Physical examination 
• Weight 
• ECOG performance status (Appendix A) 
• Vital signs 
• Concomitant medications and procedures 
• Hematology 
• Serum chemistry 
• Magnesium, phosphate and lipase 
• TSH measurement 
• CA 19-9 and/or CEA measurement 
• Serum or urine pregnancy test 
• Correlative Research Blood samples will be obtained for Serum, PBMC, and Circulating 
tumor material 


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• Tumor assessment scans if patient discontinued therapy for reasons other than radiologic 
disease progression and if previous tumor assessment scan was performed ≥8 weeks prior 
to EOT visit. 
• AE monitoring 
• Study drug accountability 
 
 
7.5 
30-day Follow-up Visit 
The following procedures will be performed for all patients at 30 (±3) days after the last dose of 
study therapy. At least 2 documented attempts will be performed by study team to contact the 
subject. 
• AE monitoring (ongoing SAEs should be followed until resolution or stabilization) 
• If tumor assessment scans were not performed at End of Treatment or within 30 days 
prior to End of Treatment, a CT scan should be performed at the 30-day follow-up visit. 
 
 
7.6 
90 or 100 Day Follow-up Visit for MDS/AML 
All patients will have intermittent monitoring for MDS/AML for up to 5 years as described in 
long-term follow up Section 7.7. Patients who received nivolumab (Arm A) will have an 
additional follow-up visit at 100 days (±14) days after the last dose of study therapy. Patients 
who received ipilimumab (Arm B) will have an additional follow-up visit at 90 days (±14) days 
after the last dose of study therapy. At least 2 documented attempts will be performed by study 
team to contact the subject. 
• AE monitoring (ongoing SAEs should be followed until resolution or stabilization) 
• MDS and AML are Adverse Events of Special Interest (Section 10.1.4) and should be 
reported to the PI and sponsor. Follow-up for MDS/AML can be performed via the 
telephone. If subject reports a diagnosis of MDS/AML and if feasible at least 2 
documented attempts will be made to obtain appropriate documentation (i.e., laboratory 
and/or pathology reports). 
 
 
7.7 
Long-term Follow-Up 
All subjects will be followed annually for survival and MDS and/or AML until death, loss to 
follow-up, withdrawal of consent from study or for 5 years, whichever occurs first. 
• For Overall survival information and MDS/AML follow-up can be performed via 
telephone, email or, Electronic Medical Record (EMR) review. At least 2 documented 
attempts will be performed by study team to contact the subject. If attempts to contact 
are unsuccessful the subject will be considered lost to follow up. Death Records and 
SSDI will still be used for survival purposes. 


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7.8 
Subject Withdrawal 
Subjects may withdraw from the study at any time without impact to their care. They may also 
be discontinued from the study at the discretion of the Investigator for lack of adherence to 
intervention or study procedures or visit schedules or AEs. The Investigator or the Sponsor (if 
applicable) may also withdraw subjects who violate the study plan, or to protect the subject for 
reasons of safety or for administrative reasons. It will be documented whether or not each 
subject completes the clinical study. Subjects who withdraw early will have one final visit to 
collect investigational product and to follow up regarding adverse events. 
 
7.8.1 
Data Collection and Follow-up for Withdrawn Subjects 
Subjects who withdraw consent to participate in the study will be seen for one final visit to 
collect the investigational product. During this visit they will be asked for permission to have the 
study team look into their survival status via publicly available means. 
 
8 STUDY EVALUATIONS AND MEASUREMENTS 
8.1 
Medical Record Review 
The following information will be extracted from the medical record of each subject prior to the 
first dose of study therapy. 
• Past medical/oncologic history including date of diagnosis, prior treatments, date of 
progression, and radiology and/or medical report(s) to support assessment of disease 
progression, and, if applicable, intolerable toxicity to chemotherapy. 
• Detailed family history of all cancers 
• Any previously performed genetic testing or sequencing (of tumor tissue, circulating 
tumor DNA and/or germline) 
 
8.2 
Physical Examination 
Physical examination will include all of the major body systems. Physical examinations will be 
performed at screening (complete) and at most study visits (limited as appropriate). 
 
8.3 
Body Weight and Height 
Height will be measured during the Screening visit only. Weight will be measured per 
institutional guidelines. 
 
8.4 
Vital Signs 
Vital signs will include blood pressure, pulse and body temperature. Vital signs will be 
performed at most study visits. 
8.5 
ECOG Performance Status 
ECOG performance status (16.1 Appendix A) will be assessed at Screening, on Day 1 of each 
cycle, and at the End of Treatment visit. ECOG performance status should be assessed by the 


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same study personnel at each visit, if possible. Care will be taken to accurately score 
performance status, especially during screening for study eligibility purposes. Additional 
consideration should be given to borderline ECOG performance status to avoid enrolling patients 
with significant impairment. 
 
8.6 
Clinical Laboratory Evaluations 
Certified local laboratories will perform study-related clinical laboratory tests according to 
institutional procedures, and the results will be reviewed by the investigator. The panels of 
laboratory tests to be performed are shown below: 
Hematology: Hemoglobin, hematocrit, WBC and differential (with ANC), sample collection 
(whole blood) for cytogenetic analysis, and platelet count at Screening, during treatment, and at 
the End of Treatment visit. Screening hematology results must be reviewed by the investigator 
prior to the start of treatment with study treatment. During the treatment phase, results must be 
evaluated by the investigator and acted upon, as appropriate, within 24 hrs. of receipt. 
Clinical Chemistry: Total protein, albumin, creatinine or estimated GFR using the Cockcroft 
Gault formula, BUN or urea, total bilirubin, alkaline phosphatase (ALP), ALT, AST, TSH, 
glucose, sodium, potassium, chloride, CO2, calcium, and phosphorus at Screening, during 
treatment, and at the End of Treatment visit. 
Tumor Markers: CA 19-9 and/or CEA (whichever is appropriate for the patient) will be 
measured on day 1 of each cycle and at the End of Treatment visit. 
Serum/Urine Pregnancy: For women of childbearing potential only. Serum pregnancy test is to 
be performed within 24 hours prior to first dose of niraparib, nivolumab or ipilimumab and at the 
End of Treatment visit. Serum or urine pregnancy test (per investigator’s discretion) is to be 
performed ≤3 days prior to the start of every cycle during the treatment phase. 
Laboratory reports will be reviewed by the investigator or sub-investigator who will then 
comment on out-of-range parameters and assess clinical significance. Clinically significant 
abnormalities and associated panel results, as well as results of any additional tests performed as 
follow-up to the abnormalities, will be documented on the eCRF as an AE. Refer to Section 10.4 
for guidelines on reporting of abnormal laboratory values as AEs. 
 
8.7 
Efficacy Evaluations 
8.7.1 
Tumor Assessments 
Tumor assessments will be performed at Screening and within 7 days prior to the start of, of 
every 2nd cycle (Arm A) or every 3rd cycle (Arm B) and at the End of Treatment visit. If a CT 
scan was not performed at the End of Treatment visit, a CT scan should be performed at the 28- 
day Follow-up visit. Tumor response will be interpreted using RECIST Version 1.1 
(16.2 Appendix B). 
Tumor assessments should consist of clinical examination and appropriate imaging techniques 
(CT scans of the chest, abdomen, and pelvis with appropriate slice thickness per RECIST); other 
studies (MRI, X-ray, PET, and ultrasound) may be performed if required. If a patient has known 
brain metastases, this disease should be evaluated at each required assessment. The same 
methods used to detect lesions at baseline are to be used to follow the same lesions throughout 


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the clinical study. Investigators should perform scans of the anatomical sites that, in their 
judgment, are appropriate to assess based on each patient’s tumor status. 
8.7.2 
Tumor Markers 
CA 19-9 and/or CEA (whichever is appropriate for the patient) will be collected on Day 1 of 
every cycle and at the End of Treatment visit. 
 
8.8 
Genetic Testing and Correlative Science 
All enrolled patients will undergo whole exome sequencing (WES) of their tumor tissue and 
blood once they are enrolled in the trial, though results do not impact treatment decision or 
enrollment. Allele specific loss of heterozygosity will also be assessed in those with an 
identified HRD, as described below. 
Allele specific copy number states were determined using Sequenza and used to calculate the 
HRD scores non-telomeric allelic imbalance (NtAI)[17], large state transitions (LST)[18], and 
genomic LOH (HRD-LOH)[19] using custom R-scripts, which are available upon request. Non- 
telomeric allelic imbalance (NtAI) scores were derived from the Sequenza data by summing the 
number of segments of allelic imbalance that were post-centromeric to the sub-telomeric regions 
and >11Mb in length. Large state transition (LST) scores were derived from the Sequenza data 
by summing the number of breakpoints creating >3Mb segments that were >10Mb from one 
another. Raw LST scores were corrected for ploidy (LSTm) using the equation LSTm = LST – 
15.5 x ploidy. Genomic loss of heterozygosity (HRD-LOH) scores were derived from Sequenza 
data by summing the number of segments of LOH >15Mb in length excluding segments found 
on Chromosome 17. HRD-scores were calculated blinded to locus-specific LOH status. 
Our specific choice of sequencing tests will be determined by available resources and 
technology. The 
 Laboratory will perform this sequencing. 
Copies of any previously performed sequencing results (tissue, circulating tumor DNA or 
germline) will be collected. 
Results of testing performed for whole exome sequencing in 
 lab will be neither 
included in the medical record nor shared with the subject. Results may prompt additional testing 
that would be conducted in a CLIA certified lab. 
8.9 
Immune Endpoints 
8.9.1 
Specimen Collection 
Tumor tissue (fresh or if not available, archival) must be available or collected prior to the start 
of treatment. A second treatment biopsy will also be obtained prior to C2D1, if considered safe 
and feasible. Blood for plasma and peripheral blood mononuclear cells (PBMC) will be 
collected at baseline and serially during therapy as noted above. Tumor samples and blood 
samples will be processed according to the study Laboratory Manual in the Vonderheide 
Laboratory (Human Immunology Core – HIC). 
8.9.2 
Immune Correlative Science 
Analysis of Myeloid and B cell Activation: Using un-manipulated peripheral blood, 
monocytes, B cells, dendritic cells before and after treatment can be analyzed using flow 


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cytometry to measure cell surface immune markers using a panel of immune parameters such as 
CD11b, CD19, CD123, CD11c (to define the subsets) and CD86, MHC class I and II, CD70, and 
CD54 (to measure activation). For each parameter and each cell type, the percentage of cells 
positive for the marker and/or MFI at time points after treated can be compared to baseline and 
the change are calculated as %after/%baseline or MFIafter/MFIbaseline. 
 
8.9.3 
Immune Biomarkers 
Depending on sample availability, a battery of immune assays is planned, including but not 
necessarily limited to the following: 
Tissue Assessment: Tissue can be analyzed by hematoxylin and eosin staining and by IHC for 
PD-L1 and for immune markers (such as CD45, CD68, CD3, CD8, CD4, Foxp3, CD20, 
myeloperoxidase), tumor markers (Ki-67, cleaved caspase 3), vascular (CD31) and stromal 
markers (collagen type I); and by Masson’s trichrome. The tumor may also be assessed by a 
mutational panel and if sufficient material is available, tumor whole exome sequencing (WES) 
and RNA sequencing may be performed. If RNA quality is insufficient, Nanostring technology 
or equivalent for immune activation gene expression may be performed instead of RNAseq or in 
addition. From germline WES from PBMC, HLA type can be determined. From tumor WES, 
tumor RNA-Seq, and germline WES, patient specific neo epitopes arising from tumor somatic 
missense mutations can be predicted bio-informatically. 
Analysis of T-cell activation: Together with complete blood count differentials, multiplex flow 
cytometry analysis of PBMC can be used to measure both the percentages and absolute count 
(cells/mm3) of important T cell subsets defined by immunophenotyping, such as total CD3+ 
cells, CD3+ CD8+ T cells, CD3+ CD4+ T cells, and CD3+ CD4+ Foxp3+ regulatory T cells. 
For each subset, differentiation status (e.g., naïve, central memory, effector memory) or 
activation vs. exhaustion status can be assessed using additional markers such as Eomes, Tbet, 
Granzyme B, Ki-67, CD45RA, ICOS, CD45RO, CCR7, CD28, CD27, CD57, CD25, CD69, 
HLA-DR, CTLA4, and PD-1. When possible, trends will be tracked in T cell subsets based on 
analysis of multiple post-treatment samples. NK cells subsets will also be assessed using CD16 
and CD56, with CD69 as an activation marker. 
An analysis of PBMC may be additionally performed using CyTof technology for deeper 
analysis of immune subsets and activation status in peripheral blood. 
Immune activation may be additionally assessed using RNAseq of PBMC. 
Inflammatory Cytokines/Chemokines: Plasma will be used to determine concentrations of 
cytokines including TGF-β, IL-1, TNF-α, IL-6 and others using a multiplex platform. 
TCR Deep Sequencing: DNA isolated from PBMC (as well as from paraffin embedded tissue) 
can be analyzed by deep sequencing to detect and track specific TCR clones. This technique 
permits assessment of specific adaptive immune response independent of having to know the 
particular relevant tumor antigen, which of course may vary patient to patient. Comparison of 
TCR beta sequence data in serial samples from blood and tumor can demonstrate de novo 
evolution of an anti-tumor T cell repertoire. 
Circulating tumor material: Plasma samples may be tested for circulating biomarkers 
including cell free DNA and tumor cells. Testing will be performed at the 
 Laboratory, 
University of Pennsylvania. 


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Additional research: Beyond the assays noted above, and provided that sample material is left 
over, and with approval of the overall PI and sponsor, investigators may perform additional 
research assays on tumor or blood samples collected in this protocol. 
 
9 STATISTICAL PLAN 
This is a two-arm Phase Ib/II study to evaluate safety and progression-free survival in 84 eligible 
patients. Enrollment is expected to continue for 36 months and follow-up will continue for 6 
additional months, prior to the final analysis of PFS. The null hypothesis is that the PFS rate at 6 
months (PFS6 rate) is 44% (same as reported for standard therapies) and the alternative 
hypothesis is that the PFS6 rate has been increased to 60%. 
 
9.1 
Primary Endpoints 
Safety and progression-free survival at 6 months are primary endpoints. Safety will be assessed 
in 6 patients. If 1 or fewer DLTs are observed in 6 patients, then the current Niraparib dose will 
be declared the MTD. Progression-free survival defined as the time from start of experimental 
therapy to the occurrence of disease progression according to RECIST v1.1, as assessed by the 
investigator, or death from any cause. Patients who are alive and progression-free will be 
censored on the most recent date that documents progression-free status (i.e., scan date or clinic 
visit date). The PFS6 rate and 95% confidence interval will be estimated from the Kaplan-Meier 
curve. 
 
9.2 
Secondary Endpoints 
The secondary endpoints are: 
1. The incidence of adverse events (AEs), clinical laboratory abnormalities and dose 
modifications. 
2. Objective response will be scored per RECIST v.1.1 as assessed by radiology review. 
3. Objective response rate (ORR) is defined as the proportion of patients who achieve a 
complete or partial response, as determined by RECIST. 
4. Overall survival (OS) is defined as the time from start of study therapy to death due to 
any cause. Patients who are alive will be censored on the most recent date of patient 
contact. 
 
 


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9.3 
Sample Size and Power Determination 
9.3.1 
Statistical Methods 
We plan to enroll 84 patients in a two-arm phase Ib/II design. Patients will be randomized in a 
1:1 allocation to either Niraparib + Ipilimumab or Niraparib + Nivolumab. First, safety will be 
assessed in the first 6 patients on each arm. If 1 or fewer of 6 patients have DLT, then the current 
dose of Niraparib will be declared the MTD. Otherwise, the dose of Niraparib will be de- 
escalated and 6 more patients will be treated. Progression-free survival rate at 6 months (PFS6) 
will be the other primary clinical outcome and it will be estimated using the Kaplan-Meier 
method. Based on prior research [1, 2, 20, 21] the null hypothesis is that the PFS6 rate in this 
population of subjects is 44%. The alternative hypothesis is that the PFS6 rate is 60%. Forty-two 
patients per arm, expected to give 30 events, (this number includes the first 6 patients upon 
which safety was established) provide 81% power per arm for a log rank test, to detect this 
increase in PFS6, at a two-sided 5% significance level, assuming an exponential distribution and 
that enrollment will continue for 36 months with an additional 6 months of follow-up prior to the 
final statistical analysis. Secondary outcomes include overall survival (OS) and objective 
response rate (ORR); median OS and 95% confidence interval will be estimated by the Kaplan- 
Meier method and ORR will be an estimated percentage with 95% confidence interval. 
Toxicities will be graded and tabulated and Grade 3 or higher toxicity rates will be calculated. 
With 42 patients per arm, we have 88% power to detect any toxicity occurring at a rate of 5% or 
more. 
Translational Statistics: Genomic and immune endpoints will also be assessed. Serial testing 
of the presence of mutations using tissue and peripheral blood will be described using graphical 
plots and descriptive statistics. 
 
9.3.2 
Baseline Data 
All demographic and baseline characteristics will be summarized for the safety population. 
The following variables will be summarized with frequent tabulations: 
• Time since diagnosis (months) 
• Baseline laboratory parameters: graded based on NCI CTCAE version 5.0 
 
Descriptive statistics may also be used to summarize these variables. 
 
9.3.3 
Efficacy Analysis 
All efficacy evaluations will be conducted using the efficacy population (Section 9.4). If the 
lower bound of the 95% confidence interval for PFS6 is > 44% (the null hypothesis value) then 
the study will be declared a success. 
 
9.3.4 
Safety Analysis 
All safety evaluations will be conducted using the safety population (Section 9.4). 


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9.4 
Subject Population(s) for Analysis 
The following analysis populations are defined for the study: 
Safety Population: The safety population will consist of all patients who received at least one 
dose of study treatment. 
Efficacy Population: The efficacy population will consist of all patients who received at least one 
dose of study treatment and had a least one post-treatment assessment of response by RECIST 
v.1.1 (16.1 Appendix A). Patients who do not have at least one post-treatment assessment of 
response will be replaced. 
 
10 SAFETY AND ADVERSE EVENTS 
10.1 Definitions 
10.1.1 
Unanticipated Problems Involving Risk to Subjects or others 
Any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in nature, severity, or frequency (i.e. not described in study-related 
documents such as the IRB-approved protocol or consent form, the investigators 
brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means 
there is a reasonable possibility that the incident experience, or outcome may have been 
caused by the procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
10.1.2 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study. Intercurrent illnesses or injuries should be regarded as 
adverse events. Abnormal results of diagnostic procedures are considered to be adverse events if 
the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests is considered by the 
investigator to be of clinical significance 
 
10.1.3 
Serious Adverse Event 
Any untoward medical occurrence that, at any dose; 


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• Results in death; 
• Is life threatening (i.e., an event in which the patient was at risk of death at the time of the 
event; it does not refer to an event that hypothetically might have caused death if it were 
more severe); 
• Requires inpatient hospitalization* or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Is a congenital anomaly/birth defect; or 
• Is an important medical event** 
 
*Exception: Preplanned (at time of informed consent) hospitalization for elective procedures, for 
protocol compliance or social reasons, or for observation will not be considered criteria for an 
SAE. The reason for the planned hospitalization should be documented. Complications 
experienced during these hospitalizations must be reported as SAEs if hospitalization is 
prolonged due to AE, or if the complication meets other serious criteria). 
**Medical and scientific judgment should be exercised in determining whether situations or 
events should be considered serious adverse events: an important medical event may not be 
immediately life-threatening or result in death or require hospitalization but may jeopardize the 
patient or require intervention to prevent one of the above outcomes. Examples of such events 
are allergic bronchospasm, blood dyscrasias, or convulsions that may require intensive treatment 
in an emergency room or at home but do not result in hospitalization, development of drug 
dependency or drug abuse, and transmission of disease associated with the administration of the 
study drug. 
Events of progression of the patient’s underlying cancer as well as events clearly 
related to progression of the patient’s cancer (signs and symptoms of progression) 
should not be reported as a serious adverse event unless the outcome is fatal within the 
safety reporting period. If the event has a fatal outcome within the safety reporting 
period, then the event of Progression of Disease must be recorded as an AE and as a 
SAE with CTC Grade 5 (fatal outcome) indicated. 
 
10.1.4 
Adverse Events of Special Interest (AESIs) for Niraparib 
An Adverse Event of Special Interest is defined as any AE (serious or non-serious) that is of 
scientific and medical concern specific to the study treatment. 
Adverse Events of Special Interest (AESI) for niraparib include the following: 
• Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) 
• Secondary cancers (new malignancies [other than MDS or AML]) 
• Embryo-fetal toxicity 
 
AESIs should be reported on SAE/ MedWatch Report Forms whether serious or not and reported 
to the Sponsor in 24 hours 


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10.2 Recording of Adverse Events 
At each contact with the patient, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF). All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis. All adverse events occurring during the study period must be recorded. The 
clinical course of each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause. Serious adverse events that 
are still ongoing at the end of the study period must be followed up to determine the final 
outcome. Any serious adverse event that occurs after the study period and is considered to be 
possibly related to the study treatment or study participation should be recorded and reported 
immediately. 
AEs that meet the criteria of serious, related to study intervention, and unexpected for the study 
intervention, qualify for expedited reporting to the Sponsor and regulatory authorities. The Site 
Investigator will assess all SAEs occurring at his/her site and evaluate for “unexpectedness” and 
relationship to study drug. The Site Investigator is required to complete a Report for the events 
identified as serious, study drug related and unexpected, using the SAE/Medwatch Form. 
A copy of this report should be kept at the site. 
 
10.3 Intensity of Adverse Events 
The severity of each AE will be graded using the NCI CTCAE, Version 5.0 grading scale 
For AEs not covered by NCI CTCAE, the severity will be characterized as mild, moderate, 
severe, or life-threatening according to the following definitions: 
• Mild events are usually transient and do not interfere with the patient’s daily activities 
• Moderate events introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities 
• Severe events interrupt the patient’s usual daily activities and hospitalization (or 
prolongation of hospitalization) may be required 
• Life-threatening events require urgent intervention to prevent death 
 
 
10.4 Causal Relationship of Adverse Events to Study Drugs 
Medical judgment should be used to determine the cause of the AE considering all relevant 
factors such as, but not limited to, the underlying study indication, coexisting disease, 
concomitant medication, relevant history, pattern of the AE, temporal relationship to the study 
medication, de-challenge or re-challenge with the study drugs. 


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Table 14. 
Causal Relationship of Adverse Events to Study Drugs 
 
Not Related To 
Study Drugs 
• An AE that is clearly due to extraneous causes (e.g., concurrent disease, concomitant 
medications, disease under study, etc.) 
• It does not follow a reasonable temporal sequence from administration of the study drug. 
• It does not follow a known pattern of response to study drug 
• It does not reappear or worsen when study drug is restarted. 
• An alternative explanation is likely, but not clearly identifiable. 
Possibly, 
Probably or 
Definitely 
Related to Study 
Drugs 
• An AE that is difficult to assign to alternative causes. 
• It follows a strong or reasonable temporal sequence from administration of study drug. 
• It could not be reasonably explained by the patient’s clinical state, concurrent disease, or 
other concomitant therapy administered to the patient. 
• It follows a known response pattern to study drug 
• It is confirmed with a positive re-challenge or supporting laboratory data. 
 
Causality and expectancy of the adverse events will be assessed for the individual drugs and the 
combination. 
 
10.5 Outcome and Action Taken 
The investigator will record the action taken and outcome for each AE according to the 
following criteria: 
Action Taken with Study Drug (note all that apply) 
• None 
• Dose reduced/delayed 
• Study drug temporarily interrupted 
• Study drug permanently discontinued 
• Other (specify) 
 
Outcome 
• Recovered 
• Recovered with sequelae 
• Recovering/ Resolving/ Improving 
• Ongoing 
• Death 
• Lost to follow-up 


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10.6 Adverse Event Reporting Period 
The study period during which AEs must be reported is defined as the period from the initiation 
of consent through 100 days (nivolumab patients) or 90 days (all patients) after patient End of 
Treatment Visit. 
All AEs (including SAEs and AESIs) occurring during the study are to be followed up in 
accordance with good medical and good clinical practice until resolved; judged no longer 
clinically significant; or, if a chronic condition, until fully characterized through 100 days 
(nivolumab patients) or 90 days (ipilimumab patients) after the last dose of study drug. Any 
SAEs, AESIs, and treatment related Grade 3/4 AEs must be followed until resolution or 
stabilization, or until lost to follow-up. 
 
10.7 Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition 
should be recorded as an AE if the frequency, intensity, or the character of the condition worsens 
during the study period 
 
10.8 General Physical Examination Finding 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition. At the end of the study, any new clinically significant findings/abnormalities that meet 
the definition of an AE must also be recorded and documented as an AE. 
 
10.9 Post-Study Adverse Event 
All unresolved AEs should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the AE is otherwise explained. At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study. 
The investigator should notify the study sponsor of any death or AE occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this 
study. The sponsor should also be notified if the investigator should become aware of the 
development of cancer or of a congenital anomaly in a subsequently conceived offspring of a 
subject that has participated in this study. 
 
10.10 Abnormal Laboratory Values 
It is the responsibility of the investigator to assess the clinical significance of all abnormal values 
as defined by the list of reference ranges from the local laboratory. In some cases, significant 
changes in lab values within the normal range will require similar judgment. 
An abnormal laboratory value that is not already associated with an AE is to be recorded as an 
AE only if any one of the following criteria is met: 
• an action on the study drug is made as a result of the abnormality 
• intervention for management of the abnormality is required 
• at the discretion of the investigator should the abnormality be deemed clinically 
significant 
 
 


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10.11 Pregnancy or Drug Exposure 
If a patient becomes pregnant during the study the investigator is to stop dosing with study 
drug(s) immediately. 
A pregnancy is not considered to be an AE or SAE; however, any pregnancy occurring in a study 
patient during study participation or within 6 months of last dosing, or pregnancy occurring in a 
partner of a study patient during study participation or within 90 days of last dosing must be 
reported to the Penn Sponsor within 1 business day on a MedWatch Form. Elective abortions 
without complications should not be considered AEs unless they were therapeutic abortions, but 
should be reported to the Sponsor Institution. Hospitalization for normal delivery of a healthy 
newborn should not be considered an SAE. Pregnancy is not considered an SAE unless there is 
an associated serious outcome (e.g., maternal serious complications, spontaneous abortions 
therapeutic abortion, ectopic pregnancy, stillbirth, neonatal death, congenital anomaly, and birth 
defect). 
A pregnancy should be followed through to outcome, whenever possible. Once the outcome of 
the pregnancy is known, an updated MedWatch form should be completed and reported to the 
UPenn Sponsor. 
AEs, SAEs, or AESIs that occur during pregnancy will be assessed and processed according to 
the AE or SAE/AESI processes using the appropriate MedWatch report form. 
 
10.12 Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE unless specifically instructed otherwise in this protocol. Any condition 
responsible for surgery should be documented as an AE if the condition meets the criteria for an 
AE. 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
AE in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition. Surgery should not be reported as an outcome of an AE if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for 
the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 


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10.13 Reporting to the UPenn Sponsor 
10.13.1 Adverse Events 
The study clinician will immediately report (1 business day) to the sponsor any serious adverse 
events, whether or not considered related to one of the three investigational products, including 
those listed in the protocol or investigator brochure and must include an assessment of whether 
there is a reasonable possibility that one of the three investigational caused the event. 
The study clinician will immediately report Adverse Events of Special Interest to the sponsor. 
Investigators and the protocol sponsor must conform to the AE reporting timelines, formats and 
requirements of the various entities to which they are responsible, but at a minimum, those 
events that must be reported are those that are: 
• Related to study participation, 
• Unexpected, and 
• Serious or involve risks to subjects or others 
 
If the AE is considered serious, the investigator should report this event to the sponsor within 
one (1) business day. The IRB should be notified as per institutional guidelines. The sponsor 
medical director and site IRB, as appropriate, will make an immediate determination about the 
necessity to modify the protocol, include additional information in the consent form, inform 
previous participants, temporarily hold enrollment of patients, or terminate the study. The study 
will proceed only if the medical director and site IRB all agree on this course of action. 
The investigator or qualified designee will enter the required information regarding the SAE into 
the appropriate module of the eCRF. The event, including the investigator-determined causality 
to study drug should be reported via SAE/MedWatch (link below) to the Medical Monitor. 
For reporting information, please refer to the Manual of Procedures. 
 
Events significant enough to necessitate modification of study drug dosing will be captured on an 
appropriate eCRF module (“Study Drug Dosing” page). 
New information regarding the SAE shall be reported as it becomes available and in the same 
manner that the initial SAE (MedWatch form). All serious adverse events (SAEs) will be 
followed until satisfactory resolution or until the site investigator deems the event to be chronic 
or the participant is stable. Other supporting documentation of the event may be requested by the 
study sponsor and should be provided as soon as possible. 
 
10.13.2 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 investigator or qualified designee to the UPenn 
Sponsor. 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 


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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. 
 
10.14 Investigator Reporting: Local Reporting Requirements 
The investigator will report AEs and SAEs to the IRB/EC of record and other local regulatory 
groups per the local requirements. 
 
10.15 Protocol Exceptions 
A one time, intentional action (planned prospectively) or process that departs from the IRB and 
CTSRMC approved study protocol, intended for one occurrence. Advance documented IRB and 
DSMC approval is required. 
For in-house studies with a Medical Monitor or Safety Monitoring Committee (not DSMB), 
approval must be obtained from the Medical Monitor or Safety Monitoring Committee prior to 
submitting your exception request to the DSMC. 
The following information must be contained in your exception request: 
• When it is needed and why it is needed in that timeframe 
• Has the Medical Monitor or Sponsor approved and provide the documentation of 
approval 
• Is this an exception from eligibility, treatment, disease progression, study calendar 
windows, etc. 
• Why the exception is needed (cite the section(s) of the protocol) along with the full 
clinical details of the subject. This must be determined by the sub-Investigator or PI. 
• The reason why the protocol currently doesn't allow the situation for which an exception 
is being requested. This must be determined by the sub-Investigator or PI. 
• If there are plans to amend the protocol and if not, why not. 
 
If additional follow-up or interventions will be required in order to protect the subject as a result 
of this exception. 
Exceptions to eligibility, treatment/dosing, contraindicated treatment/therapies/interventions or 
safety tests may be rejected by the Sponsor. 
 
10.16 Protocol Deviations 
Any unintentional action or process that departs from IRB approval and is identified 
retrospectively. The deviation is reportable to the DSMC and the IRB within 10 days from the 
time the event becomes known to the study team only when: one or more participants were 
placed at increased risk of harm, or, the event has the potential to occur again, or the event has 
the potential to qualify as serious or continuing noncompliance. 
If the PI determines that a deviation has any potential to impact participant safety (harm and/or 
risk), or the integrity of data produced from the participant, or some other overall impact on the 


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study, the PI must report the deviation to the IRB and DSMC as described above. The IRB will 
make the final assessment of the impact. The DSMC will assess for additional safety and 
scientific integrity concerns. 
The following information must be contained in your deviation report: 
• When it happened? When the study team (any member) became aware 
• The full description of the deviation including important dates, test results, actions taken 
towards the subject, etc. Also, why it happened and how it was identified. 
• Was the Medical Monitor or Sponsor notified? If so, their response? 
• The PIs assessment of the impact on risk, safety and/or outcome. If no impact, why. If 
impact, what and what will happen next. 
• The corrective actions that have been implemented to date and the impact of those 
corrective action plans. 
• Future corrective action plans (if applicable) and the impact of those plans. 
• If there are plans to amend the protocol (if applicable to prevent future deviations) and if 
not, why not. 
 
If the PI determines that the event had no potential to impact participant safety (harm and/or risk) 
or the integrity of data produced from the participant, the PI must fully document his/her 
rationale for each category (risk, harm, and participant data). 
 
10.17 Investigator Reporting to Sponsor of Exceptions and Deviations 
The PI is required to report all SAEs, exceptions and deviations to the Sponsor within 1 business 
day of learning. The Study Sponsor will report to collaborators per contract and the FDA 
according to 21 CFR 312. 
 
10.18 Medical Monitor 
It is the responsibility of the Principal Investigator to oversee the safety of the study. This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as adherence to the study protocol. Medical monitoring will include real time 
reporting (one Business Day) and an assessment annually of the number and type of adverse 
events to the study medical monitor, 
. Additionally, the Medical Monitor will 
be consulted for protocol exceptions and deviations and as needed for enrollment decisions as 
noted above. 
 
10.19 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 


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• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
 
10.20 Data Collection and Management 
This study will use Velos (Penn CTMS) as the data management system. The study case report 
form (CRF) is the primary data collection instrument for the study and will be electronically 
created and completed in Velos. CRFs will be provided for each patient. Subjects must not be 
identified by name on any CRFs. Subjects will be identified by their patient identification 
number (PID). All data requested on the CRF must be recorded. All missing data must be 
explained. If a space on the CRF is left blank because the procedure was not done or the question 
was not asked, write “N/D”. If the item is not applicable to the individual case, write “N/A”. 
 
10.21 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period if required by an agreement with the drug manufacturer. In 
such an instance, it is the responsibility of the drug manufacturer to inform the 
investigator/institution as to when these documents no longer need to be retained. 
 
11 STUDY MONITORING, AUDITING, AND INSPECTING 
11.1 Study Monitoring Plan 
It is the responsibility of the Sponsor to oversee the safety of the study. This safety monitoring 
will include careful assessment and appropriate reporting of adverse events as noted above, as 
well as the construction and implementation of a site data and safety-monitoring plan. This 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
11.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the 
Sponsor, government regulatory bodies, and University compliance and quality assurance groups 
of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.). The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 


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Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
This study will be monitored in accordance with the specific plan developed for this protocol. 
 
12 ETHICAL CONSIDERATIONS 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study conduct. The decision of the IRB concerning the conduct of the study will 
be made in writing to the investigator and a copy of this decision will be provided to TESARO 
and Bristol-Myer Squibb before commencement of this study. 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
and CTSRMC for the study. The formal consent of a subject, using the IRB-approved consent 
form, must be obtained before that subject undergoes any study procedure. The consent form 
must be signed by the subject and the investigator-designated research professional obtaining the 
consent. 
 
13 STUDY FINANCES 
13.1 Funding Source 
This clinical study will be supported by funds provided by TESARO and by Bristol-Myers 
Squibb. 
 
13.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy 
on Conflicts of Interest Related to Research. 
 
14 PUBLICATION PLAN 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor. Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 


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15 REFERENCES 
1. 
Conroy, T., et al., FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N 
Engl J Med, 2011. 364(19): p. 1817-25. 
2. 
Von Hoff, D.D., et al., Increased survival in pancreatic cancer with nab-paclitaxel plus 
gemcitabine. N Engl J Med, 2013. 369(18): p. 1691-703. 
3. 
Waddell, N., et al., Whole genomes redefine the mutational landscape of pancreatic 
cancer. Nature, 2015. 518(7540): p. 495-501. 
4. 
Holter, S., et al., Germline BRCA Mutations in a Large Clinic-Based Cohort of Patients 
With Pancreatic Adenocarcinoma. J Clin Oncol, 2015. 33(28): p. 3124-9. 
5. 
Goggins, M., et al., Germline BRCA2 gene mutations in patients with apparently 
sporadic pancreatic carcinomas. Cancer Res, 1996. 56(23): p. 5360-4. 
6. 
Carnevale, J. and A. Ashworth, Assessing the Significance of BRCA1 and BRCA2 
Mutations in Pancreatic Cancer. J Clin Oncol, 2015. 33(28): p. 3080-1. 
7. 
Cerami, E., et al., The cBio cancer genomics portal: an open platform for exploring 
multidimensional cancer genomics data. Cancer Discov, 2012. 2(5): p. 401-4. 
8. 
Gao, J., et al., Integrative analysis of complex cancer genomics and clinical profiles using 
the cBioPortal. Sci Signal, 2013. 6(269): p. pl1. 
9. 
Alexandrov, L.B., et al., Signatures of mutational processes in human cancer. Nature, 
2013. 500(7463): p. 415-21. 
10. 
Kaufman, B., et al., Olaparib monotherapy in patients with advanced cancer and a 
germline BRCA1/2 mutation. J Clin Oncol, 2015. 33(3): p. 244-50. 
11. 
Mateo, J., et al., DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N 
Engl J Med, 2015. 373(18): p. 1697-708. 
12. 
Choi, Y.E., et al., Platinum and PARP Inhibitor Resistance Due to Overexpression of 
MicroRNA-622 in BRCA1-Mutant Ovarian Cancer. Cell Rep, 2016. 14(3): p. 429-39. 
13. 
Clark, C.E., G.L. Beatty, and R.H. Vonderheide, Immunosurveillance of pancreatic 
adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer 
Lett, 2009. 279(1): p. 1-7. 
14. 
Higuchi, T., et al., CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in 
BRCA1-Deficient Ovarian Cancer. Cancer Immunol Res, 2015. 
15. 
TESARO Summarizes ZEJULA and TSR-042 Data Presented at the 2017 ESMO Annual 
Meeting. 2017; Available from: 
http://ir.tesarobio.com/releasedetail.cfm?releaseid=1039856. 
16. 
Momtaz, P., et al., Safety of Infusing Ipilimumab Over 30 Minutes. J Clin Oncol, 2015. 
33(30): p. 3454-8. 
17. 
Birkbak, N.J., et al., Telomeric allelic imbalance indicates defective DNA repair and 
sensitivity to DNA-damaging agents. Cancer Discov, 2012. 2(4): p. 366-75. 
18. 
Popova, T., et al., Ploidy and large-scale genomic instability consistently identify basal- 
like breast carcinomas with BRCA1/2 inactivation. Cancer Res, 2012. 72(21): p. 5454-62. 
19. 
Abkevich, V., et al., Patterns of genomic loss of heterozygosity predict homologous 
recombination repair defects in epithelial ovarian cancer. Br J Cancer, 2012. 107(10): p. 
1776-82. 
20. 
Golan, T., et al., Overall survival and clinical characteristics of pancreatic cancer in 
BRCA mutation carriers. Br J Cancer, 2014. 111(6): p. 1132-8. 


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21. 
Heinemann, V., et al., Randomized phase III trial of gemcitabine plus cisplatin compared 
with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol, 2006. 24(24): p. 
3946-52. 
22. 
National Cancer Institute. Common Terminology Criteria for Adverse Events, Version 
4.03. 14 June 2010 [cited 19 November 2014]; Available from: 
http://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06- 
14_QuickReference_5x7.pdf. 
23. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 


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16 APPENDIX 
16.1 Appendix A: ECOG 
Table 15. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale 
 
ECOG Performance Status 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary 
nature (eg light house work or office work). 
2 
Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more 
than 50% of waking hours. 
3 
Capable only of limited self care; confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self care. Totally confined to bed or chair. 
5 
Dead. 
 
16.2 
Appendix B: Response Evaluation Criteria in Solid Tumors Criteria 
The RECIST guidelines (Version 1.1) are described in Eisenhauer (2009)[23] and at 
http://www.eortc.be/Recist/Default.htm. A short summary is given below. 
Measurable Disease: 
Tumor lesions: measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with the following: 
• A minimum size of 10 mm by CT scan (CT scan thickness no greater than 5 mm). 
• A minimum size of 10 mm caliper measurement by clinical exam (lesions that cannot be 
accurately measured with calipers should be recorded as nonmeasurable). 
• A minimum size of 20 mm by chest X-ray. 
 
All tumor measurements must be recorded n millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes: to be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be not greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Nonmeasurable Disease: 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), as well as truly nonmeasurable 
lesions, are considered nonmeasurable disease. Lesions considered truly nonmeasurable include 
leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, 
lymphangitic involvement of skin and lung, and abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 


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Bone Lesions: 
Bone lesions, cystic lesion, and lesions previously treated with local therapy require particular 
comment. Bone scan, PET scan, or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
Lytic bone lesions or mixed lytic–blastic lesions with identifiable soft tissue components that can 
be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
Blastic bone lesions are nonmeasurable. 
Cystic Lesions: 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor nonmeasurable) because they are, by definition, 
simple cysts. 
Cystic lesions thought to represent cystic metastases can be considered as measurable lesions if 
they meet the definition of measurability described above. However, if noncystic lesions are 
present in the same patient, these are preferred as target lesions. 
Lesions with Prior Local Treatment: 
Tumor lesions situated in a previous irradiated area or in an area subjected to other locoregional 
therapy are usually not considered measurable unless there has been demonstrated progression in 
the lesion. 
Target Lesions: 
All measurable lesions up to a maximum of two lesions per organ and five 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. 
Non-target Lesions: 
RECIST criteria require unequivocal quantification of the changes in tumor size for adequate 
interpretation of the sum of target lesions. Consequently, when the boundaries of the primary are 
difficult to delineate, this tumor should not be considered a target lesion. 
Guidelines for Evaluation of Measurable Disease: 
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. 


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Table 16. 
Evaluation of Target Lesions 
 
Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes (whether target 
or nontarget) must have reduction in short axis to <10mm 
Partial Response 
At least a 30% decrease in the sum of the LD of target lesions, taking as reference 
the baseline sum LD. 
Stable Disease 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as a reference the smallest sum LD since the treatment started. 
Progressive Disease 
At least a 20% increase in the sum of all the LD of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5mm. The appearance of one or more new lesions is 
also considered progression. 
 
Table 17. 
Evaluation of Nontarget Lesions 
 
Complete Response 
Disappearance of all non-target lesions and normalization of tumor marker levels. 
Stable Disease/ 
Incomplete Response 
Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker 
level above the normal limits. 
Progressive Disease 
Appearance of one or more lesions and/or unequivocal progression of existing non- 
target lesions. 
 
If tumor markers are initially above the institutional ULN, they must normalize for a patient to 
be considered to be a complete responder. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
Table 18. 
Evaluation of Best Overall Response 
 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not evaluated 
No 
PR 
SD 
Non-PD or not evaluated 
No 
SD 
Not Evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NE = not evaluable 
 


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Patients with global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having symptomatic 
deterioration. Every effort should be made to document the objective progression, even after 
discontinuation of treatment. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When evaluation of CR depends on this determination, it is recommended that the residual lesion 
be investigated (fine needle aspiration/biopsy) prior to confirming the complete response status. 
Confirmatory Measurement/Duration of Response 
Confirmation 
CT scans are required at screening and within 7 days prior to the start of every odd numbered 
cycle (i.e., Cycles 3, 5, 7, etc.). If an initial CR or PR is noted, confirmatory scans must be 
performed >4 weeks later. 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded since the treatment 
started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
SD is measured from the start of the treatment until the criteria for progression are met, taking as 
reference the smallest measurements recorded since the treatment started. 
 


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16.3 Appendix C: COVID-19 Study Implication Memo 
 
 


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