Clinical trial NCT03061188
Conditions: Advanced Solid Neoplasm Aggressive Non-Hodgkin Lymphoma Recurrent Solid Neoplasm Refractory Mantle Cell Lymphoma T-Cell Non-Hodgkin Lymphoma Unresectable Solid Neoplasm
Sponsor: Northwestern University
Start date: 2017-05-23; Completion date: 2020-08-04
Enrollment: 15 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this research study is to determine the highest and safest dose of the experimental drug veliparib when combined with nivolumab. We will also study how safely this combination of medication can be given in advanced cancer and lymphoma and benefits of receiving this therapy. Nivolumab is currently approved in certain cancers such as melanoma, lung cancer and kidney cancer. Veliparib is not yet approved for use in the United States, and is considered experimental. Veliparib inhibits (blocks) the activity of the enzyme PARP. This blocking activity may prevent the cancer cell from repairing itself and resume growing. Nivolumab increases T cells in your immune system, which allows your immune system to attack the cancer. We think the combination of these drugs will be more effective against your cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To identify maximum tolerated dose (MTD) for the combination treatment of nivolumab and veliparib in patients with advanced refractory solid cancers and lymphoma.

SECONDARY OBJECTIVES:

I. To evaluate the safety and tolerability of nivolumab and veliparib in patients with advanced refractory solid cancers and lymphoma with and without mutations in selected DNA repair genes.

II. To evaluate the efficacy of treatment with nivolumab and veliparib in this population by objective response rate (ORR, defined as partial response \[PR\] + complete response \[CR\]), clinical benefit rate (CBR, defined as stable disease \[SD\] for \>= 12 weeks, PR, + CR), and progression free survival (PFS, defined as the time from treatment initiation to documented disease progression) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria version (v)1.1 or Lugano criteria.

III. To evaluate efficacy of treatment with nivolumab and veliparib in this population by ORR, CBR, and immune-related PFS (irPFS) using irRECIST criteria.

IV. To evaluate overall survival (OS) in this population at 3 years from the start of treatment.

V. To evaluate the proportion of patients alive and progression free at 24 weeks in this population.

VI. To evaluate ORR to nivolumab and veliparib in patients with prior exposure to single agent PD-1/PD-L1 inhibitors.

TERTIARY OBJECTIVES:

I. To evaluate if any of the following predict response to veliparib in combination with nivolumab: tissue PD-L1 protein expression, immune cell infiltration markers.

II. To demonstrate the pharmacodynamic effects of veliparib and nivolumab on biomarkers including PD-L1, TILs, T cell subpopulations, and T cell receptor genotype.

III. To explore the pattern of clonal changes through circulating cell free DNA assay.

IV. To assess the dynamic change in both immune and genomic biomarkers in blood that may correlate with response to veliparib.

OUTLINE: This is a dose-escalation study of veliparib.

Patients receive veliparib orally (PO) twice daily (BID) on day 1 and nivolumab intravenously (IV) over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months and then every 6 months for 3 years.

Arms: arm 1: Patients receive veliparib PO BID on day 1 and nivolumab IV over 30 minutes on days 1 and 15 of courses 1-4 and IV over 60 minutes on day 1 of subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Nivolumab intervention 3: Pharmacological Study intervention 4: Veliparib
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Phase I/Ib Study of Nivolumab and Veliparib in Patients with Advanced Solid Tumors and 
Lymphoma with and without Alterations in Selected DNA Repair Genes
Principal Investigator:
Young Kwang Chae, MD, MPH, MBA
Developmental Therapeutics Program of Division of 
Hematology Oncology
645 N. Michigan Avenue Suite 1006
Chicago, IL 60611
312-926-4248
Fax: 312-695-0370
E-mail:    young.chae@northwestern.edu
Sub-Investigator(s):
Developmental Therapeutics Program of Division of Hematology 
Oncology:
Sunandana Chandra, MD 
 
Jason Kaplan, MD
 
Aparna Kalyan, MD 
Massimo Cristofanilli, MD
Victoria Villaflor, MD
Valerie Nelson, MD
Neal Christiansen, MD
Alok Pant, MD
Mark Agulnik, MD
Biostatistician:
Borko Jovanovic, PhD
Study Intervention(s):
Nivolumab, Veliparib
IND Number:
133333
IND Holder:
 Young Kwang Chae, MD, MPH, MBA
Funding Source:
  Rare Population Malignancy Program (RPMP) grant from BMS 
                                                     Veliparib supply from Abbvie
Version Date:
3/3/2020 (Amendment 7)
Coordinating Center:
Clinical Trial Office
Robert H. Lurie Comprehensive Cancer Center 
Northwestern University
676 N. St. Clair, Suite 1200
Chicago, IL 60611 
http://cancer.northwestern.edu/cro/index.cfm
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
TABLE OF CONTENTS
LIST OF ABBREVIATIONS..............................................................................................................................3
STUDY SUMMARY ..........................................................................................................................................6
1.0
INTRODUCTION – BACKGROUND & RATIONALE...................................................................11
2.0
OBJECTIVES & ENDPOINTS......................................................................................................18
3.0
PATIENT ELIGIBILITY .................................................................................................................20
4.0
TREATMENT PLAN.....................................................................................................................23
5.0
STUDY PROCEDURES ...............................................................................................................42
6.0
ENDPOINT ASSESSMENT..........................................................................................................45
7.0
ADVERSE EVENTS .....................................................................................................................48
8.0
DRUG INFORMATION.................................................................................................................53
9.0
CORRELATIVES/SPECIAL STUDIES .........................................................................................59
10.0
STATISTICAL CONSIDERATIONS..............................................................................................60
11.0
STUDY MANAGEMENT...............................................................................................................62
REFERENCES ...............................................................................................................................................65
APPENDICES ................................................................................................................................................67
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
3
LIST OF ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest 
ALT
Alanine Aminotransferase
  ALK
lk
Anaplastic lymphoma kinase
ALC
Absolute Lymphocyte Count
AST
Aspartate Aminotransferase
BMS
Bristol-Myers Squibb 
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CLIA
Certified Laboratory Improvement Amendments
CMP
Comprehensive Metabolic Panel
CR
Complete Response
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLBCL
Diffuse Large B-cell Lymphoma
DLT
Dose Limiting Toxicity
DSMB
Data and Safety Monitoring Board
ECOG
Eastern Cooperative Oncology Group
HR
Heart rate
irAE
Immune-related Adverse Event
irRECIST
Immune-related RECIST
IV (or iv)
Intravenously
LTF
Lost to Follow-up
MMR
Mismatch Repair
MSI-H
Microsatellite Instability High
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NSCLC
Non Small-Cell Lung Cancer
ORR
Overall Response Rate or Objective Response Rate
OS
Overall Survival
PARP
Poly (ADP-ribose) Polymerases
PBMCs
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PD-1
Programmed Death-1
PFS
Progression Free Survival
PO (or p.o.)
Per os/by mouth/orally
PR
Partial Response
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
4
SJS
Stevens-Johnson Syndrome
SPGT
Serum Glutamic Pyruvic Transaminase
TEN
Toxic Epidermal Necrolysis
TIL
Tumor Infiltrating Lymphocyte 
TMZ 
Temozolomide 
TNBC
Triple Negative Breast Cancer
WBC
White Blood Cells
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
STUDY SCHEMA
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
5
1 cycle = 28 days

Veliparib*: Assigned dose PO twice daily starting as 
monotherapy 7 days prior to Cycle 1 Day 1 

Nivolumab: 
Cycle 1-4: 240 mg IV every 14 days (Days 1 & 15) +
Cycle 5+: 480mg IV every 28 days (Day 1)
*Dose escalation for veliparib is based on a 3+3 design starting 
at 300mg PO BID.
 Additional 6 patients will be enrolled in the expansion cohort 
(Phase 1B) once MTD is established with 6 patients on it (15 
total; 3 at lower dose and 6+6 at MTD)
[A preliminary efficacy analysis will be done with the 10 patients 
with genetic mutation]
Response Assessment every 2 cycles (8 weeks) by CT or MRI
Once off treatment continue follow-up at 3, 6, 9, and 12 months then 
every 6 months up to 3 years or until the time of death
Patients may continue on therapy until progression, intolerability, 
or withdrawal of consent (as specified in Sections 4.1.1 and 
4.1.2).
Stage IV advanced solid tumors and lymphoma 
NOTE: For Phase IB, patients must have 
mutations in selected DNA repair genes
This study will 
be closed after 
the 6 additional 
patients will 
have been 
recruited .  
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
6
STUDY SUMMARY
Title
Phase I/IB study of nivolumab and veliparib in patients with advanced 
solid tumors and lymphoma with and without mutations in selected DNA 
repair genes 
Version
3/3/2020 (Amendment 7)
Study Design
   Phase I/IB
Study Center
Northwestern University
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
7
Primary Objectives:
A.
To Identify the maximum tolerated dose (MTD) for combination 
treatment of nivolumab and veliparib in patients with advanced solid 
tumors and lymphoma with and without mutations in selected DNA 
repair genes.
Secondary Objectives:
A.
To evaluate the toxicities and tolerability of nivolumab and veliparib 
in the study population.
B.
To evaluate the efficacy of veliparib and nivolumab measured by overall 
response rate (ORR), clinical benefit rate (CBR), and progression free 
survival (PFS) using RECIST v1.1, Lugano classification, and irRECIST.  
For the preliminary efficacy analysis, ORR will be computed at the first 
imaging (8 weeks). Preliminary efficacy will be evaluated by RECISTv 1.1. 
As exploratory analysis, irRECIST will be used to obtain preliminary 
efficacy as well.  All ORR will use the first imaging time point whether 
RECIST or irRECIST.
C.
To evaluate Overall Survival (OS) at 3 years from the start of treatment.
D.
To evaluate the proportion of patients alive and progression free at 24 
weeks in this population.
Exploratory Objectives:
A.
Biomarker tests will be performed at baseline using fresh tissue (or 
archived if a fresh biopsy is not feasible), as well as from blood samples at 
Cycle 1 Day 1, Cycle 3 Day 1, and the End of Treatment visit.To evaluate if 
any of the following predict response to veliparib in combination with nivolumab:
Tissue PD-L1 protein expression
Immune cell infiltration markers
B.
To demonstrate the pharmacodynamic effects of veliparib and nivolumab 
on biomarkers including PD-L1, TILs, T cell subpopulations, and T cell 
receptor genotype.
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
8
Sample size
The initial study design was to accrue a total of up to 50 patients for 48 evaluable) 
to the study in two phases: dose escalation and dose expansion. The original 
design anticipated a total of 6-18 patients with advanced solid tumors or lymphoma 
in the dose escalation phase; 9 patients were enrolled, including 3 at lowest dose and 
6 that were treated at the MTD of 400 mg BID. It is still planned for 6 patients with 
advanced solid tumors and lymphoma with mutations in selected DNA repair 
genes to be enrolled into the expansion cohort to receive the maximum tolerated 
dose of veliparib in combination with nivolumab. However, due to funding issues, the 
study will perform an early analysis of preliminary efficacy after the next 6 patients are 
enrolled in the expansion cohort, all with the genetic mutation. Of the 6 patients already at 
MTD, 4 have the genetic mutation. No responses were observed in any patient at MTD. 
Total number of patients at the end of adding 6 more patients with mutation will be 
4+6=10. The study will be considered a “success” if the lower exact 90%  confidence limit 
is > 10%, i.e. when 3 or more successes are observed. 
. According to the modified plan for the current trial, the study will be closed after the 6 
additional patients will have been recruited.”
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
9
Diagnosis & 
Key 
Eligibility 
Criteria
Key Inclusion Criteria:
1.
Patients must have a histologically documented (either primary or 
metastatic site) diagnosis of metastatic or advanced solid cancer (stage IV 
or unresectable) or aggressive lymphoma. 
NOTE: The following histologies will be excluded given known response 
to PD-1/PD-L1 inhibitor monotherapy; non-small cell lung cancer, 
squamous cell carcinoma of head and neck, melanoma, renal cell 
carcinoma, bladder cancer, Hodgkin’s lymphoma, Merkel cell carcinoma, 
and MSI-H colorectal cancer.
2.
All patients must have received at least one line of systemic treatment. 
3.
Patients who progressed on single agent PD-1/PD-L1 inhibitors are allowed. 
4.
Patients must be ECOG performance status of 2 or less and have normal 
organ function. 
5.
For expansion cohort, patients should have alterations in selected DNA repair 
genes in their tumors, as listed in 3.1.6.
Please note: This eligibility criteria is also applicable for patients enrolled for the 
preliminary expansion cohort to conduct preliminary efficacy analysis.
Key Exclusion criteria: 
1.
Patients who have had chemotherapy or radiotherapy ≤ 14 days prior to 
entering the study are not eligible.
2.
Patients may not have received systemic chemotherapy ≤ 28 days prior to 
registration.
3.
Patients are not eligible who have had major surgery ≤ 14 days of 
registration.
4.
Patients are not eligible who have received prior PARP inhibitors (including 
but not limited to veliparib, talazoparib, rucaparib, and olaparib).
5.
Patients are not eligible who have received prior immunotherapy including 
interleukin-2 and immune checkpoint antagonists and/or agonists (including 
but not limited to PD-1, PD-L1, CD137, or OX40). 
NOTE: Single agent anti-CTLA4 monoclonal antibody treatments are 
permitted. Cancer vaccine therapies are permitted.
6.
Patients are not eligible who have had a prior allogeneic stem cell 
transplant.
NOTE: Autologous stem cell transplant is acceptable.
Patients with autoimmune diseases are excluded.
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
10
Treatment Plan
Patients will be treated using a dose escalation plan based on a 3+3 design. 
The starting dosing for veliparib will be 300 mg PO twice daily, and treatment 
will begin as monotherapy during a 7-day induction period. Patients in Phase 
Ib will be treated at the MTD.
Nivolumab combination therapy will begin Cycle 1 Day 1 as follows:
Cycle 1-4: 240 mg IV every 14 days (Day 1 & 15)
Cycle 5+: 480mg IV every 28 days (Day 1 of each cycle).  
Combination treatment will continue until disease progression unacceptable 
toxicity, or withdrawal of consent.
This treatment plan is applicable for patients in both the dose escalation and 
dose expansion cohorts.
Statistical 
Methodology
The primary analysis will be based on toxicity and maximum tolerated dose. 
For all analyses, the intent-to-treat (ITT) population will be used to include all 
evaluable patients. Clinical benefit rate will be defined as stable disease (for 
≥12 weeks) and complete or partial response by the Response Evaluation 
Criteria in Solid Tumors (RECIST). Lugano classification will be used for 
lymphomas. Maximum response prior to disease progression will be used. The 
overall response rate will be estimated by the proportion of overall response, 
and its 90% lower bound will be estimated using the exact binomial distribution. 
If this lower bound > 10% (ie. at least three responses are observed) the trial 
will be considered a success. 
Additionally, we will evaluate overall response rate, separately for patients with 
and for those without genetic mutation entertained in this study, Early analysis of 
preliminary efficacy will be based on the patients with genetic mutation (n=10). 
Response is defined as complete or partial response using RECIST guidelines 
in a similar manner. We will also perform similar analyses using Immune 
Related RECIST (irRECIST). Duration of response, defined as the duration 
from the first documentation of clinical benefit to the first documented 
progressive disease or death of any cause, whichever occurs first, will also be 
analyzed. For patients alive and progression-free at the time of data cut off, 
duration of response will be censored as of the last tumor assessment date. 
Duration of response will only be evaluated for the subgroup of patients with a 
clinical benefit using the Kaplan-Meier method. 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
11
1.0
INTRODUCTION – BACKGROUND & RATIONALE
1.1 
Significant unmet need in treatment of advanced cancers: 
Despite the success of molecularly targeted drugs against the activity of one or more 
proteins involved in tumorigenesis, these agents only benefit a small proportion of 
patients. Many tumors do not possess an actionable mutation and have limited 
therapeutic options for subsequent therapy. The advent of immune checkpoint inhibitors 
has expanded therapeutic options and produced durable responses among immunogenic 
tumors. However, response is only seen in a poorly defined subset of patients and many 
patients are refractory to such treatment or relapse after such therapy. We must 
investigate ways to increase the number of patients with different histologies that may 
benefit from immune checkpoint inhibition and extend duration of response through the 
use of novel combination therapy.
1.2 
Synthetic lethality of PARP inhibitors: 
Inhibitors of poly (ADP-ribose) polymerases (PARP) have demonstrated the biological 
concept of synthetic lethality.1-3 Two genes are synthetically lethal if loss of either alone is 
viable whereas concurrent loss results in cell death.4 It has been demonstrated that 
BRCA1 and BRCA2 dysfunction sensitized cells to PARP inhibition, resulting in genomic 
instability, cell cycle arrest, and apoptosis.5 It is thought that PARP inhibitors utilize the 
homologous recombination 6 deficiency in BRCA-deficient cells to cause an increase in 
persistent single strand breaks (SSBs), resulting in collapsed replication forks and 
ultimately creating double strand breaks (DSB).2,7 HR-deficient cells are unable to 
maintain the integrity of the genome and become nonviable. PARP inhibitors have now 
demonstrated efficacy for the treatment of ovarian cancer with BRCA mutations.8,9 
Identification of other mediators of cellular response to PARP inhibitors may reveal 
additional patient populations that could benefit from this therapeutic approach.
1.3 
Tumors with BRCA-like gene defects as a distinct entity: 
We have queried a publicly available database (COSMIC) to obtain the overall frequency 
of mutations of DNA repair genes. We demonstrated that DNA repair genes are mutated 
at the average frequency of 5% across various tumor types. As with ALK rearranged non-
small cell lung cancer, these unique subgroup of patients make up a molecularly defined 
rare group of cancer. It is well known that germ-line mutations in DNA repair pathway 
genes have been associated with various hereditary cancer syndromes. BRCA 1/2 
mutated hereditary breast and ovarian cancer syndrome is a prime example. 
There are a number of solid tumors that harbor defects in homologous recombination 
repair outside of BRCA 1/2 that are referred to as “BRCA-like” tumors or possessing 
“BRCAness.”10 Loss or disruption of proteins necessary for HR such as RAD51, ATM, 
ATR, CHK1, CHK2, FANCD2, and FANCA are observed in a variety of tumors. In 
muscle-invasive bladder cancer, patients with tumors with mutations in DNA repair genes 
such as ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2 demonstrated better 
survival outcome after cystectomy compared to patients with tumors without mutations. In 
pancreatic cancer, genomic instability co-segregated with inactivation of DNA repair 
genes including ATM, BRCA1, BRCA2 or PALB2. The individuals with defects in these 
DNA repair mechanisms demonstrated better treatment responses. These observations 
suggest that somatic mutations in HR DNA repair pathway genes may form a distinct 
entity across different histologies.
Recently it has been shown that BRCA1/2-mutated tumors were associated with 
significantly higher CD8+/CD4+ ratio of tumor infiltrating lymphocytes (TILs) and 
significantly higher peritumoral T cells. These findings support an additional mechanism 
for the improved survival of patients with BRCA1/2-mutated ovarian cancers in addition to 
increased sensitivity to platinum chemotherapy11.
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
12
1.4 
Rationale of PARP inhibitors in BRCA like tumors: 
It is expected that tumors displaying inherent or acquired DNA repair defects would most 
likely respond to PARP inhibition12. Ongoing research suggests HR deficiency, rather 
than a specific mutation in the BRCA genes, may be the main driver of cytotoxicity of 
PARP inhibition.13 The BRCA-like behavior has been described based on clinical and 
molecular features that parallel germline BRCA mutation-associated cancer 
characteristics. The major clinical BRCA-like behavior identified is susceptibility to 
platinum compounds and other DNA-damaging agents.14,15 
Recent trial (ARIEL2) in ovarian cancer demonstrated that a use of PARP inhibitor 
(rucaparib) was associated with higher PFS rates among patients with BRCA mutations 
and BRCA-like wild-type ovarian cancer compared to biomarker-negative tumors. The 
median PFS for mutation carriers was not reached after 9.4 months, compared with 7.1 
months for patients with BRCA-like tumors and 3.7 months for participants who were 
biomarker negative16. There are also ongoing efforts to develop a predictive genomic 
companion diagnostics of HR deficiency that can help determine potential patients who 
would benefit from PARP inhibitor treatment.
1.5
Overall somatic mutation burden of tumor and defects in DNA repair mechanisms: 
Mutations in critical genes such as those involved in DNA repair will likely result in 
genomic instability and subsequent hypermutability. For example, it is well known that 
mismatch repair (MMR) deficient tumors have extremely high mutation rates. Similarly, in 
muscle-invasive bladder cancer, mutations in either of the DNA repair genes (ATM, 
ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) were associated with higher somatic 
mutation burden as measured by non-synonymous single nucleotide variant (SNV) and 
higher T cell clonality as measured by lower T cell receptor (TCR) diversity index. This 
hypermutable state generated by defects in the DNA repair mechanism may be 
responsible for altering the tumor ‘mutanome’, resulting in the production of highly tumor-
specific mutated ‘neo-antigens’, potentially increasing the efficacy of immunotherapies.17 
Tumor infiltrating lymphocytes (TILs) from adoptive cell transfer-treated melanoma 
patients were found to show specificity for mutated tumor proteins, and further screening 
to estimate their ability to bind T cell major histocompatibility complex positively 
correlated with tumor regression. In multiple tumor types, immunogenicity of mutated 
tumor neo-antigens correlated with patient survival and increased TILs. Patients with 
MMR deficient colorectal cancer as well as MMR deficient non-colorectal cancers treated 
with PD-1 inhibitors have demonstrated better response compared with patients MMR 
proficient tumors. Furthermore, in ovarian cancer and triple negative breast cancer 
(TNBC) where BRCA1 or 2 mutations are more prevalent than other subtypes, favorable 
responses to immune checkpoint inhibitors have also been reported. 
1.6 
Veliparib
1.6.1 
Clinical development of Veliparib
Veliparib is a novel small molecule that is a potent inhibitor of PARP-1 and 
PARP-2 (Investigator's Brochure; edition 9 – 12 June 2015). PARPs are 
enzymes involved in DNA repair. In cells under oxidative stress, veliparib inhibits 
the PARP induced formation of poly-(ADP-ribose) (PAR). In cellular assays, 
veliparib increases sensitivity of tumor cells to DNA-damaging agents including 
platinum agents, irinotecan, cyclophosphamide, temozolomide (TMZ) and 
radiation. In preclinical tumor models, veliparib enhances the anti-tumor efficacy 
of DNA crosslinking agents (cisplatin, carboplatin), alkylating/methylating agents 
(TMZ, cyclophosphamide), topoisomerase inhibitors (irinotecan) and radiation. 
Veliparib has been shown to enhance the efficacy of carboplatin in several 
xenograft tumor models. In the BRCA1 deficient MX-1 model, veliparib 
administered at doses as low as 25 mg/kg/day significantly enhanced the efficacy 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
13
of carboplatin. (Investigator's Brochure; edition 9 – 12 June 2015)
Veliparib is being investigated in AbbVie-sponsored studies, in Investigator 
initiated
studies (IIS), and in CTEP-sponsored studies. In these studies, veliparib is 
administered as monotherapy, combined with a variety of chemotherapeutic 
agents, including alkylating agents, platinums, and topoisomerase inhibitors, and 
radiation or combined with radiation therapy across an array of tumor types, 
including melanoma, glioma, prostate, breast, and colon. 
1.6.2 
Clinical efficacy of Veliparib
Summary preliminary or final efficacy data from AbbVie sponsored studies have 
shown that veliparib has activity in combination with temozolomide (TMZ), 
radiotherapy and chemotherapy. A phase II study evaluating veliparib in the 
treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary 
peritoneal cancer in patients who carry a germline BRCA1or BRCA2 mutation 
showed a response rate of 26% (90% CI: 16%-38%, CR: 2, PR: 11); for 
platinum-resistant and platinum-sensitive patients the proportion responding was 
20% and 35%, respectively.9 Data from non-AbbVie sponsored studies show 
veliparib has activity as monotherapy for treatment of ovarian cancer18 and 
activity in combination with carboplatin + paclitaxel for treatment of early breast 
cancer.19 Veliparib is currently in Phase 2 and Phase 3 clinical development in 
combination with several DNA-damaging agents across a variety of cancer 
indications including a planned combination of Nivolumab in NSCLC.
1.6.3 
Clinical safety of Veliparib
In the veliparib clinical development program, veliparib has been administered as 
monotherapy and as combination therapy to subjects with various solid tumors. 
Veliparib has been administered in doses up to 500 mg BID as monotherapy and 
up to 400 mg BID in combination with cytotoxic chemotherapies or radiation 
therapy. (Investigator's Brochure; edition 9 – 12 June 2015). The overall safety 
experience with veliparib, as monotherapy or in combination with other 
therapeutics, is based on experience in approximately 3700 subjects treated to 
date (of which approximately 250 patients treated with single agent veliparib). 
Some of the common side effects with veliparib monotherapy (≥10%) include 
constitutional symptoms such as fatigue, loss of appetite, dysguesia, feeling 
dizzy, sleep disturbance; Gastrointestinal side effects such as nausea, vomiting, 
diarrhea, constipation; hematological toxicity such as anemia, leucopenia and 
thrombocytopenia; increased liver enzymes and blood sugars. Less frequent 
(<10%), but potentially severe events included dehydration and seizures. Very 
rare side effects include secondary malignancy (<1%) and Myelodysplastic 
syndrome (<0.1%), however were not seen in veliparib monotherapy studies. 
1.7 
Nivolumab
1.7.1 
Clinical development of Nivolumab
Nivolumab (BMS-936558, MDX-1106) is a fully human monoclonal 
immunoglobulin G4 (IgG4) antibody (HunMab) that is specific for human 
programmed death-1 (PD-1, cluster of differentiation 279 [cd279]) cell surface 
membrane receptor (Investigator Brochure version 2014). PD-1, a 55-kDa type 1 
transmembrane protein, is a member of the CD28 family of T-cell co-stimulatory 
receptors that include Ig super family member CD28, CTLA-4, inducible co-
stimulator (ICOS), and B and T lymphocyte attenuator (BTLA). PD-1 is a 
negative regulatory molecule that is expressed transiently following T-cell 
activation and on chronically stimulated T cells characterized by an “exhausted” 
phenotype. Nivolumab anti-tumor activity has been investigated in patients with 
melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). 
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PD-1 knockout mice develop strain-specific lupus-like glomerulonephritis 
(C57BL/6) and cardiomyopathy (BALB/c). In transplantable tumor models that 
expressed PD-1 and LAG-3 on tumor-infiltrating CD4+ and CD8+ T cells dual 
anti-LAG-3/anti-PD-1 antibody treatment cured most mice of established tumors 
that were largely resistant to single antibody treatment 21. Despite minimal 
immunopathologic sequelae in PD-1 and LAG-3 single knockout mice, dual 
knockout mice abrogated self-tolerance with resultant autoimmune infiltrates in 
multiple organs, leading to eventual lethality. PD-L1 expression is found on a 
number of tumors, and is associated with poor prognoses based on OS in many 
tumors, including melanoma, renal, esophageal, gastric, ovarian, pancreatic, 
lung, and other cancers (Investigator Brochure version 2014) 22-28. 
Nivolumab has been evaluated as monotherapy and in combination with 
cytotoxic chemotherapy, other immunotherapy (such as ipilimumab), anti-
angiogenesis therapy, and targeted therapies in completed and ongoing BMS-
sponsored clinical trials in NSCLC, melanoma, RCC, hepatocellular carcinoma 
(HCC), gastrointestinal (GI) malignancies including colorectal cancer with 
microsatellite instability (MSI), and triple-negative breast cancer (TNBC) with an 
expanding group of indications (Investigator Brochure version 2014). Nivolumab 
is currently FDA approved for the treatment of patients with: (i) unresectable or 
metastatic melanoma and disease progression after ipilimumab and, if BRAF 
V600 mutation positive, a BRAF inhibitor; (ii) patients with metastatic squamous 
non-small cell lung cancer with progression on or after platinum-based 
chemotherapy.
1.7.2
Clinical efficacy
Nivolumab has demonstrated clinical activity as monotherapy and as 
combination therapy with ipilimumab in several tumor types, including RCC, 
melanoma, NSCLC, and some lymphomas. The majority of responses was 
durable and exceeded 6 months (Investigator Brochure version 2014). 
Nivolumab is being investigated both as monotherapy and in combination with 
chemotherapy, targeted therapies, and other immunotherapies. 
In a phase 1 (1, 3, and 10 mg/kg nivolumab doses) dose-escalation study the 3 
mg/kg dose was chosen for expanded cohorts. Among 236 patients, objective 
responses (ORs) (complete or partial responses [CR or PR]) were seen in 
NSCLC, melanoma, and RCC. ORs were observed at all doses. Median OS was 
16.8 months across doses and 20.3 months at the 3 mg/kg dose. Heavily 
pretreated patients with NSCLC treated with nivolumab (1, 3, or 10mg/kg) 
achieved median OS across all dose cohorts of 9.9 months with response rates 
of 17% and median duration of response 17 months 29. In addition, responses 
were similar between both squamous and non-squamous carcinoma cohorts in 
this study. A subsequent phase 3 study compared nivolumab to docetaxel in 
second-line treatment setting of advanced squamous cell carcinoma among 272 
patients. Nivolumab arm demonstrated superior median OS (9 vs 6 months), 1 
year survival rate (42 vs 24%), response rates (20 vs 9%), and significantly lower 
rates of grade 3-4 treatment related adverse events (7 vs 55%) 30. These results 
supported the FDA approval of nivolumab for second-line treatment of advanced 
squamous cell carcinoma following treatment with platinum-based 
chemotherapy. 
Nivolumab has also clinically meaningful activity in RCC. A phase II study treated 
168 patients with advanced clear cell RCC with progression after agents 
targeting VEGF pathway at three doses of nivolumab (0.3, 2 and 10mg/kg) 31. 
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Median overall survival was 18, 25, and 24 months for the three dose cohorts, 
respectively. Response rates were in average 20% with only 11% incidence of 
grade 3-4 treatment-related adverse events. In an advanced melanoma phase 1 
study, nivolumab and ipilimumab were administered IV every 3 weeks for 4 
doses followed by nivolumab alone every 3 weeks for 4 doses (concurrent 
regimen) 20. The combined treatment was subsequently administered every 12 
weeks for up to 8 doses. In a sequenced regimen, patients previously treated 
with ipilimumab received nivolumab every 2 weeks for up to 48 doses. In the 
concurrent regimen (53 patients), 53% of patients had an OR at doses 1 mg/kg 
nivolumab and 3 mg/kg ipilimumab, with tumor reduction of 80% or more 
(modified World Health Organization criteria). In the sequenced-regimen (33 
patients), the objective response rate (ORR) was 20%. These results 
demonstrate significant clinical activity of nivolumab across multiple histologies 
with favorable toxicity profile. 
1.7.3
Clinical safety
The overall safety experience with nivolumab, as monotherapy or in combination 
with other therapeutics, is based on experience in approximately 4,000 subjects 
treated to date. For monotherapy, the safety profile is similar across tumor types. 
The only exception is pulmonary inflammation adverse events (AEs), which may 
be numerically greater in subjects with NSCLC, because in some cases, it can be 
difficult to distinguish between nivolumab-related and unrelated causes of 
pulmonary symptoms and radiographic changes. There is no pattern in the 
incidence, severity, or causality of AEs to nivolumab dose level. In several 
ongoing clinical trials, the safety of nivolumab in combination with other 
therapeutics such as ipilimumab, cytotoxic chemotherapy, anti-angiogenics, and 
targeted therapies is being explored. Most studies are ongoing and, as such, the 
safety profile of nivolumab combinations continues to evolve. The most advanced 
combination under development is nivolumab + ipilimumab in subjects with 
melanoma. Thus far, the combination of both agents results in a safety profile 
with similar types of AEs as either agent alone, but in some cases with a greater 
frequency 20. 
1.8 
Rationale for Nivolumab and Veliparib combination: 
Previous studies have demonstrated that tumors with the highest genomic instability and 
somatic mutational burden, such as melanoma, non-small cell lung cancer, and bladder 
cancer have favorable responses with immune checkpoint inhibitor therapy (Figure 1). 
The widely acceptable hypothesis is that tumors with more mutations likely generate 
more neoepitopes, which can be recognized by tumor infiltrating T cells. Checkpoint 
blocking antibodies activate these T cells in vivo and induce anti-tumor immunity, thereby 
causing tumor responses. 
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Figure 1. 
Somatic mutation frequency and various tumor types
Higher genomic instability may also predict response to PARP inhibitors. For instance, 
smokers with non-small cell lung cancer (NSCLC) that also had higher genomic 
mutational burden, showed better response to a PARP inhibitor compared with 
nonsmokers. Screening for defective DNA repair mechanisms may select patients with 
higher mutation burden who will likely respond to combination therapy.
In addition to utilizing the concept of synthetic lethality by utilizing PARP inhibition in 
tumors with defects in selected DNA repair mechanisms, we hope to increase the 
genomic instability and mutational epitopes produced in these tumors, making them more 
susceptible to the immune checkpoint inhibitor therapy. With the help of immunotherapy, 
durable responses likely difficult to achieve with targeted therapy with PARP inhibitors 
may be realized via functioning memory T cells targeting tumor mutanomes generated 
and activated by the immune checkpoint inhibitors. 
Recently, it has been shown in a syngeneic murine model of BRCA-/- ovarian cancer that 
PARP inhibition (talazoparib) significantly increased the number of peritoneal CD8+ T 
cells and NK cells as well as their production of IFN-γ and TNF-α32. This implies that 
PARP inhibition induces not only cancer cell-intrinsic apoptosis but also cancer cell-
extrinsic antitumor immune effects. This finding suggests possible synergistic effect of 
PARP inhibitor and immunotherapy in cancer. 
Nivolumab is an immune checkpoint inhibitor to programmed cell death protein 1 (PD-1) 
that is FDA approved for the treatment of advanced melanoma and metastatic squamous 
cell carcinoma of the lung. Veliparib is a PARP inhibitor that has shown promising activity 
in the treatment of germline BRCA1/2 mutated ovarian tumors. Given the non-
overlapping side effect profiles and different therapeutic targets of these agents, this 
combination of agents may improve efficacy without compromising toxicity. Compared to 
monotherapy with either of these agents, the combination approach may increase the 
ORR and survival outcome and possibly broaden number of tumor histologies and their 
subtypes that will respond to such treatment. Therefore, we propose a clinical trial with 
nivolumab and veliparib combination.
PARP inhibitor monotherapy or immune checkpoint inhibition may each result in clinical 
responses in a select group of tumors, especially tumors that are characterized by the 
presence of high mutational burden.  Genomic instability due to mutations in DNA repair 
has been shown in both pre-clinical and clinical studies to predict response to PARP 
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inhibitors  Immune checkpoint inhibitors yield impressive clinical responses in melanoma 
and non-small cell lung cancer, two cancers with very high mutational loads   NSCLC that 
arise in smokers, the subset of lung tumors with the highest mutational load, are 
particularly susceptible to treatment with nivolumab or with veliparib .   Smokers with 
NSCLC treated with nivolumab had a significantly higher response rate and improved 
survival outcomes relative to non-smokers . Similar data showing RR, PFS, and OS 
improvements in subjects who smoke were recently published for veliparib .  
Advanced Solid Tumors and Lymphoma Harboring Alterations in Selected DNA Repair 
Genes are a rational target for treatment with PARP inhibition with checkpoint inhibitors, 
because approximately 5% are defective in the homologous recombination DNA repair 
pathway due to germline, somatic and epigenetic mutations in BRCA1 and BRCA2 and, 
to a lesser extent, from mutations in other homologous repair proteins .  These 
indications therefore have an increased mutational load, suggesting a moderate amount 
of neoantigen derived from point mutations, which could be increased in the presence of 
PARP inhibition .
In pre-clinical studies, PARP inhibitors are associated with immunomodulation. PARP 
inhibitors promote local antigen release after tumor exposure to radiation or DNA-
damaging agents, which may result in systemic antitumor response. . In a BRCA1-
mutated ovarian cancer xenograft model, PARP inhibition increased the number of 
peritoneal CD8+ T cells and natural killer cells, and increased production of interferon γ 
and tumor necrosis factor α  . Though data from pre-clinical cancer models treated with 
combination PARP inhibition and checkpoint inhibition are limited, veliparib does not 
antagonize α-PD-1 in a MC-38 syngeneic mouse model (AbbVie Investigator’s Brochure, 
data on file).
Taken together, these data suggest that PARP inhibition with veliparib may be 
complementary to immune checkpoint modulation with nivolumab in yielding clinical 
benefit in patients with Advanced Solid Tumors and Lymphoma Harboring Alterations in 
Selected DNA Repair Genes
1.9 
Rationale for the current study design
The study will be done in patients with advanced solid tumors or lymphoma with or 
without identified mutations in specified DNA repair genes involved in homologous 
recombination repair pathway (only the expansion cohort will require such mutations). 
Therefore, it will be a multi-histology basket trial with a molecularly driven expansion 
cohort. The effect of veliparib monotherapy has been shown in germline BRCA1/2 
mutated ovarian cancer. Hence, this patient group will be excluded from the population. 
In addition to safety evaluation, this study is designed as a multi-histology navigation trial 
to explore the proof-of-principle in efficacy in this novel combination treatment in various 
cancer types that are refractory to standard of care treatment options. 
The initial study design was to accrue a total of up to 50 patients (for 48 evaluable) to the 
study in two phases: dose escalation and dose expansion. The original design 
anticipated enrolling 6-18 patients with advanced solid tumors or lymphoma in the dose 
escalation phase, followed by 15-32 patients in a two-stage expansion phase. For the dose 
escalation, a standard 3+3 design was chosen to determine the MTD of the novel 
combination To date, 9 patients have been enrolled and the dose escalation phase is 
complete, including 6 patients that were treated at the MTD of 400 mg BID. 
However, due to funding issues, the study will adopt a modified plan for the expansion 
cohort, and will perform an early analysis of preliminary efficacy after the next 6 patients are 
enrolled in the expansion cohort. 
This modified plan for expansion cohort, will accrue 6 new patients with genetic 
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alteration for early preliminary efficacy assessment, which together with 4 previously 
treated patients with genetic mutation will provide total of 6+4=10 patients, with genetic 
mutation. ORR will be computed at the first imaging (8 weeks). Preliminary efficacy will 
be evaluated by RECISTv 1.1. As exploratory analysis, irRECIST will be used to obtain 
preliminary efficacy as well.  All ORR will use the first imaging time point whether 
RECIST or irRECIST.
The study will be considered a success if the lower 90% exact confidence bound will 
be > 10% , i.e. if three or more successes out of n=10 are observed. 
. According to the modified plan for the current trial, the study will be closed after the 6 
additional patients will have been recruited.
This same treatment plan will be used for patients in both the dose escalation and 
dose expansion cohorts.
. 
1.10
Rationale for Dosing 
1.10.1
Nivolumab flat dose regimen
The safety and efficacy of 240 mg (monotherapy) Q2W flat dose of nivolumab 
has recently received IRB approval and is expected to be similar to the 3 mg/kg 
Q2W dosing regimen. Using the population PK (PPK) model, exposure of 
nivolumab at 240 mg flat doses is identical to a dose of 3 mg/kg for subjects 
weighing 80 kg, which is the approximate median body weight in nivolumab 
clinical trials. Across the various tumor types in the clinical program, nivolumab 
has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and 
the relationship between nivolumab exposure produced by 3 mg/kg and efficacy 
and safety has been found to be relatively flat. Given the similarity of nivolumab 
PK across tumor types and the similar exposures predicted following 
administration of 240 mg flat doses compared to 1mg/kg and 3 mg/kg, it is 
expected that the safety and efficacy profile of 240 mg nivolumab will be similar 
to that of 3 mg/kg nivolumab. 
In addition, nivolumab 480 mg administered once every 4 weeks (Q4W) is 
currently under investigation. The less frequent dosing regimen is designed to 
afford more convenience to the target patient populations. The nivolumab dose of 
480 mg Q4W was selected based on clinical data and modeling and simulation 
approaches using PPK and exposure-response analyses of data from studies in 
multiple tumor types (melanoma, NSCLC, and RCC) to provide an approximately 
equivalent dose of nivolumab 3 mg/kg Q2W. Exposures following nivolumab 480 
mg Q4W regimen are predicted to be within the exposure ranges observed at 
doses up to 10 mg/kg Q2W used in the nivolumab clinical program, and are not 
considered to put participants at increased risk. Hence, the flat doses of 240mg 
and 480mg nivolumab are under investigation.
1.10.2
Veliparib Dosing
A veliparib dose of 400mg po bid is the phase 2 recommended dose for veliparib 
monotherapy. A prior phase 1 study shows that it is safe to start at 300mg po bid 
in combination with nivolumab. Thus the dose escalation will begin at 300mg 
veliparib twice a day and escalate to a final dose level 2 of 400mg.
2.0
OBJECTIVES & ENDPOINTS
2.1
Primary Objective & Endpoint
To identify maximum tolerated dose (MTD) for the combination treatment of nivolumab 
and veliparib in patients with advanced refractory solid cancers and lymphoma. 
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2.2
Secondary Objectives & Endpoints
2.2.1
To evaluate the safety and tolerability of nivolumab and veliparib in 
patients with advanced refractory solid cancers and lymphoma with and 
without mutations in selected DNA repair genes.
The endpoint will be the number, frequency, and severity of adverse 
events (as defined by the NCI CTCAE v4.03).
2.2.2
To evaluate the efficacy of treatment with nivolumab and veliparib in 
this population by objective response rate (ORR, defined as partial 
response (PR) + complete response (CR)), clinical benefit rate (CBR, 
defined as stable disease (SD) for ≥12 weeks, PR, + CR), and 
Progression Free Survival (PFS, defined as the time from treatment 
initiation to documented disease progression) using RECIST criteria 
v1.1 or Lugano criteria. 
For the preliminary efficacy analysis, ORR will be done at the first 
imaging (8 weeks). Preliminary efficacy will be evaluated by RECISTv 
1.1. As exploratory analysis, irRECIST will be used to obtain preliminary 
efficacy as well.  All ORR will use the first imaging time point whether 
RECIST or irRECIST.
2.2.3
To evaluate efficacy of treatment with nivolumab and veliparib in this 
population by ORR, CBR, and immune-related PFS (irPFS) using 
irRECIST criteria.
2.2.4
To evaluate Overall Survival (OS) in this population at 3 years from the 
start of treatment. OS is defined as the time from treatment initiation until 
death due to any cause.
2.2.5
To evaluate the proportion of patients alive and progression free at 24 
weeks in this population.
2.3
Exploratory Objectives & Endpoints
The main goals of the objectives listed below are to identify predictive biomarkers 
beyond the genetic mutations by which treatment is assigned, and to identify 
resistance mechanisms to the nivolumab and veliparib combination using additional 
genetics and tumor immunology-based assessment platforms
Biomarker tests will be done at baseline using fresh tissue (or archived if a fresh 
biopsy is not feasible) , as well as from blood samples at Induction Day 1, Cycle 1 Day 
1, Cycle 3 Day 1, and the End of Treatment visit.
2.3.1
To evaluate if any of the following predict response to veliparib in combination with 
nivolumab:

Tissue PD-L1 protein expression 

Immune cell infiltration markers
2.3.2
To demonstrate the pharmacodynamic effects of veliparib and nivolumab on 
biomarkers including PD-L1, TILs, T cell subpopulations, and T cell receptor 
genotype.
2.3.3
To assess the dynamic change in both immune and genomic biomarkers in 
blood that may correlate with response to veliparib.
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3.0
PATIENT ELIGIBILITY
The target population for this study is patients with advanced solid tumors and lymphoma with 
and without mutations in selected DNA repair genes, where the expansion cohort will be 
reserved for patients with DNA repair gene mutations as listed in 3.1.6. This will be a single-
center trial conducted at Northwestern University.
The initial study design was to accrue a total of up to 50 patients for 48 evaluable) to the study in 
two phases: dose escalation and dose expansion. The original design anticipated a total of 6-18 
patients with advanced solid tumors or lymphoma in the dose escalation phase; 9 patients were 
enrolled, including 3 at lowest dose and 6 that were treated at the MTD of 400 mg BID. It is still 
planned for 6 patients with advanced solid tumors and lymphoma with mutations in selected DNA 
repair genes to be enrolled into the expansion cohort to receive the maximum tolerated dose of 
veliparib in combination with nivolumab. However, due to funding issues, the study will perform an 
early analysis of preliminary efficacy after the next 6 patients are enrolled in the expansion cohort, all with 
the genetic mutation.. According to the modified plan for the current trial, the study will be closed after the 
6 additional patients will have been recruited.
 
Approximately 5 potentially eligible patients will be seen per month, and it is anticipated that at 
least 2 per month will be accrued. Patients will be recruited by all participating investigators in 
respective clinics within the Northwestern University Cancer Center network. Potential 
patients may be referred to the Principal Investigator (PI) at Northwestern University, Dr. Young 
Kwang Chae at (312) 926-4248.
Eligibility will be evaluated by the study team according to the following criteria. Eligibility 
waivers are not permitted. Subjects must meet all of the inclusion and none of the exclusion 
criteria to be registered to the study. Study treatment may not begin until a subject is 
registered. Please refer to Section 11 for complete instructions regarding registration 
procedures.
3.1
Inclusion Criteria
3.1.1
Patients must have a histologically documented (either primary or metastatic 
site) diagnosis of advanced solid tumor cancer (stage IV or unresectable) or 
aggressive lymphoma (diffuse large B cell lymphoma, mantle cell lymphoma, 
T cell lymphoma, and NK cell lymphoma). 
NOTE: The following histologies will be excluded given known response to 
PD-1/PD-L1 inhibitor monotherapy: non-small cell lung cancer, squamous cell 
carcinoma of head and neck, melanoma, renal cell carcinoma, bladder 
cancer, Hodgkin’s lymphoma, Merkel cell carcinoma, and MSI-H colorectal 
cancer.
NOTE: Patients with deleterious BRCA 1/2 mutated ovarian cancer will be 
excluded given its presumed efficacy with veliparib monotherapy.
3.1.2
All patients must have received, and be relapsed/refractory to at least one line 
of systemic therapy. 
NOTE: This does not include surgery or radiation alone. Patients may have 
received any number of systemic therapies
NOTE: For patients with aggressive lymphoma, there should be no other 
standard therapies that would confer survival benefit.
3.1.3
All patients with relapsed/refractory lymphoma must have received or be 
ineligible for autologous stem cell transplant or be ineligible for allogeneic 
stem cell transplant.
NOTE: Patients must not have had a prior allogeneic stem cell transplant. 
3.1.4
Patients must have measurable disease as per appropriate guidelines:
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
Solid tumors: by RECIST v1.1 

Lymphoma: Patient has at least one measurable nodal lesion (≥2 cm) 
according to Lugano classification. If the patient has no measurable nodal 
lesions ≥2 cm in the long axis at screening, then the patient must have at 
least one measurable extra-nodal lesion. 
3.1.5
Patients must have the ability to understand and the willingness to sign a 
written consent prior to registration in the study.
3.1.6
For expansion cohort patients, the profiling must reveal at least one 
mutation in the following selected DNA repair genes involved in cell cycle 
arrest signal transduction, BRCA1 pathway, Fanconi’s proteins pathway, 
and RAD51 pathway: [ATR, ATM, CHEK1, CHEK2, BRCA1, BRIP1, BAP1, 
BARD1, FANCD2, FANCE, FANCC, RAD50, FANCA, RAD51, BRCA2, 
PALB2, CDK12 (ENSG00000167258, also known as CRK7, CRKR, 
CRKRS), POLE, POLD1, BRAC2, PRKDC, ERCC2, POLQ, MRE11A, NBN 
(MBS1)], or at least one gene amplification in FANCD2, FANCE, FANCC, 
FANCA, C11orf30 (EMSY). 
Please note: This eligibility criteria is also applicable for patients enrolled for the 
preliminary expansion cohort to conduct preliminary efficacy analysis.
NOTE: Tissue or blood cell free DNA are allowed for genomic profiling of 
tumor. Profiling should have been performed at a CLIA certified lab ≤1 year 
prior to registration. 
NOTE: Patients in the dose escalation phase are not required to have such 
mutations. Although genomic profiling is not required for dose escalation 
patients, it is encouraged in these patients prior to or after study registration 
if feasible.
3.1.7
Patients must be age ≥ 18 years; both male and females are eligible.
3.1.8
Patients must exhibit an ECOG performance status of ≤2.
3.1.9 
Patients must have adequate organ and bone marrow function ≤ 14 days 
prior to registration, as defined below (Note: Blood transfusion or growth 
factors is not permitted within 14 days of registration):
absolute neutrophil count
≥ 1.5 x 10^9/L
hemoglobin
≥ 9 g/dL
platelets
≥ 100 x 10(9)/L
Total bilirubin
≤ 1.5 x ULN
Alanine amino transferase 
and aspartate 
aminotransferase
≤ 5 x ULN
Calculated creatinine  
clearance according
to the Cockcroft and Gault 
equation
≥ 50 mL/min  
3.1.10
Females of child-bearing potential (FOCBP) and men who are sexually 
active with FOCBP must agree to follow instructions for method(s) of 
contraception for the duration of treatment and the designated post-
treatment period (5 months for females and 7 months for males; see 
Appendix A for details on appropriate contraception methods) 
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NOTE: A FOCBP is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the 
following criteria:

Has not undergone a hysterectomy or bilateral oophorectomy

Has had menses at any time in the preceding 12 consecutive months 
(and therefore has not been naturally postmenopausal for > 12 months)
3.1.11
FOCBP must have a negative pregnancy test ≤7 days prior to registration.
3.1.12
Patients must be able to swallow oral medication.
3.2
Exclusion Criteria
3.2.1
Patients who have had  radiotherapy ≤ 14 days prior to registration are not 
eligible.
3.2.2
Patients  who have received systemic chemotherapy or investigational agents ≤ 
28 days prior to registration are not eligible.
3.2.3
Patients are not eligible who have had major surgery ≤ 14 days prior to 
registration. Please contact PI and QAM for questions about specific surgical 
procedures.
3.2.4
Patients are not eligible who have received prior PARP inhibitors (including but 
not limited to veliparib, talazoparib, rucaparib, and olaparib).
3.2.5
Patients are not eligible who have received prior immunotherapy including 
interleukin-2 and immune checkpoint antagonists and/or agonists (including but 
not limited to PD-1, PD-L1, CD137, or OX40). 
NOTE: Single agent anti-CTLA4 monoclonal antibody treatments are 
permitted. Cancer vaccine therapies are permitted.
3.2.6
Patients with the following histologies are not eligible for either study cohort 
given known response to PD-1/PD-L1 inhibitor monotherapy:
Non-small cell lung cancer, squamous cell carcinoma of head and neck, 
melanoma, renal cell carcinoma, bladder cancer, Hodgkin’s lymphoma, 
Merkel cell carcinoma, and MSI-H colorectal cancer
3.2.7
Patients with deleterious BRCA 1/2 mutated ovarian cancer are not eligible.
3.2.8
Patients are not eligible who have had a prior allogeneic stem cell transplant.
NOTE: Autologous stem cell transplant is acceptable.
3.2.9
Patients who are taking any herbal (alternative) medicines are NOT eligible 
for participation. Patients must be off any such medications by the time of 
registration for ≥ 14 days.
NOTE: Vitamin supplements are acceptable.
3.2.10
Patients requiring systemic treatment with corticosteroids (>10mg daily 
prednisone equivalents) or other immunosuppressive medications ≤14 days 
prior to first dose of study drug are not eligible.
NOTE: Inhaled and intranasal corticosteroids are permitted. A brief (less 
than 3 weeks) course of corticosteroids for prophylaxis (eg, contrast dye 
allergy) or for treatment of non-autoimmune conditions (eg, delayed-type 
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Amendment 7: 3.3.2020 
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hypersensitivity reaction caused by a contact allergen) is permitted.
3.2.11
Patients who receive a live attenuated vaccine ≤28 days prior to registration 
are not eligible. 
3.2.12
Patients must have no history of CNS metastasis at the screening 
assessment. 
NOTE: Patients with stable brain mets which have been treated are eligible. 
Patients with suspected symptoms of CNS metastasis should undergo CNS 
imaging at the time of screening to rule out active metastasis. 
3.2.13
Patients who have had a prior severe infusion reaction to a monoclonal antibody 
are not eligible.
3.2.14
Patients are not eligible who have a history of or active autoimmune disease 
within the past 3 years with the following exceptions:

Vitiligo or alopecia

Hypothyroidism on stable doses of thyroid replacement therapy

Psoriasis not requiring systemic therapy within the past 3 years
3.2.15
Patients with a history of primary immunodeficiency disease or tuberculosis are 
not eligible.
3.2.16
Patients who have an uncontrolled current illness including, but not limited to 
any of the following, are not eligible:

Uncontrolled pulmonary, renal, or hepatic dysfunction

Ongoing or active infection requiring systemic treatment including hepatitis B 
and hepatitis C

Known active or chronic viral hepatitis or human immunodeficiency 
virus (HIV)

Psychiatric illness/social situations that would limit compliance with 
study requirements

Clinically significant gastrointestinal disease or digestive dysfunction 
compromising absorption of veliparib

Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety 
or study endpoints
3.2.17
Female patients who are pregnant or nursing are not eligible. 
3.2.18
Patients with a prior diagnosis of cancer must not have received treatment in 
the last 3 years prior to registration.
NOTE: treatments used as a recurrence prevent are eligible.
NOTE: Patients with a history of completely resected non-melanomatous 
skin carcinoma or successfully treated in situ carcinoma are eligible.
3.2.19
Patients must not have a history of prior stroke, transient ischemic attack 
(TIA), pulmonary embolism, or untreated deep vein thrombosis. 
NOTE: Patients may be eligible if they have received at least 3 months of 
anticoagulation for a deep vein thrombosis. 
4.0
TREATMENT PLAN
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4.1
Overview
In Phase 1, patients will be treated with a dose escalation plan for veliparib based on 
a 3+3 study design. The initial patient cohort will be treated with veliparib 300 mg PO 
twice daily and nivolumab as follows (1 cycle = 28 days):
Cycle 1-4: 240 mg IV every 2 weeks and 
Cycle 5+: 480mg IV every 4 weeks 
See section 4.2 for treatment administration and dosing modifications based on the 
planned 3+3 study design. Total cycle length is 28 days (4 weeks). Combination 
treatment will continue until progression of disease or intolerability with scans 
occurring every 8 weeks (see section 4.7.1 for possible treatment beyond progression). 
Patients in the expansion cohort (Phase1B) will be treated with the MTD, that is now 
established. This same treatment plan will be used for patients in both the dose 
escalation and dose expansion cohorts. 
Patients will undergo a fresh tissue biopsy prior to study enrollment, unless deemed to 
be clinically inappropriate per PI, to evaluate pharmacodynamic changes in immune-
related biomarkers. Correlatives will be assessed as detailed in section 9.0.
[Please note: . According to the modified plan for the current trial, the study will be closed 
after the 6 additional patients in the expansion cohort will have been recruited.]
4.2
Treatment Administration
Table 4.1: Dosing of Nivolumab and Veliparib
Drug
Dose
Route
Schedule
Nivolumab 
(Opdivo)
C1-4: 240mg
C5+: 480mg
IV
Cycle 1-4: every 14 days 
Cycle 5+: every 28 days until progression 
of disease, intolerable toxicity, or withdrawal 
of consent
Veliparib
Phase I: Starting 
dose 300mg (see 
4.3 for escalation)
Phase Ib: MTD
PO
Twice a day about 12 hours apart starting 
7 days before C1D1 (Induction 
monotherapy) continuing until progression 
of disease, intolerable toxicity, or 
withdrawal of consent
4.2.1
Veliparib
Veliparib is administered orally twice a day starting on Day 1 of each cycle. 
Subjects will self-administer the morning and evening doses of veliparib 
approximately 12 hours apart in the same calendar day.  Each dose of veliparib 
will be taken with a glass of water and consumed over as short a time as 
possible (i.e., not slower than 1 capsule every 2 minutes) with or without food. 
During veliparib treatment, standard antiemetic therapy may be administered as 
appropriate, including a combination of standard antiemetic’s (i.e., 5-HT3 
receptor antagonists, steroids, and prochlorperazine, and/or promethazine).
It is recommended that if a subject misses a scheduled dose of veliparib and less 
than 6 hours have passed since the scheduled dosing time, the dose should be 
immediately taken.  It is recommended that if more than 6 hours have passed 
since the scheduled dosing time, the subject should not take the missed dose but 
should wait and take the next regularly scheduled dose.
If the subject vomits within 15 minutes of taking veliparib, another dose will be 
administered.  The dose may only be repeated once.  If more than 15 minutes 
has passed from the time of oral dosing then no additional doses will be taken. 
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Patients will maintain a drug diary for dosing compliance each cycle. Completed 
drug diaries will be returned at the beginning of each cycle along with any 
leftover veliparib tablets and drug bottles.
See section 4.3 for details on dose escalation during Phase I and section 4.4 for 
toxicity management 
4.2.2.
Nivolumab
During Cycle 1-4, nivolumab will be administered at a fixed dose of 240 mg 
intravenously over approximately 30 minutes (-5 / +15 minutes) every 2 weeks 
(Day 1 and 15 of each cycle). Starting with Cycle 5, nivolumab will be 
administered at 480mg IV over 30 minutes (-10 / +15 minutes) every 4 weeks 
(Day 1 of each cycle). There is no premedication required for infusion. Veliparib 
oral doses can be taken independently of the nivolumab administration schedule.
4.2.2.1 Treatment Monitoring
Subjects will be monitored before, during, and after the 30- or 60-
minute infusion of nivolumab with vital signs as follows:
Table 4.2: Time Points for Vital Signs 
Before Infusion
Pre-dose
Vitals up to 30 minutes prior
During Infusion
Every 15 minutes
Vitals ± 5 minutes
After infusion
Immediately following
Vitals within 5 minutes after
30 minutes post
Vitals ± 5 minutes
60 minutes post (1st & 2nd 
doses)
Vitals ± 5 minutes
3 hour observation (1st dose 
only)
Observation only
In the event of a Grade ≤ 2 infusion-related reaction, the infusion rate 
of nivolumab may be decreased by 50% or interrupted until resolution 
of the event (up to 4 hours) and re-initiated at 50% of the initial rate 
until completion of the infusion. In subjects experiencing Grade ≤ 2 
infusion-related reaction, subsequent infusions may be administered 
at 50% of the initial rate. Acetaminophen and/or an antihistamine (eg, 
diphenhydramine) may be administered at the discretion of the 
investigator. If the infusion-related reaction is severe or prolonged, 
methylprednisolone 125 mg (or the equivalent) should be 
administered as well. Investigators may administer steroids at their 
discretion as clinically indicated and per their institution’s guidelines. 
Appropriate drugs and medical equipment to treat acute anaphylactic 
reactions must be immediately available, and study personnel must 
be trained to recognize and treat anaphylaxis.
4.3
Dose Escalation
Table 4.3: Dose levels based on 3 + 3 design for veliparib and nivolumab
Dose Level
Veliparib
Nivolumab
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Amendment 7: 3.3.2020 
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-1
200 mg PO twice daily
C1-4: 240 mg IV every 2 weeks
C5+: 480mg IV every 4 weeks
1
300 mg PO twice daily
C1-4: 240 mg IV every 2 weeks
C5+: 480mg IV every 4 weeks
2
400 mg PO twice daily
C1-4: 240 mg IV every 2 weeks
C5+: 480mg IV every 4 weeks
The above dose escalation plan is based on a 3 + 3 design with the starting dose of 
veliparib as 300 mg PO twice daily and nivolumab as 240mg IV every 2 weeks. Each 
cycle will be 28 days (4 weeks) in length.  
4.3.1
Definition of DLT (Dose limiting toxicity)
Toxicity will be assessed using the National Cancer Institute (NCI) Common 
Toxicity Criteria for Adverse Events (CTCAE), version 4.03 unless otherwise 
specified. A DLT is defined as an AE or abnormal laboratory value assessed as 
at least possibly related to the study medication, occurs ≤ 28 days following the 
first dose of veliparib and nivolumab and meets any of the criteria listed below. 
Whenever a patient experiences toxicity that fulfills the criteria for a DLT, 
treatment with the study drug combination will be interrupted until resolution to ≤ 
Grade 1 or baseline, and the toxicity will be followed up until resolution. All 
adverse events specified below will be DLT’s except those that are clearly and 
incontrovertibly due to extraneous causes. 
The following events will be considered DLT’s:
1. Grade ≥ 3 non-hematologic toxicities that represent at least a 2-grade 
increase from baseline with the following exceptions:
a. Nausea, vomiting, and diarrhea lasting ≤48 hours
b. Electrolyte abnormalities resolving within ≤24 hours
c. Hypersensitivity reactions
d. Alopecia 
2. Grade 4 thrombocytopenia (platelets < 25.0 x 109/L)
3. Grade 3 thrombocytopenia with bleeding (platelets <50.0 x 109/L)
4. Grade 4 neutropenia (ANC < 0.5 x 109/L)
5. Grade 3 febrile neutropenia with fever lasting for > 7 days
6. Grade 4 febrile neutropenia of any duration 
7. Dosing delay due to toxicity for > 14 consecutive days from the date 
nivolumab or veliparib is due.
4.3.2
Dose Escalation 3+3 Rule
Table 4.4: Dose escalation plan based on 3 + 3 design for veliparib and nivolumab
Number of Subjects with 
DLT in the First Cycle
Escalation Decision Rule
0 out of 3
Enter 3 subjects at the next dose level. 
1 out of 3
Add 3 more subjects at current dose level. 
 If < 2 of 6 subjects (or < 33% of subjects) experience DLT, 
dose escalation will proceed to the next dose level. 
 If ≥ 2 of total 6 subjects (or ≥ 33% of subjects) experience 
DLTs, then dose escalation will be stopped.*
≥ 2 out of 3 or 6
Dose escalation will be stopped.* 
*For dose level 1, additional subjects will be enrolled at the previous lower 
dose level (-1) as needed to establish MTD with 6 patients. 
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*If dose escalation is stopped at dose level 2, dose level 1 will be 
established as the MTD if it enrolled 6 patients (<2 of 6 patients had 
DLT). If dose level 1 enrolled only 3 patients (0 of 3 had DLT’s), 3 more 
patients will be added to dose level 1 to establish the MTD. From there, 
dose level -1 will be utilized in the case that ≥2 patients have DLT.
NOTE: Whichever dose level is declared the MTD must have 6 total 
patients treated at that level. For example, if 3 patients are treated at level 2 
and 0 patients experience DLT, escalation would then proceed to level 3. 
However, if ≥ 2 patients at level 3 experience DLT, enrollment to level 2 
would need to be re-opened to enroll an additional 3 patients at that level 
(with 0 or 1 DLT observed in 6 total patients) in order to declare level 2 the 
MTD.
4.3.3 Dose expansion: 
The initial study design was to accrue a total of up to 50 patients (for 48 evaluable) to 
the study in two phases: dose escalation and dose expansion. The original design 
anticipated a total of 6-18 patients with advanced solid tumors or lymphoma in the dose 
escalation phase.9 patients were enrolled, including 6 that were treated at the MTD of 400 
mg BID. 
However, due to funding issues, the study will adopt a modified plan for the expansion 
cohort, and will perform an early analysis of preliminary efficacy after the next 6 patients are 
enrolled in the expansion cohort.
This modified plan for expansion cohort, will accrue 6 new patients with genetic 
alteration for early preliminary efficacy assessment, which together with 4 previously 
treated patients with genetic mutation will provide total of 6+4=10 patients, with genetic 
mutation. ORR will be computed at the first imaging (8 weeks). Preliminary efficacy will 
be evaluated by RECISTv 1.1. As exploratory analysis, irRECIST will be used to obtain 
preliminary efficacy as well.  All ORR will use the first imaging time point whether 
RECIST or irRECIST.
Patients in this cohort will be treated at the MTD and the same treatment schedule will be 
followed as was done in the escalation phase. 
The study will be considered a success if the lower 90% exact confidence bound will be > 
10% , i.e. if three or more successes out of n=10 are observed. 
 According to the modified plan for the current trial, the study will be closed after the 6 
additional patients will have been recruited. 
4.4
Toxicity Management & Dose Delays/Modifications
Each patient will be assessed for the development of toxicity according to the timeframe 
referenced in Table 5. Toxicity will be assessed according to the NCI CTCAE V4.03.
Veliparib doses may be reduced or delayed up to 28 days according to Table 4.3 and 
the toxicity management guidelines in Table 4.5. Missed doses will be skipped with each 
cycle continuing as originally planned. 
Nivolumab doses cannot be modified but can be delayed or discontinued according to 
Table 4.6. Missed doses will be skipped, resuming at the next scheduled treatment visit.
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Since the mechanism of action of nivolumab leads to T-cell activation and proliferation, 
immune related adverse events (irAE) may be observed, and be similar to that of other 
PD-1/PD-L1 checkpoint inhibitors, and may include immune-mediated pneumonitis, 
enterocolitis, dermatitis, hepatitis, and endocrinopathies.
Subjects should be monitored for signs and symptoms of irAEs. In the absence of an 
alternate etiology (i.e. infection or PD), an immune-mediated etiology should be 
considered for signs or symptoms of pneumonitis, enterocolitis, dermatitis, hepatitis, 
and endocrinopathy. In addition to the dose modifications shown in Tables 4.4 and 
4.5, it is recommended that management of irAEs follow the guidelines outlined for 
other immune checkpoint inhibitors. These guidelines recommend the following:

Subjects should be evaluated to identify any alternative etiology

In the absence of clear alternative etiology, all events of an inflammatory 
nature should be considered to be immune-related

Topical or inhaled steroid therapy should be considered for low-grade events

Systemic corticosteroids should be considered for a persistent low-grade event 
or for a severe event

More potent immunosuppressives (i.e. infliximab, mycophenolate mofetil, 
etc.) should be considered for events not responding to systemic steroids
If the investigator has any question in regards to an AE being an irAE, the investigator 
should immediately contact the principal investigator. Treatment modifications will not be 
required for AEs that are clearly not attributed to investigational drugs (such as an accident) 
or for laboratory abnormalities that are not deemed to be clinically significant.
Nausea and vomiting have been commonly observed in clinical trials with veliparib.
Gastrointestinal toxicities, predominantly nausea and vomiting, were observed with 
veliparib as single-agent therapy and most frequently reported at higher doses (300 – 
400 mg BID). Of the subjects treated with single agent veliparib at 300 – 400 mg BID 
dose levels, 15% required dose reduction, 5% delayed or interrupted dosing and 2% 
discontinued due to nausea.  To optimize dose intensity and maintain subject quality of 
life, early initiation or prophylactic management with scheduled anti-emetic therapy (5HT-
3 antagonists, metoclopramide, prochlorperazine) and/or lorazepam should be 
considered. In addition, it has also been observed that tolerance to these toxicities may 
develop over time. Management should include counseling regarding these toxicities and 
may include interruption of dosing, dose modification or veliparib discontinuation.
Treatment modifications may be required in the event of treatment-related toxicity. General 
guidelines regarding treatment modification are provided in Table 4.5 and 4.6. Dose 
modifications should be implemented only if toxicities are attributed to 
respective drugs (nivolumab or veliparib). If there is uncertainty or 
overlapping toxicities, both drugs should be held and or dose modified 
according to the guidelines.
All toxicities will be graded according to NCI CTCAE V4.03 (Appendix B).
Should a female patient become pregnant or suspect she is pregnant while participating in 
this study, she should inform her treating physician immediately. Similarly if a male patient 
impregnates a female, the treating physician should be informed.
4.5
Dose Reductions
4.5.1
Veliparib
The following are guidelines for dose reductions, delays and discontinuation of 
veliparib monotherapy.
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Subjects should have an ANC ≥ 1,500/mm3 and a platelet count ≥ 100,000/mm3 
prior to each cycle.
For any subject who experiences Grade 3 or 4 toxicity despite optimal supportive 
care (with the exception of anemia, alopecia, and non-treatment related clinically 
insignificant laboratory abnormalities), and the toxicity is not attributable to 
underlying disease, the veliparib dose will be held until the toxicity resolves to 
Grade 1 or lower or to baseline if Grade 2 is present at the time of study entry.
Interruptions of veliparib for events that are clearly not related to therapy (e.g., 
underlying cancer, planned surgical procedures, or acute viral illnesses), do not 
necessitate a dose reduction.
The dose of veliparib will be managed according to Table 4.5 below, and the 
dose levels in Table 4.3:
Table 4.5: Veliparib related toxicity management guidelines
Toxicity
Grade
Dose Adjustment and Management 
Recommendations
Hematologic Toxicities
1
≥10.0 – LLN g/dL
No dose adjustment required.
2
≥8.0 – <10.0 g/dL
No dose adjustment required
3
<8.0 g/dL
Dose interruption for up to 28 days until recovery to 
grade ≤ 2
Re-initiate veliparib at the same dose.
Anemia
4
Life threatening 
consequences; urgent 
intervention indicated
Discontinue veliparib.
1
≥75 x 109/L
No dose adjustment required
2
≥50 x 109 /L – <75 x 109/L
Dose interruption for up to 28 days until recovery to 
≤ 1.
Re-initiate veliparib at the same dose level.
If toxicity recurs at grade 2: temporary dose 
interruption until recovery to grade ≤ 1 and reduce 
veliparib to the next lower dose level.
3
≥25 x 109 /L - <50 x 109/L 
Dose interruption for up to 28 days until recovery to 
Grade ≤ 1.
Re-initiate veliparib at the next lower dose level.
If toxicity recurs at Grade 3: temporary dose 
interruption until recovery to Grade ≤ 1 and reduce 
veliparib to the next lower dose level.
Thrombocytopenia
4
<25 x 109/L
Dose interruption for up to 28 days until recovery to 
grade ≤ 1.
Re-initiate veliparib at the next lower dose level.
If toxicity recurs at grade 4: discontinue veliparib.
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Toxicity
Grade
Dose Adjustment and Management 
Recommendations
1
≥1.5 x 109/L
No dose adjustment required
2
≥1.0 - <1.5 x 109/L
No dose adjustment required
3
≥0.5 - <1.0 x 109/L
Dose interruption for up to 28 days until recovery to 
≥1.0 x 109 /L.
Re-initiate veliparib at the same dose level.
If toxicity recurs at Grade 3: temporary dose 
interruption until recovery to > 1.0 x 109 /L and 
reduce veliparib to the next lower dose level.
Absolute 
Neutrophil Count
4
<0.5 x 109/L
Dose interruption for up to 28 days until recovery to 
≥1.0 x 109 /L.
Re-initiate veliparib at the same dose level.
If toxicity recurs at Grade 4: temporary dose 
interruption until recovery to > 1.0 x 109 /L and 
reduce veliparib to the next lower dose level.
1
≥800/mm3
No dose adjustment required
2
≥500 - <800/mm3
No dose adjustment required
3
≥200 - <500/mm3
Dose interruption for up to 28 days until recovery to 
Grade ≤ 1.
Re-initiate veliparib at the next lower dose level.
If toxicity recurs at Grade 3: temporary dose 
interruption until recovery to Grade ≤ 1 and reduce 
veliparib to the next lower dose level.
Lymphopenia
4
<200/mm3
Dose interruption for up to 28 days until recovery to 
grade ≤ 1.
Re-initiate veliparib at the next lower dose level.
If toxicity recurs at grade 4: discontinue veliparib.
Non-Hematologic Toxicities
Myelodysplastic 
syndrome/Acute 
Myeloid Leukemia
Discontinue veliparib
Pneumonitis
Discontinue veliparib
Embryro-Fetal 
Toxicity
If patient becomes pregnant, discuss with the 
patient the potential hazard to the fetus.
Nausea
5-HT3 antagonists (ondansetron, granisetron, palonosetron), dopamine antagonists 
(prochlorperazine, metoclopramide) and lorazepam were most frequently used to 
manage veliparib-associated nausea. Anti-emetics should be initially prescribed on 
a specified schedule (e.g., no PRN). Multiple concomitant anti-emetic medications 
may be needed in some cases for effective nausea management. Example 
regimens and combinations to consider include: 
○ Ondansetron 4 or 8 mg BID 
○ Lorazepam 0.5 mg Q8H 
○ Ondansetron 8 MG Q8H; prochlorperazine 10 MG Q6H 
○ Lorazepam 1 mg Q8H; prochlorperazine 10 mg Q6H; ondansetron 8 mg Q8H 
○ Lorazepam 1 mg Q8H; ondansetron 8 mg Q8H; omeprazole 20 mg QD 
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Toxicity
Grade
Dose Adjustment and Management 
Recommendations
In addition to the use of anti-emetic medications, investigators should rely on 
standard clinical practice and local/country guidelines for nausea management. 
Patients should be proactively counseled about adherence to the prescribed 
supportive care.
Dose Interruptions 
Nausea related to veliparib can be managed with dose interruptions, if it is not 
responsive to anti-emetic therapy. Due to the half-life of veliparib of approximately 4 
– 6 hours, symptom improvement/resolution typically occurs within 1 to 3 days of 
treatment interruption. If no improvement of symptoms is observed within this time 
frame, relationship of the event to veliparib should be re-evaluated. 
Dose Reductions 
Subjects experiencing nausea at the initial dose level that cannot be controlled with 
anti-emetics should be dose reduced. If the subject was receiving anti-emetics at 
the initial veliparib dose level, it is also recommended that the same anti-emetic 
regimen be continued at the reduced veliparib dose level until symptom resolution or 
significant improvement. Dose reductions to below 200 mg BID are not expected to 
be necessary. 
If nausea does not improve sufficiently at the reduced dose, further dose reduction 
to the next lower dose level is recommended. Interruption of veliparib dosing may be 
attempted to determine if nausea is indeed related to veliparib.
Grade
Dose Adjustment and Management Recommendations
1
No dose adjustment required. Initiate appropriate medical therapy and 
monitor.
2
-Dose interruption for up to 28 days until recovery to ≤ Grade 1. Initiate 
appropriate medical therapy and monitor.
-Re-initiate veliparib at the same dose
-If the same toxicity recurs at Grade 2, interrupt until recovery to ≤ Grade 
1. Re-inititate veliparib at the next lower dose level.
3
-Dose interruption for up to 28 daysuntil recovery to ≤ Grade 1. Initiate 
appropriate medical therapy and monitor.
-Re-initiate veliparib at the same dose
-If the same toxicity recurs at Grade 2, interrupt until recovery to ≤ Grade 
1. Re-inititate veliparib at the next lower dose level.
-If toxicity recurs at Grade 3, discontinue veliparib.
All non-
hematologic AE's 
attributable to 
veliparib in the 
combination 
treatment cycles
4
Discontinue veliparib and treat with appropriate medical therapy
4.5.2
Nivolumab Toxicity Management
Table 4.6: Nivolumab related toxicity management guidelines
Immune-Mediated Reactions
Immune-related Adverse Events (Overall Management)
Drug administration modifications of study drug/study regimen will be made to manage potential immune-related AEs based on 
severity of treatment- emergent toxicities graded per NCI CTCAE v4.03.
Grade
Dose Modifications
Toxicity Management
Grade 1
Continue dosing
Grade 2
Hold study drug up to 
28 days until 
resolution to ≤ Grade 
1 or baseline

If toxicity worsens 
It is recommended that management of irAEs follow the guidelines 
presented in this table and refer to the nivolumab investigator 
brochure

Subjects should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, concomitant 
medications, infections, etc.)
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then treat as 
Grade 3 or Grade 
4

If toxicity 
improves then 
treat at next 
scheduled 
treatment date
Grade 3
Depending on the 
individual toxicity, may 
permanently discontinue 
study drug/study 
regimen. Please refer to 
guidelines below
Grade 4
Permanently 
discontinue study 
drug/study regimen

In the absence of a clear alternative etiology, all events 
should be considered potentially immune related.

Symptomatic and topical therapy should be considered for low-
grade (Grade 1 or 2, unless otherwise specified) events

Systemic corticosteroids (e.g., prednisone or IV equivalent) 
should be considered for persistent low-grade or severe 
(Grade ≥3) events

If symptoms recur or worsen during corticosteroid tapering, 
increase the corticosteroid dose until stabilization or 
improvement of symptoms, then resume corticosteroid 
tapering at a slower rate

More potent immunosuppressives – TNF antagonist class (e.g., 
infliximab) or mycophenolate, etc.) should be considered for 
events not responding to systemic steroids after discussion with 
study physician

Discontinuation of study drug is not mandated for Grade3 / 
Grade4 inflammatory reactions attributed to local tumour 
response (e.g. inflammatory reaction at sites of metastatic 
disease, lymph nodes etc.)
Pneumonitis/ILD
*See section 7.2.5 for a description of AESI’s (Adverse Events of Special Interest). Such AESI’s should be 
monitored carefully and discussed with the treating physician (PI or sub-I) to determine attribution.
Grade
Dose Modifications
Toxicity Management
Any 
Grade

Monitor subjects for signs and symptoms of pneumonitis or ILD 
(new onset or worsening shortness of breath or cough). Subjects 
should be evaluated with imaging and pulmonary function tests 
including other diagnostic procedures as described below

Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), laboratory 
work-up and high-resolution CT scan.
Grade 1
No dose hold required. 
However, consider 
holding study drug/study 
regimen dosing as 
clinically appropriate and 
during diagnostic work-up 
for other etiologies.
For Grade 1 (Radiographic Changes Only)

Monitor and closely follow up in 2-3 days for clinical symptoms, 
pulse oximetry (resting and exertion) and laboratory work- up 
and then as clinically indicated

Consider pulmonary and infectious disease consult

Re-image at least every 3 weeks
Grade 2
Hold study drug up to 28 
days until resolution to ≤ 
Grade 1 or baseline:

If toxicity worsens 
then treat as Grade 
3 or Grade 4

If toxicity improves 
then treat at next 
scheduled 
treatment date
 For Grade 2 (Mild to Moderate New Symptoms)

Monitor symptoms daily and consider hospitalization

Discuss with study physician and consider systemic steroids 
(e.g., prednisone 1- 2mg/kg/day or IV equivalent)

Reimaging as clinically indicated

If no improvement within 3-5 days, additional workup and 
treatment with IV methylprednisolone 1mg/kg/day should be 
considered

If no improvement within 3-5 days, further immunosuppressive 
therapy (e.g., infliximab) should be considered.

Once improving, gradually taper steroids over ≥4 weeks and 
consider prophylactic antibiotics

Consider pulmonary and infectious disease consult
Grade 3 
or 4
Permanently discontinue 
study drug/study 
regimen
For Grade 3 or 4 (severe or new symptoms, new/worsening 
hypoxia, life threatening

Discuss with study physician

pulmonary and infectious disease consult
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NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
33

Hospitalize the patient

Supportive Care (oxygen, etc.)

Initiate empiric IV corticosteroids (e.g., methylprednisolone or 
equivalent) at 1 to 2 mg/kg/day

If no improvement within 3-5 days, additional workup and 
treatment with additional immunosuppressive therapy (e.g., 
infliximab) should be considered

Once improving, gradually taper steroids over ≥6 weeks and 
consider prophylactic antibiotics
Diarrhea/ Enterocolitis
Grade
Dose Modifications
Toxicity Management
Any 
Grade

Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes in 
bowel habits)

Subjects should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, infections, etc.)

Steroids should be considered if an alternative etiology is not 
determined, even for low grade events, in order to prevent 
potential progression to higher grade event

Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis
Grade 1
Continue dosing

Close monitoring for worsening symptoms

Consider symptomatic treatment including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic 
Association colitis diet), and loperamide
Grade 2
Hold study drug up to 28 
days until resolution to ≤ 
Grade 1 or baseline

If toxicity worsens 
then treat as Grade 
3 or Grade 4

If toxicity improves 
then treat at next 
scheduled treatment 
date

Consider symptomatic treatment including hydration, electrolyte 
replacement, dietary changes (e.g., American Dietetic 
Association colitis diet), and loperamide and/or budesonide

Rule out infectious etiologies prior to steroid initiation:
o
If event is persistent (> 3-5 days) or worsens, 
consider prednisone 0.5 to 1 mg/kg/day or IV 
equivalent
o
If not responsive within 3-5 days, consider IV 
corticosteroids (e.g., methylprednisolone IV or 
equivalent) at 0.5-1.0 mg/kg/day
o
If event is not responsive within 3-5 days or 
worsens, additional workup and treatment with IV 
methylprednisolone 1-2mg/kg/day should be 
considered

If no improvement within 3-5 days, further immunosuppressives 
(e.g., infliximab) should be considered

Consult study physician if no resolution to ≤ Grade 1 in 3-4 days

Once improving, gradually taper steroids over ≥4 weeks
Grade 3 
or 4
Permanently discontinue 
study drug/study regimen

Discuss with study physician

Monitor stool frequency and volume and maintain hydration

Urgent GI consult and imaging as appropriate

Initiate empiric IV corticosteroids (e.g., methylprednisolone IV 
or equivalent) at 1 to 2 mg/kg/day

If no improvement within 3-5 days, consider further 
immunosuppressives (e.g., infliximab).

Caution: Ensure GI consult to rule out bowel perforation and 
refer to label before using infliximab. Once improving, gradually 
taper steroids over ≥4 weeks and consider prophylactic 
antibiotics
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NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
34
Hepatitis (Elevated LFTs)
*See section for 7.2.5 for a description of AESI’s, defined as any increase in ALT or AST to greater than 3 × 
ULN and concurrent increase in bilirubin to greater than 2 × ULN. Such AESI’s should be monitored carefully 
and discussed with the treating physician (PI or sub-I) to determine attribution. 
Grade
Dose Modifications
Toxicity Management
Any 
Grade

Monitor and evaluate liver function test: AST, ALT, ALP and 
total bilirubin

Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications)
Grade 1
Continue dosing. If it 
worsens, treat as Grade 2 
event

Continue LFT monitoring per protocol
Grade 2*
Hold Study drug up to 28 
days until resolution to ≤ 
Grade 1 or baseline

If toxicity worsens 
then treat as Grade 
3 or Grade 4

If improves then 
treat at next 
scheduled treatment 
date

Discuss with study physician if no resolution to ≤ Grade 1 
in 1-2 days

Recheck LFT’s in 1 to 2 days. If event is persistent (> 3-5 days) or 
worsens, consider prednisone 0.5 to 1 mg/kg/day or IV 
equivalent.

If no improvement within 3-5 days, consider additional workup 
and treatment with IV methylprednisolone 2-4mg/kg/day
o
If no improvement within 3-5 days after 
methylprednisolone, consider further 
immunosuppressives (e.g., mycophenolate mofetil)
o
Once improving, gradually taper steroids over ≥4 
weeks and consider prophylactic antibiotics
Grade 3 
or higher
For elevations in 
transaminases ≥ 5 × 
ULN, or elevations in 
bilirubin ≥ 3 × ULN, 
permanently discontinue 
study drug/study 
regimen.

Discuss with the study physician

Initiate empiric IV corticosteroids (e.g., methylprednisolone IV or 
equivalent) at 1 to 4 mg/kg/day
o
If no improvement within 3-5 days, consider further 
immunosuppressive therapy (e.g., mycophenolate 
mofetil)
o
If still no further improvement within 3-5 days consider 
other immunosuppressive therapy per local guidelines

Hepatology consult, abdominal workup, and imaging as 
appropriate.

Once improving, gradually taper steroids over ≥4 weeks 
and consider prophylactic antibiotics
Immune-Mediated Nephritis and Renal Dysfunction
Any 
Grade

Monitor and evaluate renal function tests (comprehensive chemistry 
panel)

Evaluate for alternative etiologies
Grade 1
Continue dosing. 

Continue comprehensive chemistry plan per protocol
Grade 2 
or 3
Hold Study drug up to 
28 days until resolution 
to ≤ Grade 1 or baseline
If toxicity worsens 
then treat as Grade 

Discuss with the study physician

Consider empiric steroids at a dose of 0.5 to 1 mg/kg/day or IV 
equivalent.

Consider renal biopsy with nephrology consult
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
35
3 or Grade 4

If improves to 
baseline then treat at 
next scheduled 
treatment date

Monitor creatinine every 2-3 days
Grade 4
Permanently discontinue 
study drug/study 
regimen

Discuss with the study physician

Nephrology consult

Monitor creatinine daily 

Administer corticosteroids at a dose of 1-2 mg/kg/day prednisone 
equivalents followed by corticosteroid taper for life-threatening 
(Grade 4) serum creatinine elevation and permanently discontinue. 
For severe (Grade 3) withhold and administer corticosteroids at a 
dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by 
corticosteroid taper. If worsening or no improvement occurs, 
increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone 
equivalents and permanently discontinue.
Rash (excluding Bullous skin formations)
Grade
Dose Modifications
Toxicity Management
Any 
Grade
Monitor for signs and symptoms of dermatitis (rash and pruritus)
**IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED**
Grade 1
Continue dosing.
Consider symptomatic treatment including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea 
cream)
Grade 2
For persistent (> 1- 2 
weeks) Grade 2 events, 
hold scheduled study 
drug up to 28 days until 
resolution to ≤ Grade 1 or 
baseline

If toxicity worsens 
then treat as Grade 3

If toxicity improves 
then resume 
administration at next 
scheduled dose

Consider symptomatic treatment including oral antipruritics (e.g., 
diphenhydramine or hydroxyzine) and topical therapy (e.g., urea 
cream)

Consider moderate-strength topical steroid

If no improvement of rash/skin lesions occurs within 3-5 days or 
is worsening, discuss with study physician and consider 
systemic steroids prednisone 0.5 to 1 mg/kg/day or IV 
equivalent

Consider dermatology consult

Consider skin biopsy if persistent for >1-2 weeks or recurs
Grade 3**
Hold study drug up to 28 
days until resolution to ≤ 
Grade 1 or baseline.
If temporarily holding the 
study drug/study regimen 
does not provide 
improvement of the 
Grade 3 skin rash to ≤ 
Grade 1 or baseline within 
28 days, then 
permanently discontinue 
Study drug
Grade 4**
Permanently discontinue 

Discuss with study physician

Consider hospitalization

Monitor extent of rash [Rule of Nines]

Consult dermatology

Consider skin biopsy (preferably more than
o
as clinically feasible.

Initiate empiric IV corticosteroids (e.g., methylprednisolone IV or 
equivalent) at 1 to 2 mg/kg/day

Once improving, gradually taper steroids over ≥4 weeks and 
consider prophylactic antibiotics
**If SJS/TEN is suspected, withhold I-O therapy and refer patient 
for specialized care for assessment and treatment. If SJS or TEN 
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NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
36
study drug/study regimen is diagnosed, permanently discontinue I-O therapy.
Endocrinopathy (e.g. hyperthyroidism, hypothyroidism, hypopituitarism, adrenal insufficiency, etc.)
Grade
Dose Modifications
Toxicity Management
Any 
Grade

Monitor subjects for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, hypotension and weakness.

Subjects should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, infections, etc.)

Monitor and evaluate thyroid function tests: TSH, free T3 and free 
T4 and other relevant endocrine labs depending on suspected 
endocrinopathy.

If a subject experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, 
diabetes insipidus), the investigator should send a blood sample 
for appropriate autoimmune antibody testing
Grade 1
Continue dosing.
For Grade 1: (including those with asymptomatic TSH elevation)

Monitor patient with appropriate endocrine function tests

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 and consider endocrinology consult.
Grade 2
Hold study drug up to 28 
days  until resolution to ≤ 
Grade 1

If worsens then treat 
as Grade 3 or Grade 
4 

If toxicity improves to 
baseline then treat at 
next scheduled 
treatment date
For Grade 2: (including those with symptomatic endocrinopathy)

Discuss with study physician

Initiate hormone replacement as needed for management

Evaluate endocrine function, and as clinically indicated, 
consider pituitary scan

For subjects with abnormal endocrine work up, consider short-
term, high-dose corticosteroids (e.g., methylprednisolone or IV 
equivalent) with relevant hormone replacement (e.g., 
levothyroxine, hydrocortisone, or sex hormones)

For subjects with normal endocrine work up (lab or MRI scans), 
repeat labs/MRI as clinically indicated.
Grade 3
Hold study drug up to 
28 days until 
endocrinopathy 
symptom(s) are 
controlled.
Resume study 
drug/study regimen 
administration if 
controlled at the next 
scheduled dose.
Grade 4
Permanently discontinue 
study drug/study regimen

Discuss with study physician

Initiate empiric IV corticosteroids (e.g., methylprednisolone IV or 
equivalent) at 1 to 2 mg/kg/day

Administer hormone replacement therapy as necessary

For adrenal crisis, severe dehydration, hypotension, or shock: 
immediately initiate intravenous corticosteroids with 
mineralocorticoid activity

Consult endocrinologist

Once improving, gradually taper immunosuppressive steroids over 
≥4 weeks
Immune mediated Neurotoxicity (except Myasthenia Gravis and Guillain-Barre)
Grade
Dose Modifications
Toxicity Management
Any 
Grade

Subjects should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes and 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
37
medications, etc.)

Monitor subject for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness)

Consider appropriate diagnostic testing (e.g. electromyogram and 
nerve conduction investigations)

Symptomatic treatment with neurological consult as appropriate
Grade 1
Continue dosing
Grade 2

For acute motor 
neuropathies or 
neurotoxicity, hold 
study drug up to 28 
days until resolution 
to ≤ Grade 1

For sensory 
neuropathy/neuro 
pathic pain, consider 
holding study drug 
up to 28 days until 
resolution to ≤ 
Grade 1 or baseline.
o
If toxicity 
worsens 
then treat as 
Grade 3 or 
Grade 4
o
If toxicity 
improves 
then treat at 
next 
scheduled 
treatment 
date

Discuss with the study physician

Consider Neurology Consult

Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine, etc.)

Consider systemic steroids prednisone 1- 2mg/kg/day or IV 
equivalent at 0.5 to 1 mg/kg/day

If no improvement within 3-5 days, consider additional workup 
and treatment with additional immunosuppressive therapy (e.g. 
IVIgG)
Grade 3 
or higher
Permanently discontinue 
study drug/study regimen

Discuss with study physician

Consult Neurology Consult

Consider hospitalization

Consider empiric IV corticosteroids (e.g., methylprednisolone or 
IV equivalent) at 1 to 2 mg/kg/day

If no improvement within 3-5 days, consider additional workup 
and treatment with additional immunosuppressants (e.g. IVIgG)

Once stable, gradually taper steroids over ≥4 weeks
Immune- mediated peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis
Grade
Dose Modifications
Toxicity Management
Any 
Grade

The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain subjects may 
unpredictably experience acute decompensations which can 
result in substantial morbidity or in the worst case, death. Special 
care should be taken for certain sentinel symptoms which may 
predict a more severe outcome, such as prominent dysphagia, 
rapidly progressive weakness, and signs of respiratory 
insufficiency or autonomic instability
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
38

Subjects should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes and 
medications, etc.). It should be noted that the diagnosis of 
immune- mediated peripheral neuromotor syndromes can be 
particularly challenging in subjects with underlying cancer, due to 
the multiple potential confounding effects of cancer (and its 
treatments) throughout the neuraxis.
o
Given the importance of prompt and accurate diagnosis, 
it is essential to have a low threshold to obtain a 
neurological consult

Neurophysiologic diagnostic testing (e.g., electromyogram and 
nerve conduction investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon suspicion 
of such conditions and may be best facilitated by means of a 
neurology consultation

Important to consider that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered effective. 
Subjects requiring treatment should be considered for 
plasmapheresis (or IVIgG, as an alternative)
Grade 1
Continue dosing.

Discuss with the study physician

Care should be taken to monitor subjects for sentinel symptoms of 
a potential decompensation as described above

Consider a neurology consult unless the symptoms are very 
minor and stable
Grade 2
Hold study drug up to 28 
days until resolution to ≤ 
Grade 1 or baseline
Permanently discontinue 
study drug if it does not 
resolve to ≤ Grade 1 
within 28 days or if there 
are signs of respiratory 
insufficiency or autonomic 
instability
Grade 2 : Moderate

Discuss with the study physician

Care should be taken to monitor subjects for sentinel symptoms of 
a potential decompensation as described above

Obtain a Neurology Consult

Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin, duloxetine, etc.)
MYASTHENIA GRAVIS
o
Steroids may be successfully used to treat Myasthenia 
Gravis. Important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and 
should typically be 
administered in a monitored setting under supervision of 
a consulting neurologist.
o
Subjects unable to tolerate steroids may be candidates for 
treatment with plasmapheresis or IVIgG. Such decisions 
are best made in consultation with a neurologist, taking 
into account the unique needs of each patient.
o
If Myasthenia Gravis-like neurotoxicity present, consider 
starting acetylcholine esterase 17 inhibitor therapy in 
addition to steroids. Such therapy, if successful, can also 
serve to reinforce the diagnosis.
GUILLAIN-BARRE:
o
Important to consider here that the use of steroids as the 
primary treatment of Guillain-Barre is not typically 
considered effective.
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NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
39

Subjects requiring treatment should be considered for 
plasmapharesis (or IVIgG, as an alternative).
Grade 3 
or higher
Permanently 
discontinue study 
drug/study regimen.
For severe or life threatening (Grade 3 or 4) events:
-
Discuss with study physician
-
Recommend hospitalization
-
Monitor symptoms and obtain neurological consult
MYASTHENIA GRAVIS
o
Steroids may be successfully used to treat 
Myasthenia Gravis. It should typically be 
administered in a monitored setting under 
supervision of a consulting neurologist.
o
Subjects unable to tolerate steroids may be 
candidates for treatment with plasmapharesis or 
IVIgG.
o
If Myasthenia Gravis-like neurotoxicity present, 
consider starting acetylcholine esterase 17 inhibitor 
therapy in addition to steroids. Such therapy, if 
successful, can also serve to reinforce the 
diagnosis.
GUILLAIN-BARRE:
o
Important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective.
Subjects requiring treatment should be considered for plasmapharesis 
(or IVIgG, as an alternative).
Infusion- related reactions
Grade
Dose Modifications
Toxicity Management
Any 
Grade

Management per institutional standard at the discretion of 
investigator

Monitor subjects for signs and symptoms of infusion- related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, skin rashes etc.) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, tachycardia, etc.)
Grade 1
The infusion rate of study 
drug/study regimen may 
be decreased by 50% or 
temporarily interrupted 
until resolution of the 
event
Grade 2
The infusion rate of 
study drug/study 
regimen may be 
decreased 50% or 
temporarily 
interrupted until 
resolution of the 
event (up to 4 
hours) 
Subsequent 
infusions may be 

Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator

Consider premedication per institutional standard prior to 
subsequent doses
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NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
40
given at 50% of the 
initial infusion rate
Grade 3 
or 4
Permanently 
discontinue study 
drug/study regimen.
Manage severe infusion- related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid)
Non- immune Mediated Reactions
Grade
Dose 
Modifications
Toxicity Management
Any 
Grade 
Note: dose 
modifications are 
not required for 
adverse events not 
deemed to be 
related to study 
treatment (i.e. 
events due to 
underlying disease) 
or for laboratory 
abnormalities not 
deemed to be 
clinically significant.
Treat accordingly as per institutional standard.
1
No dose 
adjustment.
Treat accordingly as per institutional standard
2
Hold study drug up to 28 
days until resolution to ≤ 
Grade 1 or baseline
Treat accordingly as per institutional standard
3
Hold study drug up to 28 
days until resolution to ≤ 
Grade 1 or baseline For 
AEs that downgrade to ≤ 
Grade 2 within 7 days 
AND resolve to ≤ Grade 
1 or baseline within 14 
days, resume study 
drug/study regimen 
administration at next 
scheduled dose.
Otherwise, discontinue 
study drug/study 
regimen
Treat accordingly as per institutional standard
4
Discontinue Study 
drug/study regimen 
(Note for Grade 4 
labs, decision to 
discontinue would 
be based on 
accompanying 
clinical 
signs/symptoms 
Treat accordingly as per institutional standard
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NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
41
4.6
Concomitant Medications/Treatments
The investigator must be informed as soon as possible about any medication taken 
from the time of screening until the end of the clinical phase of the study (final study 
visit). Any concomitant medication(s), taken during the study will be recorded.
Investigators may prescribe concomitant medications or treatments (eg, 
acetaminophen, diphenhydramine) deemed necessary to provide adequate 
prophylactic or supportive care except for those medications identified as “excluded” as 
listed in the bulleted list below. Patients may continue baseline medications that were 
initially deemed appropriate by the investigator at screening.
Subjects must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator.
The following medications are considered exclusionary during the study:
•
Any investigational anticancer therapy (within 28 days prior to registration)
•
Any concurrent chemotherapy, radiotherapy (except palliative radiotherapy on 
non-target lesions only), immunotherapy, biologic or hormonal therapy for cancer 
treatment. (within 14 days prior to registration, 28 days for systemic 
chemotherapy)
•
Immunosuppressive medications including, but not limited to systemic 
corticosteroids at doses not exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and TNF-alpha blockers. Use of immunosuppressive 
medications for the management of investigational product-related AEs or in 
subjects with contrast allergies is acceptable. In addition, use of inhaled and 
intranasal corticosteroids is permitted. Temporary courses of corticosteroids for 
treatment of underlying or concurrent illness or in the setting of palliative 
radiotherapy may be permitted upon discussion with the PI.
•
Live attenuated vaccines during the study within 28 days prior to registration 
through 180 days after the last dose of both drugs
•
Herbal and natural remedies (within 14 days prior to registration)
4.7
Duration of Therapy (for both dose- escalation and dose- expansion phase)
Patients may continue with treatment until any of the following occur:

Disease progression, unless the patient meets criteria for continuing treatment 
beyond progression. See section 4.7.1 for details.

Development of an inter-current illness that prevents further administration 
of treatment

Unacceptable adverse event(s)

Patient decides to withdraw from either study treatment or the study as a whole 

The treating investigator determines that the patient should be taken off treatment 
for any reason (i.e. changes in condition, inability to comply with study treatment 
or procedures)
4.7.1
Continuation of Investigational Therapy after Progression
and as per 
Investigator’s 
clinical judgment 
and in consultation 
with the sponsor)
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                                                        BMS Study Number: CA 209-783
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Initial Version Date: October 6, 2016
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In the event of an initial assessment of PD (based on RECIST Version 1.1), a 
subject may continue to receive the assigned study treatment as long as none 
of the criteria listed below are met.
1.
Confirmed PD: An initial assessment of PD by RECIST 1.1 or Lugano 
criteria will be confirmed by a repeat evaluation at the next tumor 
assessment time point, but no sooner than 4 weeks later (see section 
6.1.7 & Appendix C, respectively). If any subsequent tumor assessment 
shows progression per RECIST v1.1 or Lugano criteria in the overall 
tumor burden (the sum of diameters of target lesions and new lesions), 
when compared to the initial PD assessment (the sum of diameters of 
target lesions and new lesions), then PD is confirmed.
2.
Meets any of the other investigational product discontinuation criteria 
(Section 4.6) 
3.
Clinical symptoms or signs indicating significant PD, for example the 
benefit-risk ratio of continuing therapy is no longer justified. 
4.
Decline in ECOG performance status.
5.
Threat to vital organs/critical anatomical sites (e.g., spinal cord 
compression) requiring urgent alternative medical intervention, and 
continuation of study therapy would prevent institution of such 
intervention.
4.8
Duration of Follow Up (for both dose- escalation and dose- expansion phase)
After patients come off treatment they will be followed up at 3, 6, 9, 12 months and 
then every 6 months for 3 years (from the start of the treatment) for survival and 
progression of disease via either clinic visits or phone calls. 
4.9
Removal of Subjects from Study Treatment and/or Study as a Whole
(for both dose- escalation and dose- expansion phase)
Patients can be taken off the study treatment and/or study as a whole at any time at 
their own request, or they may be withdrawn at the discretion of the investigator for 
safety, behavioral or administrative reasons. The reason(s) for discontinuation must 
be clearly documented on the appropriate eCRF and may include:

Patient voluntarily withdraws from treatment (follow-up permitted)

Patient withdraws consent (no follow-up permitted)

Patient is unable to comply with protocol requirements

Patient demonstrates disease progression

Patient experiences unacceptable toxicity

Treating physician determines that continuation on the study would not be in 
the patient’s best interest

Patient becomes pregnant

Patient develops a second malignancy that requires treatment which would 
interfere with this study

Patient becomes lost to follow-up (LTF)
Patients who are permanently discontinued from receiving investigational product will 
be followed for disease progression and safety, including the collection of any 
protocol- specified blood specimens, unless consent is withdrawn or the subject is lost 
to follow-up or administered subsequent therapy. All subjects will be followed for 
survival and disease progression. Subjects who decline to return to the site for 
evaluations will be offered follow-up by phone every 3 months as an alternative.
4.10
Patient Replacement
If a patient is enrolled in the study but comes off study before cycle 1 day 1 of 
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NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
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treatment, the patient may be replaced.
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NU Study Number: NU 16MH03
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Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
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5.0
STUDY PROCEDURES
Table 5: Study timeline
Induction 
(7 days)c
Cycle 1 
(Cycle=28 days)
Cycle 2-4
Cycle 5 +
Screeninga,b,c
D1
D1 
D8
D15
D1
D15
D1
End of 
Treatmento
Follow Upp
Study window
±1 day
±1 day
±3 days
±3 days
±3 days
±7 days
q3months
Informed Consent
X
Medical History
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
Vitals signsd,l
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
AE reportingq
X
X
X
X
X
X
X
Xq
Xq
Concomitant 
Medications
X
X
X
X
X
X
X
CMPe
X
X
X
X
X
X
X
X
X
CBC with 
differential f
X
X
X
X
X
X
X
X
X
Pregnancy test g
Xg
X
Thyroid function 
testh
X
PT/INR 
Xi
Imaging (CT or 
MRI)j
X
Xj
Xj
X
Tumor biopsyk
X
Mutation testing
Xr
Blood for Tumor 
Markersl
X
X
Xl
X
Nivolumab 
infusionm
X
X
X
X
Xm
Veliparibn
X
X
X
X
Survival
X
a.
Informed consent must be signed ≤ 30 days before registration. If signature is outside that window the patient must sign a new consent.
b.
Pre-study H&P and all labs must be ≤ 14 days before registration. Tumor measurements and radiologic evaluations must be ≤28 days before registration. 
c.
The maximum time interval between registration and the first dose of study drug will be 14 days.
d.
Vital signs include pulse and blood pressure.Weight will be recorded at baseline. Height will be recorded at baseline only.
e.
Serum Chemistry will include calcium, chloride, magnesium, phosphorus, creatinine, sodium, potassium, blood urea nitrogen, bicarbonate, glucose, 
total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, albumin, and total protein. 


NU Study Number: NU 16MH03
                                                        BMS Study Number: CA 209-783
Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
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f.
CBC: Performed pre-dose at each treatment visit (Day 1 & 15 of Cycles 1-4, and Day 1 of Cycle 5+). For patients experiencing significant drop in WBCs 
or platelets felt related to treatment, CBCs should be obtained more frequently (weekly or more frequently) to assess timing for retreatment or need for 
transfusion support.
g.
Serum or urine test only for women of childbearing potential; must be tested within 7 days prior to registration as well as C1D1 (within 24 hours prior to 
nivolumab treatment).
h.
Thyroid function tests will include thyroid stimulating hormone (TSH) with reflexfree T4. This will be done at baseline then only as clinically indicated 
thereafter. 
i.
PT/INR is required at baseline (≤ 28 days prior to registration) for patients on anticoagulants.
j.
Imaging (either CT scan or MRI and PET if applicable) will be performed at screening, ≤28 days prior to registration. The same modality used at baseline 
should be used throughout for imaging. CT imaging will include chest, abdomen, and pelvis. Neck will be included only if measurable lesions are present. 
Scans will then take place every 2 cycles (8 weeks) starting with Cycle 3 Day 1 (- 7 days). Tumor measurements will be performed using RECIST 1.1 or 
Lugano classification. Progressive Disease (PD) must be confirmed by repeat scan within 8 weeks.
k.
Patients will undergo a fresh tissue biopsy prior to study enrollment, unless deemed to be clinically inappropriate per PI. If a fresh biopsy is not feasible, an 
archival tissue sample should be obtained (a cell block is preferred, however 15 unstained slides will suffice). Tissue should be obtained by any means 
possible, but patients will not be excluded from the study if tissue is not available. The samples will be obtained for correlative studies – see section 9.0 and 
separate lab manual for details. 
l.
Study labs will be collected for tumor markers pre-dose on Induction Day 1, C1D1, C3D1, and at the End of Treatment visit. See section 9.0 and separate 
lab manual for more details.
m. Nivolumab will be administered as follows:
Cycles 1-4: given at a fixed dose of 240mg IV over 30 minutes (-5 / +15 minutes) every 2 weeks
Starting with Cycle 5 Day 1: 480mg IV over 30 minutes (-10 / +15 minutes) every 4 weeks until disease progression, intolerability, or withdrawal of 
consent. 
Vital signs will be monitored prior to, throughout, and after the nivolumab infusion according to Table 4.2.
n.
Veliparib will be taken orally at the assigned dose twice a day until disease progression, intolerability, or withdrawal of consent. It will be initiated as 
monotherapy during a 7-day induction period. Starting with Cycle 1 Day 1, veliparib will be given twice daily in combination with scheduled nivolumab 
infusions. Veliparib may be taken with or without food. Patients will be given a drug diary to maintain for compliance. Veliparib dosing may take place 
independently of nivolumab. On the day of a study visit, lab values should be checked against sections 4.4 and 4.5 for continued dosing.
o.
The end of treatment visit should occur 30 days after the last dose of study treatment (± 7 days) or before starting another line of treatment, whichever 
comes first. 
p.
After patients come off treatment they will be followed up at 3, 6, 9, and 12 months and then every 6 months for 3 years for survival and progression of 
disease via either clinic visits or phone calls.
q.
Adverse events will be followed from the time of consent until 30 days after treatment discontinuation (100 days for SAE’s).
r. 
For patients in the expansion phase of the study, mutation testing is required within 1 year of registration (see 3.1.6 for details)


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
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6.0
ENDPOINT ASSESSMENT
6.1
Solid tumors
6.1.1 Response will be evaluated using the modified Response Evaluation Criteria in Solid 
Tumors, based on RECIST v1.1.35
6.1.2 Clinical evaluation and tumor assessments will be performed as indicated in Table 6, 
based on physical examination and radiologic evaluation. 
6.1.3 Any lesion that has been previously treated with radiotherapy should be considered 
as a non-target lesion. However, if a lesion previously treated with radiotherapy has 
clearly progressed since the radiotherapy, it can be considered as a target lesion.
6.1.4 Definitions for measurable and non-measurable lesions, and criteria for response, 
should be based on RECIST v1.1.
6.1.5 Measurable Disease
Measurable lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by 
chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters).
6.1.6 Non-measurable Disease
All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 
mm [≥1 to <1.5 cm] short axis), are considered non-measurable disease. Bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal 
masses (not followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-
measurable) since 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 non- cystic lesions are present in the same patient, these are 
preferred for selection as target lesions.  
6.1.7 Response criteria

Complete Response (CR) - Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to <10mm.

Partial Response (PR) - At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline sum diameters.

Objective Response Rate – the sum of complete responses and partial 
responses 

Progressive Disease (PD) - At least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression.)

Stable Disease (SD) - Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum of 
diameters while on study.
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6.2
Lymphoma
6.2.1 Response will be evaluated, using the Lugano classification for assessment of 
Lymphoma.36 See Appendix C for specific response assessment criteria.
6.2.2 Clinical evaluation and tumor assessments will be performed periodically, as shown 
in Table 6, based on evaluation of spleen and liver, physical examination for 
superficial disease and B symptoms, radiologic evaluation, and appropriate 
laboratory studies.
6.2.3 A lesion is categorized based on the location as either a nodal lesion or an 
extranodal lesion if it is located in organs other than lymph nodes or nodal mass, but 
including spleen and liver.
6.2.4 All tumor lesions/lymph nodes will be categorized as measurable or non-measurable 
as follows:
•
Measurable nodal and extranodal lesions:
A lesion will be called measurable if it can be measured accurately in 2 
perpendicular dimensions and:
-For nodal lesion, if the long axis is >15 mm, regardless of the length of the 
short axis
-For extranodal lesion, if the long and short axes are ≥10 mm.
Patients should have at least one measurable nodal lesion greater than 20 
mm in the long axis.
In cases where the patient has no measurable nodal lesions greater than 20 
mm in the long axis at screening, then the patient must have at least one 
measurable extranodal lesion. 
6.2.5 Classification of lymph nodes
•
Lymph nodes are classified according to their size and/or relationship to the 
disease:
-A lymph node meeting the measurability requirement, but with long axis > 
15 mm (e.g. short axis cannot be measured accurately) will constitute a 
non-measurable nodal lesion.
-A lymph node not meeting the measurability criteria, but with a size of 11 
mm to 15 mm in the long axis and >10 mm in the short axis will be checked 
for relationship to disease:
-If it is thought to be disease related, it will constitute a non-
measurable nodal lesion
-If it is not thought to be disease related, it will constitute an 
abnormal lymph node, but not a lesion.
All other lymph nodes will be considered normal and will not constitute nodal 
lesions.
6.2.6 Criteria for normalization of lesions
•
The normalization of lesions is defined as follow:
-A measurable nodal lesion must become ≤ 15 mm in long axis to be 
considered normalized.
-A non-measurable nodal lesion must decrease to ≤10 mm in the short axis 
and be ≤ 15 mm in long axis to be considered normalized.
-An extranodal lesion must disappear completely (assigned a size of 0 mm 
x 0 mm) to be considered normalized.
6.3
Immune-related RECIST (irRECIST)
6.3.1 In addition to above, tumor response for both solid tumors and lymphoma will be 
assessed by the irRECIST for investigational purposes, not assessment of primary 
objective.37 In RECIST v1.1, the appearance of new lesions indicates PD. However, 
in irRECIST, new measurable lesions are incorporated in the tumor burden, which is 
used to determine irPD, immune-related partial response (irPR), and immune-related 
complete response (irCR). New nonmeasurable lesions preclude irCR. Under RECST 
v1.1, there is no confirmation for PD. Under irRECIST, responses and irPDs must be 
confirmed by consecutive scans at least 4 weeks apart, assuming no clinical deterioration. We 
will define immune-related clinical benefit rate as immune-related stable disease 
(irSD), irPR, or irCR. 
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Table 6: Immune-related Response Evaluation Criteria: Overall Response
Tumor Burden
(Baseline and New)
Non-Target Lesions
(Baseline and New)
Response
Disappearance of non-nodal 
lesions. All pathologic lymph 
nodes <10 mm (short axis)
Disappearance of non-nodal 
lesions. All pathologic lymph 
nodes < 10 mm (short axis)
irCR
≥30% decrease from baseline
Any
irPR
≥20% increase from nadir and at 
least 5 mm
Any
irPD
Neither sufficient decrease to 
qualify for PR, nor sufficient 
increase to qualify for PD
Any
irSD
Disappearance of all non-nodal 
lesions. All pathologic lymph 
nodes <10 mm
Any other than disappearance of 
all non-nodal lesions and 
reduction of pathologic lymph 
nodes <10 mm
irPR
Not all evaluated
Any
irNE
irCR = immune-related complete response; irPD = immune-related progressive disease; 
irPR = immune-related partial response; irNE = immune-related not evaluable; irSD = 
immune-related stable disease; 
-Tumor burden is the sum of single diameters (short axis for nodal lesions, longest diameter 
for other lesions) for the target lesions. In subsequent scans, the diameters of new 
measurable lesions are added to the tumor burden. 
-Best overall response based on 2 consecutive measurements at least 4 weeks apart.
6.4
Primary Endpoint
The primary objective is to identify maximum tolerated dose (MTD) for the combination 
treatment of nivolumab and veliparib. 
The MTD will be defined as the highest dose that causes dose-limiting toxicities (DLTs) 
in <2 of 6 patients and is determined for this study.. 
6.5
Secondary Endpoints
6.5.1
Secondary endpoints include the number, frequency, and severity of adverse 
events (as defined by the NCI Common Terminology Criteria for Adverse 
Events or CTCAE version 4.03) will be recorded.
6.5.2
To evaluate the efficacy of treatment with nivolumab and veliparib in this population by 
objective response rate (ORR, defined as partial response (PR) + complete response 
(CR)), clinical benefit rate (CBR, defined as stable disease (SD) for ≥12 weeks, PR, + 
CR), and Progression Free Survival (PFS, defined as the time from treatment initiation 
to documented disease progression) using RECIST criteria v1.1 or the Lugano 2014 
classification for assessment of Lymphoma36. 
For the preliminary efficacy analysis, ORR and other measures will be computed 
separately for patients with and those without genetic mutations, at the first 
imaging (8 weeks). Preliminary efficacy will be evaluated by RECISTv 1.1. As 
exploratory analysis, irRECIST will be used to obtain preliminary efficacy as well.  
All ORR will use the first imaging time point whether RECIST or irRECIST.
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6.5.3
To evaluate efficacy of treatment with nivolumab and veliparib in this population by 
ORR, CBR, and immune-related PFS (irPFS) using irRECIST criteria.
6.5.4
To evaluate Overall Survival (OS) in this population at 3 years from the start of 
treatment. OS is defined as the time from treatment initiation until death due to any 
cause.
6.5.5
To evaluate the proportion of patients alive and progression free at 24 weeks in 
this population.
6.6
Exploratory Endpoints
6.6.1
Biomarkers predictive of response include assessment of tissue-based 
immunohistochemical expression of PD-L1; TILs; peripheral T cell subpopulations; 
changes in tissue and peripheral T cell receptor sequencing, HLA genotype, and 
immune-related candidate gene signatures at baseline.
6.6.2
To demonstrate the pharmacodynamic effects of veliparib and nivolumab on 
biomarkers including PD-L1, TILs, T cell subpopulations, and T cell receptor 
genotype. 
7.0
ADVERSE EVENTS
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) of the 
Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please refer to 
Appendices for additional information). The level of risk attributed to this study requires high level 
monitoring, as outlined in the DSMP. In addition, the study will abide by all safety reporting 
regulations, as set forth in the Code of Federal Regulations.
7.1
Adverse Event Monitoring
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner from the time of consent until 30 days after treatment discontinuation (100 
days for SAE’s) at scheduled times during a trial (see Section 5 for time points). In 
addition, certain adverse events must be reported in an expedited manner to allow for 
optimal monitoring and patient safety and care.
All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be followed until:

the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;

any abnormal laboratory values have returned to baseline;

there is a satisfactory explanation other than the study drug for the changes 
observed; or

death
7.2
Definitions & Descriptions
7.2.1
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
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(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.
Recording of AEs should be done in a concise manner using standard, 
acceptable medical terms. In general, AEs are not procedures or measurements, 
but should reflect the reason for the procedure or the diagnosis based on the 
abnormal measurement. Preexisting conditions that worsen in severity or 
frequency during the study should also be recorded (a preexisting condition that 
does not worsen is not an AE). Further, a procedure or surgery is not an AE; 
rather, the event leading to the procedure or surgery is considered an AE.
If a specific medical diagnosis has been made, that diagnosis or syndrome 
should be recorded as the AE whenever possible. However, a complete 
description of the signs, symptoms and investigations which led to the diagnosis 
should be provided. For example, if clinically significant elevations of liver 
function tests are known to be secondary to hepatitis, “hepatitis” and not 
“elevated liver function tests” should be recorded. If the cause is not known, the 
abnormal test or finding should be recorded as an AE, using appropriate medical 
terminology (e/g/ thrombocytopenia, peripheral edema, QT prolongation).
7.2.2
Severity of AEs
All non-hematologic adverse events will be graded according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The 
CTCAE v4.03 is available at http://ctep.cancer.gov/reporting/ctc.html
If no CTCAE grading is available, the severity of an AE is graded as follows:

Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities.

Moderate (grade 2): the event causes discomfort that affects normal daily 
activities.

Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status.

Life-threatening (grade 4): the patient was at risk of death at the time of the 
event.

Fatal (grade 5): the event caused death.
7.2.3
Serious Adverse Events (SAEs)
All SAEs, regardless of attribution, occurring from time of signed informed 
consent, through 100 days after the last administration of study drug, must be 
reported upon discovery or occurrence.
An SAE is defined in regulatory terminology as any untoward medical occurrence 
that:

Results in death.
If death results from (progression of) the disease, the disease should be 
reported as event itself.

Is life-threatening.
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 in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours.

Results in persistent or significant disability or incapacity.

Is a congenital anomaly/birth defect.

Is an important medical event.
Any event that does not meet the above criteria, but that in the judgment of 
the investigator jeopardizes the patient, may be considered for reporting as a 
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serious adverse event. The event may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition of “Serious 
Adverse Event“.
For example: allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency.
7.2.4
Exceptions to AE and SAE definitions
Generally speaking, any adverse event that results in hospitalization or prolonged 
hospitalization should be documented and reported as an SAE, as described 
above. Likewise, any condition responsible for surgery should be documented as 
an AE if the condition meets the criteria for an AE. However, for the purposes of 
this study, neither the condition, hospitalization, prolonged hospitalization, nor 
surgery are reported as AEs or SAEs under the following circumstances:

Hospitalization or prolonged hospitalization is for a diagnostic or elective 
surgical procedure for a preexisting condition. Surgery should not be 
reported as an outcome of an adverse event if the purpose of the surgery 
was elective or diagnostic and the outcome was uneventful.

Hospitalization or prolonged hospitalization is required to allow efficacy 
measurement for the study.

Hospitalization or prolonged hospitalization is required for study-directed 
therapy of the target disease of the study, unless it is a worsening or 
increase in frequency of hospital admissions as judged by the principal 
investigator.

Hospitalization or prolonged hospitalization is due to social reasons (i.e. 
awaiting transport home).

Pregnancy is not considered a serious adverse event, any patients who 
become pregnant during the study should discontinue the study 
immediately. Patients should be instructed to notify the investigator if it is 
determined after completion of the study that they become pregnant either 
during the treatment phase of the study or within 30 days or five half-lives 
after the treatment period, whichever is longer.
7.2.5
Adverse Event of Special Interest (AESI)
An AESI is one of scientific and medical interest specific to understanding of the 
investigational product and may require close monitoring. An AESI may be serious 
or non-serious. The close monitoring and discussion of AESIs allows ongoing 
surveillance of these events in order to characterize and understand them in 
association with the use of this investigational product. The following are 
considered to be AESI:

  Hepatic Function Abnormality
Hepatic function abnormality is defined as any increase in ALT or AST to 
greater than 3 × ULN and concurrent increase in bilirubin to greater than 
2 × ULN. Concurrent findings are those that derive from a single blood draw or 
from separate blood draws taken within 8 days of each other. Follow-up 
investigations and inquiries will be initiated promptly by the investigational site 
to determine whether the findings are reproducible and/or whether there is 
objective evidence that clearly supports causation by a disease (e.g., 
cholelithiasis and bile duct obstruction with distended gallbladder) or an agent 
other than the investigational product.
If the underlying diagnosis for the hepatic function abnormality is known 
(including progression of pre-existing disease such as primary or metastatic 
malignancy), the diagnosis should be recorded as an AE/SAE.
If the underlying diagnosis for the hepatic function abnormality remains 
unknown, the term “hepatic function abnormal” should be used to report the 
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AE/SAE. Hepatic function abnormality of unknown etiology, or which is 
considered attributable to investigational product, is required to be reported 
as “hepatic function abnormal”. The investigator will review the data with the 
PI. The investigator should then use clinical judgment to establish the cause 
based on local standard of care and follow the subject by conducting testing 
as clinically indicated.

Pneumonitis
Adverse events of pneumonitis are also of interest, as pneumonitis has 
been observed with anti-PD-1 and anti-PD-L1 mAbs. Initial work-up should 
include high-resolution CT scan, ruling out infection, and pulse oximetry. 
Pulmonary consultation is highly recommended.
7.2.6
Other events requiring immediate reporting 
Overdose
An overdose is defined as a patient receiving a dose of investigational product in 
excess of dose detailed in this protocol.
Any overdose of a study patient with the investigational product, with or without 
associated AEs/SAEs, is required to be reported within 24 hours of knowledge of 
the event. If the overdose results in an AE, the AE must also be recorded on the 
AE eCRF. Overdose does not automatically make an AE serious, but if the 
consequences of the overdose are serious, for example death or hospitalization, 
the event is serious and must be reported as an SAE. The investigator will use 
clinical judgment to treat any overdose.
Pregnancy
Pregnancy in a female patient who has received investigational product is required 
to be reported within 24 hours of knowledge of the event.
Patients who become pregnant during the study period must not receive additional 
doses of investigational product but will not be withdrawn from the study. The 
pregnancy will be followed for outcome of the mother and child (including any 
premature terminations).
7.2.8
Unanticipated Problems Involving Risks to Subject or Others
A UPIRSO is a type of SAE that includes events that meet ALL of the following 
criteria:

Is unanticipated in terms of nature, severity, or frequency

Places the research subject or others at a different or greater risk of harm

Is deemed to be at least possibly related to participation in the study.
7.3
Adverse Event Reporting
7.3.1
Routine Reporting
All routine adverse events, such as those that are expected, or are unlikely or 
definitely not related to study participation, are to be reported on the appropriate 
eCRF according to the time intervals noted in the appendices. Routine AEs will 
be reviewed by the Data Monitoring Committee (DMC) according to the study’s 
phase and risk level, as outlined in the DSMP.
7.3.2
Determining if Expedited Reporting is Required
This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of 
treatment and is attributed (possibly, probably, or definitely) to the agent(s) must 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
53
also be reported accordingly.
1)
Identify the type of adverse event using the NCI CTCAE v 4.03.
2)
Grade the adverse event using the NCI CTCAE v 4.03.
3)
Determine whether the adverse event is related to the protocol therapy. 
Attribution categories are as follows:

Definite: AE is clearly related to the study treatment.

Probable: AE is likely related to the study treatment.

Possible: AE may be related to the study treatment.

Unlikely: AE not likely to be related to the study treatment.

Unrelated: AE is clearly NOT related to the study treatment.
4)
Determine the prior experience of the adverse event.
Expected events are those that have been previously identified as 
resulting from administration of the agent. An adverse event is 
considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in:

the current protocol

the drug package insert

the current Investigator’s Brochure
7.3.3
Expedited Reporting of SAEs/Other Events
7.3.3.1 Reporting to the Northwestern University QAM/DMC
All SAEs must be reported to the assigned Quality Assurance Monitor 
(QAM) within 24 hours of becoming aware of the event. Completion of 
the NU CRO SAE Form is required.
The completed form should assess whether or not the event qualifies as 
a UPIRSO. The report should also include:

Protocol description and number(s)

The patient’s identification number

A description of the event, severity, treatment, and outcome (if 
known)

Supportive laboratory results and diagnostics

The hospital discharge summary (if available/applicable)
All SAEs will be reported to, and reviewed by, the DMC at their next 
meeting.
7.3.3.2 Reporting to the Northwestern University IRB
The following information pertains to the responsibilities of the lead site 
(Northwestern University) and to participating sites whom have 
reporting responsibilities to Northwestern University.  Participating sites 
should follow their local IRB guidelines for reporting to their local IRBs. .

Any death of an NU subject that meets the NU IRB’s reporting 
criteria will be promptly reported .

Any death or unanticipated problem of a non-NU subject should be 
reported to the lead site promptly. Death and other unanticipated 
problems that meet NU IRB reporting criteria should be submitted to 
the NU IRB by the lead site per their posted timelines. .

Information pertaining to an NU subject that fits into any of the 
categories listed on the Reportable New Information page will be 
reported to the NU IRB per their posted timelines.
7.3.3.3 Reporting to the FDA (completed by the NU QAM)
The NU QAM will handle all FDA reporting in accordance with the 
following:
The FDA will be notified within 7 calendar days of any SAE that is 
associated with study treatment, is unexpected, and is fatal or life- 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
54
threatening.
The FDA will be notified within 15 calendar days of any SAE that is 
associated with the study treatment, unexpected, and serious but not 
fatal or life-threatening. This includes any previous SAEs that were not 
initially deemed reportable, but are later determined to meet the criteria 
for reporting (i.e. by the DMC).
All other SAEs will be reported on an annual basis as part of the annual 
FDA report.
7.3.3.4 Reporting to BMS and Abbvie
SAE reports (including death by any cause), up to 100 days post study 
drug discontinuation, regardless of attribution will be reported within 24 
hours to BMS Global Safety and Abbvie (using the NU CRO SAE Form 
and referencing the BMS and Abbvie study numbers, CA 209-783 and 
A15-831, respectively). The assigned study coordinator will facilitate all 
reporting to BMS Global Safety and Abbvie and email QA a copy of the 
report upon completion. 
BMS Global Safety can be notified at: 
Email Address: Worldwide.Safety@BMS.com 
Facsimile Number: 609-818-3804
Abbvie can be notified at:
Email Address: PPDINDPharmacovigilance@abbvie.com 
8.0
DRUG INFORMATION
8.1
Veliparib (generic name)
8.1.1
Other names
Chemical Name: 1H-Benzimidazole-7-carboxamide, 2-[(2R)- 2-methyl-2-
pyrrolidinyl]-
Associated Name(s): 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimadazole-4-
carboxamide,
ABT-888, A-861695.0
8.1.2
Classification - type of agent
Veliparib is a targeted PARP1 and PARP2 inhibitor
8.1.3
Mode of action
Veliparib is a poly (ADP-ribose) polymerase (PARP) inhibitor, an enzyme 
involved in DNA repair.
8.1.4
Storage and stability
Capsules should be stored in the original container at 15° to 25°C (59° to 77°F).  
All clinical supplies of the oral solution should be stored in the original container at 
15° to 25°C (59° to 77°F) and protected from light. Extended release tablets 
should be stored in the original container at 15° to 25°C (59° to 77°F).
8.1.5
Protocol dose specifics
Dose escalation will start with veliparib 300 mg PO twice daily (level 1). The 3+3 
design (per section 4.2) will be utilized to find the MTD. MTD dose will be used for 
the expansion cohort
8.1.6
Preparation
Immediate Release Capsule
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
55
Dosage Form: Immediate release capsules
Strength: 10, 20, 40, 50, and 100 mg
Components: Microcrystalline cellulose, colloidal silicon dioxide, 
magnesium stearate, gelatin, sodium lauryl sulfate, and titanium dioxide. 
May contain FD&C blue #1, FD&C yellow #6, or FD&C yellow #5
Oral Solution
Dosage Form: Oral solution
Strength: 5 and 10 mg/mL
Component: A-861695.0, water, citric acid, sodium citrate, xylitol,
sodium benzoate 
Extended Release Tablet
Dosage Form: Extended release tablets
Strength: 200 mg
Component: Hypromellose, microcrystalline cellulose, colloidal silicon 
dioxide, magnesium stearate, polyvinyl alcohol, titanium dioxide, 
polyethylene glycol, talc, iron oxide yellow, iron oxide red, iron oxide black, 
may contain anhydrous citric acid and/or mannitol
8.1.7
Route of administration for this study
The capsules will be taken by mouth (PO).
8.1.8
Incompatibilities
Veliparib is not a potent inhibitor nor inducer of cytochrome P450s. 
8.1.9
Availability & Supply
Investigational products will be supplied by AbbVie in containers with identical 
appearances in coded kits for each product respectively. Each investigational 
product kit has a unique number that is printed on all labels within the kit (i.e., 
the outer carton label and the label of each container within the carton). Each 
carton is labeled with the same unique sequence number range. Veliparib will 
be supplied in capsule form. 
Veliparib will be provided to Northwestern University by AbbVie, Northwestern 
University will request veliparib submitted via email indicating the amount of 
bottles required to the contact below:.
Email: IISoncologysupport@abbvie.com 
Please allow approximately 10 days for drug delivery.
8.1.10
Side effects
At present, there have been approximately 3700 patients exposed to veliparib 
(ABT-888).  Of these, approximately 250 patients were exposed to veliparib as a 
single agent 
In these studies, the most frequently reported adverse events (≥10%) of veliparib 
were:

Feeling sick to your stomach (Nausea) (72.7%)

Feeling tired (52.2%)

Decreased red blood cells or hemoglobin (the part of blood that carries 
oxygen to your body) (41.4%)

Vomiting (41.4%)

Decreased white blood cells; decreased lymphocytes and decreased 
neutrophils (blood cells that help fight infections) (decreased white cells 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
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29.7%, decreased lymphocytes 28.1% and neutrophil count decreased 
20.9%)

Decreased appetite (22.5%)

Diarrhea (21.7%)

Decreased platelets (blood cells which help clot blood and prevent 
bleeding) (21.3%)

Constipation (18.5%)

Stomach pain (15.7%)

Headache (14.9%)

Feeling dizzy (14.9%)

Increases in liver enzymes (AST and Blood alkaline phosphatase 
increased), that can indicate liver injury or changes in liver function (12.9% 
and 9.6%)

A change in the sense of taste (12.0%)

Difficulty falling asleep and/or staying asleep (11.6%)

Increased blood sugar (11.2%)
Less frequent (<10%), but potentially severe events include:

Dehydration (5.6%)

Seizures (1.2%)
Uncommon (<1%), but medically important event:

Secondary malignancy*
Rare (<0.1%), but medically important event:

Myelodysplastic syndrome (MDS)*
* These events were not seen in Veliparib Monotherapy studies.  The percentage 
noted is from all subjects treated with Veliparib.
8.1.11
Nursing implications
Veliparib will be administered as an oral capsule. Subjects will self-administer 
the morning dose of veliparib and the evening doses of veliparib approximately 
12 hours after the morning dose with or without food in the same calendar day. 
Veliparib dose should be followed by a glass of water (approx. 240 mL). It is 
recommended that if a subject misses a scheduled dose of veliparib and less 
than 6 hours have passed since the scheduled dosing time, the dose should be 
immediately taken. It is recommended that if more than 6 hours have passed 
since the scheduled dosing time, the subject should not take the missed dose 
but should wait for the next regularly scheduled dose.
8.1.12
Return and Retention of Study Drug
All unused investigational products will be returned to an AbbVie-authorized depot 
or disposed of upon authorization by AbbVie according to the investigational site 
policy.
8.2
Drug name: Nivolumab
8.2.1
Other names
ONO-4538, BMS-936558, or MDX1106, Opdivo
8.2.2
Classification - type of agent
Human IgG4 anti-PD-1 monoclonal antibody
8.2.3
Mode of action
Nivolumab receptor-blocking antibody which acts as an immunomodulator by 
blocking ligand activation of the programmed cell death 1 (PD-1) receptor on 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
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activated T cells.
8.2.4
Storage and stability
Nivolumab solution for infusion is a sterile, non-pyrogenic single-use, isotonic 
aqueous solution. Vials must be stored in a secure, limited-access location at 2 to 
8 degrees C (36 to 46 degrees F) and protected from light, freezing, and shaking. 
The product is a clear to opalescent solution, which may contain proteinaceous 
and extraneous particulates. The product is intended for IV administration. The 
drug product can be further diluted with normal saline in IV containers made of 
polyvinyl chloride (PVC) or non-PVC material. Opened or accessed vials should 
be immediately used to prepare the infusion solution in the IV bag and the infusion 
solution should be immediately administered.
After preparation, store the Nivolumab infusion either:
•
at room temperature for no more than 8 hours from the time of preparation. 
This includes room temperature storage of the infusion in the IV container and 
time for administration of the infusion or
•
under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours 
from the time of infusion preparation.
•
                            Do not freeze.
8.2.5
Protocol dose specifics
A fixed dose of 240 mg IV every 2 weeks for 4 cycles; 480mg IV every 4 weeks 
thereafter 
8.2.6
Preparation

Nivolumab should be prepared in a laminar flow hood or safety cabinet using 
standard precautions for the safe handling of intravenous agents applying 
aseptic technique.

Visually inspect the drug product solution for particulate matter and 
discoloration prior to administration. Discard if solution is cloudy, if there is 
pronounced discoloration (solution may have a pale-yellow color), or if there is 
foreign particulate matter other than a few translucent-to-white amorphous 
particles.

Mix by gently inverting several times. Do not shake.

Aseptically withdraw the required volume of nivolumab solution into a syringe, 
and dispense into an IV bag.

If multiple vials are needed for a subject, it is important to use a separate 
sterile syringe and needle for each vial to prevent problems such as dulling of 
needle tip, stopper coring, repeated friction of plunger against syringe barrel 
wall.

Do not enter into each vial more than once. Do not administer as an IV push or 
bolus injection. 

Nivolumab injection can be infused undiluted or diluted so as not to exceed a 
total infusion volume of 120 mL.
8.2.7
Route of administration for this study
Intravenous infusion. Do not administer as an IV push or bolus injection. 
Administer through a 0.2 micron to 1.2 micron pore size, low-protein binding 
polyethersulfone membrane in-line filter.
8.2.8
Incompatibilities
No incompatibilities between nivolumab injection and polyvinyl chloride (PVC), 
DEHP (di[2-ethylhexyl]phthalate), non-PVC/non-DEHP (di[2-ethylhexyl]phthalate) 
IV components, or glass bottles have been observed. Nivolumab should not be 
infused concomitantly in the same intravenous line with other medicinal products.
8.2.9
Availability & Supply
Nivolumab will be supplied by the study as 100 mg/Vial (10 mg/mL) clear to 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
58
opalescent, colorless to pale yellow liquid in 10-cc Type 1 flint glass vials 
stoppered with butyl stoppers and sealed with aluminum seals.  May contain 
particles. 
A supply of nivolumab may be ordered from by completing a Drug Request Form 
provided by BMS. The first request may take place upon screening of the first 
patient. The initial order should be limited to 20 vials. Allow 5 business days for 
shipment of drug from BMS receipt of the Drug Request Form. Drug is protocol 
specific, but not patient specific. All drug product will be shipped by courier in a 
temperature-controlled container. It is imperative that only drug product 
designated for this protocol number be used for this study.
Drug re-supply request form should be submitted electronically 10 business days 
before the expected delivery date.  Deliveries will be made Tuesday through Friday. 
When assessing need for resupply, keep in mind the number of vials used per 
treatment dose, and that shipments may take 14 business days from receipt of 
request. Drug is not patient-specific. 
8.2.10
Side effects
Below are safety data from 268 subjects with unresectable or metastatic 
melanoma and 117 patients with metastatic squamous NSCLC who received 
nivolumab alone. Related side effects reported in subjects receiving nivolumab 
alone were:
Very Frequent – Expected to occur in more than 20% of people (more than 20 
out of 100 people): Fatigue (50%), Dyspnea (38%), Musculoskeletal pain (36%), 
Rash (21%), Increased AST (28%), Increase alkaline phosphatase (22%), 
Hyponatremia (25-38%)
Frequent - Expected to occur in 10% to 20% of people (10 to 20 out of 100 
people): Pruritus (19%), Cough (17%), URI (11%), Peripheral edema (10%), 
Increased ALT (16%), Hyperkalemia (15%)
Not Frequent – Expected to occur in less than 10% of people (less than 10 out 
of 100 people): ventricular arrhythmia, iridocyclitis, infusion-related reactions, 
increased amylase, increased lipase, dizziness, peripheral and sensory 
neuropathy, exfoliative dermatitis, erythema multiforme, vitiligo, psoriasis
Deaths thought to be related to nivolumab when given alone were reported in 
approximately 0.5% of subjects treated (approximately 1 out 200 people). 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and 
duration than AEs caused by other therapeutic classes. Nivolumab is considered an 
immuno-oncology agent in this protocol. Early recognition and management of AEs 
associated with immuno oncology agents may mitigate severe toxicity. Management 
Algorithms have been developed to assist investigators in assessing and managing the 
following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
The above algorithms are found in the nivolumab Investigator Brochure and appendix 
D of this protocol.
8.2.11
Nursing implications
Each dose of investigational product should be administered using the following 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
59
guidelines:
1.
Investigational product must be administered at room temperature by 
controlled infusion via an infusion pump into a peripheral vein or central 
line. Prior to the start of the infusion, ensure that the bag contents are at 
room temperature to avoid an infusion-related reaction due to the 
administration of the solution at low temperatures.
2.
A physician must be present at the site or immediately available to 
respond to emergencies during all administrations of investigational 
product. Fully functional resuscitation facilities should be available. 
Investigational product must not be administered via IV push or bolus but 
as a slow IV infusion. The entire content of each IV bag will be infused 
using an infusion pump. 
3.
The infusion lines should be attached only at time of use. Lines used for 
infusion during dose administration will need to be equipped with 0.22- or 
0.2-µm in-line filters.
4.
The duration of the investigational product administration will be 
recorded.
Nivolumab will be administered as an IV infusion over approximately 30 
minutes or 60 minutes (for 240mg or 480mg dosing, respectively). Vitals will be 
measured before, during, and after each infusion (see section 4.2 for details). When an 
IV bag is used for the infusion, the IV line will be flushed with a volume of 
normal saline equal to the priming volume of the infusion set used after the 
contents of the IV bag are fully administered (unless prohibited by institutional 
practice).
8.2.12
Return and Retention of Study Drug
The clinical study team will be responsible for keeping accurate records of the 
clinical supplies received from BMS or designee, the amount dispensed to and 
returned not used by the subjects and the amount remaining at the conclusion 
of the trial. Upon completion or termination of the study, all unused and/or 
partially used investigational product will be destroyed at the site per 
institutional policy. It is the Investigator’s responsibility to arrange for disposal 
of all empty containers, provided that procedures for proper disposal have been 
established according to applicable federal, state, local and institutional 
guidelines and procedures, and provided that appropriate records of disposal 
are kept.  A copy of the drug destruction certificate must be retained at the end 
of the study for submission to BMS.
8.3
Combination of Veliparib and Nivolumab
8.3.1
Side Effects when veliparib and nivolumab are given together
To our knowledge, no clinical trials combining veliparib and nivolumab have 
Table 8 – Nivolumab Product Description:(Other names = MDX-1106, ONO-4538, anti-PD-1
Product 
Description 
and Dosage 
Form
Potency
Primary 
Packaging
(Volume)/ 
Label Type
Secondary 
Packaging
(Qty) /Label 
Type
Appearance
Storage 
Conditions
(per label)
Nivolumab 
(BMS-
936558-01)*  
for Injection 
100 mg 
(10 
mg/vial) 
10mL vial
5 vials per 
carton / open 
label
Clear to 
opalescent, 
colorless to 
pale yellow 
liquid.  May 
contain 
particles
BMS-936558-01 
Injection must be 
stored at 2 to 8 
degrees C (36 to 46 
degrees F) and 
protected from light 
and  freezing 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
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been reported. A phase 1b, open label, dose escalation and expansion study to 
investigate the safety, pharmacokinetics and antitumor activity of another anti-
PD-1 monoclonal antibody BGB-A317 in combination with the PARP Inhibitor 
BGB-290 in Subjects with advanced solid tumors is currently recruiting in 
Australia, with currently no other sites recruiting outside of Australia 
(ClinicalTrials.gov Identifier: NCT02660034). Possible side effects associated 
with the drug combination will hence be carefully monitored in the current study 
and information updated as more data becomes available.
9.0
CORRELATIVES/SPECIAL STUDIES
9.1
Sample Collection Guidelines
Tissue: A fresh tissue biopsy of the primary tumor or a metastatic site at baseline will be 
collected if appropriate. If a fresh tissue biopsy is not feasible, archival tissue should be 
collected (if available, cell block preferred or 15 unstained slides) by any means possible.  
Unavailability of tissue will not exclude patients. Fresh tissue biopsies will be performed 
using an image-guided core needle at the aforementioned time points according to 
institutional practice. Tumor samples will be stored and may be used for additional 
correlative studies at a later date such as, but not limited to, immunohistochemistry, tumor 
mutation analysis, and proteomic analysis.
Blood: Blood samples will be drawn pre-dose on Induction Day 1, C1D1, C3D1, and at the 
End of Treatment visit. See lab manual for further details and tube types. 
9.2
Sample Processing, Storage, and Shipment
Refer to the lab manual for sample collection, processing, storage, and shipment 
information.
9.3
Assay Methodology
9.3.1
Biomarker Analysis (Tissue and Blood)
Formalin-fixed, paraffin-embedded tumor specimens will be stained with anti-PD-
L1 monoclonal antibodies. PD-L1 will be scored as a percentage by two 
independent pathologists who are unaware of clinical data. PD-L1 staining as a 
predictive measure will be explored at various thresholds of positivity.
TILs (CD8+, CD4+, nuclear FOXP3+) will be quantified by immunohistochemistry 
and assessed on hematoxylin and eosin stained tumor sections. TIL subsets will 
be classified as intraepithelial (iTILs) or stromal (sTILs), where iTILs are defined 
as the percentage of lymphocytes in direct contact with tumor cells, and sTILs are 
defined as the percentage of lymphocytes relative to the tumor stroma. Scoring, 
as a continuous percentage, will be performed by two independent pathologists 
who are unaware of clinical data.
Population of CD4+, CD8+, and regulatory T cells (CD4+/CD25+) will be counted 
by cell sorting of PBMCs. Expression of CD4, CD8, and FOXP3 will be also 
examined in the tumor tissues to estimate relative ratio between T helper cells, 
killer T cells, and regulatory T cells.
Blood will be collected at C1D1, C3D1, and the End of Treatment visit for 
biomarker analysis.
9.3.2
Flow Cytometry (Blood)
Lymphocyte subsets (CD3, CD4, CD8, CD19, and CD56) will be analyzed at C1D1, 
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NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
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C3D1, and EOT according to absolute cell numbers per microliter of whole blood, 
percent representation among all lymphocytes, and coexpression of the activation 
markers CD25, HLA-DR, and CD45RO using automated flow cytometric techniques 
at the Zhang laboratory, at Northwestern University, 
Address:
Bin Zhang’s Laboratory
300 E. Superior St. 
Tarry Building 4-726
Chicago, IL 60611      
Ph: 312-503-2435
Email: Bin.Zhang@northwestern.edu
Please refer to laboratory manual for more details
9.3.3
Immune and Genomic Biomarkers 
To assess the dynamic change in both immune and genomic biomarkers in blood 
that may correlate with response to veliparib. Blood will be collected prior to starting 
veliparib (Induction Day 1) and pre-dose on C1D1.
10.0 STATISTICAL CONSIDERATIONS
10.1
Study Design/Study Endpoints
This will be a phase I/IB study of nivolumab and veliparib in patients with advanced solid 
tumors and lymphoma harboring mutations in selected DNA repair genes. 
The primary endpoint is to evaluate the toxicities and tolerability of nivolumab and 
veliparib and to identify the maximum tolerated dose for combination treatment.
Secondary endpoints include ORR according to irRECIST, PFS at 24 weeks, time until 
death or disease progression, and to identify additional predictive biomarkers and 
resistance mechanisms to treatment using additional genetic and immunology-based 
assessment platforms. For the preliminary efficacy analysis, ORR will be computed at 
the first imaging (8 weeks). Preliminary efficacy will be evaluated by RECISTv 1.1. As 
exploratory analysis, irRECIST will be used to obtain preliminary efficacy as well.  All 
ORR will use the first imaging time point whether RECIST or irRECIST.
Exploratory endpoints include biomarkers predictive of response include assessment of 
tissue-based immunohistochemical expression of PD-L1; TILs; peripheral T cell 
subpopulations; changes in tissue and peripheral T cell receptor sequencing, HLA 
genotype, and immune-related candidate gene signatures at baseline.
Pharmacodynamic biomarker assessment will include changes in tissue based 
immunohistochemical expression of PD-L1; TILs; peripheral T cell subpopulations, and T 
cell receptor genotype at baseline and after two months of treatment with veliparib and 
nivolumab.
10.2
Sample Size and Accrual
The initial study has recruited 3 patients at the lower dose and 6 at the MTD. Of these 6 
at the MTD, 4 have genetic mutation of interest, and 2 do not. The study will, due to lack 
of funding and other reasons recruit 6 more patients with genetic mutation of interest. 
The response rate will be computed separately for 4+6 = 10 patients with genetic 
mutation. 
, 
Dose Escalation Phase 
The expected number of patients in the dose escalation phase will be in the range of 6 to 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
62
18 based on the 3+3 design. 
Expansion Cohort
The initial study design was to accrue a total of up to 50 patients (for 48 evaluable) to the 
study in two phases: dose escalation and dose expansion. The original design 
anticipated a total of 6-18 patients with advanced solid tumors or lymphoma in the dose 
escalation phase; 9 patients were enrolled, including 6 that were treated at the MTD of 400 
mg BID. Due to funding issues, the study will perform an early analysis of preliminary efficacy 
after the next 6 patients are enrolled in the expansion cohort.
. 
As stated above, in the modified plan for expansion cohort, will accrue 6 new patients 
with genetic alteration for early preliminary efficacy assessment, which together with 4 
previously treated patients with genetic mutation will provide total of 6+4=10 patients, 
with genetic mutation. ORR will be computed at the first imaging (8 weeks). Preliminary 
efficacy will be evaluated by RECISTv 1.1. As exploratory analysis, irRECIST will be 
used to obtain preliminary efficacy as well.  All ORR will use the first imaging time point 
whether RECIST or irRECIST.
The study will be considered a success if the lower 90% exact confidence bound will be 
> 10% , i.e. if three or more successes out of n=10 are observed. 
I According to the modified plan for the current trial, the study will be closed after the 6 additional 
patients will have been recruited.” 
 
10.3
Data Analyses Plans
The primary analysis will be on the intent-to-treat (ITT) population, including all evaluable 
patients. Clinical benefit rate will be defined as stable disease (for ≥12 weeks), complete 
or partial response by both the Response Evaluation Criteria in Solid Tumors (RECIST) 
and irRECIST or Lugano Criteria 2014. Maximum response prior to disease progression 
will be used. The overall response rate will be estimated by the proportion of overall 
response, and its 80% confidence..
Additionally, we will evaluate overall response rate, defined as complete or partial 
response using RECIST or Lugano Criteria 2014 guidelines in a similar manner. We will 
also perform similar analyses using Immune Related RECIST (irRECIST). Duration of 
response, defined as the duration from the first documentation of clinical benefit to the 
first documented progressive disease or death of any cause, whichever occurs first, will 
also be analyzed. For patients alive and progression-free at the time of data cut off, 
duration of response will be censored as of the last tumor assessment date. Duration of 
response will only be evaluated for the subgroup of patients with a clinical benefit using 
the Kaplan-Meier method.
PFS is defined as the time from treatment initiation to documented disease progression. 
OS is defined as the time from the start of treatment until death due to any cause. For 
patients alive at the time of data cut-off, PFS and OS will be censored as of the last tumor 
assessment date or known to be alive, respectively. The PFS and OS will be estimated 
using the Kaplan-Meier method. The number, frequency, and severity of adverse events 
(as defined by the NCI Common Terminology Criteria for Adverse Events or CTCAE 
version 4.03) will be recorded.
Baseline percent PDL1 expression, TILs (sTILs, iTILs, and their ratio), and changes in T 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
63
cell subpopulations will be used as a continuous variable to predict clinical benefit or 
overall response rates using appropriate statistical summaries. Cox proportional hazards 
regression will be used to compare how these biomarkers are associated with PFS and 
OS as well.
Changes in these biomarkers will also be analyzed to assess for pharmacodynamic 
effects of treatment. Continuous variables will be analyzed using either paired t-tests, 
signed rank tests or repeated measures analysis of variance.
11.0
STUDY MANAGEMENT
11.1
Institutional Review Board (IRB) Approval and Consent
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol.
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki.
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB approved consent form.
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion.
11.2
Amendments
The Principal Investigator will formally initiate all amendments to the protocol and/or 
informed consent. All amendments will be subject to the review and approval of the 
appropriate local, institutional, and governmental regulatory bodies, as well as by BMS 
and Abbvie. In the event that external participating sites are added, amendments will be 
distributed by the lead institution (Northwestern) to all external sites upon approval by 
the Northwestern University IRB.
11.3
Registration Procedures
Patients may not begin protocol treatment prior to registration. All patient registrations will 
be registered centrally through the Clinical Research Office at Northwestern University 
before enrollment to study. Please contact the assigned QAM or email the QA 
Department (croqualityassurance@northwestern.edu) for questions regarding patient 
registration.
Prior to registration, eligibility criteria must be confirmed by the assigned QAM. The study 
coordinator will screen all subjects for potential registration via the web-based application 
NOTIS (Northwestern Oncology Trial Information System), which is available at:  
https://notis.nubic.northwestern.edu. Please note that a username and password is 
required to use this program, and will be provided during site activation prior to training on 
the NOTIS system.
BEFORE a patient can be treated on study, please complete and submit the following 
items to confirm eligibility and receive an identification number:

Patient’s signed and dated informed consent form (upload to NOTIS and keep 
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
64
original hard copy in a secure location/study chart)

Eligibility checklist (signed and dated by the treating physician – upload to NOTIS)

Eligibility eCRF (complete in NOTIS)

Copy of the pathology report (upload to NOTIS)
Training on eCRF completion will be provided at the time of site activation. Please refer 
to the eCRF demonstration videos on the CRO website for additional instructions on 
registering a patient.
The QAM will review the registration, register the patient, assign a subject identification 
number, and send a confirmation of registration to study personnel. Registration will then 
be complete and the patient may begin study treatment.
11.4
Data Submission
Once a subject is confirmed and registered to the study, eCRFs should be submitted 
according to the detailed data submission guidelines (provided in a separate document). 
Generally, all data are due within 10 days of each study visit.
11.5
Data Management and Monitoring/Auditing
This study will be conducted in compliance with the Data Safety Monitoring Plan (DSMP) 
of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University (please 
refer to NOTIS for additional information). The level of risk attributed to this study 
requires high level monitoring, as outlined in the DSMP. The assigned QAM, with 
oversight from the Data Monitoring Committee, will monitor this study in accordance with 
the study phase and risk level. Please refer to NOTIS for additional data submission 
instructions.
11.6
Adherence to the Protocol
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.
11.6.1
Emergency Modifications
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.
For any such emergency modification implemented, an IRB modification form 
must be completed within 5 business days of making the change, and the QAM 
must be notified within 24 hours of such change.
11.6.2
Other Protocol Deviations
All other deviations from the protocol must be reported to the assigned QAM 
using the appropriate form.
A protocol deviation is any unplanned variance from an IRB approved protocol 
that:

Is generally noted or recognized after it occurs.

Has no substantive effect on the risks to research participants.

Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected.

Did not result from willful or knowing misconduct on the part of the 
investigator(s).
A protocol deviation may be considered an instance of Reportable New 
Information(RNI ) if it:

Has harmed or increased the risk of harm to one or more research 
participants.

Has damaged the scientific integrity of the data collected for the study.

Results from willful or knowing misconduct on the part of the investigator(s).
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
65

Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies.
11.7
Investigator Obligations
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The PI is responsible for personally overseeing the treatment of all study 
patients. The PI must assure that all study site personnel, including sub-investigators and 
other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations 
and guidelines regarding clinical trials both during and after study completion.
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected, entered onto the appropriate eCRFs, and submitted 
within the study-specific timeframes. Periodically, monitoring visits may be conducted and 
the Principal Investigator will provide access to his/her original records to permit 
verification of proper entry of data. The study may also be subject to routine audits by the 
Clinical Trial Audit Committee (CTAC), as outlined in the DSMP.
11.8
Publication Policy
All potential publications and/or data for potential publications (e.g. manuscripts, articles, 
data, text, diagrams, abstracts, posters, charts, slides, pictures, or clinicaltrials.gov 
releases) must be approved in accordance with the policies and processes set forth in 
the Lurie Cancer Center DSMP. The assigned QAM will prepare a preliminary data 
summary (to be approved by the DMC) no later than 3 months after the study reaches its 
primary completion date (the date that the final subject is examined or receives an 
intervention for the purposes of final data collection for the primary endpoint). If the 
investigators wish to obtain DMC-approved data prior to this point (or prior to the point 
dictated by study design), the PI must send a written request for data to the QAM 
including justification. If the request is approved, data will be provided no later than 4 
weeks after this request approval. The data will be presented to the DMC at their next 
available meeting, and a final, DMC-approved dataset will be released along with any 
DMC decisions regarding publication. The investigators are expected to use only DMC-
approved data in future publications. The investigators should submit a copy of the 
manuscript to the biostatistician to confirm that the DMC-approved data are used 
appropriately. Once the biostatistician gives final approval, the manuscript may be 
submitted to external publishers. 
NU shall provide BMS with a copy of each Publication at the earliest practicable time, 
but in any event not less than thirty (30) days prior to its submission to a journal, 
publisher or meeting or fifteen (15) days prior to any public disclosure of any manuscript 
or other public disclosure (e.g., presentations)..
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
66
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Kyle Strickland BEH, Scott J. Rodig, Lauren Ritterhouse, Alan D. D'Andrea, Ursula Matulonis, 
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Gallagher DJ, Konner JA, Bell-McGuinn KM, et al. Survival in epithelial ovarian cancer: a multivariate 
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McNeish IA, Oza AM, Robert L. Coleman, et al. ARIEL2: A phase II trial to prospectively identify 
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Rugo HS OO, DiMichele A, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-
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Appleman LJ BJ, Jiang Y, et al. A phase I study of veliparib (ABT-888) in combination with carboplatin 
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IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
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22.
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Dong H, Chen L. B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med (Berl) 
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Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed 
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Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and 
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Non-Small-Cell Lung Cancer. J Clin Oncol 2015;33:2004-12.
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Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell 
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Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of 
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Huang J, Wang L, Cong Z, et al. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in 
a Brca1(-/-) murine model of ovarian cancer. Biochemical and biophysical research communications 
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Suarez F, Mahlaoui N, Canioni D, et al. Incidence, presentation, and prognosis of malignancies in 
ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J Clin Oncol 
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Schwartzberg L, Yardley D, Elias A, et al. Enzalutamide plus exemestane: A pilot study to assess 
safety, pharmacokinetics, and effects on circulating estrogens in women with advanced hormone-positive 
breast cancer. J Clin Oncol 2014;32:5s: (suppl; abstr 545).
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). European journal of cancer 2009;45:228-47.
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Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin 
Oncol 2007;25:579-86.
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Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common 
language for tumor response to immunotherapy: immune-related response criteria using unidimensional 
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Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, 
MSH2, and MSH6 genes in Lynch syndrome. Jama 2011;305:2304-10.
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
68
APPENDICES
APPENDIX A- CONTRACEPTION REQUIREMENTS
Investigators shall counsel FOCBP and male subjects who are sexually active with FOCBP on
the importance of pregnancy prevention and the implications of an unexpected pregnancy
Investigators shall advise FOCBP and male subjects who are sexually active with FOCBP on the
use of highly effective methods of contraception from the time of treatment initiation to 5 months (for 
FOCBP) or 7 months (for males with FOCBP partners) after the last dose of nivolumab. Highly 
effective methods of contraception have
a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method
being highly effective and the other method being either highly effective or less effective as listed
below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
a) Male condoms with spermicide
b) Hormonal methods of contraception including combined oral contraceptive pills, vaginal
ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by FOCBP
subject or male subject’s FOCBP partner. Female partners of male subjects participating
in the study may use hormone based contraceptives as one of the acceptable methods of
contraception since they will not be receiving study drug.
c) Nonhormonal IUDs, such as ParaGard®
d) Tubal ligation
e) Vasectomy.
f) Complete Abstinence*
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence
are not required to use a second method of contraception, but female subjects must continue to
have pregnancy tests. Acceptable alternate methods of highly effective contraception must be
discussed in the event that the subject chooses to forego complete abstinence.
LESS EFFECTIVE METHODS OF CONTRACEPTION
a) Diaphragm with spermicide
b) Cervical cap with spermicide
c) Vaginal sponge
d) Male Condom without spermicide*
e) Progestin only pills by FOCBP subject or male subject’s FOCBP partner
f) Female Condom*
*A male and female condom must not be used together
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
69
APPENDIX B- COMMON TOXICITY CRITERIA FOR ADVERSE EVENTS
Toxicity will be graded according to the NCI’s Common Toxicity Criteria for Adverse Events 
(CTCAE) version 4.0. The CTCAE version 4.0 can be accessed at the following link:
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
70
APPENDIX C – LUGANO 2014 RESPONSE CRITERIA
Response and Site
PET-CT–Based Response
CT-Based Response
Complete
Lymph nodes and 
extralymphatic sites
Nonmeasured lesion 
Organ enlargement 
New lesions
Bone marrow
Complete metabolic response
Score 1, 2, or 3* with or without a residual 
mass on 5PS†
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic uptake 
or with activation within spleen or marrow (eg, 
with chemotherapy or myeloid colony-
stimulating factors), uptake may be greater 
than normal mediastinum and/or liver. In this 
circumstance, complete metabolic response 
may be inferred if uptake at sites of initial 
involvement is no greater than surrounding 
normal tissue even if the tissue has high 
physiologic uptake
Not applicable 
Not applicable 
None
No evidence of FDG-avid disease in marrow
Complete radiologic response (all of 
the following)
Target nodes/nodal masses must regress 
to < 1.5 cm in LDi No extralymphatic sites 
of disease
Absent
Regress to normal 
None
Normal by morphology; if indeterminate, 
IHC negative
Partial
Lymph nodes and 
extralymphatic sites
Nonmeasured  lesions 
Organ enlargement
New lesions 
Bone marrow
Partial metabolic response
Score 4 or 5† with reduced uptake compared 
with baseline and residual mass(es) of any 
size
At interim, these findings suggest responding 
disease
At end of treatment, these findings indicate 
residual disease
Not applicable 
Not applicable
None
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake compatible 
with reactive changes from 
chemotherapy allowed). If there are 
persistent focal changes in the marrow 
in the context of a nodal response, 
consideration should be given to further 
evaluation with MRI or biopsy or an 
interval scan
Partial remission (all of the following)
≥50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites
When a lesion is too small to measure on 
CT, assign 5 mm x 5 mm as the default 
value
When no longer visible, 0 x 0 mm
For a node > 5 mm x 5 mm, but smaller 
than normal, use actual measurement for 
calculation
Absent/normal, regressed, but no 
increase
Spleen must have regressed by > 50% in 
length beyond normal
None
Not applicable
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
71
No response or stable 
disease
Target nodes/nodal 
masses, extranodal 
lesions
Nonmeasured  lesions 
Organ enlargement 
New lesions
Bone marrow
No metabolic response
Score 4 or 5 with no significant change in 
FDG uptake from baseline at interim or end of 
treatment
Not applicable 
Not applicable 
None
No change from baseline
Stable disease
< 50% decrease from baseline in SPD of 
up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for 
progressive disease are met
No increase consistent with progression 
No increase consistent with progression 
None
Not applicable
Progressive disease
Individual target 
nodes/nodal masses
Extranodal lesions
Nonmeasured lesions
New lesions 
Bone marrow 
Progressive metabolic disease
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or
New FDG-avid foci consistent with lymphoma 
at interim or end-of-treatment   assessment
None
New FDG-avid foci consistent with lymphoma 
rather than
another etiology (eg, infection, inflammation). 
If
uncertain regarding etiology of new lesions, 
biopsy or
interval scan may be considered
New or recurrent FDG-avid foci
Progressive disease requires at least 1 
of the following 
PPD progression:
An individual node/lesion must be 
abnormal with: LDi > 1.5 cm and
Increase by ≥ 50% from PPD nadir and 
An increase in LDi or SDi from nadir
0.5 cm for lesions < 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by > 50% of 
the extent of its prior increase beyond 
baseline (eg, a 15-cm spleen must 
increase to
> 16 cm). If no prior splenomegaly, must 
increase by at least 2 cm from baseline
New or recurrent splenomegaly
New or clear progression of preexisting 
nonmeasured lesions
Regrowth of previously resolved lesions
A new node _ 1.5 cm in any axis
A new extranodal site _ 1.0 cm in any 
axis; if _ 1.0 cm in
any axis, its presence must be 
unequivocal and must be
attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to
Lymphoma
New or recurrent involvement
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
72
APPENDIX D – ADVERSE EVENT ALGORITHMS
Recommended management algorithms for suspected nivolumab related endocrinopathy, gastrointestinal toxicity, hepatotoxicity, neurologic toxicity, 
pulmonary toxicity, renal toxicity and skin toxicity.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
73


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
74


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
75


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
76


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
77


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
78


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
79
APPENDIX E- PROTOCOL SUMMARY OF CHANGES
Amendment 1 (FDA Response) –  December 20, 2016 
Section(s) Affected
Prior version
Amendment 1
Rationale
Cover Page
Listed IND Number as 
“TBD”
Includes IND Number: 133333
New information 
available
Study Summary 
(Objectives); 
2.2.6 (Secondary 
Objectives & 
Endpoints); 6.5.6 
(Secondary 
Endpoints)
Included the following 
secondary objective: “To 
evaluate ORR to 
nivolumab and veliparib 
in patients with prior 
exposure to single agent 
PD-1/PD-L1 inhibitors”
Removes secondary objective 
of ORR in patients with prior 
exposure to PD-1/PD-L1
To correct 
discrepancy; patients 
who have prior PD-
1/PD-L1 exposure 
are excluded by 
3.2.5
3.0 (Patient Eligibility)
15-30 patients would be 
accrued in the expansion 
cohort
n/a
15-32 patients will be accrued 
to the expansion cohort. 
Adds: “Patients will be 
recruited by all participating 
investigators in respective 
clinics within the Northwestern 
University Cancer Center 
network.”
To account for 
evaluable patients 
and add up to a total 
accrual of up to 50 
patients
Clarification at IRB 
request
3.1.1 (Inclusion 
Criteria); 3.2.7 
(Exclusion Criteria)
n/a
Adds the following note / 
exclusion: “Patients with 
germline BRCA 1/2 mutated 
ovarian cancer will be 
excluded given its presumed 
efficacy with veliparib 
monotherapy.”
Clarification 
requested by FDA to 
be consistent with 
language in section 
1.9
3.1.2 (Inclusion 
Criteria)
n/a
Adds the following note: “For 
patients with aggressive 
lymphoma, there should be no 
other standard therapies that 
would confer survival benefit.”
Clarification 
requested by FDA
4.0 (Treatment Plan)
Numbered tables 1-
Re-numbers tables 4.1-4.
Simplification for 
clarity
4.3.1 (Definition of 
DLT)
“The treating physician 
should provide attribution 
to study drugs for all AE’s 
to the best of his or her 
ability, however the 
following events will still 
be classified as DLT’s if 
attribution is not 
available.”
Removes prior language and 
adds: 
“All adverse events specified 
below will be DLT’s except 
those that are clearly and 
incontrovertibly due to 
extraneous causes.”
Clarification 
requested by FDA. 
Investigator 
attribution is not 
appropriate for a new 
combination 
treatment including 
an unapproved 
therapy 
4.3.1 (Definition of 
DLT)
Did not include 
hematologic toxicity as 
DLT
Adds the following hematologic 
DLTs:
Grade 4 thrombocytopenia 
(platelets < 25.0 x 109/L)
Grade 4 neutropenia (ANC < 
0.5 x 109/L)
Grade 3 febrile neutropenia 
with fever lasting for > 7 
days
Grade 4 febrile neutropenia 
of any duration 
FDA request given 
the possible 
hematologic toxicities 
associated with 
veliparib. 
Lists the following DLT’s:
Changes non-hematologic 
Simplified based on 
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NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
80
Grade 4 vomiting or 
diarrhea
Grade 3 nausea, 
vomiting, or diarrhea 
lasting for >72 hours
Other Grade ≥ 3 
toxicities possibly 
related to either 
veliparib or nivolumab 
(Note: any alopecia 
and transient grade 3-4 
laboratory 
abnormalities including 
asymptomatic 
LFTs/amylase/lipase 
that are not clinically 
significant will not be 
considered DLTs.
DLT criteria to read as follows:
Grade ≥ 3 non-hematologic 
toxicities that represent at least 
a 2-grade increase from 
baseline and are possibly 
related to either veliparib or 
nivolumab with the following 
exceptions:
a. Nausea and vomiting lasting 
≤48 hours
b. Electrolyte abnormalities 
resolving within ≤24 hours
c. Hypersensitivity 
reactions
d. Alopecia
language from 
another Phase I/II 
protocol using 
veliparib in 
combination therapy. 
FDA request to 
remove LFT’s as 
exception and 
elaborate on 
“transient” lab 
abnormalities. New 
language is more 
concise and clear.
4.3.2 (Dose 
Escalation 3+3 Rule)
Allowed for up to 9 
patients to be enrolled at 
dose level 1 to establish 
the MTD at dose level 1.
Removes this language – 
only 6 patients may be 
treated to establish MTD, 
and there are no exceptions 
for dose level 1.
Exception to dose level 1 
has been clarified – if dose 
escalation is stopped at dose 
level 1, patients may be 
enrolled at dose level -1 to 
establish MTD.
FDA safety 
request that MTD 
is reached when 2 
out of 6 patients 
experience a DLT. 
Clarification. Was 
previously unclear 
when dose level -1 
would be utilized. 
4.4 (Toxicity 
Management & Dose 
Delays/Modifications)
Referred to the “Schedule 
of Events Table”
Changes to “Table 5”
Corrected for 
consistency
10.2 (Sample Size 
and Accrual)
Sample size referenced 
30 total patients without 
differentiating between 
the overall sample size 
and that in the expansion 
cohort. Also referenced 
30 patients “per 
histological cohort”
Adds separate headings for 
the dose escalation phase and 
the expansion cohort, and 
removes language referring to 
histological cohorts. 
FDA request for 
clarification on non-
coherent language. 
Clarifies that 30 total 
patients refers only 
to the expansion 
cohort, and that total 
accrual for the study 
will be up to 50. The 
histological cohorts 
were included by 
mistake and do not 
align with the study 
design. 
Amendment 1 (FDA Response 2.0) –  December 21, 2016 
Section(s) Affected
Prior version
Amendment 1
Rationale
4.3.1 (Definition of 
DLT)
Listed as DLT:
“Grade ≥ 3 non-
hematologic toxicities that 
represent at least a 2-
grade increase from 
baseline and are possibly 
related to either veliparib 
or nivolumab with the 
Removes phrase “and are 
possibly related to either 
veliparib or nivolumab”
FDA request to 
eliminate physician 
attribution in the case 
of DLT’s for new 
combination 
treatment including 
an unapproved 
therapy
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NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
81
following exceptions”
4.3.1 (Definition of 
DLT)
n/a
Adds the following DLT:
“Grade 3 thrombocytopenia 
with bleeding (platelets <50.0 x 
109/L)”
FDA request given 
possible hematologic 
toxicities associated 
with veliparib
4.7.1 (Continuation of 
Investigational 
Therapy after 
Progression)
Patients were allowed to 
continue treatment 
beyond progression 
unless confirmed by a 
subsequent scan; 
however, there was a 
concession for patients to 
continue treatment if PD 
was confirmed but they 
were receiving clinical 
benefit.
Replaces language to mirror 
another ongoing 
immunotherapy trial and 
remove the concession for 
clinical benefit:
“Confirmed PD: An initial 
assessment of PD by RECIST 
1.1 or Lugano criteria will be 
confirmed by a repeat 
evaluation at the next tumor 
assessment time point, but no 
sooner than 4 weeks later (see 
section 6.1.7 & Appendix C, 
respectively). If any 
subsequent tumor assessment 
shows progression per 
RECIST v1.1 or Lugano 
criteria in the overall tumor 
burden (the sum of diameters 
of target lesions and new 
lesions), when compared to 
the initial PD assessment (the 
sum of diameters of target 
lesions and new lesions), then 
PD is confirmed.”
FDA request to align 
more closely with 
current 
immunotherapy 
trials.
5.0 (Study 
Procedures)
Superscript on scan 
procedures listed as “g”
Scan superscripts refer to 
footnote “h”
Correction of 
discrepancy.
Amendment 2  –  April 27, 2017 
Approved by Scientific Review Committee: May 2, 2017
Section(s) 
Affected
Prior version
Amendment 2
Rationale
Cover Page
Listed all faculty and staff from 
the Authorized Personnel List 
(APL)
Removes Ricardo Costa, 
Amanda Williams, Ellen 
Dammrich, Hannah Garrett, 
and Frank Giles from sub-
investigator list 
Administrative – it is 
no longer a 
requirement to list all 
people from APL on 
the cover page
Abbreviations
Abbreviation list was 
incomplete
Adds relevant abbreviations 
from the protocol
Administrative
Schema; 
Study Summary; 
4.1 (Overview)
n/a
Re-formats treatment plan 
description for simplicity 
Clarifications 
Schema
n/a
Adds that response 
assessment will be by CT or 
MRI
Clarifications 
Study Summary
Objectives had inconsistent 
description of study population
Includes full description of 
the study population in the 
primary objective, leaving the 
others vague
Clarifications to 
simplify
Study Summary; 
2.3 (Exploratory 
Objectives and 
Endpoints); 
6.6 (Exploratory 
Correlative samples were to be 
sent for cfDNA analysis at 
Guardant laboratories
Removes objective and 
correlative sample collection 
for cfDNA
Removed due to 
logistical issues with 
Guardant
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
82
Endpoints); 9.3.2 
(Flow Cytometry)
Study Summary
Patients in the expansion 
cohort must have alterations in 
selected DNA repair genes
Adds note to refer to 3.1.6, 
which lists specific examples 
of DNA repair genes
Clarification 
Study Summary; 
3.2 (Exclusion 
Criteria)
Patients cannot have 
chemotherapy or radiation 
within 14 days, but further down 
it states that patients cannot 
have systemic chemotherapy 
within 28 days
Reformats eligibility so that 
these two statements are 
next to each other
Clarification to avoid 
confusion of 
chemotherapy 
washout period
3.2.1, 3.2.3 
(Exclusion 
Criteria)
Exclusionary statements were 
ambiguous:
“…≤ 14 days prior to entering 
the study”
“…≤ 14 days of registration”
Revises language to be more 
clear:
 “…≤ 14 days prior to 
registration”
Revised for 
cohesiveness
3.2.10, 3.2.11 
(Exclusion 
Criteria)
Corticosteroids and live 
attenuated vaccines were listed 
as exclusionary medications in 
section 4.6 but not listed in 
exclusion criteria
Adds corticosteroids and live 
attenuated vaccines to 
exclusion criteria
Revised for 
consistency 
4.2 (Treatment 
Administration 
n/a
Adds table to summarize 
dosing details and schedules 
of both study drugs; updates 
subsequent table numbers 
and references to be 
sequential
Added for clarity
4.2.1 (Veliparib)
n/a
Patients will maintain a drug 
diary and return drug bottles, 
extra drug, and diaries at 
each study visit
Added for clarity 
4.2.2 
(Nivolumab); 5.0 
(Study 
Procedures)
Nivolumab infusion windows 
were as follows:
Over 30 mins (±5 mins)
Over 60 mins (±10 mins)
Updates nivolumab infusion 
windows:
Over 30 mins (-5 / +15 mins)
Over 60 mins (-10 / +15 
mins)
Allows for flexibility of 
infusion duration 
without 
compromising safe 
administration
4.5.1 (Veliparib)
Dose delays and 
discontinuation were 
referenced for veliparib/placebo
Removes reference to 
placebo
Correction – there is 
no placebo in the 
study
4.5.2 (Nivolumab 
Toxicity 
Management)
Some toxicity 
recommendations were 
inconsistent with the I-O 
algorithms in Appendix G
Updates table 4.6 as follows:
Prior version
Changed 
to 
“No dose 
modifications”
“Continue 
dosing”
Reduced dosing 
recommendations for 
methylprednisolone dosing 
under G2 and G3 
pneumonitis, G2 and G3 
diarrhea
Pneumonitis
Refers to section 7.2.5 for 
management for AESI’s
G1: monitor 
for 2-4 days
Monitor for 
2-3 days
Re-image 
To align with BMS-
provided AE 
algorithms for 
immune-oncology 
products and correct 
discrepancies 
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NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
83
every 3 
weeks
G3: Taper 
over 4 weeks
Taper over 
6 weeks
Hepatitis
Refers to section 7.2.5 for 
management of AESI’s
Nephritis
Discontinue 
for G3 or G4
Discontinue 
only for G4
G2 or 3 Adds:
Consider renal biopsy; 
Monitor creatinine q2-3 days
G4 Adds:
Monitor creatinine daily 
4.6 (Concomitant 
Medications / 
Treatments)
Excluded medications did not 
have washout window listed
Adds washout periods to 
align with exclusion criteria 
and as clinically appropriate
Added for clarity 
4.6 (Concomitant 
Medications / 
Treatments); 
7.2.5 (Adverse 
Events of Special 
Interest)
Referred to Medical Monitor for 
discussion on corticosteroids 
Replaces “Medical monitor” 
with “PI”
Since Northwestern 
is the sponsor, there 
is no medical monitor
Listed “HPI”
Replaces “HPI” with “Medical 
History”
Medical history 
should include more 
than just “History of 
Present Illness”
n/a
Adds specifications for vitals 
(pulse, blood pressure, 
weight, and height at 
screening, footnote d)
Clarification 
Thyroid function tests were to 
include free T3
Removes free T3 from 
thyroid testing
Not clinically 
necessary
n/a
Adds “Mutation testing” as a 
screening requirement within 
1 year for patients in the 
expansion cohort (footnote q)
To align with 
requirements of 
eligibility criteria 
5.0 (Study 
Procedures)
n/a
Adds q3months to “Follow-
up” column
Clarification 
7.2.5 (Adverse 
Event of Special 
Interest (AESI))
The description of AESI’s 
referenced rapid 
communication from the 
investigator to the sponsor.
Removes references to rapid 
reporting (within 24 hours) 
and the “sponsor” or 
“medical monitor”. AESI’s will 
just merit close monitoring 
and discussion with the PI.
There are no 
reporting 
requirements for 
such AESI’s, but PI 
feels that they are 
worthy of close 
monitoring and 
further discussion.
8.1.9 (Availability 
& Supply)
Listed two individual emails for 
ordering veliparib:
Bina.patel@abbvie.com  
Kathleen.ramsdell@abbvie.com 
Removes individual emails 
and replaces with: 
IISoncologysupport@abbvie.
com
Administrative. 
Updated information 
from Abbvie.
9.3.2 (Flow 
Cytometry)
Flow analysis was to be 
performed in Bin Zhang’s 
laboratory
Flow analysis will be 
performed in Northwestern’s 
Flow Core
Correction
10.3 (Data 
Analysis Plan)
Response will be evaluated by 
RECIST and irRECIST
Adds that response will be 
evaluated by Lugano Criteria
Clarification to 
include lymphoma 
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NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
84
patients 
Amendment 3  –  May 26, 2017 
Approved by Scientific Review Committee: June 7, 2017
Section(s) 
Affected
Prior version
Amendment 3
Rationale
5.0 (Study 
Procedures “m”)
On the day of a study visit, 
veliparib should be taken in 
clinic after the blood draw.
Veliparib dosing may take 
place independently of 
nivolumab. On the day of a 
study visit, lab values should 
be checked against sections 
4.4 and 4.5 for continued 
dosing.
Not necessary to 
delay dosing until 
after blood draw 
since there are no 
PK’s. Patients should 
follow their normal 
schedule to avoid 
confusion and 
missed doses.
Amendment 4  –  November 15, 2017 
Approved by Scientific Review Committee: 
Section(s) 
Affected
Prior version
Amendment 4
Rationale
Cover Page
Included Benedito Carneiro and 
Cesar Santa-Maria as sub-
investigators
Removes Benedito Carneiro 
and Cesar Santa-Maria as 
sub-investigators
Administrative; 
faculty members no 
longer work at 
Northwestern
Abbreviations
n/a
Adds SJS and TEN as 
abbreviations
To account for 
updates in nivolumab 
toxicity management 
and Appendix D
4.5.2 (Nivolumab 
Toxicity 
Management)
Grade 3 or higher hepatitis: 
discontinue for elevations in 
transaminases ≥8x ULN or 
bilirubin ≥5x ULN
Grade 2 or 3 renal 
dysfunction: “Consider renal 
biopsy”
n/a
Grade 3 or higher 
hepatitis: discontinue for 
elevations in 
transaminases ≥5x ULN or 
bilirubin ≥3x ULN
Grade 2 or 3 renal 
dysfunction: “Consider 
renal biopsy with 
nephrology consult”
Grade 3 or 4 rash:
Adds note to monitor for 
SJS and TEN and 
discontinue if confirmed
To align with AE 
algorithms in 
Appendix D
5.0 (Study 
Procedures)
 n/a
Adds PT/INR at baseline for 
patients on anticoagulants
Updates footnote lettering
Elevated INR may be 
considered a DLT. 
DSMC requested a 
baseline requirement 
to serve as a 
reference for 
possible DLT’s.
8.2.4 (Storage 
and Stability); 
8.2.6 
(Preparation); 
8.2.8 
(Incompatibilities)
n/a
Replaces language with 
internal nivolumab template 
language (same content)
For consistency with 
other protocols 
involving nivolumab
8.2.9 (Availability 
& Supply)
Did not specify timing for drug 
re-supply requests
Replaces language with 
internal nivolumab template 
language. Drug re-supply 
should be submitted 10 
Updated for accuracy 
per BMS
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NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
85
business days before the 
delivery date
8.2.12 (Return & 
Retention of 
Study Drug)
n/a
Updates table to reflect 
accurate packaging of 
nivolumab product
Clarification 
Appendix A
n/a
Adds timeframe of 
contraception requirements 
for both females (5 months) 
and males (7 months) after 
the last dose of nivolumab
To align with BMS 
template and 
requirements
Appendix D
Contained outdated AE 
Management Algorithms. 
Specific outdated parameters 
include:
Hepatic:
Discontinue for AST/ALT 
>5xULN and/or Tbili >3xULN
Pulmonary (G3-4):
Includes example 
immunosuppression
Renal (G2-3):
“Consider renal biopsy”
Skin (G3-4):
n/a
Updates AE Management 
Algorithms to align with 
nivolumab IB v16. Specific 
changes to AE management 
include:
Hepatic:
Discontinue for AST/ALT > 
5xULN or Tbili > 3xULN
Pulmonary (G3-4):
Removes examples of 
immunosuppression 
Renal (G2-3):
“Consider renal biopsy with 
nephrology consult”
Skin (G3-4):
Adds footnote: “If SJS/TEN 
is suspected, withhold I-O 
therapy and refer patient for 
specialized care for 
assessment and treatment. 
If SJS or TEN is diagnosed, 
permanently discontinue I-O 
therapy.”
Updated per BMS for 
consistency with new 
nivolumab IB v16 
and additional or 
clarified safety 
measures.
Amendment 5  –  February 20th, 2019
Section(s) 
Affected
Prior version
Amendment 5
Rationale
Study summary
Study schema
Background 
section 1.9 ,
Section 3.0;
Section 
4.1(treatment 
overview) and 
Section 4.3.3
(Dose 
expansion) 
4.7,4.8,4.9 and 
Statistics section 
10.
Previous language stating the 
design and analysis plan of the 
dose escalation and dose 
expansion phases of this Phase 
1/1B study.
The initial study design was to 
accrue a total of up to 50 
patients for 48 evaluable) to the 
study in two phases: dose 
escalation and dose expansion.
This language along with 
adequate details and 
calculations have been 
added for the new plan :
According to this modified dose 
expansion plan, the study will 
perform an early analysis of 
preliminary efficacy after the 6 
more patients are enrolled in 
the expansion cohort, all with 
the genetic mutation. Of the 6 
patients already at MTD, 4 
have the genetic mutation. 
Total number of patients at the 
end of adding 6 more patients 
with mutation will be 4+6=10. 
The patients will be treated 
at MTD and the same 
To facilitate future 
funding for  a 
possible larger 
scale trial
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NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
86
treatment schedule will 
applicable for these patients 
as was used in the 
escalation phase. 
The study will be considered a 
“success” if the lower exact 
90% confidence limit is > 10%, 
i.e. when 3 or more successes 
are observed. 
According to the modified plan 
for the current trial, the study 
will be closed after the 6 
additional patients will have 
been recruited. 
Study summary
Section 2 and 
Section 6
(Objectives and 
endpoints)
and Section 
10(statistics)
Previous list of objectives and 
endpoints
Added language to state that 
“For the preliminary 
efficacy analysis, 
ORR will be 
computed at the first 
imaging (8 weeks). 
Preliminary efficacy 
will be evaluated by 
RECISTv 1.1. As 
exploratory analysis, 
irRECIST will be 
used to obtain 
preliminary efficacy 
as well.  All ORR will 
use the first imaging 
time point whether 
RECIST or 
irRECIST.”
To align with the 
preliminary efficacy  
analysis plan for 
the expansion 
cohort, as stated in 
the rest of the 
protocol
Study summary
and
Section 3.1.6
(Inclusion criteria
Language stating that the 
patients in the expansion 
cohort should have alterations 
in selected DNA repair genes 
in their tumors.
Added a note to clarify that 
this criteria is also 
applicable for the patients 
enrolled in the preliminary 
efficacy portion of the 
expansion cohort.
Added BRIP1 mutation in 
the eligible mutated gene 
list. 
For clarity
Recent data 
supports the the 
fact that it is BRCA 
related gene.
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
87
Section 3.1.10
Inclusion criteria
Details about use of 
contraception during and 
after study treatment 
Added language stating that 
the post treatment period is 
5 months for females and 7 
months for males, for which 
they are required to agree 
to follow instructions for use 
of contraception. 
Based on 
information 
provided by BMS
Throughout
Language indicating that MTD 
will be established in the future
Language updated to 
indicate that MTD has been 
established
MTD has been 
established with 6 
patients(4 with 
mutation and 2 
without mutation)
Section 4.5.2
Table 4.6
Nivolumab 
Toxicity 
management
Details about Nivolumab 
related toxicity management 
guidelines
Added language that in 
addition to the 
recommendation that 
management of irAEs follow 
the guidelines presented in 
the table , users should also 
refer to the Nivolumab IB 
As mandated by 
BMS
Section 4.2.2 and 
Section 5 
(footnote ‘m’)
Nivolumab 
infusion
Language indicated that 
starting with Cycle 5, nivolumab 
will be administered at 480mg 
IV over 60 minutes (-10 / +15 
minutes) every 4 weeks (Day 1 
of each cycle)
The infusion time for 
nivolumab in this situation 
has been modified to 
30mins (-10/+15 minutes)
Based on 
Nivolumab IB, 
version 17
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
88
Section 7.3.3.4
Reporting to 
BMS and Abbvie
Details about SAE reporting
Added language to state 
that SAEs will be reported 
up to 100days post study 
drug discontinuation
For clarity and to 
be consistent with 
rest of the protocol
Section 8.2.12
Return and 
retention of study 
drug Nivolumab
Details regarding return and 
retention of Nivolumab stating 
responsibilities of the site and 
Investigator
Added language to state 
that a copy of the drug 
destruction certificate must 
be retained at the end of the 
study for submission to 
BMS
For clarity
Section 11.8
Publication policy
Template language indicated 
that BMS may be included as 
an author in publications
Removed this language 
since the contract with BMS 
does not allow it.
To align with BMS 
policy
Amendment 6  – October 3rd  , 2019
Section(s) 
Affected
Prior version
Amendment 6
Rationale
Exclusion criteria 
3.2.1 
Patients who have had  
chemotherapy or radiotherapy
 ≤ 14 days prior to registration 
are not eligible.
NOTE: Patients may not have 
had systemic chemotherapy 
within 28 days.
Exclusion criteria modified to 
state : “Patients who have had   
radiotherapy
 ≤ 14 days prior to registration 
are not eligible.”
The note has been removed. 
For clarity.
Chemotherapy has 
been addressed in 
criteria 3.2.2
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
89
Exclusion criteria 
3.2.2
Patients  are not eligible who 
have received systemic 
chemotherapy or 
investigational agents ≤ 28 
days prior to registration 
Criteria reworded to state:
“Patients  who have received 
systemic chemotherapy or 
investigational agents ≤ 28 
days prior to registration are 
not eligible” 
For better 
presentation and 
clarity.
Exclusion criteria 
3.2.18
Patients with a prior 
diagnosis of cancer must not 
have received treatment in 
the last 3 years prior to 
registration.
Added a caveat to this 
criteria
“NOTE: treatments used as a 
recurrence prevent are 
eligible.”
For flexibility and 
clarity
Section 5,
footnote d
Vital signs included pulse, 
blood pressure and weight with 
height being recorded only at 
baseline. 
Vital signs now include 
pulse and blood pressure 
only .Weight will now be 
recorded at baseline along 
with height. 
To minimize 
deviations and for 
ease in clinic. 
Section 5 
footnote h
“Thyroid function tests will 
include thyroid stimulating 
hormone and free T4.”
Footnote modified to state: 
“Thyroid function tests will 
include thyroid stimulating 
hormone (TSH) with reflex 
free T4.” 
To facilitate only 
necessary 
procedures.
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.


NU Study Number: NU 16MH03
                                             BMS Study Number: CA 209-783
       Abbvie Study Number: A15-831
Initial Version Date: October 6, 2016
Amendment 7: 3.3.2020 
90
Section 9.3.2
Flow cytometry 
The samples were being 
delivered to the Flow Core at 
Northwestern University
The samples will now be 
delivered to Zhang 
laboratory, at Northwestern 
University.
Address:
Bin Zhang’s Laboratory
300 E. Superior St. 
Tarry Building 4-726
Chicago, IL 60611      
Ph: 312-503-2435
Email: 
Bin.Zhang@northwestern.ed
u
Automated flow 
cytometric analysis 
will be done at the 
Zhang laboratory 
Amendment 7 dated 3.3.2020
Section(s) 
Affected
Prior version
Amendment 7
Rationale
Title page
Sarika Jain, MD was listed as a 
Sub-Investigator
Removed
 Sarika Jain, MD
Dr.Jain has left NU
Section 7.3.3.2
Reporting to NU 
IRB
Previous template language 
Replaced with current 
language that aligns with NU 
IRB policies. 
To align with 
current 
requirements and 
policies
IRB #: STU00204250-MOD0043 Approved by NU IRB for use on or after 3/16/2020 through 9/29/2020.