Randomized Phase II Study of 2nd Line FOLFIRI Versus Modified FOLFIRI With PARP Inhibitor ABT-888 (Veliparib) (NSC-737664) in Metastatic Pancreatic Cancer
Phase: PHASE2
Conditions: Metastatic Pancreatic Adenocarcinoma, Recurrent Pancreatic Carcinoma, Stage IV Pancreatic Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)



 
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Revision #2 (contd.) 
 
Page 2 
 
 
 
 
The above-referenced protocol and consent has been revised as follows. 
 
1. 
Title page: Version date has been updated.  
 
2. 
Section 3.1.c: 
 
• 
Added New Risk: 
• 
Rare But Serious: Leukemia secondary to oncology chemotherapy 
 
• 
Increase in Risk Attribution 
• 
Changed to Rare But Serious from Also Reported on ABT-888 Trials 
But With Insufficient Evidence for Attribution: Myelodysplastic 
syndrome; Treatment related secondary malignancy 
 
• 
Provided Further Clarification: 
• 
Blood and lymphatic system disorders - Other (bone marrow failure) 
is now reported as Bone marrow hypocellular. 
• 
Infections and infestations - Other (shingles) (CTCAE 4.0 language) 
is now reported as Shingles.  
• 
Injury, poisoning and procedural complications - Other (radiation 
proctitis) (CTCAE 4.0 language) is now reported as Radiation recall 
reaction (dermatologic).  
• 
Musculoskeletal and connective tissue disorder - Other (muscle 
spasms) (CTCAE 4.0 language) is now reported as Muscle cramp. 
• 
Renal and urinary disorders - Other (dysuria) (CTCAE 4.0 language) 
is now reported as Dysuria. 
• 
Skin and subcutaneous tissue disorders - Other (nail bed changes) 
(CTCAE 4.0 language) is now reported as Nail changes.  
 
3. 
ICD: 
 
• 
Added: 
• 
Rare: Cancer of bone marrow caused by chemotherapy; A new 
cancer resulting from treatment of earlier cancer; Damage to the 
bone marrow (irreversible) which may cause infection, bleeding, 
may require transfusions. 
 
This memorandum serves to notify the NCI and the SWOG Statistics and Data 
Management Center. 
 
cc:   
PROTOCOL & INFORMATION OFFICE 
 
– Merck 
 
 Merck 
Merck 
 

 
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PRIVILEGED COMMUNICATION 
Activated September 1, 2016 
FOR INVESTIGATIONAL USE ONLY 
 
 
SWOG 
 
 
 
 
RANDOMIZED PHASE II STUDY OF 2ND LINE FOLFIRI VERSUS MODIFIED FOLFIRI WITH PARP 
INHIBITOR ABT-888 (VELIPARIB) (NSC-737664) IN METASTATIC PANCREATIC CANCER 
 
NCT#02890355 
 
STUDY CHAIRS: 
AGENTS: 
 
Elena Gabriela Chiorean, M.D.  
IND-Exempt Agents: 
   (Medical Oncology) 
Fluorouracil (5-FU, Adrucil ®) (NSC-19893) 
University of Washington 
Irinotecan (Camptosar ®) (NSC-616348) 
825 Eastlake Ave E, G4830 
Leucovorin (NSC-3590) 
Seattle, WA 98109 
 
Phone: 206/288-6248 
 
FAX: 206/288-2042 
NCI Supplied Investigational Agents (DCTD sponsored): 
E-mail: gchiorea@uw.edu  
ABT-888 (Veliparib) (NSC-737664) (IND-129716) 
 
, M.D., Ph.D., 
 
BIOSTATISTICIANS: 
Karmanos Cancer Center (Medical Oncology) 
 
Wayne State University 
, M.S. 
4100 John R Street 4HWCRC 
, Ph.D. 
Detroit  MI 48201 
SWOG Statistical Center 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue N, M3-C102 
P.O. Box 19024 
 
Seattle, WA 98109-1024 
, M.D. (Translational 
University of Washington      Medicine) 
Box 356460 
1959 NE Pacific Street 
Seattle, WA 98195 
ALLIANCE STUDY CHAIRS: 
 
 M.D., Ph.D. 
 
Lombardi Comprehensive Cancer Center 
, M.D. (Pathology) 
Georgetown University 
University of Washington 
3800 Reservoir Rd NW 
Box 359791 
Washington  DC 20007 
325 Ninth Avenue 
Seattle, WA 98104 
ECOG STUDY CHAIRS: 
 
 
, MD 
 
Ingram Professor of Cancer Research 
 
 
 
 
 

 
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PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 
 
 

 
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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 5 
SCHEMA ....................................................................................................................................................... 6 
1.0 
OBJECTIVES .................................................................................................................................. 7 
1.1 
Primary Objective ............................................................................................................................. 7 
1.2 
Secondary Objectives ...................................................................................................................... 7 
1.3 
Translational Objectives ................................................................................................................... 7 
2.0 
BACKGROUND ............................................................................................................................... 7 
3.0 
DRUG INFORMATION .................................................................................................................. 14 
3.1 
ABT-888 (Veliparib) (NSC-737664) (IND-129716) ........................................................................ 14 
3.2 
Fluorouracil (5-FU, Adrucil®) (NSC-19893) ................................................................................... 20 
3.3 
Irinotecan (Camptosar®) (NSC-616348) ....................................................................................... 22 
3.4 
Leucovorin (NSC-3590) ................................................................................................................. 23 
4.0 
STAGING CRITERIA ..................................................................................................................... 24 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 24 
5.1 
Disease Related Criteria ................................................................................................................ 25 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 25 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 25 
5.4 
Specimen Submission Criteria ....................................................................................................... 26 
5.5 
Regulatory Criteria ......................................................................................................................... 27 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 27 
7.0 
TREATMENT PLAN ...................................................................................................................... 27 
7.1 
Pre-Medication ............................................................................................................................... 27 
7.2 
Treatment – Arm 1: ABT-888 + mFOLFIRI .................................................................................... 27 
7.3 
Treatment – Arm 2: FOLFIRI ......................................................................................................... 28 
7.4 
Drug Compliance Documentation .................................................................................................. 28 
7.5 
Full CDUS Reporting Requirement ................................................................................................ 29 
7.6 
Criteria for Removal from Protocol Treatment ............................................................................... 29 
7.7 
Discontinuation of Treatment ......................................................................................................... 29 
7.8 
Follow-Up Period ............................................................................................................................ 29 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 29 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 29 
8.2 
Dose Modifications ......................................................................................................................... 29 
8.3 
Dose Modification for ABT-888 ...................................................................................................... 30 
8.4 
Dose Modification for FOLFIRI ...................................................................................................... 32 
8.5 
Dose Modifications Contacts ......................................................................................................... 34 
8.6 
Adverse Event Reporting ............................................................................................................... 34 
9.0 
STUDY CALENDAR ...................................................................................................................... 35 
9.1 
Arm 1: ABT-888 + mFOLFIRI ........................................................................................................ 35 
9.2 
Arm 2: FOLFIRB ............................................................................................................................ 36 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 38 
10.1 
Measurability of Lesions................................................................................................................. 38 
10.2 
Objective Status at Each Disease Evaluation ................................................................................ 39 
10.3 
Best Response ............................................................................................................................... 40 
10.4 
Performance Status: ...................................................................................................................... 41 
10.5 
Progression-Free Survival.............................................................................................................. 41 
10.6 
Time to Death ................................................................................................................................. 41 
10.7 
Duration of Response (DoR) .......................................................................................................... 42 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 42 
11.1 
Sample Size and Accrual Goals .................................................................................................... 42 
11.2 
Analysis of Primary Endpoint ......................................................................................................... 42 
11.3 
Interim Analysis .............................................................................................................................. 42 
11.4 
Secondary Endpoints ..................................................................................................................... 42 
11.5 
Translational Endpoints.................................................................................................................. 43 

 
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11.6 
Data and Safety Monitoring ........................................................................................................... 44 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 44 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 44 
13.1 
Registration Timing ........................................................................................................................ 44 
13.2 
Investigator/Site Registration ......................................................................................................... 44 
13.3 
OPEN Registration Requirements ................................................................................................. 46 
13.4 
Registration Procedures................................................................................................................. 47 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 48 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 48 
14.1 
Data Submission Requirement ...................................................................................................... 48 
14.2 
Master Forms ................................................................................................................................. 48 
14.3 
Data Submission Procedures ........................................................................................................ 48 
14.4 
Data Submission Overview and Timepoints .................................................................................. 49 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 51 
15.1 
Translational Medicine ................................................................................................................... 51 
15.2 
Specimens for Banking .................................................................................................................. 52 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 52 
16.1 
Adverse Event Reporting Requirements........................................................................................ 55 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 60 
18.0 
APPENDIX ..................................................................................................................................... 67 
18.1 
Intake Calendar – ABT-888 (Veliparib) SWOG Study: S1513 ....................................................... 68 
18.2 
Patient Drug Information Handout and Wallet Card ...................................................................... 69 
18.3 
New York Heart Association Criteria .............................................................................................. 71 
18.4 
Translational Medicine: HRD and BROCA-HR .............................................................................. 72 
 
 
 
 

 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
Phone – 1-866-651-CTSU 
 
Fax – 215-569-0206 
 
Email: 
CTSURegulatory@ctsu.coccg.org 
(for submitting regulatory documents 
only) 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at 
ctsucontact@westat.com. 
 
Data collection for this study 
will be done exclusively 
through Medidata 
Rave.  Please see the data 
submission section of the 
protocol for further 
instructions.  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at 
https://www.ctsu.org.  Access to the CTSU members’ website is managed through the Cancer Therapy 
and Evaluation Program - Identity and Access Management (CTEP-IAM) registration system and 
requires user log on with CTEP-IAM username and password. 
For clinical questions (i.e. patient eligibility or treatment-related) contact the SWOG Data 
Operations Center by phone or email: 
206-652-2267 
giquestion@crab.org 
 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org 
 
 
 
 
 

 
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SCHEMA 
 
Metastatic Pancreatic Adenocarcinoma 
 
 
 
REGISTRATION & RANDOMIZATION 
 
 
 
 
ARM 1: 
ARM 2: 
 
ABT-888 + mFOLFIRI 
FOLFIRI 
 
 
 
 
 
PROGRESSION, SYMPTOMATIC  
PROGRESSION, SYMPTOMATIC 
  
DETERIORATION 
DETERIORATION 
 
 
 
 
 
OFF TREATMENT 
OFF TREATMENT 
 
 
 
 
 
 
 
 
NOTE:  Patients with known BRCA1/2 mutations are eligible to participate, will be randomized, and will be 
subject to all other study requirements regarding specimen sample submission. 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
a. 
To evaluate the overall survival (OS) of metastatic pancreatic cancer patients 
treated with fluorouracil, irinotecan, leucovorin (modified FOLFIRI) and ABT-888 
compared to a control arm of fluorouracil, irinotecan, and leucovorin (FOLFIRI). 
 
1.2 
Secondary Objectives 
 
a. 
To evaluate the frequency and severity of toxicity associated with each of the 
treatment arms in this patient population. 
 
b. 
To evaluate the progression-free survival (PFS) in each of the treatment arms in 
this patient population. 
 
c. 
To evaluate the overall response rate (confirmed and unconfirmed; complete 
response + partial response), disease control rate (confirmed and unconfirmed; 
complete response + partial response + stable disease), and duration of response 
in each of the treatment arms in this patient population. 
 
1.3 
Translational Objectives 
 
a. 
To evaluate if BRCA1 and BRCA2 mutations (somatic or germline) are associated 
with improved clinical outcomes [overall survival (OS), progression-free survival 
(PFS) and overall response rates (ORR)] in each treatment arm. 
 
b. 
To evaluate the impact of Homologous Recombination Deficiency (HRD) score on 
clinical outcomes in each treatment arm. 
 
c. 
To evaluate the impact of genomic alterations identified by the BROCA-HR assay, 
other than BRCA1/2, on clinical outcomes in each treatment arm 
 
d. 
To bank tissue for future translational medicine studies. 
 
 
2.0 
BACKGROUND 
 
Pancreatic Cancer Overview 
 
Approximately 277,000 new cases of pancreatic cancer are diagnosed each year in the world,  
among which roughly 49,000 each occur in the United States and Europe. (1,2,3) Despite modest 
improvements in detection, which may have contributed to its rise in incidence, the 5-year overall 
survival rate only increased from 5% to 6% in the past 3 decades. (4,5) While currently pancreatic 
cancer represents the 4th leading cause of cancer death in the United States (approximately 40,000 
deaths annually), it is expected to become the 2nd cause of cancer related deaths in the US in the 
next decade. (6) More than 50% of pancreatic cancers are metastatic at diagnosis, where survival 
rates range from 7-11 months. (7,8) After progression from first line regimens such as gemcitabine 
plus nab-paclitaxel, or folinic acid (leucovorin), fluorouracil (5-FU) with irinotecan and oxaliplatin 
(FOLFIRINOX), second line regimens commonly used in practice are 5-FU with oxaliplatin 
(FOLFOX) or 5-FU with irinotecan (FOLFIRI), which both yield overall survival (OS) rates of 
approximately 6 months, and progression-free survival rates of 3 months. (9,10,11) In a randomized 
Phase II study using FOLFIRI versus FOLFOX chemotherapy, results were similar (PFS 8.3 vs 6 
weeks, and OS 16.6 vs 14.9 weeks). (12) Most recently, the liposomal irinotecan agent MM-398 
demonstrated OS rates of 6.1 months and progression-free survival (PFS) of 4.1 months in 
combination with 5-FU in the randomized Phase III Napoli -1 study. (13) While these results seem 
comparable to those with FOLFIRI, no randomized study to date has compared FOLFIRI with 
MM398 plus 5-FU in pancreatic cancer.  

 
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DNA Repair in Pancreatic Cancer 
 
Pancreatic cancer is characterized by genomic instability. (14,15,16) Several DNA repair defects 
occur through mutations in DNA mismatch repair genes such as MLH1, MSH2 or MSH6 (3-15% 
incidence), tumor suppressor genes TP53 (tumor protein 53, 50% incidence), and the Fanconi 
anemia pathway genes BRCA1/2 (breast cancer genes 1,2) and PALB2 (partner and localizer of 
BRCA2), (7% incidence in sporadic pancreatic cancer, and up to 17% in familial cases), as well as 
FANCC (Fanconi anemia group C) and FANCG (Fanconi anemia group G) (5-10%). 
(17,18,19,20,21,22,23.24,25,26) Other key factors and pathways in DNA repair including ATM 
(ataxia-telangiectasia mutated)/Chk2 (checkpoint-like kinase 2), ATR (ataxia-telangiectasia and 
Rad3-related)/Chk1 (checkpoint kinase 1), Rad51, ERCC1 (excision repair cross-complementation 
group 1), and PTEN (phosphatase and tensin homolog), can be mutated or inactivated in 
pancreatic cancer. (27,28,29,30,31,32,33) Whereas among patients with familial pancreatic cancer 
syndrome, overall, the BRCA2 mutations have been reported in up to 17% of patients through 
retrospective analysis, a recent prospective cohort study of 306 patients with newly diagnosed 
pancreatic cancer identified pathogenic germline BRCA2 mutations in 3.6%, and BRCA1 mutations 
in 1% of patients. (34) Impaired DNA damage response pathways in pancreatic cancer create 
vulnerabilities that can be exploited therapeutically, and DNA-cross linking agents such as platinum 
and mitomycin C, topoisomerase inhibitors like irinotecan, and PARP inhibitors are of particular 
interest.  
 
PARP Inhibitors and Pancreatic Cancer 
 
Poly-(ADP-ribose) polymerases are nuclear enzymes activated by DNA single- (SSB) or double-
strand breaks (DSB) which are able to synthesize poly(ADP-ribose) [pADPr] polymers leading to 
DNA repair. (35,36) Among the seventeen PARP family members identified, only three (PARP1, 
PARP2 and PARP3) have established roles in DNA repair. (37) 
 
PARP1, the best characterized PARP enzyme, plays multiple roles in DNA repair pathways which 
have been extensively reviewed in the literature, and are summarized here: 1) base excision repair 
(BER) the repair of a single damaged base; 2) repair of DSB by recruitment of DNA repair proteins 
MRE11 and NSB1 to initiate homologous recombination (HR) and allowing one copy of a gene to 
serve as template for the second copy of the same gene to be restored; 3) prevents activation of 
the error-prone non-homologous end-joining recombination (NHEJ) DSB repair pathway; 4) 
alternative end-joining repair; 5) restarts replication forks; 6) modulates gene transcription; 7) 
regulates chromatin structure; 8) alters microRNA activity; and 9) affects energy metabolism. 
(38,39,40,41,42,43,44,45,46,47,48,49,50) 
 
The development of PARP inhibitors has been exploited mostly in patients with breast and ovarian 
cancers, with known defects in the HR pathway such as BRCA1/2 or PALB2 mutations, given the 
synthetic lethality by treatment with a PARP inhibitor. (51,52) Molecular alterations besides those 
previously described in DNA repair pathways have been noted to benefit from PARP inhibition, 
such as HER2 overexpression, EGFR mutations, and PI3K pathway activation. (53,54,55) In 
addition to the benefit observed in tumors harboring HR deficiencies, PARP inhibitors have shown 
activity after pharmacologic induction of HR deficiency, such as with epidermal growth factor 
receptor inhibitors, and cyclin dependent kinase 1 (CDK1) blockade (which lead to BRCA1 
translocation to the cytoplasm), and phosphatidyl-inositol 3-kinase (PI3K) inhibitors which decrease 
RAD51 and BRCA1/2 expression. (56,57,58,59)   
 
PARP inhibitors have also shown activity in combination with DNA damaging agents such as 
cytotoxic chemotherapy and radiation therapy. (60,61) The high lethality of pancreatic cancer stems 
partially from its resistance to multiple cytotoxic agents. Since DNA damaging agents are the 
cornerstone treatment for this disease, blocking DNA repair may prevent chemo-resistance. 
 
Topoisomerase inhibitors, such as irinotecan induce PARP cleavage. (62,63) In turn, PARP 
recognizes topoisomerase I cleavage complexes (Top1cc) resulting from treatment with 
camptothecin and irinotecan, and recruits tyrosyl-DNA phosphodiesterase 1 (TDP1), a key repair 

 
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enzyme for trapped Top1cc, and downstream base-excision repair (BER) proteins. (64)  Combined 
treatment of irinotecan with PARP inhibitors results in persistent and increased DNA damage 
breaks and apoptosis compared to irinotecan alone. (65,66,67,68,69,70) These mechanisms 
explain the synergistic cytotoxicity observed between topoisomerase and PARP inhibitors in 
preclinical models. (71,72,73) 
 
To date PARP inhibitors have demonstrated clinical activity as single agents in pancreatic cancers 
harboring BRCA1/2 or PALB2 mutations. Olaparib demonstrated 22% response rates and median 
PFS and OS rates of 4.6 and 9.8 months, respectively in patients who received at least 2 prior lines 
of therapy, while ABT-888 showed 31% 4 months+ stable disease rate, and a median PFS of 
approximately 2 months in refractory disease. (74,75,76) ABT-888 in combination with FOLFOX, 
gemcitabine/cisplatin, or FOLFIRI chemotherapy in first or second+ line setting demonstrated 
sustained responses in BRCA mutated or non-mutated patients, and response rates were 14-56%, 
and OS rates were up to 7.7 months. (77,78,79) The combination of FOLFIRI with ABT-888 has 
been tested in a Phase I trial among 92 patients with refractory solid tumors, including 13 patients 
with refractory pancreatic cancer irrespective of BRCA1/2 status. (80) Response and stable 
disease rates were 15% (n=2) and 46% (n=6), respectively, and the 6-month time-to-progression 
was 27%. Both responses were long lasting (308 and 749 days respectively), and occurred in non-
BRCA mutated patients. Clearly the DNA-repair pathway should be further explored and genomic 
characterization beyond BRCA1/2/PALB2 status should be determined for a “personalized” 
approach in a larger patient population. 
 
ABT-888 Clinical Experience 
 
ABT-888 has been investigated as a single agent and in combination with various DNA-damaging 
agents in subjects with different cancer types.  Overall, approximately 1,255 cancer subjects have 
been exposed to ABT-888 in company sponsored studies as of 24 March 2014.  Additionally, in the 
Cancer Therapy Evaluation Program (CTEP) sponsored studies of ABT-888, approximately 1,687 
adult subjects and 44 pediatric subjects have been exposed to ABT-888 as of 31 March 2014. 
 
Company sponsored studies included the evaluation of ABT-888 in combination with 
temozolomide, whole brain radiation therapy, concurrent radiation therapy and temozolomide, 
carboplatin and gemcitabine, carboplatin and paclitaxel, and FOLFIRI in Phase I and Phase II 
clinical studies.  The main toxicities associated with ABT-888 to date are mechanism based and 
are not clearly distinguished from those expected of the base regimens with which ABT-888 is 
combined.  Hematological toxicities, such as thrombocytopenia and neutropenia, and 
gastrointestinal (GI) disturbances such as nausea and vomiting, are the main toxicities observed 
to date. 
 
Study M10-977 was a Phase I, open-label dose escalation study evaluating the safety and 
tolerability of ABT-888 in combination with modified bimonthly FOLFIRI. (81) As of 14 March 2014, 
96 subjects had been enrolled, enrollment was complete, and 6 patients remained on study.  
Although combining ABT-888 with standard FOLFIRI including a 5-FU bolus (400 mg/m2) was not 
tolerated, ABT-888 was dose escalated from 10 mg to 300 mg BID using a modified FOLFIRI 
regimen omitting the 5-FU bolus (irinotecan 150 mg/m2, 5-FU 2400 mg/m2, leucovorin 400 mg/m2).  
It is relevant to note that a CTEP-sponsored Phase I dose escalation study of ABT-888 in 
combination with FOLFOX independently reached the same conclusion that a 5-FU bolus is not 
tolerated with ABT-888 After 67 patients, the FOLFIRI dose was modified to irinotecan 180 mg/m2, 
5-FU 2400 mg/m2 and a second dose escalation of ABT-888 starting at 100 mg BID was conducted.  
(82) Leucovorin was removed from this regimen as there was a US supply shortage and it was 
deemed unnecessary due to the absence of a 5-FU bolus.  ABT-888 200 mg BID was tolerated in 
this higher irinotecan dose.  As doses exceeding ABT-888 200 mg BID were not tolerated in the 
lower dose FOLFIRI regimen, further dose escalation was not pursued.  The most common 
treatment-emergent adverse events, reported in ≥ 30% of all subjects, were diarrhea (57 subjects, 
62.0%), nausea (55 subjects, 59.8%), vomiting (44 subjects, 47.8%), fatigue (43 subjects, 46.7%), 
alopecia (37 subjects, 40.2%), neutropenia (55 subjects, 60.9%), decreased appetite (30 subjects, 
32.6%), and anemia (39 subjects, 42.4%).  The most commonly reported treatment-emergent 
Grade 3 or 4 adverse events (rate > 5%) were neutropenia (33 subjects, 35.9%), anemia (9 

 
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subjects, 9.8%), diarrhea (5 subjects, 5.4%), dehydration (5 subjects, 5.4%) and hypokalemia (5 
subjects, 5.4%).  Two patients in the ABT-888 270 mg BID dose level experienced dose-limiting 
toxicities (one patient with Grade 3 severe gastritis and Grade 3 vomiting and another patient with 
Grade 4 neutropenia).  The recommended Phase II dose combination was determined to be ABT-
888 200 mg BID, irinotecan 180 mg/m2, 5-FU 2400 mg/m2, and leucovorin 400 mg/m2.  Although 
encouraging efficacy was noted in this study (17/96 PR, 42/96 SD), this was a heavily pre-treated 
population and thus efficacy comparisons with first-line FOLFIRI studies are not valid. 
 
Additional details regarding clinical data can be found in the ABT-888 Investigator's Brochure. (83) 
 
Rationale for FOLFIRI and PARP inhibitor ABT-888 in pancreatic adenocarcinoma 
 
It is well known that PARP contributes in the repair from topoisomerase 1-associated DNA damage. 
Genetic PARP inactivation sensitizes cells to topoisomerase inhibitors and PARP inhibitors 
increase the cytotoxicity and DNA breaks from camptothecins in preclinical models. (84,85) 
Preclinical evidence suggests that MLH1 loss, RAD51 mutations, and ERCC1 loss may particularly 
enhance cytotoxicity from PARP inhibition plus irinotecan/SN38 combination. (86,87,88) While 
FOLFIRI is one of the standard second-line therapy options in pancreatic cancer, overall survival 
rates are only 6 months, and novel treatments are urgently needed. (89) Given the key role of the 
DNA repair mechanisms in pancreatic cancer oncogenesis and progression, the preclinical 
synergism between topoisomerase I with PARP inhibitors, and the safety observed in Phase I trials, 
a randomized clinical trial of FOLFIRI with ABT-888 versus FOLFIRI alone for pancreatic cancer 
patients who progressed on prior chemotherapy has been proposed. (90,91) Tumor samples will 
be collected to perform a retrospective analysis of biomarkers to help inform the development of 
future Phase III clinical trials with this treatment combination, and with PARP inhibitors in general. 
No competing trials exist, per study team knowledge, with the combination of FOLFIRI and PARP 
inhibitors in second line therapy of pancreatic cancer, and given the high incidence of DNA repair 
pathways abnormalities in this tumor (up to 25%), this study expects to observe a meaningful 
improvement in the primary outcome, overall survival, and also to identify the patient population 
most likely to benefit from this targeted therapeutic approach with retrospective analysis of 
biomarkers.  
 
Rationale for BRCA1/2 Mutations, BROCA-HR and HRD Score Translational Medicine 
 
DNA repair defects in pancreatic cancer (PC) involve DNA mismatch repair genes MLH1, MSH2 
and MSH6 (3-15% incidence), tumor suppressor genes TP53 (50%), BRCA1/2 and PALB2 (7% in 
sporadic and up to 17% in familial cases), other Fanconi anemia-homologous recombination (HR) 
genes FANCC and FANCG (5-10%), ATM/Chk2, ATR/ Chk1, Rad51, ERCC1, and PTEN. (78-87) 
The marked susceptibility of patients with germline BRCA mutated (gBRCAm)-associated cancers 
has validated gBRCAm as a predictive biomarker for PARP inhibitors (PARPi) response. (88) 
Several mechanisms lead to HR deficiency thus it is unlikely that a single test will detect all patients 
with the HRD (or BRCAness) phenotype. In addition to gene mutations, gene rearrangements, DNA 
methylation and mRNA expression can also affect the HR pathway. We hypothesize that assays 
that test capacity for homologous recombination (HR) DNA repair will identify subsets of PC 
patients with HRD. These biomarkers could guide future Phase III trials in PC, specifically with 
DNA-damaging agents and/or PARPi. The Myriad Genetics HRD test and the BROCA-HR assay 
(which includes BRCA1/2 mutations analysis) have been evaluated in breast and ovarian cancer 
clinical trials using DNA damaging agents and/or PARPi, and have shown correlations with clinical 
outcomes. Given the current knowledge regarding the presence of germline or somatic BRCA1/2 
mutations, including in PC and benefit from PARPi, we consider the BRCA1/2 testing as integrated 
biomarkers, while the HRD assay and remainder of the BROCA-HR assay to be exploratory 
biomarkers in S1513. (92,93)  
 
HRD Assay 
 
The homologous recombination deficiency (HRD) assay developed by Myriad Genetics (myChoice 
HRDTM) combines genomic patterns of loss of heterozygosity (LOH) “footprint”, telomeric allelic 
imbalance (TAI), and large-scale state transitions (LST) scores as an indicator of HR deficiency 

 
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regardless of mechanism. (94,95,96) The HRD assay is a DNA-based, next generation sequencing 
assay that detects tumors with the HRD phenotype. The assay main components include the HRD 
score and somatic BRCA1/2 mutations. Deleterious or suspected deleterious somatic mutations in 
BRCA1/2 define a tumor as having the HRD phenotype (regardless of HRD score). The HRD score 
is the sum of its three individual components: 1) LOH score is the number of LOH regions of 
intermediate size (> 15 Mb and < whole chromosome), 2) LST score is the number of chromosome 
breaks points (translocations, inversions or deletions) in adjacent segments of DNA of at least 
10Mb, 3) TAI score is the number of regions with allelic imbalance which extend to the subtelomere 
but do not cross the centromere. The HRD Score is the unweighted sum of LOH, TAI and LST 
measurements on a scale from 0-100. The three HRD components demonstrate significant 
correlation with each other (correlation coefficients 0.77 and 0.83). Although highly correlated, the 
three scores contain different information and combining them generates a more robust predictor 
of HRD. (97,98) Based on molecular data further tested in clinical trials, HRD positive tumors 
(breast and ovarian cancers) were those with an HRD score of ≥ 42 or a deleterious mutation in 
BRCA1/2 gene. Although the primary clinical application of the HRD score will be to enrich for 
responders to HR targeted therapies, this was not the criteria for selecting the threshold. A 
threshold has not been yet described in PC. Response is highly dependent on the treatment 
regimen and activity of a specific drug.  In contrast, a threshold based on the underlying biology of 
the tumor, i.e., HRD, should be independent of treatment effect.  Establishing a predefined 
threshold value based on the biology of HRD, rather than a specific treatment outcome, allows the 
validation of the test to be conducted independent of the effect of a specific therapy. 
 
The HRD assay is a next generation sequencing assay that targets ~54,000 SNPs which are evenly 
dispersed across the human genome. A by-product of this assay is the generation of 400 bp of 
sequence flanking each SNP location, resulting in a total of 21 Mb of genome sequencing data 
from each tumor sample analyzed. By cataloging the frequency of microsatellite repeat mutations 
and random somatic mutations within this 21 Mb of sequence data we are able to identify tumors 
with MSI or high somatic mutation burden due to underlying defects independent of MMR defects. 
In addition, the assay directly targets 43 genes known to be involved in DNA damage repair 
pathways and/or tumorigenesis, allowing the identification of both germline and somatic mutations 
within these genes (AKT1, ATM, ATR, BAP1, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, 
CHEK2, CTNNB1, ERCC4, FAM175A, FANCA, FANCD2, FANCE, FANCI, FANCL, KRAS, MLH1, 
MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PPP2R2A, PTEN, RAD50, RAD51, 
RAD51B, RAD51C, RAD51D, RAD52, RAD54B, RAD54L, RPA1, TP53, TP53BP1, XRCC2, 
XRCC3). Finally, hypermethylation of the BRCA1 promoter has been proposed as a mechanism 
for BRCA1 epigenetic inactivation, and will be evaluated in this assay. 
 
One hundred thirty four PC samples derived from resected pancreatic tumors were analyzed (Dr. 
 collaboration). All samples were submitted as tumor cores from formalin fixed 
paraffin embedded (FFPE) tissue. Among 134 samples, 76 passed HRD analysis (failures were 
primarily to due to high non-tumor DNA content, > 70%). Approximately 7% of tumors carried 
BRCA1/2/PALB2 deleterious mutations. Germline DNA was not available. Twenty other samples 
were analyzed from fine needle aspirate (FNA) specimens of patients with metastatic PC (Dr. . 
 collaboration). Fifteen samples provided sufficient DNA for HRD analysis. 80% 
of samples (12/15) passed HRD analysis. Failures were due to high non-tumor content. For this 
metastatic sample study, the HRD score ranged from 11 to 46. Among the 15 evaluable samples, 
4 showed other deleterious mutations: 3 RAD52 mutations, and 1 BRCA2 mutation (HRD score 
46). HRD score range for both studies was 0 - 53. The distribution of scores in samples with 
BRCA1/2/PALB2 mutations was lower than observed in breast/ovarian cancer, suggesting the cut-
off may need to be < 42 in PC. 
 
BROCA-HR Assay 
 
BROCA-HR is a targeted capture and massively parallel sequencing assay designed to detect all 
mutation classes including gene rearrangements, copy number variations, and gene aberrations 
within the Fanconi Anemia-BRCA homologous recombination (HR), non-homologous end joining 
(NHEJ) DNA repair, and DNA mismatch repair pathways. BROCA-HR has been successfully used 
to characterize tumor samples from patients with breast and ovarian cancer, and provided useful 

 
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data of correlation with overall prognosis and prediction of response to platinum-based therapies. 
(99,100,101) In order to respond to PARPi, cancer cells seem to need to be deficient in HR but 
proficient in the alternative error prone non-homologous end joining (NHEJ) DNA repair pathway. 
(102,103) Thus, loss of HR is not, by itself, sufficient for PARPi sensitivity, and an accurate predictor 
of PARPi responsiveness could require assessment of many components of both the HR and NHEJ 
pathways. Recent evidence suggests that BRCA1/2 deficient cancers exhibit global DNA 
alterations termed “genomic scarring” that are consistent with their reliance on the NHEJ pathway. 
(104,105,106) This genomic scar could serve as a downstream functional output to measure DNA 
repair capacity, indicative of both HR deficiency and NHEJ proficiency. Therefore, mutations in 
NHEJ and other pathways that could affect HR as well as genomic scarring will also be evaluated 
as exploratory biomarkers.  
 
BROCA-HR and genomic scarring: preliminary data in breast and ovarian cancer 
Using BROCA, Walsh et al demonstrated that nearly 
one-fourth of women with ovarian carcinoma have 
germline loss of function mutations in at least 12 
genes. (107) After BRCA1/2, the most common genes 
mutated in women with ovarian cancer (which have 
also been reported in PC) are BRIP1 (FANCJ), 
RAD51D, RAD51C (FANCO), and PALB2 (FANCN). 
(108,109) Pennington et al applied BROCA to detect 
somatic mutations in tumor DNA from 363 women with 
ovarian carcinoma. (110) The presence of either a 
germline or somatic FA/HR mutation was highly 
predictive of an improved primary response to platinum 
chemotherapy (p<0.0005) and longer overall survival 
(p=0.001, Figure 1).  
BROCA-HR includes additional DNA repair genes (75 
total genes) as well as 3000 SNPs. The GOG3005 study in ovarian cancer uses BROCA-HR as an 
integrated assay to correlate with treatment response to chemotherapy and PARPi, and S1416 
utilizes blood BROCA-HR in breast cancer patients. Similar sequencing accuracy and sensitivity is 
obtained from FFPE, fresh blood and flash frozen specimens. BROCA-HR includes genes that are 
targets of both somatic and germline mutations. (111) The BROCA design is flexible and can be 
altered to include any genes of research interest. The current design for BROCA-HR includes the 
following genes (n=75): 
 
a. 
FA-BRCA HR pathway: ATM, ATR, BABAM1, BAP1, BARD1, BLM, BRCA1, BRCA2 
(FANCD1), BRIP1 (FANCJ), BRCC3, BRE, CHEK1, CHEK2, ERCC1, ERCC4 (FANCQ), 
FAM175A (abraxas), FANCA,FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG 
(XRCCC9), FANCI, FANCL, FAMCM, GEN1,MRE11A, NBN, PALB2 (FANCO), RAD50, 
RAD51C (FANCO), RAD51D, RBBP8 (CtIP), SLX4 (FANCP), UIMC1 (RAP80), XRCC2  
 
b. 
DNA mismatch repair MLH1, MSH2 (and EPCAM), MSH6, PMS2  
 
c. 
Other DNA repair, surveillance genes, or modifier genes: CDK12, CDH4, HELQ, 
NEIL1, PPM1D, POLD1, POLE, RIF1, TP53, ID4, PAXIP1, POLQ, RINT1, TP53BP1, 
USP28, WRN, XRCC3  
 
d. 
NER genes: ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, DDB1, XPA, XPC  
 
e. 
NHEJ genes: DCLRE1C, LIG4, PRKDC, TOBP1, XRCC4, XRCC5, XRCC6  
 
f. 
PI3K pathway: PTEN, PI3KCA 
 
A common characteristic of “genomic scarring” is large (> 15Mb) but sub-chromosomal deletions. 
Therefore, fine mapping of LOH is not necessary to identify the HRD genomic scar. We tested the 
theoretical ability of 3000 SNPs to define “genomic scarring” in existing TCGA ovarian cancer data 
(unpublished data, Figure 2). Indeed, using only 3000 SNPs can define cases with high LOH which 
Survival (months)
Percent survival
0
50
100
150
200
0
25
50
75
100
Germline HR mutation
Somatic HR mutation
No HR mutation
Figure 1 

 
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cells compared to normal cells has been linked to drug resistance and the overall 
ability of cancer cells to sustain genotoxic stress. 
 
ABT-888 is a small molecule (molecular weight=244.29) that is a potent PARP-1 
and PARP-2 inhibitor. ABT-888 delays the repair of DNA damage induced by 
chemotherapeutic drugs. It increases the sensitivity of tumor cells to DNA-
damaging agents in vitro; has demonstrated PARP inhibition in murine and human 
tumor cell lines xenographs in vivo; and in human peripheral blood mononuclear 
cells (PBMCs) ex vivo. In nonclinical tumor models, ABT-888 improved the 
antitumor activity significantly when administered at a schedule that overlapped 
the administration of DNA-damaging agents. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: After oral administration, ABT-888 absorption is relatively fast.  
Plasma concentrations peak at approximately 1 to 2 hours after dosing 
across dose levels.  Food does not have a significant effect on ABT-888 
bioavailability.  Administration of ABT-888 with a high-fat meal results in a 
slight decrease in ABT-888 maximum plasma concentration (17%) and a 
delay of approximately one hour in ABT-888 reaching the maximum 
concentration.  The effect on the area under the plasma concentration-
time curve (AUC) is insignificant. The exposure of ABT-888 is closely 
proportional across doses of between 10 mg and 500 mg. 
 
2. 
Distribution: ABT-888 binding to plasma proteins is low-to-moderate 
across species. Following a single dose of 10mg. 25mg and 50mg, the 
volume of distribution is large (134 ± 33, 166 ± 26, and 250 ± 122 liter, 
respectively). ABT-888 crosses the blood brain barrier.   
 
3. 
Metabolism: ABT-888 is cleared primarily in the urine as intact parent drug 
with minor contributions from metabolism. The renal clearance and 
minimal metabolism observed in rats and dogs and the minimal 
metabolism observed in vitro in all species evaluated are consistent with 
the low molecular weight and good solubility of ABT-888. These data are 
supported by results from clinical studies which show that ABT-888 is 
cleared primarily as intact parent drug in urine. 
 
4. 
Elimination: Renal excretion is a major pathway in ABT-888 elimination. In 
one clinical trial, after oral administration, the mean urinary recovery of 
unchanged ABT-888 was 72% and the total urinary recovery of ABT-888 
(as parent compound and a metabolite) was 86%.  The terminal half-life 
(t1/2) of ABT-888 is about 6 hours, with minimal accumulation following 
multiple twice daily dosing. 
 
c. 
ADVERSE EFFECTS 
 
1. 
Adverse Effects: 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset 
of AEs (SPEER) is a list of events that are protocol specific exceptions to 
expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, 
NCI Guidelines: Adverse Event Reporting Requirements' 

 
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infection; Lymph gland infection; Mucosal infection; Sepsis; Shingles; Skin 
infection; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - 
Bruising; Dermatitis radiation; Radiation recall reaction (dermatologic) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline 
phosphatase increased; Aspartate aminotransferase increased; Blood 
bilirubin increased; Cardiac troponin I increased; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; Lipase increased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; 
Hypernatremia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypokalemia; 
Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Arthralgia; Arthritis; Back pain; Bone pain; Generalized muscle weakness; 
Muscle cramp; Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) -Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; 
Depressed level of consciousness; Dysarthria; Extrapyramidal disorder; 
Intracranial hemorrhage; Lethargy; Memory impairment; Movements 
involuntary; Paresthesia; Peripheral motor neuropathy; Peripheral sensory 
neuropathy; Presyncope; Reversible posterior leukoencephalopathy 
syndrome; Stroke; Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; 
Insomnia; Psychiatric disorders - Other (emotional instability); Psychosis; 
Restlessness 
RENAL AND URINARY DISORDERS - Dysuria; Hematuria; Proteinuria  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Cough; 
Dyspnea; 
Epistaxis; 
Hypoxia; 
Nasal 
congestion; 
Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; 
Nail 
changes; 
Palmar-plantar 
erythrodysesthesia 
syndrome; Pruritus; Purpura; Rash acneiform 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; 
Hypotension; Vascular disorders - Other (brainstem infarction)  
 
Note: ABT-888 (Veliparib) in combination with other agents could cause 
an exacerbation of any adverse event currently known to be caused by the 
other agent, or the combination may result in events never previously 
associated with either agent. 
 
2. 
Pregnancy and Lactation: The potential for ABT-888 to cause teratogenic 
and developmental effects was evaluated in embryofetal toxicity studies in 
rats and rabbits and showed dose-dependent maternal and embryofetal 
toxicity that is considered a result of PARP inhibition. No human data 
regarding pregnancy are available. Based on ABT-888 mechanism of 
action and preclinical studies, pregnancy is to be avoided in all clinical 
trials. It is not known if ABT-888 is excreted in human milk.  
 
3. 
Drug Interactions: ABT-888 is not a potent inhibitor of the major human 
cytochrome P450 proteins (CYPs) and does not significantly induce 
activities of major human CYP isoenzymes. Therefore there is a minimal 
potential for CYP-mediated drug-drug interactions at the anticipated 
therapeutic concentrations. 
 
At therapeutically efficacious doses for combination therapy (e.g., 40 mg 
twice daily), ABT-888 has a low potential for clinical pharmacokinetic drug-
drug interactions with transporters that have been assessed like P-

 
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Management (IAM) account <https://eapps-ctep.nci.nih.gov/iam/> and the 
maintenance of an “active” account status and a “current” password.   For 
questions about drug orders, transfers, returns, or accountability, call 
240/276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) 
or email PMBAfterHours@mail.nih.gov anytime. 
 
2. 
Drug Handling and Accountability 
 
a. 
The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, 
disposition, and return of all drugs received from the PMB using 
the NCI Oral Drug Accountability Record Form available on the 
CTEP home page (http://ctep.cancer.gov).   
 
b. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF.  
 
3. 
Drug return and/or disposition instruction  
 
a. 
Only undispensed clinical supplies should be returned to the 
PMB.  When it is necessary to return study drug (e.g., sealed 
bottles at study termination or, expired bottles recalled by the 
PMB), investigators should return the study drug to the PMB using 
the NCI Return Drug List available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the PMB at 240/276-6575. 
Opened bottles with remaining capsules should be documented 
in the NCI Oral Drug Accountability Record Form (i.e., logged in 
as “returned by patient” and logged out as “destroyed on site”) and 
destroyed on-site in accordance with institutional policy. 
 
b. 
Drug expiration:  If packaging does not have expiration date, 
check with drug ordering designee and/or PI at site to confirm 
receipt of ongoing stability testing letter from NCI. If packaging has 
expiration date, indicate drug expiration date on the DARF under 
Manufacturer and Lot # and use the drug lots with shorter 
expiration date first.   
 
4. 
Contact Information:  Call the PMB at 240/276-6575 Monday through 
Friday 
between 
8:30 
am 
and 
4:30 
pm 
(ET) 
or 
email 
PMBAfterHours@mail.nih.gov anytime. 
 
3.2 
Fluorouracil (5-FU, Adrucil®) (NSC-19893) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Fluorouracil is a pyrimidine analog antimetabolite that 
interferes with DNA and RNA synthesis in the S phase of cell division. After 
activation, the active metabolite F-UMP is incorporated into RNA to replace uracil 
and inhibit cell growth. The active metabolite, F-dUMP, inhibits thymidylate 
synthetase and depletes thymidine triphosphate. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Rapid intravenous injection of fluorouracil results in high early 
levels of drug achieved both in plasma and bone marrow with a rapid fall 
afterwards. Prolonged infusions of fluorouracil show constant levels of the 
drug in plasma and significantly less in bone marrow. 
 

 
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2. 
Distribution: Fluorouracil distributes into tumors, intestinal mucosa, bone 
marrow, liver, third space fluids and other tissues.  Fluorouracil diffuses 
readily across the blood-brain barrier and distributes into cerebrospinal 
fluid and brain tissue. 
 
3. 
Metabolism: Fluorouracil is primarily metabolized in the liver via 
dihydropyrimidine dehydrogenase (DPD) to the active metabolites 5-
fluoroxyuridine monophosphate (F-UMP) and 5-5-fluoro-2’-deoxyuridine-
5’-O-monophosphate (F-dUMP). 
 
4. 
Elimination: The mean elimination half-life of fluorouracil from plasma is 
approximately 16 minutes, with a range of 8 to 20 minutes, and is dose 
dependent. Seven to 20% of fluorouracil is excreted unchanged in the 
urine. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Fluorouracil: 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Common (> 20%): alopecia, hand-foot syndrome, maculopapular rash, 
photosensitivity, 
pruritis, 
diarrhea, 
nausea, 
vomiting, 
anorexia, 
esophagopharyngitis, stomatitis, indigestion, headache 
 
Less common (4 to ≤ 20%): angina, coronary arteriosclerosis, 
thrombophlebitis, gastrointestinal ulcer, bleeding, anemia, leucopenia, 
agranulocytosis, pancytopenia, thrombocytopenia, cough, hoarseness, 
epistaxis, anaphylaxis, hypersensitivity reaction, confusion, nystagmus, 
visual changes, lacrimation, lacrimal duct stenosis, photophobia,  
dermatitis, acute cerebellar syndrome 
 
Rare (≤ 3%): cardiotoxicity, secondary malignancy  
 
2. 
Pregnancy and Lactation: Pregnancy Category D. Excretion in human 
breast milk is unknown and the manufacturer recommends against 
breastfeeding while receiving fluorouracil.  
 
3. 
Drug Interactions: Fluorouracil is a strong inhibitor of CYP2C9. Refer to 
the current FDA-approved package insert for additional information. Due 
to potential drug interactions, a complete patient medication list, including 
fluorouracil, should be screened prior to initiation of and during treatment 
with fluorouracil. See Section 8.0 Toxicities to be Monitored and Dosage 
Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan. 
 
e. 
HOW SUPPLIED  
 
Fluorouracil is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
 
 

 
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3.3 
Irinotecan (Camptosar®) (NSC-616348) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Irinotecan and its metabolite SN-38 inhibit topoisomerase I. 
Topoisomerase I relieves torsional strain in the DNA helix during replication and 
RNA transcription by inducing single-strand breaks. By binding with the 
topoisomerase I—DNA complex, irinotecan or SN-38 prevents the relegation of 
the single-strand breaks. Irreversible DNA damage occurs when a DNA replication 
fork encounters the irinotecan or SN-38/topoisomerase I complexes resulting in 
double-strand DNA breaks. Camptothecins are highly S-phase specific in their 
activity due the requirement of DNA synthesis. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: N/A 
 
2. 
Distribution: Protein binding of irinotecan is 30-70%, whereas SN-38 
shows a higher protein binding of 95%. Both irinotecan and SN-38 are 
primarily bound to albumin. Volume of distribution of irinotecan is 
approximately 110-234 L/m2. 
 
3. 
Metabolism: Irinotecan is metabolized primarily in the liver by 
carboxylesterase to SN-38, and via hepatic cytochrome P450 (CYP) 3A4 
to aminopentane carboxylic acid (APC). SN-38 is conjugated to form a 
glucuronide metabolite by the enzyme UDP-glucuronosyl transferase 1A1 
(UGT1A1). Genetic polymorphisms exist in the enzyme UGT1A1, leading 
to different levels of exposure and toxicity among patients.  In addition, 
both irinotecan and SN-38 undergo plasma hydrolysis between their active 
(lactone) and inactive forms (carboxylate). Finally, a small amount of 
irinotecan is metabolized by the intestinal wall. 
 
4. 
Elimination: Approximately 10-25% of irinotecan is recovered unchanged 
in urine whereas only small amounts of SN-38 have been found. 
Clearance is approximately 13.5 L/hr/m2. In addition, irinotecan has 
approximately 25% biliary excretion. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of irinotecan: 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in >20% to 100% of subjects treated with 
irinotecan include: diarrhea and cholinergic reaction (may be severe), 
constipation, 
nausea, 
vomiting, 
asthenia, 
infection, 
leukopenia, 
neutropenia, alopecia, anorexia, weight loss, anemia, fatigue,  fever, pain, 
dizziness, cough, dyspnea, mucositis, rash, thrombocytopenia. 
Adverse effects reported in 4% to 20% of subjects include: gastrointestinal 
perforation, 
hypersensitivity 
reaction, 
cardiovascular 
events, 
thromboembolic events, interstitial lung disease. 
 
2. 
Pregnancy and Lactation: Pregnancy Category D. It is not known whether 
irinotecan or its derivatives are excreted in human milk. 
 

 
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3. 
Drug Interactions: Irinotecan and its active metabolite SN-38 may be 
substrates 
for 
CYP3A4, 
CYP2B6, 
OATP1B1/SCLO1B1, 
P-
glycoprotein/ABCB1 and UGT1A1. Inducers or inhibitors may affect serum 
concentrations of irinotecan. Due to potential drug interactions, a complete 
patient medication list, including irinotecan, should be screened prior to 
initiation of and during treatment with irinotecan. Refer to the current FDA-
approved package insert. See Section 8.0 Toxicities to be Monitored and 
Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan. 
 
e. 
HOW SUPPLIED  
 
Irinotecan is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
 
3.4 
Leucovorin (NSC-3590) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: During normal processes, thymidylate synthetase forms a 
noncovalent ternary complex with deoxyuridylate (dUMP) and the reduced folate 
cofactor of leucovorin 5-methyl-tetrahydrofolate (5MTHF). The reduced folate 
facilitates the association and disassociation of the complex and the formation of 
thymidylate (dTMP) and dihydrofolate. Fluorouracil inhibits thymidylate synthetase 
through the covalent binding of 5-fluorodeoxyuridine monophosphate (FdUMP) 
and 5MTHF. The binding of FdUMP is dependent upon the intracellular 
concentration of 5MTHF. Since l-leucovorin is metabolized to 5MTHF, it increases 
and stabilizes the binding of FdUMP to thymidylate synthetase, thus increasing the 
cytotoxic effects of fluorouracil. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Oral bioavailability of leucovorin is concentration dependent 
and saturable at doses greater than 25 mg. Studies have produced 
bioavailabilities of 97%, 75% and 37% for doses of 25 mg, 50mg and 
100mg respectively. 
 
2. 
Distribution: Leucovorin is rapidly converted to 5-methyl-tetrahydrofolate 
(5MTHF) and widely distributed to tissues including the CNS. The time to 
peak concentration for oral, folate isomers and 5MTHF is 2 hours, 10 
minutes and 1 hour respectively. 
 
3. 
Metabolism: Leucovorin is metabolized by intestinal mucosa and 
hepatically to the active form 5MTHF.  
 
4. 
Elimination:  Leucovorin is primarily excreted unchanged in the urine and 
minimally in the feces. Leucovorin has a half-life elimination of 
approximately 4 to 8 hours. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Refer to package insert or manufacturer website for the most complete 
and up to date information on contraindications, warnings and precautions, 
and adverse reactions. 
 

 
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In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Days 14, 28 or 42 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must have histologically or cytologically documented pancreatic 
adenocarcinoma. Patients with pancreatic neuroendocrine tumors, lymphoma of 
the pancreas, or ampullary cancer are not eligible. 
 
b. 
Patients must have metastatic disease that is measurable, as defined in Section 
10.1. CT scans or MRIs of the chest, abdomen, and pelvis used to assess 
measurable disease must have been completed within 28 days prior to registration. 
CT Scans or MRIs used to assess non-measurable disease must have been 
completed within 42 days prior to registration. All disease must be assessed and 
documented on the Baseline Tumor Assessment Form. 
 
c. 
Patients must not have history of brain metastases. 
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Patients must have had one and only one prior regimen of systemic therapy for 
metastatic disease unless the patient meets the criteria in Section 5.2c. 
 
b. 
Prior systemic therapy and chemoradiotherapy for treatment of resectable, 
borderline resectable or locally advanced unresectable disease is allowed and 
does not count toward prior therapy for metastatic disease. 
 
c. 
Patients who received systemic therapy with gemcitabine/nab-paclitaxel for 
resectable or borderline/locally advanced unresectable disease and progressed 
with metastatic disease within 3 months of the past dose of systemic therapy are 
eligible. 
 
d. 
Patients must have completed systemic therapy at least 14 days prior to 
registration, any surgical procedure must have been performed at least 14 days 
prior to registration, and radiation therapy must be completed at least 7 days prior 
to registration. Patients must have recovered from major side effects of prior 
therapies or procedures in the opinion of the local site investigator prior to 
registration. 
 
e. 
Patients must not have received prior irinotecan-based chemotherapy (e.g. 
FOLFIRINOX or FOLFIRI). 
 
f. 
Patients must not have received prior PARP inhibitor therapy including, but not 
limited to ABT-888, olaparib, rucaparib, and BMN637. 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have a Zubrod Performance Status of 0-1 (see Section 10.4). 
 
b. 
Patients must be ≥ 18 years of age. 
 
c. 
Patients must have adequate hematologic function as evidenced by all of the 
following within 14 days prior to registration: ANC ≥ 1,500/mcL; hemoglobin ≥ 9 
g/dL; and platelets ≥ 100,000/mcL. 
 

 
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d. 
Patients must have adequate hepatic function as evidenced by all of the following 
within 14 days prior to registration: total bilirubin ≤ 1.5 x Institutional Upper Limit of 
Normal (IULN); serum albumin ≥ 3.0 g/dL; and AST and ALT ≤ 2.5 x IULN. Patients 
with liver metastases may have AST and ALT of ≤ 5.0 x IULN. 
 
e. 
Patients must have adequate renal function as evidenced by the following within 
14 days prior to registration: serum creatinine ≤ 2.0 mg/dL. 
 
f. 
Patients must have CA19-9 obtained within 14 days prior to registration. If CA19-
9 is normal, then CEA must be tested within 14 days prior to registration. 
 
g. 
Patients must have BUN, alkaline phosphatase, sodium, potassium, calcium, 
glucose, chloride, and carbon dioxide levels obtained within 14 days prior to 
registration. 
 
h. 
Patients must not have any clinically significant and uncontrolled major medical 
condition(s) including, but not limited to uncontrolled nausea/vomiting/diarrhea; 
active uncontrolled infection; symptomatic congestive heart failure (NYHA Class > 
II) (see Section 18.2); unstable angina pectoris or cardiac arrhythmia; psychiatric 
illness/social situation that would limit compliance with study requirements. 
 
i. 
Patients must not have active seizure or history of seizure. 
 
j. 
Patients must be able to swallow whole capsule. 
 
k. 
Patients must have a complete physical examination and medical history within 28 
days prior to registration. 
 
l. 
Patients must not have known Gilbert’s Syndrome. 
 
m. 
Patients must not have known hypersensitivity to irinotecan, fluorouracil, or 
leucovorin. 
 
n. 
Patients of childbearing potential must have a negative pregnancy test within 28 
days prior to registration and must not be nursing due to the risk of fetal or nursing 
infant harm.  Women/men of reproductive potential must have agreed to use an 
effective contraceptive method during the study and for 6 months following 
completion of treatment.  A woman is considered to be of "reproductive potential" 
if she has had menses at any time in the preceding 12 consecutive months.  In 
addition to routine contraceptive methods, "effective contraception" also includes 
heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-
effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy 
or bilateral tubal ligation.  However, if at any point a previously celibate patient 
chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for 
beginning contraceptive measures. 
 
5.4 
Specimen Submission Criteria 
 
a. 
Patients must be willing and able to undergo a biopsy after signed consent and 
prior to registration. Patients must have tumor tissue and blood samples available 
and be willing to submit tumor and blood samples as described in Section 15.1. 
 
NOTE: Core biopsy required. FNA is not an acceptable substitute for core biopsy 
 
b. 
If archival tumor is available for submission, patients must be willing to submit 
tumor sample as described in Section 15.1b. 
 

 
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c. 
Patients must be offered the opportunity to participate in specimen banking for 
future use (see Section 15.2). 
 
5.5 
Regulatory Criteria 
 
a. 
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines. 
 
b. 
As a part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
6.0 
STRATIFICATION FACTORS 
 
Patients will be randomized using a dynamic balancing algorithm with stratification based on prior 
systemic treatment for metastatic disease: yes vs no. 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Chiorean at 206/288-6248 or Dr. 
.  For dosing principles or questions, please consult the SWOG Policy #38 
"Dosing Principles for Patients on Clinical Trials" at http://swog.org (then click on "Policies and 
Manuals" under the "About" menu and choose Policy 38). 
 
7.1 
Pre-Medication 
 
Antiemetics may be given at the discretion of the treating physician, but aprepitant may not 
be given prior to FOLFIRI/mFOLFIRI. 
 
It is recommended that atropine, 0.25 – 1.0 mg IV or SC (subcutaneously) or similar 
anticholinergic medication be used as needed or during irinotecan administration to prevent 
cholinergic symptoms (e.g., hot flashes, abdominal cramping, diarrhea, lacrimation). 
 
7.2 
Treatment – Arm 1: ABT-888 + mFOLFIRI 
 
Patients assigned to Arm 1 will receive the following treatment (outpatient setting) until 
meeting one of the criteria in Section 7.6. NOTE:  Patients on this arm will receive modified 
FOLFIRI which does not include the bolus fluorouracil. 
 
a. 
Arm A 
 
Agent 
Dose 
Route 
Day 
Schedule 
 
 
 
ABT-888 
400 mg 
PO BID** 
1-7 
Every 12 hours. Given 
 
(200 mg per dose)  
 
1 hr ± 30 min prior to 
 
 
 
 
irinotecan on Day 3 
 
Irinotecan 
180 mg/m2 
IV over 
3 
Given concurrently 
 
 
90-120 min 
 
with leucovorin α 
 
Leucovorin 
400 mg/m2 
IV over 
3 
Given concurrently 
 
 
90-120 min 
 
with irinotecan α 
 
Fluorouracil  
2,400 mg/m2 
IV over 46 hr β 
3-5 
Given after Irinotecan  
 
  
 
and leucovorin 
 
* Note:  One cycle = 14 days 

 
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** Morning and evening dose should be approximately 12 hours apart, with or without food 
in the same calendar day. Patients will take two 100 mg capsules in the morning and 
two 100 mg capsules in the evening for a total daily dose of 400 mg. It is recommended 
that if a patient misses a scheduled dose and less than 6 hours have passed since 
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 patient should 
not take the missed dose, but should wait for the next regularly scheduled dose. If the 
patient vomits within 15 minutes of taking drug, another dose is to be taken. 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. NOTE: Patients should be instructed 
to take Day 3 dose at treating institution and not at home. ABT-888 should be 
taken 1 hour (± 30 minutes) before irinotecan on Day 3. 
α  Irinotecan and leucovorin are administered via separated lines concurrently, or per 
institutional guidelines they may be administered sequentially.  
β  Fluorouracil will be administered as a continuous intravenous infusion delivered by an 
infusion pump via a central venous infusion port placed subcutaneously. The specific 
chemotherapy port and infusion pump to be used are at the discretion of the treating 
physician. 
 
7.3 
Treatment – Arm 2: FOLFIRI 
 
Patients assigned to Arm 2 will receive the following treatment (outpatient setting) until 
meeting one of the criteria in Section 7.6.  
 
Agent 
Dose 
Route 
 
Day 
Schedule* 
 
Irinotecan 
180 mg/m2 
IV over 90-120 min 
1 
Given concurrently 
 
 
 
 
with leucovorin ** 
 
Leucovorin 
400 mg/m2 
IV over 90-120 min 
1 
Given concurrently 
 
 
 
 
with irinotecan ** 
 
Fluorouracil (bolus) 
400 mg/m2 
IV over 15 min 
1 
Given after 
 
 
 
irinotecan  
 
 
 
and leucovorin 
 
Fluorouracil ᵝ 
2,400 mg/m2 
IV over 46 hr α 
1-3 
Given after 
 
 
 
fluorouracil bolus 
 
*  Note:  One cycle = 14 days 
** Irinotecan and leucovorin are administered via separated lines concurrently, or per 
institutional guidelines they may be administered sequentially. 
α Fluorouracil will be administered as a continuous intravenous infusion delivered by an 
infusion pump via a central venous infusion port placed subcutaneously. The specific 
chemotherapy port and infusion pump to be used are at the discretion of the treating 
physician. 
ᵝ Fluorouracil bolus may be administered per institutional guidelines. 
 
7.4 
Drug Compliance Documentation 
 
Drug compliance will be recorded by patients in the Intake Calendar (see Section 18.1). 
Institutional CRAs will review and ascertain patient adherence with protocol therapy at the 
end of treatment for each cycle.  Calendar should be kept in the patient's clinic chart.  Note 
that the Intake Calendar is provided only as a tool for tracking patient compliance.  Sites 
may utilize institutional pill diaries or other source documentation in place of the Intake 
Calendar at the discretion of the treating physician. 
 
 

 
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7.5 
Full CDUS Reporting Requirement 
 
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4b, the S1513 Treatment Form, and 
the S1513 Adverse Event Form).  A cycle is defined as 14 days. 
 
7.6 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease or symptomatic deterioration (as defined in Section 10.2). 
 
b. 
Unacceptable toxicity.  
 
c. 
Treatment delay for any reason > 4 weeks. 
 
d. 
The patients may withdraw from the study at any time for any reason. 
 
e. 
Pregnancy or breastfeeding. 
 
7.7 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.8 
Follow-Up Period 
 
All patients will be followed until death or 3 years after registration, whichever occurs first. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE Version 
4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 4.0. 
 
8.2 
Dose Modifications  
 
a. 
If patient experiences adverse events that result in the dose modification (including 
dose delay, reduction, or discontinuation) of ABT-888, or FOLFIRI during a cycle, 
the patient will complete the planned activities of the cycle as scheduled per 
Section 9.0 until resuming protocol therapy. If dose interruption is needed, the 
patient will continue to have study visits as planned. The timing of dose resumption 
should be at the discretion of the treating physician as long as it is within 4 weeks. 
 
b. 
Dose interruptions for events that are clearly not related to the protocol therapy 
(e.g., underlying cancer, planned surgical procedures, or acute viral illnesses) 
should not necessitate a dose reduction. 
 
c. 
Patients may be treated with antibiotic therapy if they develop severe neutropenia. 
A new cycle of treatment may not begin until the ANC is ≥ 1,500/mcL, the platelet 
count is ≥ 75,000/mcL, and any treatment-related gastrointestinal toxicity has 
resolved to ≤ Grade 1. White blood cell growth factors, including biosimilars, must 
be used per ASCO guidelines (http://jco.ascopubs.org/content/24/19/3187.full) 
and NCCN Guidelines ® Myeloid Growth Factors. 

 
S1513 
 
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(http://nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf). 
 
d. 
No dose re-escalations are permitted. If the patient experiences toxicity requiring 
a dose reduction, the dose will remain lowered for subsequent cycles. 
 
e. 
Where several toxicities with different grades or severity occur at the same time, 
the dose modification applied should be the greatest reduction applicable. 
 
f. 
For toxicities that are considered by the treating physician to be unlikely to develop 
into serious or life-threatening events (e.g., alopecia, altered taste, etc.), treatment 
will be continued at the same dose without reduction or interruption. In addition, no 
dose reductions or interruptions will be required for anemia (non-hemolytic) as it 
can be satisfactorily managed by transfusions. 
 
g. 
The maximum dose delay for any reason is 4 weeks. If the treatment is delayed 
for > 4 weeks, patients must be removed from protocol therapy. 
 
h. 
Dose omitted during a cycle will not be made up. 
 
8.3 
Dose Modification for ABT-888 
 
a. 
Guidelines 
 
1. 
Any event of seizure, regardless of grade or attribution, requires 
interruption of ABT-888 and discussion with one of the Study Chairs 
regarding the decision to resume treatment. 
 
2. 
ABT-888 will be held until the toxicity(ies) (Grade 3 or 4) recover to ≤ 
Grade 1 or baseline grade if present at registration. Upon resuming ABT-
888 treatment, the dose is to be reduced one dose level as shown. Unless 
otherwise specified, treatment should continue unmodified for toxicities < 
Grade 3 
 
3. 
If a patient begins ABT-888 on Day 1, but subsequently experiences an 
event requiring delay of the modified FOLFIRI dosing on Day 3, the patient 
is to stop ABT-888 dosing immediately. Upon resolution of the event, the 
patient may restart the current cycle by repeating Day 1 and Day 2. For 
such delays, a new ABT-888 supply will be dispensed to restart the cycle 
at Day 1. 
 
4. 
For the purposes of this study, only three dose reductions of ABT-888 are 
allowed. All dose reductions are permanent. If a dose reduction is required 
beyond dose level -3, patients should discontinue all protocol therapy. If 
an intolerable toxicity does not develop, treatment with additional cycles of 
protocol therapy may be continued indefinitely as long as patient has not 
met any of the criteria in Section 7.6. 
 
5. 
ABT-888 may exacerbate neutropenia and thrombocytopenia associated 
with modified FOLFIRI. ABT-888 dose should be reduced one dose level, 
as appropriate. Patients should not receive ABT-888 while fluorouracil 
infusion and irinotecan are suspended. Skipped doses of ABT-888 
during Days 3-7 of each cycle are not made up. 
 
 

 
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b. 
Dose Levels for Treatment Modifications 
 
Agent 
Starting Dose 
Level -1  
Level -2 
Level -3 
 
ABT-888 
200 mg BID 
150 mg BID 
100 mg BID 
50 mg BID 
 
(400 mg daily 
(300 mg daily 
(200 mg daily 
(100 mg daily 
 
total) 
total) 
total) 
total) 
 
 
c. 
Neutrophil Count Decreased 
 
Hold treatment for up to four weeks until recovery to at least Grade 1 (ANC > 
1,500/mcL). If patient has not recovered to < Grade 1 in four weeks, discontinue 
treatment. Follow drug specific modifications below for subsequent cycles. In 
addition, it is recommended that pegfilgrastim 6 mg subcutaneously, be 
administered with each subsequent dose, on the day of fluorouracil pump 
discontinuation. 
 
Toxicity Grade   
Modification 
 
 
3-4 
1 dose level reduction. At 4th occurrence, discontinue all 
protocol treatment. 
 
 
 
d. 
Platelet Count Decreased 
 
Hold treatment for up to four weeks until recovery to at least Grade 1 (PLT > 
75,000/mcL). If patient has not recovered to < Grade 1 in four weeks, discontinue 
treatment. Follow drug specific modifications below for subsequent cycles.  
 
Toxicity Grade   
Modification 
 
 
3-4 
1st 
occurrence, 
maintain 
dose. 
For 
subsequent 
occurrences, continue ABT-888 at 1 dose level reduction. 
At 5th occurrence, discontinue all protocol treatment. 
 
 
 
e. 
Nausea/Vomiting 
 
Toxicity Grade   
Modification 
 
 
3-4 
Hold treatment for up to four weeks until recovery to at 
least Grade 1. Continue ABT-888 at 1 dose level 
reduction. At 4th occurrence, discontinue all protocol 
treatment. 
 
 
 
 
f. 
Diarrhea 
 
Patients should be instructed in the use of loperamide as treatment for diarrhea. 
No ABT-888 dose modifications are required for diarrhea. Patients should not 
receive ABT-888 while fluorouracil infusion and irinotecan are suspended. Skipped 
doses are not made up. 
 
 

 
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g. 
Mucositis 
 
No ABT-888 dose modifications are required for mucositis. Patients should not 
receive ABT-888 while fluorouracil infusion and irinotecan are suspended. Skipped 
doses are not made up. 
 
h. 
Other Non-Hematologic Toxicities 
 
For all other > Grade 3 non-hematologic toxicities not described above, hold ABT-
888 and monitor at least weekly. If toxicity resolves to < Grade 1 within four weeks, 
protocol therapy may be resumed. ABT-888 may be reduced at the treating 
physician’s discretion. 
 
8.4 
Dose Modification for FOLFIRI 
 
a. 
Guidelines 
 
Dose modifications for the current cycle and reduction for subsequent cycles 
should be carried out as shown below. Dose adjustments of irinotecan and 
fluorouracil infusion may be made independently based on the specific types of 
toxicities observed as discussed in Sections 8.4c-i. For the purposes of this study, 
only three dose reductions of FOLFIRI are allowed. If a dose reduction is required 
beyond dose level -3 for irinotecan, discontinue irinotecan, but continue ABT-888, 
fluorouracil, and leucovorin. If a dose reduction is required beyond dose level -3 
for continuous infusion fluorouracil, discontinue all protocol therapy. 
 
Patients should not receive ABT-888 while fluorouracil infusion and 
irinotecan are suspended.  Skipped doses of ABT-888 during Days 3-7 of 
each cycle are not made up. 
 
Note: The fluorouracil bolus can only be skipped or discontinued. 
 
b. 
Dose Levels for Treatment Modifications 
 
Agent 
Starting Dose 
Level -1  
Level -2 
Level -3 
 
Fluorouracil 
400 mg/m2 
Discontinue 
N/A 
N/A  
(bolus)* 
 
Fluorouracil 
2,400 mg/m2 
1920 mg/m2 
1600 mg/m2 
1360 mg/m2 
 
Irinotecan 
180 mg/m2 
150 mg/m2 
120 mg/m2 
100 mg/m2 
 
Leucovorin** 
400 mg/m2 
No dose adjustments allowed 
 
* Fluorouracil bolus is only given in Arm 2. 
** Leucovorin is always administered at 400 mg/m2 IV prior to fluorouracil. If 
fluorouracil 46-48 hour infusion needs to be skipped, leucovorin must also be 
skipped. 
α Patients known to be homozygous for UGT1A1*28 are recommended to start 
irinotecan with a 30% dose reduction. 
 
 

 
S1513 
 
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c. 
Neutrophil Count Decreased 
 
Toxicity Grade  Modification:  
 
 
3-4 
Hold treatment for up to four weeks until recovery to at least Grade 1.  If 
patient has not recovered to ≤ Grade 1 in four weeks, permanently 
discontinue treatment. If patient recovers to ≤ Grade 1, one dose level 
reduction of fluorouracil and irinotecan. At 4th occurrence, discontinue all 
protocol treatment. NOTE: For patients in Arm 2, discontinue bolus 
fluorouracil at first occurrence. 
 
 
d. 
Platelet Count Decreased 
 
Toxicity Grade  Modification:    
 
 
3-4 
 
Hold treatment for up to four weeks until recovery to at least Grade 
1.  If patient has not recovered to ≤ Grade 1 in four weeks, 
discontinue treatment. If patient recovers to ≤ Grade 1, one dose 
level reduction of fluorouracil. At 4th occurrence, discontinue all 
protocol treatment. For the first occurrence, maintain irinotecan 
dose level and for subsequent occurrences 1 dose level reduction 
up to 2 steps down. NOTE: For patients in Arm 2, discontinue 
bolus fluorouracil at first occurrence. 
 
 
e. 
Diarrhea 
 
Patients should be instructed in the use of loperamide as treatment for diarrhea. 
Patient should not be retreated with irinotecan until recovery from diarrhea has 
occurred.  
 
Toxicity Grade  Modification 
 
 
3-4 
 
 Hold treatment. Check weekly. When resolves to ≤ Grade 1, 
continue at next lowest dose level. If patient recovers to ≤ Grade 
1, one dose level reduction of fluorouracil and irinotecan. At 4th 
occurrence, discontinue all protocol treatment. NOTE: For 
patients in Arm 2, discontinue bolus fluorouracil at first 
occurrence. 
 
 
 
f. 
Mucositis 
 
 
 
Toxicity Grade  Modification: Fluorouracil and irinotecan 
 
 
2-4 
Hold treatment. Check weekly. When resolves to ≤ Grade 1, 
continue at next lowest dose level. NOTE: For patients in Arm 2, 
discontinue bolus fluorouracil at first occurrence. 
 
 
 

 
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g. 
Hand-Foot Skin Reaction 
 
Toxicity Grade  Modification: 
 
 
 
3-4 
Hold treatment. Check weekly. When resolves to ≤ Grade 1, 
continue irinotecan at next lowest dose level. Reduce fluorouracil 
infusion by 1 dose level. 
 
 
h. 
Nausea/Vomiting 
 
Toxicity Grade   
Modification 
 
 
3-4 
 
Hold treatment. Check weekly. When resolves to ≤ Grade 
1, continue at 1 dose level reduction of fluorouracil and 
irinotecan up to 3 steps down. At 4th occurrence, discontinue 
all protocol treatment. NOTE: For patients in Arm 2, 
discontinue bolus fluorouracil at first occurrence treatment  
 
 
i. 
Other non-hematologic toxicities 
 
All treatment related non-hematological toxicities ≥ Grade 3 (with the exception of 
hair loss) must resolve to Grade 1 prior to starting next cycle of therapy.  Treatment 
should continue unmodified for toxicities < Grade 3. 
 
Toxicity Grade  
Modification: Fluorouracil and irinotecan 
 
 
3 
Hold all drugs until resolution to < Grade 1. Then resume 
treatment at the next lower dose level. Fluorouracil bolus 
should be discontinued in Arm 2. 
 
4 
Discontinue all protocol treatment 
 
 
 
8.5 
Dose Modifications Contacts 
 
For treatment or dose modification questions, please contact Dr. Chiorean at 206/288-6248 
or Dr. 
   
 
8.6 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.1 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 
 
 
 

 
S1513 
 
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9.0 
STUDY CALENDAR 
 
9.1 
Arm 1: ABT-888 + mFOLFIRI 
 
∑ 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Ω 
% 
REQUIRED STUDIES 
PRE 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
FU 
prior to 
prog 
FU 
after 
prog 
  
STUDY 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
History and Physical Exam ◊ 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
Weight and Performance Status 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Disease Assessment 
X 
  
  
  
  
  
  
  
  
X 
  
  
  
Toxicity Notation 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Baseline Abnormalities 
X 
  
  
  
  
  
  
  
  
  
  
  
  
LABORATORY π d 
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC/Differential/Platelets 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
CA19-9/CEA $ 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
AST/ALT, total bilirubin, serum albumin, 
serum creatinine 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Chemistry ** 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Pregnancy test ⌂ 
X 
X ⌂ 
 
 
 
 
 
 
 
 
 
X ⌂ 
 
X-RAYS AND SCANS c 
  
  
  
  
  
  
  
  
  
  
  
  
  
CT/MRI for disease assessment 
X 
  
  
  
  
  
  
  
  
X 
  
X 
  
SPECIMEN SUBMISSION 
  
  
  
  
  
  
  
  
  
  
  
  
  
Tissue block or slides for TM (required) δ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Archival tissue slides for TM (required) δ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Blood for TM (required) δ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Tissue for banking (optional) δ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
ABT-888  ¿ 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Irinotecan  ⱷ 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Leucovorin  ⱷ 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Fluorouracil  Ⱡ 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Click here for footnotes. 
 
 

 
S1513 
 
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9.2 
Arm 2: FOLFIRB 
 
∑ 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Ω 
% 
REQUIRED STUDIES 
PRE 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Follow up 
prior to 
prog 
Follow 
up after 
prog 
  
STUDY 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
History and Physical Exam 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
Weight and Performance Status 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Disease Assessment 
X 
  
  
  
  
  
  
  
  
X 
  
  
  
Toxicity Notation 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Baseline Abnormalities 
X 
  
  
  
  
  
  
  
  
  
  
  
  
LABORATORY π d 
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC/Differential/Platelets 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
CA19-9/CEA $ 
X 
X 
  
  
  
X 
  
  
  
X 
  
  
  
AST/ALT, total bilirubin, serum albumin, 
serum creatinine 
X 
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Chemistry ** 
X 
X  
  
X 
  
X 
  
X 
  
X 
  
  
  
X-RAYS AND SCANS c 
  
  
  
  
  
  
  
  
  
  
  
  
  
CT/MRI for disease assessment 
X 
  
  
  
  
  
  
  
  
X 
  
X 
  
SPECIMEN SUBMISSION 
  
  
  
  
  
  
  
  
  
  
  
  
  
Tissue block or slides for TM (required) δ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Archival tissue slides for TM (required) δ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Blood for TM (required) δ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Tissue for banking (optional) δ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
Irinotecan  β 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Leucovorin  β 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Fluorouracil bolus  α 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Fluorouracil  γ 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
Click here for footnotes. 
 
 

 
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Footnotes: 
∑  Protocol treatment and physical, laboratory, and scan parameters will continue at these intervals indicated in the Cycle 2-5 columns 
until progression of disease or until patient has met any of the guidelines in Section 7.6. 
Ω  After off treatment prior to disease progression, scans for disease assessment and physical assessments (with lab tests performed at 
the discretion of the treating investigator) should take place every 8 weeks until progression. 
% After off treatment following disease progression, physical assessments (with lab tests performed at the discretion of the treating 
investigator) should take place once every 3 months for three years from the time of registration. 
¿ Oral capsule taken twice daily on Days 1-7 of every cycle.  Day 3 dose should be taken at treating institution 1 hour (± 30 minutes) 
prior to irinotecan (see Section 7.2). 
ⱷ Infusion to be given on Day 3 of every cycle (see Section 7.2). 
Ⱡ Infusion to be given starting on Day 3 over 46-48 hours (see Section 7.2). 
α  Bolus to be given on Day 1 prior to 46 hour infusion (see Section 7.3). 
β  Infusion to be given on Day 1 of every cycle (see Section 7.3).  
γ  Infusion to be given starting on Day 1 over 46-48 hours (see Section 7.3). 
δ  See Section 15.0 for more information. 
**  BUN, alkaline phosphatase, sodium, potassium, calcium, glucose, albumin, chloride, carbon dioxide/bicarbonate 
π  Labs do not need to be repeated if pre-study labs were done within 7 days prior to Cycle 1 Day 1.  
$ CA19-9 should be repeated every 4 weeks if abnormal at baseline. If CA19-9 normal at baseline, CEA must be tested and if CEA is 
abnormal, should be repeated every 4 weeks. 
⌂ Women of childbearing potential must have a negative serum or urine pregnancy test at screening within 28 days prior to registration.  
If randomized to Arm 1, serum or urine pregnancy tests are required within 72 hours prior to the first dose of study treatment.  At 
discontinuation, a pregnancy test must be done within 4 weeks after the last dose of study drug.  A pregnancy test should be done at 
any time there are clinical concerns for possible pregnancy. 
◊ History prior to each treatment initiation to include a menstrual, sexual, and contraceptive use history, including date of last menstrual 
period (for women of childbearing potential) which will help determine the need for pregnancy testing.  Similar questions regarding 
contraceptive use to be asked to men who are sexually active with women of childbearing potential. 
c CT or MRI, of chest, abdomen, and pelvis for disease assessment must be performed every 8 weeks while on study treatment. 
d Labs are to be drawn on Day 1 of each cycle. If the labs are satisfactory, they do not need to be repeated on Day 3 prior to FOLFIRI. If 
the labs drawn on Day 1 are not satisfactory for FOLFIRI therapy, the local investigator may repeat them prior to Day 3, as clinically 
indicated. 
 
 
 
 
 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
This study will use the RECIST 1.1 guidelines.  (112) 
 
10.1 
Measurability of Lesions 
 
a. 
Measurable disease 
 
Measurable disease is defined differently for lymph nodes compared with other 
disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm  by chest x-ray, by ≥ 1.0 cm  
with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All tumor 
measurements must be recorded in decimal fractions of centimeters (or 
millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by scan 
(CT scan slice recommended being no greater than 0.5 cm). 
 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm 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 non-measurable as are previously radiated 
lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior 
scans.  Body scans should be performed with breath-hold scanning 
techniques, if possible.  
 
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for RECIST 
measurements and can be used interchangeably with conventional CT. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
4. 
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. 
 
 

 
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5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 
 
10.2 
Objective Status at Each Disease Evaluation   
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-measurable 
disease.   
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the “target” 
areas. Therefore, in these studies it is not acceptable to image only the “target” areas of 
the body in follow-up scans. For study-specific imaging requirements, see the Study 
Calendar in Section 9.0.   
 
a. 
Complete Response (CR):  Complete disappearance of all target and non-target 
lesions (with the exception of lymph nodes mentioned below).  No new lesions.  
No disease related symptoms.   Any lymph nodes (whether target or non-target) 
must have reduction in short axis to < 1.0 cm.  All disease must be assessed using 
the same technique as baseline. 
 
b. 
Partial Response (PR): Applies only to patients with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c. 
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
d. 
Progression: One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum observed 
(over baseline if no decrease during therapy) using the same techniques as 
baseline, as well as an absolute increase of at least 0.5 cm.  Unequivocal 
progression of non-measurable disease in the opinion of the treating physician (an 
explanation must be provided).  Appearance of any new lesion/site.  Death due to 
disease without prior documentation of progression and without symptomatic 
deterioration (see Section 10.2e). 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm.  
 
1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of progression based on a new lesion. 
 
2. 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a confirmation 
by anatomical assessment (e.g. CT, MRI, x-ray) as new site of disease to 
be considered progressive disease.  In such a case, the date of 
progressive disease will be the date of the initial abnormal FDG-PET. 
 

 
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e. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 
f. 
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment methods 
were used. 
 
g. 
Objective status notes: 
 
1. 
Non-measurable and non-target measurable disease do not affect 
Objective Status  in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician).  
 
2. 
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression.   
 
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.  
 
5. 
For bone disease documented on bone scan only, increased uptake does 
not constitute unequivocal progression. However, increase in the soft 
tissue component of a lesion as measured by CT or MRI would constitute 
progression. 
 
6. 
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. 
Increase in the size of an existing effusion does not constitute unequivocal 
progression, since the fluid status of the patient could alter the size of the 
effusion.  
 
7. 
If CR determination depends on a lesion for which the status is unclear by 
the required tests, it is recommended the residual lesion be investigated 
with biopsy.  
 
10.3 
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 
 

 
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b. 
PR: Two or more objective statuses of PR or better a minimum of four weeks apart 
documented before progression or symptomatic deterioration, but not qualifying as 
CR. 
 
c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 
d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above.   
 
g. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 12 
weeks of registration, not qualifying as anything else above.   
 
h. 
Inadequate assessment, response unknown:  Progression or symptomatic 
deterioration greater than 12 weeks after registration and no other response 
category applies. 
 
10.4 
Performance Status:   
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT  
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework, office 
work. 
 
2 
Ambulatory and capable of self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours.   
 
3 
Capable of limited self-care, confined to bed or chair more than 50% of 
waking hours.   
 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair.   
 
10.5 
Progression-Free Survival 
 
From date of registration to date of first documentation of progression or symptomatic 
deterioration (as defined above), or death due to any cause.  Patients last known to be 
alive without report of progression are censored at date of last contact. 
 
10.6 
Time to Death 
 
From date of registration to date of death due to any cause.  Patients last known to be alive 
are censored at date of last contact. 
 
 

 
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10.7 
Duration of Response (DoR) 
 
 
From date of first documentation of response (CR or PR) to date of first documentation of 
progression or symptomatic deterioration (as defined above), or death due to any cause 
among patients, who achieve a response (CR or PR). Patients last known to be alive 
without report of progression are censored at date of last contact. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Sample Size and Accrual Goals 
 
The primary objective of the study is to compare overall survival (OS) between the 2 
treatment arms. We estimate the median OS of patients treated with FOLFIRI to be 6 
months in this population. (113,114) Assuming that the addition of ABT-888 offers an 
increase in OS to 9 months (HR 1.5), we will need 128 eligible patients, based on a 1:1 
randomization, a one-sided type 1 error of 10% and 80% power. Allowing for an 
approximately 10% ineligibility rate, accrual will be to a total of 143 patients. We expect 28 
months of accrual and 10 months of follow-up.  Our accrual rate estimate is based on the 
observed accrual to SWOG study S1115. 
 
11.2 
Analysis of Primary Endpoint 
 
The primary analysis of OS will be conducted in all eligible patients according to the intent-
to-treat principle, using the log-rank test with stratification by prior systemic treatment for 
metastatic disease. Distributions of overall survival in Arms 1 and 2 will be estimated using 
the method of Kaplan-Meier. The final analysis will take place upon the observation of 
approximately 110 deaths.  
 
11.3 
Interim Analysis 
 
An interim futility analysis of progression-free survival (PFS) by treatment arm will be 
performed by testing an alternative hypothesis of a 1.5 HR at p<0.05 when approximately 
35% of the expected PFS events in the control arm have been observed.  We expect this 
analysis to occur when approximately 50% of the study sample has been accrued.  Unless 
there are toxicity concerns or extenuating circumstances, the study will not close during 
this interim assessment.  If this alternative hypothesis is rejected at p<0.05 then the study 
may be closed to further accrual and the experimental agent declared of no interest for 
further development.  If we fail to reject this hypothesis, the study will complete accrual.  
 
11.4 
Secondary Endpoints 
 
Secondary endpoints include toxicity, PFS, overall response rate, disease control rate, and 
duration of response (DoR). The chi-square test will be used to compare toxicity, response 
rates, and disease control rates and a stratified log-rank test will be used to compare PFS 
between treatment arms. The distribution of PFS and DoR (among patients who achieve 
CR/PR) in each treatment arm will be estimated using the Kaplan-Meier method. The 
overall response rate (confirmed and unconfirmed, complete and partial) in each treatment 
arm will be assessed in the subset of patients with measurable disease. At least 64 eligible 
patients in each arm are sufficient to estimate the disease response rate to within 13% 
(95% confidence interval).  
 
Patients receiving at least one dose of any drug on any arm will be included in the 
assessment of adverse events. Adverse event monitoring is conducted by the study chairs, 
disease committee chair, Adverse Event Coordinator and study statistician on an ongoing 
basis, with notification to the DSMC and CTEP should any concerns arise. Any events 
reported through the CTEP-AERS system are reported immediately, and reports are sent 
to the above group for all other AEs on a monthly basis. At least 64 eligible patients in each 
arm are sufficient to estimate the probability of a particular toxicity to within 13% (95% 

 
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confidence interval). Any toxicity occurring with at least a 5% probability is likely (96% 
chance) to be seen at least once. 
 
11.5 
Translational Endpoints 
 
We assume that 90% of eligible patients will submit tissue and 80% of these will be 
successfully assayed. With 128 eligible patients enrolled on S1513, it is estimated that for 
each arm, 46 patients (n=92 total) will be included in analyses. The overall prevalence of 
each biomarker can be estimated to within 10% (95% confidence interval). 
   
a. 
The primary translational objective is to evaluate if BRCA1 and BRCA2 mutations 
(somatic or germline) are associated with improved clinical outcomes (OS, PFS, 
and ORR) in each treatment arm. Prevalences of BRCA1 and BRCA2 mutations 
in this patient population are estimated to be approximately 1-2% and 5-7%, 
respectively.   
 
b. 
Secondly, we will evaluate the impact of HRD positivity on clinical outcomes in 
each treatment arm. Although the HRD score threshold for positivity has yet to be 
determined in this disease, we will first dichotomize the score at its observed 
median value (represented as 50% prevalence in the tables below), and estimate 
the associations between that binary predictor and clinical outcomes. We will also 
assess the associations of HRD score as a continuous variable with clinical 
outcomes.  
 
c. 
Additionally, we will evaluate the impact of other exploratory genomic alterations 
(other than BRCA1/2 mutations) identified by the BROCA-HR assay on clinical 
outcomes in each treatment arm.  
 
We will evaluate if each potential biomarker is associated with the clinical outcomes of 
overall survival (OS), progression-free survival (PFS), and response rate (ORR) separately 
by treatment arm. The associations between each potential biomarker and both OS and 
PFS will be explored via Kaplan-Meier curves and Cox regression. We assume the 
baseline median OS is 6 months, 46 patients enrolled over 28 months and an additional 
10 months of follow-up. The following table shows approximate power to detect OS hazard 
ratios of 2.5, 3, and 3.5, corresponding to median OS of 15, 18, and 21 months in the 
biomarker-positive subgroup, using a two-sided alpha of 0.1, for a range of biomarker 
frequencies.   
 
Biomarker Prevalence 
Power 
 
HR=2.5 
HR = 3 
HR = 3.5 
5% 
30% 
35% 
39% 
10% 
45% 
54% 
60% 
25% 
73% 
83% 
89% 
50% 
86% 
93% 
97% 
 
Assuming a baseline median PFS of 3 months, the following table shows approximate 
power to detect PFS hazard ratios of 2.5, 3, and 3.5, corresponding to median PFS of 7.5, 
9, and 10.5 months in the biomarker-positive subgroup, using a two-sided alpha of 0.1, for 
a range of biomarker frequencies. 
 
Biomarker Prevalence 
Power 
 
HR = 2.5 
HR = 3 
HR = 3.5 
5% 
35% 
43% 
50% 
10% 
54% 
65% 
73% 
25% 
82% 
91% 
95% 
50% 
91% 
97% 
99% 
 

 
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Assuming a null ORR of 10%, the following table describes the approximate power to 
detect differences in response rate of 25%, 30%, and 35% (corresponding to ORR of 35%, 
40%, and 45%) in the biomarker-positive sub-group, using a two-sided 0.1 level test of 
proportions across a range of biomarker frequencies. 
 
Biomarker Prevalence 
Power 
 
Δ = 25% 
Δ = 30% 
Δ = 35% 
10% 
20% 
30% 
39% 
25% 
44% 
56% 
67% 
50% 
50% 
64% 
76% 
 
We also plan to estimate an HRD score threshold for positivity in this population by 
applying receiver operating characteristic curves, classifying patients by overall disease 
response.  The precision of this estimate will depend not only on the number of patients 
with available data but also on the prevalence of disease response. 
 
11.6 
Data and Safety Monitoring 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistical Center, and will meet at the Group's bi-annual 
meetings as necessary.  The Committee will be responsible for decisions regarding 
possible termination and/or early reporting of the study. 
 
 
12.0 
DISCIPLINE REVIEW 
 
Discipline review is not applicable in this study. 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than five working days 
prior to planned start of treatment). 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a NCTN Group.  Each investigator must have an NCI investigator number and must 
maintain an “active” investigator registration status through the annual submission of a 
complete investigator registration packet to CTEP. 
 
a. 
CTEP Investigator Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all investigators participating in any NCI-sponsored clinical trial 
to register and to renew their registration annually. 
 
Registration requires the submission of: 
 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an 
original signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original signature 

 
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Fillable PDF forms and additional information can be found on the CTEP website 
at <http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.   
 
For questions, please contact the CTEP Investigator Registration Help Desk by 
email at <pmbregpend@ctep.nci.nih.gov>. 
 
b. 
CTEP Associate Registration Procedures 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended for use by both 
Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical 
trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored 
clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration 
and annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering 
with CTEP as an Investigator, which must be completed before a CTEP-IAM 
account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU 
members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  
For 
questions, please contact the CTEP Associate Registration Help Desk by email 
at <ctepreghelp@ctep.nci.nih.gov>. 
 
c. 
CTSU Registration Procedures 
 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 
to the CTSU Regulatory Office before they can be approved to enroll 
patients.  Study centers can check the status of their registration packets by 
querying the Regulatory Support System (RSS) site registration status page of the 
CTSU members’ website by entering credentials at https://www.ctsu.org. For sites 
under the CIRB initiative, IRB data will automatically load to RSS. 
 
Note:  Sites participating on the NCI CIRB initiative and accepting CIRB approval 
for the study are not required to submit separate IRB approval documentation to 
the CTSU Regulatory Office for initial, continuing or amendment review.  This 
information will be provided to the CTSU Regulatory Office from the CIRB at the 
time the site’s Signatory Institution accepts the CIRB approval.  The Signatory site 
may be contacted by the CTSU Regulatory Office or asked to complete information 
verifying the participating institutions on the study.  Other site registration 
requirements (i.e., laboratory certifications, protocol-specific training certifications, 
or modality credentialing) must be submitted to the CTSU Regulatory Office or 
compliance communicated per protocol instructions. 
 
1. 
Downloading Site Registration Documents: 
 
Site registration forms may be downloaded from the S1513 protocol page 
located on the CTSU members’ website.  
 

 
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• 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
• 
Click on the Protocols tab in the upper left of your screen 
• 
Click on the By Lead Organization folder to expand 
• 
Click on the SWOG link to expand, then select trial protocol 
S1513 
• 
Click on LPO Documents, select the Site Registration documents 
link, and download and complete the forms provided. 
 
2. 
Requirements for S1513 Site Registration: 
 
• 
CTSU IRB Certification (for sites not participating via the NCI 
CIRB) 
• 
CTSU IRB/Regulatory Approval Transmittal Sheet (for sites not 
participating via the NCI CIRB) 
 
3. 
Submitting Regulatory Documents: 
 
Submit completed forms along with a copy of your IRB Approval to the 
CTSU Regulatory Office, where they will be entered and tracked in the 
CTSU RSS.  
 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Phone: 1-866-651-2878 
Fax: 215-569-0206 
E-mail: CTSURegulatory@ctsu.coccg.org (for regulatory document submission only) 
 
 
4. 
Checking Your Site’s Registration Status: 
 
Check the status of your site’s registration packets by querying the RSS 
site registration status page of the members’ section of the CTSU 
website.  (Note: Sites will not receive formal notification of regulatory 
approval from the CTSU Regulatory Office.) 
• 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
• 
Click on the Regulatory tab at the top of your screen 
• 
Click on the Site Registration tab 
Enter your 5-character CTEP Institution Code and click on Go 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 

 
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b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database.  OPEN can be accessed at 
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 

 
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b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate. Site staff should 
refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.   Please print this confirmation for your records. 
 
d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 888/823-5923 or 
ctsucontact@westat.com. 
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details. 
 
14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata Rave® 
clinical data management system. Access to the trial in Rave is granted through 
the iMedidata application to all persons with the appropriate roles assigned in 
Regulatory Support System (RSS). To access Rave via iMedidata, you must have 
an 
active 
CTEP-IAM 
account 
(check 
at 
https://eapps-
ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave CRA, Read-
Only, Site Investigator) on either the LPO or participating organization roster at the 
enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 

 
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iMedidata. To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk at 
888/823-5923 or by e-mail at ctsucontact@westat.com 
 
b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on Workbenches, 
then CRA Workbench to access the home page for the CRA Workbench and follow 
the link to Rave® provided in the left-hand navigation panel. 
 
To access the CRA Workbench the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, 
3. 
Your Web User Administrator has added you as a web user and has given 
you the appropriate system permissions to view data for that institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  For 
point 3, contact your local Web User Administrator (refer to the "Who is my Web 
User Administrator?" function on the swog.org Members logon page). 
 
For difficulties with the CRA Workbench, please email  
technicalquestion@crab.org. 
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
DAY OF BLOOD DRAW (before or within 5 days after registration prior to 
treatment): 
 
Submit the following: 
 
Blood specimen as outlined in Section 15.1c.  
 
b. 
WITHIN 7 DAYS OF REGISTRATION: 
 
Submit the following: 
 
S1513 Onstudy Form 
 
S1513 Baseline Abnormalities Form 

 
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Baseline Tumor Assessment Form (RECIST 1.1) 
 
Pathology Reports: Initial diagnosis, metastatic (if done), and fresh biopsy (NOTE: 
Upload reports via the Source Documentation: Baseline form in Rave®.) 
 
Submit radiology reports from all scans performed to assess disease at baseline. 
(NOTE: Upload reports via the Source Documentation: Baseline form in Rave®.) 
 
c. 
WITHIN 28 DAYS OF REGISTRATION: 
 
Tissue specimens as outlined in Sections 15.1 and 15.2. 
 
d. 
WITHIN 14 DAYS AFTER EACH CYCLE OF TREATMENT: 
 
Submit the following: 
 
S1513 Treatment Form 
 
S1513 Adverse Event Form 
 
e. 
WITHIN 14 DAYS AFTER EACH CA19-9 OR CEA TEST (every 4 weeks): 
 
Submit the following: 
 
S1513 CA19-9 (CEA) Form 
 
f. 
WITHIN 14 DAYS AFTER EACH DISEASE ASSESSMENT (INCLUDING BOTH 
ON 
TREATMENT 
AND 
OFF 
TREATMENT 
PRIOR 
TO 
DISEASE 
PROGRESSION): 
 
Submit the following: 
 
Follow Up Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports from all scans performed to assess disease (NOTE: Upload 
reports via the Source Documentation: Follow-up form in Rave®.) 
 
g. 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT: 
 
Submit the following: 
 
Off Treatment Notice 
 
S1513 Treatment Form 
 
S1513 Adverse Event Form 
 
h. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit the following: 
 
Follow-up Tumor Assessment Form (RECIST 1.1) 
 
Off Treatment Notice (if the patient was still on protocol treatment)  
 
Final S1513 Treatment Form (if the patient was still on protocol treatment) 
 

 
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Final S1513 Adverse Event Form 
 
Follow-Up Form (if the patient was off protocol treatment) documenting date, site 
and method for determining progression/relapse. 
 
Radiology Reports (NOTE: Upload reports via the Source Documentation: Follow-
up form in Rave®.) 
 
i. 
AFTER OFF ALL PROTOCOL TREATMENT, EVERY 3 MONTHS UNTIL 3 
YEARS FROM REGISTRATION: 
 
Submit the following: 
 
Follow Up Form 
 
Late Adverse Events Form (if prior to treatment for progression or relapse or a 
second primary, and prior to non-protocol treatment, the patient experiences any 
severe [Grade ≥ 3] long term toxicity that has not been previously reported) 
 
j. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death and final S1513 Treatment Form and Adverse Event 
Form (if the patient was still on protocol treatment) or Follow-Up Form (if the patient 
was off protocol treatment) documenting death information. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Translational Medicine 
 
Specimens for HRD and BROCA-HR (submitted to the SWOG Specimen Repository – 
Solid Tissue, Myeloma and Lymphoma Division, Lab #201): 
 
Note: If patient consented to banking, see additional requirements in Section 15.2. 
 
a. 
Tissue specimens from pre-treatment biopsy for translational medicine (required 
for patient) must be submitted within 28 days of registration: 
 
1. 
One 5-micron charged slide*. 
 
2. 
Nine to fourteen 10-micron unstained, uncharged slides*. The tissue 
should not be cover-slipped and should not be baked.  
 
*Sites may submit block in lieu of specific slides listed above. 
 
NOTE: Pre-treatment biopsy may be from either the primary or metastatic tumor 
site. Core biopsy required. FNA is not an acceptable substitute for core biopsy. A 
local standard surgical consent form must be obtained. The biopsy can be obtained 
as per local institutional guidelines. The use of imaging to facilitate biopsies will be 
decided by members of the Interventional Radiology team at the clinical site and 
may include ultrasound, CT scan, or MRI. 
 
b. 
Archival tissue from the time of initial diagnosis specimens for translational 
medicine (required, if available) must be submitted within 28 days of registration: 
 
1. 
Two 10-micron unstained archival tumor (FFPE) slides. NOTE: Archival 
tissue from initial diagnosis. 
 

 
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c. 
Blood specimen for translational medicine (required for patient) must be submitted 
within 5 days of registration (prior to beginning treatment): 
 
1. 
7mL whole blood collected in yellow top (ACD solution A) tube at baseline. 
The filled tube must be maintained at ambient (15-30˚C) temperature, 
avoiding extremes of heat and cold, at all times. If Yellow Top, ACD, tubes 
are not available, EDTA tubes are allowed and will be accepted. ONLY 
COLLECT AND SHIP SAMPLES TO THE SWOG SPECIMEN 
REPOSITORY MONDAY THROUGH THURSDAY. DO NOT COLLECT 
SAMPLES ON FRIDAY OR THE DAY BEFORE A HOLIDAY. THIS 
SPECIMEN MUST BE SHIPPED THE DAY OF COLLECTION FOR 
OVERNIGHT DELIVERY TO LAB #201 AT AMBIENT TEMPERATURE.  
 
d. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage  
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp).  Please 
note that all tissue specimens should be accompanied by a pathology report. 
 
e. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
f. 
Any leftover specimens not consumed by testing will be banked for future use 
according to the patient’s selection on the “Optional Biobanking for Possible Future 
Studies” section of the consent form.  
 
15.2 
Specimens for Banking 
 
Specimens for banking (submitted to the SWOG Specimen Repository – Solid Tissue, Myeloma 
and Lymphoma Division, Lab #201) (optional for patient): 
 
a. 
With patient’s consent, pre-treatment biopsy specimens must be submitted within 
28 days of registration (see Section 9.0): 
 
1. 
Tumor block or fifteen 10 micron unstained tumor sections (FFPE) from 
primary or metastatic tumor site. 
NOTE:  If tissue block is submitted for Section 15.1, this additional tissue is not 
required. 
 
b. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage  
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp). 
Please 
note that all tissue specimens should be accompanied by a pathology report. 
 
c. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 

 
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must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312. 
 
Publication and Industry Contact 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies)  
(hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines in addition to the provisions in the 
"Intellectual Property Option to Collaborator"  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award apply to the use of the Agent in this study: 
 
1. 
Agent(s) may not be used outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 
as such by the investigators.  The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of 
the NCI.  If a copy of this protocol is requested by a patient or patient’s family member 
participating on the study, the individual should sign a confidentiality agreement. A suitable 
model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different Collaborative Agreements, 
the access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data"): 
 
a. 
NCI will provide all Collaborators with written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations which would 
tend to restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own 
investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-
Party Data solely for development, regulatory approval, and commercialization of 
its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate 

 
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and unless additional disclosure is required by law or court order as described in the IP 
Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, all 
Clinical Data and Results and Raw Data will be collected, used and disclosed consistent 
with all applicable federal statutes and regulations for the protection of human subjects, 
including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to the Collaborator(s) for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator's confidential 
and proprietary data, in addition to the Collaborator(s)'s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) 
for courtesy review as soon as possible and preferably at least three (3) days prior to 
submission, but in any case, prior to presentation at the meeting or publication in the 
proceedings.  Press releases and other media presentations must also be forwarded to 
CTEP prior to release.  Copies of any manuscript, abstract and/or press release/media 
presentation should be sent to: 
 
E-mail:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to the Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
protocol- and patient-specific CDUS data will be submitted electronically to CTEP on a quarterly 
basis, either by FTP burst of data or via the CDS web application.  Reports are due January 31, 
April 30, July 31, and October 31.  Instructions for submitting data using the CDUS can be found 
on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above.  If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS. 
 
Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
 

 
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16.1 
Adverse Event Reporting Requirements 
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients 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 at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for more timely monitoring of 
patient safety and care. The following guidelines prescribe expedited adverse 
event reporting for this protocol.  
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically 
via 
the 
CTEP-AERS Web-based 
application 
located 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.  
 
When the adverse event requires expedited reporting, submit the report within the 
number of calendar days of learning of the event, as specified in Table 16.1.  
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301-897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection. 
 
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided in 
Table 16.1. The investigational agent(s) used in Arm 1 of this study is ABT-888. If 
there is any question about the reportability of an adverse event or if on-line CTEP-
AERS cannot be used, please telephone or email the SAE Specialist at the 
Operations Office, 210/614-8808 or adr@swog.org, before preparing the report. 
 
 
 

 
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h. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
 
CTEP requires all secondary malignancies that occur following treatment 
with an agent under an NCI IND to be reported via CTEP-AERS.  Three 
options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in 
each protocol. 
 
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the initial 
malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf  
 
2. 
Any supporting documentation should be submitted to CTEP per NCI 
guidelines for AE reporting located at: 
http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/
aeguidelines.pdf.  
 
A copy of the report and the following supporting documentation must also 
be submitted to SWOG Operations Office within 30 days by fax to 210-
614-0006 or mail to the address below: 
 
• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored study, the 
report must be submitted for the most recent trial. 
 
 
i. 
Reporting Pregnancy, Fetal Death, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 

 
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(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation” should be 
reported expeditiously as Grade 4 “pregnancy, puerperium and 
perinatal conditions – Other (pregnancy loss)” under the Pregnancy, 
puerperium and perinatal conditions SOC.   
 
3. 
Death Neonatal  Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” 
that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.   
 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the 
General disorders and administration SOC. 
 
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-230-0159.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm. 
 
 
 
 
 

 
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17.0 
BIBLIOGRAPHY 
1  
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2  
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 65(1): p. 5-29, 2015. 
 
3  
Bosetti C, et al. Cancer mortality in Europe, 2005-2009, and an overview of trends since 1980. Ann 
Oncol 24(10): p. 2657-71, 2013. 
 
4  
Bosetti C, et al. Cancer mortality in Europe, 2005-2009, and an overview of trends since 1980. Ann 
Oncol 24(10): p. 2657-71, 2013. 
 
5  
Siegel R, et al. Cancer statistics CA Cancer J Clin, 2014. 64(1): p. 9-29, 2014. 
 
6  
Siegel R, et al. Cancer statistics CA Cancer J Clin, 2014. 64(1): p. 9-29, 2014. 
 
7  
Conroy T, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 
364(19): p. 1817-25, 2011. 
 
8  
Von Hoff DD, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N 
Engl J Med 369(18): p. 1691-703, 2013. 
 
9  
Moretto R, et al. FOLFIRI in patients with locally advanced or metastatic pancreatic or biliary tract 
carcinoma: a monoinstitutional experience. Anticancer Drugs 24(9): p. 980-5, 2013. 
 
10  
Neuzillet C, et al. FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to 
gemcitabine and platinum-salts. World J Gastroenterol 18(33): p. 4533-41, 2012. 
 
11  
Zaniboni A, et al. FOLFIRI as second-line chemotherapy for advanced pancreatic cancer: a 
GISCAD multicenter phase II study. Cancer Chemother Pharmacol 69(6): p. 1641-5, 2012. 
 
12  
Yoo C, et al. A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-
line therapy in patients with gemcitabine-refractory advanced pancreatic cancer. Br J Cancer 
101(10): p. 1658-63, 2009. 
 
13  
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Lowery MA KD. Smith C, et al. Phase II trial of veliparib in patients with previously treated BRCA 
or PALB2 mutated pancreas adenocarcinoma. in Gastrointestinal Cancers Symposium J Clin 
Oncol, 2015. 
 
77  
Pishvaian MJ, W.H., Zhuan T, et al.  . A phase I/II study of ABT-888 in combination with 5-
fluorouracil and oxaliplatin in patients with metastatic pancreatic cancer. in ASCO J Clin Oncol, 
2013. 
 
78  
O'Reilly EM, L.M., Segal MF, et al. Phase Ib trial of cisplatin, gemcitabine, and veliparib in patients 
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79  
Berlin J, R.R., Strickler JH, et al. A phase 1 dose-escalation study of veliparib with bimonthly 
FOLFIRI in patients with advanced solid tumors. in ASCO J Clin Oncol, 2014. 
 
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FOLFIRI in patients with advanced solid tumors. in ASCO J Clin Oncol, 2014. 
 
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FOLFIRI in patients with advanced solid tumors. in ASCO J Clin Oncol, 2014. 
 
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Pishvaian MJ, W.H., Zhuan T, et al.  . A phase I/II study of ABT-888 in combination with 5-
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2013. 
 
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AbbVie Veliparib Investigator Brochure V9, 2015. 
 
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85  
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10.3892/ijo.2013.1932, 2013. 
 
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Mol cancer Ther 13(5):1170-80. Doi: 10.1158/1535-7163, 2014. 
 
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in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells. 
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91  
Berlin J, R.R., Strickler JH, et al. A phase 1 dose-escalation study of veliparib with bimonthly 
FOLFIRI in patients with advanced solid tumors. in ASCO J Clin Oncol, 2014. 
 
92  
Kaufman B, Shapira-Frommer R, Schmutzler RK, et al: Olaparib Monotherapy in Patients With 
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Lowery MA, Kelsen, D.P., Smith, S.C., et al: Phase II trial of veliparib in patients with previously 
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2012. 
 
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inactivation. Cancer Res 72:5454-62, 2012. 
 
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Walsh T, Lee MK, Casadei S, et al: Detection of inherited mutations for breast and ovarian cancer 
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peritoneal carcinomas. Clin Cancer Res 20:764-75, 2014. PMID: 24240112 
 
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Adamo A, Collis SJ, Adelman CA, et al. Preventing nonhomologous end joining suppresses DNA 
repair defects of Fanconi anemia. Mol Cell;39:25-35, 2010. 
 
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Patel AG, Sarkaria JN, Kaufmann SH. Nonhomologous end joining drives poly(ADP-ribose) 
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Birkbak NJ, Wang ZC, Kim JY, et al. Telomeric allelic imbalance indicates defective DNA repair 
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108  
Walsh T, Casadei S, Lee MK, et al: Mutations in 12 genes for inherited ovarian, fallopian tube, and 
peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A 
108:18032-7, 2011. PMID: 22006311 
 
109  
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using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A 107:12629-
33, 2010. PMID: 20616022 
 
110  
Pennington KP, Walsh T, Harrell MI, et al: Germline and somatic mutations in homologous 
recombination genes predict platinum response and survival in ovarian, fallopian tube, and 
peritoneal carcinomas. Clin Cancer Res 20:764-75, 2014. PMID: 24240112 
 
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inhibitor and platinum resistance. Proceedings of the National Academy of Sciences of the United 
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364(19): p. 1817-25, 2011. 
 
 
 
 

 
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18.0 
APPENDIX 
 
18.1 
Intake Calendar  
 
18.2 
Patient Drug Information Handout and Wallet Card 
 
18.3  
New York Heart Association Criteria 
 
18.4 
Translational Medicine: HRD and BROCA-HR 
 
 
 

 
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18.1 
Intake Calendar – ABT-888 (Veliparib) SWOG Study: S1513 
 
Cycle: ________    Start Date: 
  Start Day (circle one): Sun  M  Tu  W Th  Fr  Sat   
Instructions for the participant: 
This is a 14 day cycle calendar on which you are to record the number of ABT-888 tablets you take each 
day.  ABT-888 should be taken twice daily at the same time of day ± 2 hours, unless otherwise instructed, 
with or without food.  ABT-888 capsules should be swallowed whole; do not chew them prior to swallowing. 
No capsule should be ingested if it is broken, cracked, or otherwise not intact.    
• 
Missed doses are to be omitted rather than made up if more than 6 hours have passed from the 
original dose time. 
• 
If you vomit a dose within 15 minutes, a replacement dose can be taken. If more than 15 minutes 
have passed since the dose, you should not take another dose. 
• 
If you develop any side effects from the tablet, mark this on the calendar on the day you note the 
effect.  Contact site personnel listed below. 
• 
On Day 3 of each cycle, ABT-888 must be taken at your treating institution 1 hour (± 30 minutes) 
before starting irinotecan.  
Put the date in the box on the calendar for and note the times of dose for each day.  Take medication as 
directed by study doctor. Line through the days medication is not taken. 
Storage: 
ABT-888 capsules should be stored at 
 in their original container.  
Keep the medication in the bottles provided and do not transfer it to any other container. 
Site Personnel: 
The patient number should be recorded on the bottle label in the spaces provided by site personnel at the 
time of assignment to patient. Site personnel must ensure that patients clearly understand the guidelines 
for self-medication.  Patients should be given a sufficient supply to last until their next study visit.  Unused 
drug and/or empty bottles should be returned to the site at the next study visit.   
If you have questions contact: ____________________ Telephone: _____________________ 
Special instructions: 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 
Time: 
_______ 
 
Time: 
 
 
 
 

 
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18.2 
Patient Drug Information Handout and Wallet Card 
  
Information for Patients, Their Caregivers and Non-Study Healthcare Team on 
Possible Interactions with Other Drugs and Herbal Supplements  
 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to 
the patient at the time of enrollment.  Use or modify the text as appropriate for the study 
agent, so that the patient is aware of the risks and can communicate with their regular 
prescriber(s) and pharmacist.  A convenient wallet-sized information card is also included 
for the patient to clip out and retain at all times.  If you choose to use them, please note 
that the information sheet and wallet card will require IRB approval before distribution to 
patients.] 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental study drug ABT-888 (veliparib).  This clinical trial is sponsored by the 
National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
ABT-888 (veliparib) interacts with certain transporter proteins that help move drugs in 
and out of cells. 
 
• 
The proteins in question are OCT2, MATE1, MATE2K, and P-gp.  ABT-888 
(veliparib) is a substrate of P-gp, OCT2, and MATE1/2K and may be affected by 
other drugs that inhibit these protein transporters. ABT-888 is an inhibitor of 
OATP1B1, OATP1B3, MATE1/2K, OAT1/3and OCT1 and may affect transport of 
other drugs in and out of cells.  
 
To the patient: Take this paper with you to your medical appointments and keep the 
attached information card in your wallet.   
 
ABT-888 (veliparib) may interact with other drugs which can cause side effects.  For this 
reason, it is very important to tell your study doctors of any medicines you are taking 
before you enroll onto this clinical trial.  It is also very important to tell your doctors if you 
stop taking any regular medicines, or if you start taking a new medicine while you take 
part in this study.  When you talk about your current medications with your doctors, include 
medicine you buy without a prescription (over-the-counter remedy), or herbal 
supplements such as St. John’s Wort.  It is helpful to bring your medication bottles or an 
updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care 
providers (doctors, physician assistants, nurse practitioners, or pharmacists) you are 
taking part in a clinical trial.  
 
These are the things that you and they need to know:  
 
Use caution when administering ABT-888 (veliparib) with other medicines that need 
certain transport protein to be effective or to be cleared from your system.  Before 
you enroll onto the clinical trial, your study doctor will work with your regular health care 
providers to review any medicines and herbal supplements that are considered “strong 
inducers/inhibitors of P-gp, OCT2, and MATE1/2K. 
 
• 
Please be very careful!  Over-the-counter drugs (including herbal supplements) 
may contain ingredients that could interact with your study drug.  Speak to your 

 
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doctors or pharmacist to determine if there could be any side effects.  
• 
Your regular health care provider should check a frequently updated medical 
reference or call your study doctor before prescribing any new medicine or 
discontinuing any medicine.  Your study doctor’s name is _______________ and 
can be contacted at___________________________. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY DRUG INFORMATION WALLET CARD   
 
STUDY DRUG INFORMATION WALLET CARD   
 
You are enrolled on a clinical trial using the experimental study drug ABT-
888 (veliparib).  This clinical trial is sponsored by the NCI.      ABT-888 
(veliparib) may interact with drugs that need certain transport proteins in 
your body.  Because of this, it is very important to: 
➢ Tell your doctors if you stop taking any medicines or if you start taking 
any new medicines. 
➢ Tell all of your health care providers (doctors, physician assistants, nurse 
practitioners, or pharmacists) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
Use caution as ABT-888 (veliparib) may interact with medicines that 
stop transport proteins MATE1/2K, OCT2, and P-gp to process 
further in the body.  
➢ 
Before you enroll onto the clinical trial, your study doctor will 
work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong 
inducers/inhibitors of P-gp, MATE1/2K, and OCT2.” 
➢ Before prescribing new medicines, your regular prescribers 
should go to a frequently-updated medical reference for a list of 
drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is ________________________  
and can be contacted at _________________________. 

 
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18.3 
New York Heart Association Criteria 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
* To control or relieve symptoms, as determined by the patient, rather than as advised by the physician. 
** At accustomed occupation or usual tasks. 
 
 
 

 
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18.4 
Translational Medicine: HRD and BROCA-HR 
 
 
 
 
 
 
a. 
HRD Assay 
 
Tumor Homologous Recombination Deficiency (HRD) assay and somatic BRCA 
mutation testing will be done simultaneously as part of one single test.  
 
In addition to BRCA1 and BRCA2, there are many additional homologous 
recombination-related genes that may be altered by mutation, rearrangement, 
DNA methylation or mRNA expression that are hypothesized to result in 
impairment of the homologous recombination pathway.  A Homologous 
Recombination Deficiency (HRD) assay has been developed by Myriad Inc., which 
evaluates three different types of genomic “scarring” (LOH (the number of regions 
of loss of heterozygosity (LOH) that are longer than 15 Mb but shorter than a whole 
chromosome), TAI (the number of regions of allelic imbalance that start at the 
subtelomere and do not cross the centromere), and LST (the number of 
breakpoints between different regions which are both longer than 10 Mb)). High 
levels of these genomic “scars” are an indicator of HR deficiency and thus allows 
for the detection of homologous recombination deficiency regardless of its etiology 
or mechanism. The assay is compatible with FFPE tumor tissue, requires 50-200 
ng of tumor DNA and has high sensitivity for identification of BRCA-deficient 
tumors. (
1,2,3) 
 
Results of the HRD assay and somatic BRCA mutation testing will not be provided 
to the treating physicians or the patients.  
 
Laboratory conducting the assay:  
Myriad Laboratory Inc  
320 Wakara Way, Salt Lake City, UT 84108  
Attention: 
 M.D. and 
 Ph.D. 
CLIA ID No: 
 
Expiration: 8/14/15 
Purpose 
Specimens 
Sites to Ship 
to 
Laboratory 
Performing Testing 
Funding 
BROCA-
HR 
(including 
BRCA1 
& 
BRCA2) 
• Archival 
tissue: 
two 
10-micron 
slides 
• Pre-treatment 
tissue: four 10-
micron slides 
• 7mL whole blood 
(Bank to process 
PBMCs for DNA) 
SWOG 
Specimen 
Repository 
– 
Solid 
Tissue, 
Myeloma, and 
Lymphoma 
Division #201 
 Lab 
University 
of 
Washington 
1959 NE Pacific St,  
Health 
Science 
Building, K154 
Seattle, WA 98195 
Phone: 
 
BIQSFP to fund 
biopsy and tumor 
BRCA1 and 
BRCA2 analysis 
 
Pharmaceutical 
Company 
(Abbvie) to fund 
the exploratory 
BROCA-HR 
assays (BROCA-
HR excluding 
BRCA1 and 
BRCA2) 
HRD 
Pre-treatment 
tissue: 
• One 
5-micron 
H&E 
charged 
slide 
• Five to ten 10-
micron slides 
Specimen 
Repository 
– 
Solid 
Tissue, 
Myeloma, and 
Lymphoma 
Division #201 
Myriad 
Laboratory 
Inc. 
320 Wakara Way 
Salt Lake City, UT 
84108 
Pharmaceutical 
Company 
(Myriad) 

 
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Description of the assay:  
Extraction of DNA from FFPE tumors: A 5 micron H&E slide will be reviewed by 
a pathologist to facilitate enrichment of tumor derived DNA. Ten micron sections 
will be cut and regions of highest tumor cell density will be scraped from the slide. 
For DNA extraction, the Promega Maxwell 16 FFPE Plus LEV DNA purification kit 
(Promega, Madison, WI) will be used. Tissue will be incubated overnight at 56 
degrees Celsius with proteinase K in a shaking heat block.  After the overnight 
incubation undigested material is spun out and the Maxwell cartridges are loaded. 
gDNA will be eluted in 60 ul of low TE. 
 
Hybridization capture and sequencing: A custom capture panel will be used 
targeting 54,091 SNPs. 50 – 200 ng of genomic DNA will be sheared to an average 
size of 150 base pairs on a Covaris E220 focused ultrasonicator. Sheared DNA 
end repair, A-base tailing, and adapter ligation reactions and indexed library 
amplification will be performed according to manufactures recommendations 
(Kapa Biosystems, cat. # KK8200).  Kapa HiFi PCR will be performed for 6 cycles 
with the following cycling parameters: 98°C for 45 seconds; 8 cycles of 98°C for 
15 seconds, 60°C for 30 seconds, 72°C for 30 seconds; 72°C for 1 minute.  
Genomic libraries will then pooled at an equal molar ratio and hybridized with the 
SureSelectxt2 capture library according to manufactures recommendations 
(Agilent Technologies, cat. # 5190-4867).  Post hybridization amplification will then 
performed on pooled indexed libraries using Kapa HiFi PCR for 8 cycles with the 
following parameters: 98°C for 45 seconds; 8 cycles of 98°C for 15 seconds, 60°C 
for 30 seconds, 72°C for 30 seconds; 72°C for 1 minute.  Libraries will be quantified 
on an Agilent 2200 TapeStation, normalized to 2nM, and denatured using 0.1 
NaOH prior to sequencing.  Sequencing will be performed on an Illumina HiSeq 
2500 according to manufacturer’s protocols (Illumina). 
 
Tumor BRCA1 and BRCA2 mutation screening: Sequence reads generated on 
the HiSeq2500 are trimmed at both the start and end to remove low quality bases 
that could generate spurious variant calls. To call variants each read is aligned 
with the expected wild-type sequence of the exon. This alignment is a pairwise 
alignment performed by JAligner (http://jaligner.sourceforge.net/). Any differences 
represent variants. Variant calls from all reads for a sample are compiled in order 
to calculate the frequencies of all identified variants. Mutation Sequencing does 
not differentiate between germline and somatic mutations.  Specifically, we are not 
assessing for inherited BRCA1 and 2 mutations. 
 
b. 
BROCA-HR Assay including BRCA1 and BRCA2 Testing 
 
BRCA1 and BRCA2 testing  
 
BRCA1 and BRCA2 (BRCA1/2) are tumor suppressor genes, in which inherited 
loss-of-function mutations confer a higher lifetime risk of breast and ovarian 
carcinoma, as well as an increased risk of pancreatic adenocarcinoma 
(standardized incidence ratios (SIR) 3.5-5.8 for BRCA2, and SIR 4.1 for BRCA1 
mutations, respectively). (4,5,6,7) BRCA1/2 are key components of the BRCA-
Fanconi anemia (FA) pathway, which is critical to homologous recombination (HR)-
mediated DNA repair. 
 
PARP enzymes recognize DNA damage and facilitate DNA repair to maintain 
genomic stability. Preclinical studies demonstrate that PARP inhibition in the 
presence of BRCA deficiency leads to synthetic lethality. (8) PARP inhibitors (i) 
have shown preclinical and clinical activity in targeting tumors with pre-existing 
DNA repair defects, in particular BRCA1 and BRCA2 deficient advanced breast, 
ovarian, and pancreatic tumors. (9,10,11,12,13,14,15,16,17,18) 
 

 
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In addition to BRCA1/2 mutations, many genes involved in homologous 
recombination may be altered by mutation, rearrangement, DNA methylation or 
attenuated mRNA expression and can result in impairment of the HR pathway. It 
is speculated that if other factors beyond germline BRCA mutations are 
comprehensively evaluated, 20-25% of pancreatic cancers will demonstrate HR 
deficiency (HRD phenotype) or BRCAness. (19,20)  
 
Preclinical evidence suggests that MLH1 loss, RAD51 mutations, and ERCC1 loss 
may particularly enhance cytotoxicity from PARP inhibition plus irinotecan/SN38 
combination. (21,22,23) It is not yet known whether BRCA1/2 mutations will 
sensitize pancreatic cancer to treatment with irinotecan and PARP inhibitors. 
 
The secondary aim of this randomized Phase II study is to investigate whether the 
addition of a PARP inhibitor (ABT-888) to irinotecan-based therapy (mFOLFIRI) 
will improve response, progression free survival (PFS), and overall survival (OS) 
for patients with germline or somatic BRCA1/2 mutation-associated pancreatic 
cancers. Thus, gBRCA1/2 and somatic tumor BRCA1/2 testing for the entire study 
cohort is an essential integrated biomarker.  
 
Exploratory translational aims will assess whether BRCAness or HRD phenotype 
(by BROCA-HR and the HRD assay described previously in Section 18.4a) 
correlate with response, PFS and OS in each treatment arm. 
 
The current design for BROCA-HR includes the following genes (n=75): 
 
a. 
FA-BRCA HR pathway: ATM, ATR, BABAM1, BAP1, BARD1, BLM, 
BRCA1, BRCA2 (FANCD1), BRIP1 (FANCJ), BRCC3, BRE, CHEK1, 
CHEK2, 
ERCC1, 
ERCC4 
(FANCQ), 
FAM175A 
(abraxas), 
FANCA,FANCB, 
FANCC, 
FANCD2, 
FANCE, 
FANCF, 
FANCG 
(XRCCC9), FANCI, FANCL, FAMCM, GEN1,MRE11A, NBN, PALB2 
(FANCO), RAD50, RAD51C (FANCO), RAD51D, RBBP8 (CtIP), SLX4 
(FANCP), UIMC1 (RAP80), XRCC2  
b.   
DNA mismatch repair MLH1, MSH2 (and EPCAM), MSH6, PMS2  
c.    
Other DNA repair, surveillance genes, or modifier genes: CDK12, CDH4,  
HELQ, NEIL1, PPM1D, POLD1, POLE, RIF1, TP53, ID4, PAXIP1, POLQ, 
RINT1, TP53BP1, USP28, WRN, XRCC3  
d.    
NER genes: ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, DDB1, XPA, 
XPC  
e.    
NHEJ genes: DCLRE1C, LIG4, PRKDC, TOBP1, XRCC4, XRCC5, 
XRCC6  
f.    
PI3K pathway: PTEN, PI3KCA 
 
A common characteristic of “genomic scarring” is large (>15Mb) but sub-
chromosomal deletions. Therefore, fine mapping of loss of heterozygosity (LOH) 
is not necessary to identify the HRD genomic scar. We tested the theoretical ability 
of 3000 SNPs to define “genomic scarring” in existing TCGA ovarian cancer data 
(unpublished data). Indeed, using only 3000 SNPs can define cases with high LOH 
which have better prognosis. Combining the BROCA-HR mutational status and the 
LOH profile provides additional prognostic information. S1513 will assay 3000 
SNPs with the same BROCA-HR mutational assay which will provide an LOH 
profile to assess genomic scarring as an exploratory biomarker. We will then 
combine the mutation information from BROCA combined biomarker as outlined 
in Figure 18.4b, with the prediction that HR proficient cancers would achieve no 
significant benefit from the addition of PARPi. 
 

 
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Description of the specimens, and anticipated methods for specimen 
acquisition and processing: 
Specimen collected for germline and somatic BRCA1/2 testing will be utilized for 
testing of the non-BRCA BROCA-HR genes including genomic LOH “scarring” 
phenotype and added specimen will not be needed.  
 
-FFPE Slides archival tumor: 2 consecutive unstained 10 micron slides, minimum 
20% tumor 
-FFPE Slides pre-treatment tumor: 4 consecutive unstained 10 micron slides, 
minimum 20% tumor 
-7mL whole blood 
 
Tumor Tissue: DNA will be extracted from FFPE tumor tissue containing at least  
20% tumor nuclei. A targeted capture and massively parallel sequencing approach 
called BROCA will be applied to samples. Library preparation has been fully 
automated to increase sample turnaround and lower cost. Paired-end libraries with 
350bp inserts will be prepared from 1g of constitutional DNA and hybridize to a 
custom pool of oligonucleotides targeting genomic regions as previously described 
using the SureSelectXT enrichment system on a Bravo liquid-handling instrument 
(Agilent). (96) Following capture, samples will be barcoded with 48 different 
indexed primers. The pooled samples are sequenced on a single lane of a HiSeq 
flowcell (Illumina) with 2x101bp paired end reads and a 7bp index read to allow for 
de-multiplexing and binning of individual samples. Single nucleotide variants and 
insertions and deletions will be detected as previously described with some 
updates in the bioinformatics pipeline. (24,25) Deletions and duplications of exons 
will be detected by a combination of depth of coverage and split read analysis as 
previously described, supplemented with additional alignments generated by 
SLOPE. (26,27) All loss of function mutations in cancer susceptibility genes will be 
confirmed with PCR amplification and Sanger sequencing. 
 
Tumor specimens should be shipped at room temperature to the SWOG repository 
(Nationwide). Specimens will be stored at the SWOG repository at room 
temperature until ready to be shipped to 
Laboratory for analysis. 
 
Blood: 7ml whole blood 
Minimum Volume: 3.5 mL 
Instructions: Collect in yellow top (ACD solution A) tube. Specimen to be shipped 
at ambient temperature for overnight delivery. 
Specimen Stability: Room temperature: 3 days; Refrigerated: N/A; Frozen: N/A 
Specimen processing: DNA will be extracted from peripheral blood mononuclear 
cells (PBMCs). The targeted capture and parallel sequencing BROCA-HR 
described above will be used 
 
The results will be reported as deleterious somatic and/or germline BRCA mutation 
“present” or absent. Variants of uncertain significance will not be reported. 
 

 
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The expected distribution of the biomarker in the study population: 
It is estimated that 7-10% of the study population will demonstrate deleterious 
germline or somatic BRCA1/2 mutations. Cutpoints will not be used for BRCA 
testing. Test results will be described as deleterious germline or somatic mutation 
“present” or “absent”. In gBRCA or somatic BRCA mutation-positive patients 
median PFS of 3 months is assumed for Arm 2 (FOLFIRI) that improves to 5 
months for Arm 1 (mFOLFIRI + ABT-888). 
 
It is estimated that 20-25% of the study population will demonstrate germline or 
somatic alterations in other BROCA-HR panel genes or evidence of “genomic 
scarring” by SNPs analysis.  
 
The accessibility of the biomarker assay results: 
Clinically significant germline BRCA and BROCA-HR testing reports will be 
provided to the treating physician. Genetic counselling and discussion of results 
with patient are the responsibility of the treating physician. 
 
Data on the analytical performance of the assay for BRCA1/2 mutations: 
Accuracy and precision BROCA HR captures > 99% of known deleterious BRCA1 
and 2 Mutations. (28) Deleterious BRCA1 and BRCA2 mutations will be defined in 
the standard fashion to include protein truncating mutations (with the exception on 
the benign variant BRCA2 K3326*), and missense mutations demonstrated 
experimentally to be damaging. Both “BIC”, and “HGVS” nomenclatures will be 
used to report the deleterious mutations. Variants of uncertain significance will not 
be reported. 
Turn-around time: 4-8 weeks 
Failure rate: < 1%.  (29) 
 
Data on the analytical performance of the assay for BROCA-HR:  
Accuracy and precision BROCA HR captures > 99% of known deleterious germline 
mutations in the FA-BRCA HR, DNA mismatch repair, NER, NHEJ pathways, and 
surveillance and modifier genes of interest previously listed. (126) 
 
Reportable range, reference ranges/intervals (normal values): Deleterious 
mutations will be defined in the standard fashion to include protein truncating 
mutations, and missense mutations demonstrated experimentally to be damaging. 
Both “BIC” and “HGVS” nomenclatures will be used to report the deleterious 
mutations. Variants of uncertain significance will not be reported. 
Turn-around time: 12 weeks 
Failure rate: < 1%. (30) 
 
Discrepancy between prior germline BRCA testing and trial testing:  
Although germline BRCA testing may have been previously performed  for some 
pancreatic cancer patients with strong family history of breast/ovarian cancer 
syndrome or family history of pancreatic cancer, we expect that <10% of patients 
will have had prior testing.  We expect to find a deleterious BRCA mutation via the 
BROCA test in small percentage (< 2%) of patients who have had a prior negative 
BRCA test. This will be typically due to missed gene-disrupting large 
rearrangements. With the BROCA test, the chances of not detecting a previously 
known deleterious BRCA mutation are virtually nil (centralized BRCA testing has 
been done by BROCA-HR on >3000 cancer patients on clinical trials, and all 
previously known BRCA mutations were detected, personal communication Dr. 
). 
 
BROCA-HR testing which includes BRCA1/2 will be done post randomization for 
all patients. 
 
 

 
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Laboratory conducting the BROCA-HR assay:  
 
, MD 
Professor, Dept Ob/Gyn 
University of Washington 
1959 NE Pacific St 
Seattle, WA 98195 
 
 
Laboratory: 
 Lab 
University of Washington 
1959 NE Pacific St,  
Health Science Building, K154 
Seattle, WA 98195 
 
CLIA ID No: 
 
Expiration: 9/27/2019 
 
 
 

 
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18.4 Bibliography  
1  
Abkevich V, Timms KM, Hennessy BT, Potter J, Carey MS, Meyer LA, et al. Patterns of genomic 
loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. 
Br J Cancer 107:1776-82. PMID: 23047548, 2012. 
 
2  
Timms KM, Abkevich V, Hughes E, Neff C, Reid J, Morris B, et al. Association of BRCA1/2 defects 
with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. 
Breast Cancer Res 16:475. PMID: 25475740, 2014. 
 
3  
Telli M, Jensen KC, Abkevich V, et al. Homologous recombination deficiency (HRD) score predicts 
pathologic response following neoadjuvant platinum-based therapy in triple negative and BRCA1/2 
mutation-associated breast cancer. Cancer Re 72:PD09-04, 2012. 
4  
Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25:1329-33, 
2007. 
 
5  
The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer 
Inst 91:1310-1316, 1999. 
 
6  
Mersch J, Jackson MA, Park M, et al. Cancers associated with BRCA1 and BRCA2 mutations other 
than breast and ovarian. Cancer 121(2):269-75. Doi:10.1002/cncr.29041, 2015. 
 
7  
Mocci E, Milne RL. Mendez-Villamil EY, et al Risk of pancreatic cancer in breast cancer families 
from the Breast Cancer Family Registry. Cancer Epidemiol Biomarkers Prev 22(5): 803-811, 2013. 
 
8  
Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for 
the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 26:3785-90, 
2008. 
 
9  
Kaufman B, et al.,Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 
mutation. J Clin Oncol 33(3): p. 244-50, 2015. 
 
10  
Lowery MA KD. Smith C, et al. Phase II trial of veliparib in patients with previously treated BRCA 
or PALB2 mutated pancreas adenocarcinoma. in Gastrointestinal Cancers Symposium J Clin 
Oncol, 2015. 
 
11  
Audeh M, Carmichael J, Penson R, et al: Oral poly (ADP-ribose) polymerase inhibitor olaparib in 
patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. 
The Lancet 376:245-251, 2010. 
 
12  
Bryant H, Schultz N, Thomas H, et al. Specific killing of BRCA2-deficient tumours with inhibitors of 
poly(ADP-ribose) polymerase. Nature 434:913-917, 2005. 
 
13  
Farmer H, McCabe N, Lord C, et al. Targeting the DNA repair defect in BRCA mutant cells as a 
therapeutic strategy. Nature 434:917-21, 2005. 
 
14  
Fong P, Boss D, Yap T, et al. Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA 
mutation carriers. N Engl J Med 361:123-34, 2009. 
 
15  
Tutt A, Robson M, Garber J, et al: Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients 
with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of concept trial. The Lancet 
376:235-244, 2010. 
 
16  
Mina L, et al. BMN673 is a PARP inhibitor in clinical development for the treatment of breast cancer 
patients with deleterious germline BRCA1 and 2 mutations. San Antonio Breast Cancer 
Symposium, 2013. 
 
 

 
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17  
Sandhu S, Schelman W, Wilding G, et al. The poly(ADP-ribose) polymerase inhibitor niraparib 
(MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation 
trial. Lancet Oncol Aug; 14(9): 882-92, 2013. 
 
18  
Shen Y, Rehman F, Feng Y, et al: BMN 673, a novel and highly potent PARP1/2 inhibitor for the 
treatment of human cancers with DNA repair deficiency. Clin Cancer Res 19:5003-15, 2013. 
19  
Biankin AV, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. 
Nature 491(7424): p. 399-405, 2012. 
 
20  
Waddell N, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 
518(7540): p. 495-501, 2015. 
 
21  
Tentori L, Leonetti C, Muzi A, et al. Influence of MLH1 on colon cancer sensitivity to poly(ADP-
ribose) polymerase inhibitor combined with irinotecan. Int J Onco 43(1): 210-218. Doi: 
10.3892/ijo.2013.1932, 2013. 
 
22  
Tahara M, Inoue T, Sato F, et al. The use of Olaparib (AZD2281) potentiates SN-38 cytotoxicity in 
colon cancer cells by indirect inhibition of Rad51-mediated repair of DNA double-strand breaks. 
Mol cancer Ther 13(5):1170-80. Doi: 10.1158/1535-7163, 2014. 
 
23  
Zhang YW, Regairaz M, Seler JA, ey al. Poly(ADP-ribose) polymerase and XPF-ERCC1 participate 
in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells. 
Nucleic Acids Res 39(9): 3607-3620. Doi 10.1093, 2011. 
 
24  
Bouwman P, Aly A, Escandell JM, et al. 53BP1 loss rescues BRCA1 deficiency and is associated 
with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol;17:688-95, 2010. 
 
25  
Pritchard CC, Smith C, et al. ColoSeq Provides Comprehensive Lynch and Polyposis Syndrome 
Mutational Analysis Using Massively Parallel Sequencing. J Mol Diagn 14(4): 357-366, 2012. 
 
26  
Bouwman P, Aly A, Escandell JM, et al. 53BP1 loss rescues BRCA1 deficiency and is associated 
with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol;17:688-95, 2010. 
 
27  
Pritchard CC, Salipante SJ, et al. Validation and implementation of targeted capture and 
sequencing for the detection of actionable mutation, copy number variation, and gene 
rearrangement in clinical cancer specimens. J Mol Diagn: 16(1): 56-67, 2014. 
 
28  
Walsh T, Lee M, Casadei S, et al: Detection of inherited mutations for breast and ovarian cancer 
using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A 107:12629-
33, 2010. 
 
29  
Walsh T, Casadei S, Lee M, et al. "Mutations in 12 genes for inherited ovarian, fallopian tube, and 
peritoneal carcinoma identified by massively parallel sequencing." Proc Natl Acad Sci USA. 2011. 
 
30  
Walsh T, Casadei S, Lee M, et al. "Mutations in 12 genes for inherited ovarian, fallopian tube, and 
peritoneal carcinoma identified by massively parallel sequencing." Proc Natl Acad Sci USA. 2011.