Clinical trial NCT02305758
Conditions: Untreated Metastatic Colorectal Cancer
Keywords: PARP inhibitor veliparib metastatic colorectal cancer ABT-888 first line previously untreated colorectal cancer colon cancer rectal cancer FOLFIRI fluorouracil 5-FU leucovorin irinotecan
Sponsor: AbbVie
Start date: 2014-12-02; Completion date: 2017-09-22
Enrollment: 130 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a blinded, randomized, placebo-controlled Phase 2 multicenter study evaluating the efficacy and tolerability of veliparib plus irinotecan, fluorouracil, and leucovorin chemotherapy regimen (FOLFIRI) compared to placebo plus FOLFIRI in participants with previously untreated metastatic colorectal cancer. Participants could also have been treated with bevacizumab at the discretion of the Investigator.

Detailed description:
Participants were randomized to one of 2 groups: veliparib plus FOLFIRI ± bevacizumab (veliparib group) or placebo plus FOLFIRI ± bevacizumab (placebo group), and stratified by planned use of bevacizumab (planned bevacizumab use compared to unplanned use of bevacizumab) and regions of the world (North America versus rest of world). In this study, the term FOLFIRI was used to describe both the standard regimen containing a fluorouracil bolus that was administered to participants randomized to the placebo arm, and a modified regimen with a saline bolus that was administered to participants randomized to the veliparib arm. One cycle of protocol therapy consisted of 14 days, defined as Day -2 through Day 12. Dosing of oral veliparib/placebo began 2 days prior to the start of FOLFIRI and continued twice a day for a total of 7 consecutive days. At the discretion of the Investigator, bevacizumab could be administered intravenously immediately preceding FOLFIRI. Study visits were conducted on Day 1 and Day 8 of the first and second cycles, then on Day 1 of each subsequent cycle. Participants were to continue protocol therapy and study visits until they met one of the defined discontinuation criteria. When the Investigator determined that a participant met the criteria for discontinuation, a final visit was conducted. Participants were to have had one follow-up visit approximately 30 days after the last dose of protocol therapy. Sites began collecting post-treatment and survival information 4 weeks after the last clinical assessment. Post-baseline radiographic tumor assessment was to be conducted every 8 weeks from Cycle 1, Day 1 (prior to the start of a new cycle) until radiographic progression.

Arms: arm 1: Dosing of oral veliparib (200 mg) began 2 days prior to the start of FOLFIRI and continued twice a day (BID) for a total of 7 consecutive days. At the discretion of the Investigator, bevacizumab (5 mg/kg) could be administered intravenously (IV) immediately preceding FOLFIRI. Modified FOLFIRI was administered as irinotecan 180 mg/m\^2 (90-minute infusion ± 30 minutes); leucovorin 400 mg/m\^2 (90-minute infusion ± 30 minutes); and saline bolus (up to 15-minute infusion) immediately followed by fluorouracil 2400 mg/m\^2 (46-hour continuous infusion ± 4 hours) starting on Day 1 of each 14-day cycle. arm 2: Dosing of oral placebo (200 mg) began 2 days prior to the start of FOLFIRI and continued twice a day (BID) for a total of 7 consecutive days. At the discretion of the Investigator, bevacizumab (5 mg/kg) could be administered intravenously (IV) immediately preceding FOLFIRI. Standard FOLFIRI was administered as irinotecan 180 mg/m\^2 (90-minute infusion ± 30 minutes); leucovorin 400 mg/m\^2 (90-minute infusion ± 30 minutes); and fluorouracil bolus 400 mg/m\^2 (up to 15-minute infusion) immediately followed by fluorouracil 2400 mg/m\^2 (46-hour continuous infusion ± 4 hours) on Day 1 of each 14-day cycle.
Interventions: intervention 1: Veliparib intervention 2: Placebo intervention 3: Modified FOLFIRI intervention 4: FOLFIRI intervention 5: Bevacizumab intervention 6: Fluorouracil infusion
Intervention descriptions: intervention 1: 200 mg oral dose beginning 2 days prior to the start of FOLFIRI and continuing twice a day (BID) for a total of 7 consecutive days intervention 2: 200 mg oral dose beginning 2 days prior to the start of FOLFIRI and continuing twice a day (BID) for a total of 7 consecutive days intervention 3: Irinotecan 180 mg/m\^2 (90-minute infusion ± 30 minutes); leucovorin 400 mg/m\^2 (90-minute infusion ± 30 minutes); and saline bolus (up to 15-minute infusion) on Day 1 of each 14-day cycle intervention 4: Irinotecan 180 mg/m\^2 (90-minute infusion ± 30 minutes); leucovorin 400 mg/m\^2 (90-minute infusion ± 30 minutes); and fluorouracil bolus 400 mg/m\^2 (up to 15-minute infusion) on Day 1 of each 14-day cycle intervention 5: At the discretion of the Investigator, 5 mg/kg may be administered intravenously immediately preceding FOLFIRI dosing intervention 6: 2400 mg/m\^2 (46-hour continuous infusion ± 4 hours) starting on Day 1 of each 14-day cycle

Protocol documents:
Prot_000.pdf: 
Veliparib
M14-217 Protocol Amendment 2
EudraCT 2014-002866-65
1
1.0
Title Page
Clinical Study Protocol M14-217
Randomized, Blinded, Multicenter, Phase 2 Study 
Comparing Veliparib Plus FOLFIRI ± Bevacizumab 
Versus Placebo Plus FOLFIRI ± Bevacizumab in 
Previously Untreated Metastatic Colorectal Cancer
Incorporating Amendments 1 and 2
AbbVie Investigational
  Product:
Veliparib (ABT-888)
Date:
16 July 2015
Development Phase:
2
Study Design:
Randomized, Blinded, Multicenter, Phase 2 Study Comparing 
Veliparib Plus FOLFIRI ± Bevacizumab Versus Placebo Plus 
FOLFIRI ± Bevacizumab in Previously Untreated Metastatic 
Colorectal Cancer
EudraCT Number:
2014-002866-65
Investigator:
Multicenter Trial: Investigator information is on file at AbbVie
Sponsor:
AbbVie Inc.*
*The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
/$5


Veliparib
M14-217 Protocol Amendment 2
EudraCT 2014-002866-65
2
1.1
Protocol Amendment:  Summary of Changes
The purpose of this amendment is to:
●
Update contact information for the AbbVie Study Designated Physician.
Rationale:  Change in Study Designated Physician assigned to the trial.
●
Provide timing windows around the infusion duration of fluorouracil, 
irinotecan, leucovorin and bevacizumab.
Rationale:  To allow reasonable flexibility in the administration of protocol 
therapy.
●
Section 1.2, Synopsis, add bevacizumab as a reference therapy in the table.
Rationale: Bevacizumab was missing in the previous version of the protocol.
●
Section 1.2, Synopsis, and Section 5.2.2, Exclusion Criteria, clarify that 
Exclusion Criterion 3 pertains to neoadjuvant chemotherapy in addition to 
adjuvant therapy and change "prior to colorectal cancer recurrence" to "prior to 
C1D–2."
Rationale:  To remove ambiguity around the timing of treatment and to 
increase uniformity of elapsed time between prior treatment and study entry, 
as time to recurrence could be subjective/unknown in many cases.
●
Section 1.2, Synopsis, and Section 5.2.2, Exclusion Criteria, add a definition to 
symptomatic congestive heart failure.
Rationale:  Clarify what constitutes as clinically significant using a 
well-established classifier.
●
Section 3.8, Clinical Experience, correct inaccurate adverse event frequencies 
from Study M10-977, Phase 1 dose escalation study.
Rationale:  Incorrect information was included in the previous version of the 
protocol.
●
Section 5.1, Overall Study Design and Plan:  Description, update Figure 1 to 
reflect that subjects will receive either fluorouracil or saline bolus and 
illustrate that the 46-hour 5-FU infusion will continue into Day 3.
Rationale:  The option of a saline bolus was missing from the figure.


Veliparib
M14-217 Protocol Amendment 2
EudraCT 2014-002866-65
3
●
Section 5.1, Overall Study Design and Plan:  Description, and Section 5.4.5, 
Timing and Collection of Survival and Post-Treatment Cancer Information, 
clarify that the survival information and post-treatment cancer information will 
be collected beginning 4 weeks after the last clinical assessment.
Rationale:  The previous version of the protocol noted "after the last study 
visit" which could be interpreted as the Final Visit or the Follow-up Visit.
●
Section 5.3.1, Efficacy and Safety Measurements Assessed and Flow Chart, 
remove physical exam requirement at C1D1.
Rationale:  From a medical perspective, the physical exam at C1D–2 is 
sufficient for this population.
●
Section 5.3.1.1, Study Procedures, clarify that RAS, BRAF and MSI status 
only need to be captured in Medical History if known.
Rationale:  Not all sites perform these tests as part of their standard of care.
●
Section 5.3.1.1, Study Procedures, Table 7, Clinical Laboratory Tests, update 
clinical chemistry terminology.  
Rationale:  To standardize medical terminology for clinical labs and comply 
with the current protocol template.
●
Section 5.3.2.1, Blood Samples for Pharmacokinetic Analysis, update the 
information that is to be captured.
Rationale:  Clarify that the date and time of sample collection, the date and 
time of the veliparib/placebo dose on PK sampling days and the date and time 
of the two doses of veliparib/placebo prior to PK sampling on C2D1 and 
C3D1 will be captured.
●
Section 5.3.2.2, Measurement Methods, revise "non-GLP" to "non-validated."
Rationale:  To clarify the meaning of "non-GLP."
●
Section 5.3.2.3, Blood Samples for Pharmacogenetic Analysis, revise the label 
for the pharmacogenetic sample collection tube from "PG-DNA" to "PG-DNA 
blood."
Rationale:  To comply with the current protocol template.
●
Section 5.3.7, Pharmacodynamic Variables, and Section 5.4, Removal 
(Discontinuation) of Subjects from Protocol Therapy and Study Visits, update 
storage and retention language for the pharmacodynamics samples.


Veliparib
M14-217 Protocol Amendment 2
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4
Rationale:  To ensure consistency with the template language and align with 
the informed consent.
●
Section 5.4, Removal (Discontinuation) of Subjects from Protocol Therapy 
and Study Visits, update language regarding consent withdrawal and the 
pharmacodynamic samples.
Rationale:  To ensure consistency with the template language.
●
Section 5.5.1, Protocol Therapy Administered, specify that sites can use their 
own method for calculating body surface area (BSA), and dose re-calculations 
must be made if a subject's weight increases or decreases by more than 10%.
Rationale:  To allow reasonable flexibility in the administration of protocol 
therapy.
●
Section 5.5.1, Protocol Therapy Administered, update protocol therapy 
administration to allow for sequential infusion of irinotecan followed by 
leucovorin.
Rationale:  To address equipment shortages in European countries that 
preclude concurrent administration.
●
Section 5.5.9, Blinding, update language regarding unblinded AbbVie study 
personnel.
Rationale:  To clarify the role of unblinded internal study team members.
●
Section 6.7, Adverse Event Reporting, update information regarding reporting 
SAEs if the site does not have access to EDC or the system is not operable and 
update the 24-hour AbbVie Medical Escalation Hotline information.
Rationale:  To comply with the current protocol template.
●
Section 7.0, Protocol Deviations, update language regarding 
intentional/prospective deviations from the protocol.
Rationale:  To comply with the current protocol template.
●
Section 8.1.7, Interim Analysis, update interim analysis plan.
Rationale:  To clarify timing, scope and rationale of the two planned interim 
analyses.
●
Appendix I, Toxicity Management Guidelines for Protocol Therapy, update 
language regarding dose modifications and unresolved toxicity.


Veliparib
M14-217 Protocol Amendment 2
EudraCT 2014-002866-65
5
Rationale:  To clarify when dose modifications should be made with respect to 
timing of unresolved toxicity.
●
Additional minor corrections and clarifications.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix J.


Veliparib
M14-217 Protocol Amendment 2
EudraCT 2014-002866-65
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-217
Name of Study Drug:  Veliparib or ABT-888 
Phase of Development:  2
Name of Active Ingredient:  Not applicable 
Date of Protocol Synopsis:  16 July 2015
Protocol Title:  Randomized, Blinded, Multicenter, Phase 2 Study Comparing Veliparib Plus FOLFIRI 
± Bevacizumab Versus Placebo Plus FOLFIRI ± Bevacizumab in Previously Untreated Metastatic 
Colorectal Cancer
Objectives:  The primary objectives of the study are to assess whether the addition of oral veliparib to 
FOLFIRI will improve progression-free survival (PFS) in subjects with metastatic colorectal cancer 
(mCRC).  The secondary objectives of the study are to assess overall survival (OS), objective response 
rate (ORR), safety, and tolerability.  The tertiary objectives of the study are to assess duration of overall 
response (DOR) and performance status.
Investigators:  Multicenter
Study Sites:  Approximately 60
Study Population:  Subjects with metastatic adenocarcinoma of the colon or rectum who have not 
received prior chemotherapy for their mCRC.  Subjects must have at least one unresectable lesion that is 
measurable per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1.
Number of Subjects to be Enrolled:  Approximately 120
Methodology:  
This is a blinded, randomized, placebo-controlled study to evaluate the efficacy and tolerability of 
veliparib in combination with FOLFIRI ± bevacizumab (bevacizumab will be administered at the 
discretion of the Investigator) in previously untreated metastatic adenocarcinoma of the colon or rectum.  
Subjects will be randomized to one of two protocol therapy groups as follows:
a.
Veliparib plus FOLFIRI ± bevacizumab
b.
Placebo plus FOLFIRI ± bevacizumab
Note that for the purposes of this protocol, FOLFIRI is used to describe both the standard regimen 
containing a 5-FU bolus that will be administered to subjects randomized to the placebo arm, and a 
modified regimen with a saline bolus that will be administered to subjects randomized to the veliparib 
arm.  Randomization will be conducted to ensure that at least 60 subjects are enrolled in both the 
"planned bevacizumab use" group and "no planned bevacizumab use" group for a total of ~120 subjects.


Veliparib
M14-217 Protocol Amendment 2
EudraCT 2014-002866-65
7
Methodology (Continued):  
Protocol Therapy
For the purposes of this study, protocol therapy will be defined as veliparib/placebo in combination with 
FOLFIRI ± bevacizumab at the following dose levels.  One cycle of protocol therapy consists of 14 days, 
defined from Day –2 through Day 12.  Dosing of oral veliparib/placebo will begin 2 days prior to the start 
of FOLFIRI and will continue twice a day (BID) for a total of 7 consecutive days.  At the discretion of 
the Investigator, bevacizumab (5 mg/kg) may be administered intravenously immediately preceding 
FOLFIRI.  Subjects randomized to the veliparib arm will receive modified FOLFIRI as irinotecan 
180 mg/m2 (90 minute infusion ± 30 minutes); leucovorin 400 mg/m2 (90 minute infusion ± 30 minutes); 
saline bolus (up to 15 minute infusion) immediately followed by 5-FU 2400 mg/m2 (46-hour continuous 
infusion ± 4 hours) starting on Day 1 of each 14-day cycle.  Subjects randomized to the placebo arm will 
receive standard FOLFIRI as irinotecan 180 mg/m2 (90 minute infusion ± 30 minutes); leucovorin 
400 mg/m2 (90 minute infusion ± 30 minutes); 5-FU bolus 400 mg/m2 (up to 15 minute infusion) 
immediately followed by 5-FU 2400 mg/m2 (46-hour continuous infusion ± 4 hours) on Day 1 of each 
14-day cycle.  FOLFIRI is only to be given after veliparib/placebo dosing on cycle Day –2 and Day –1 
are confirmed.  Subjects should continue to follow the dosing schedule for protocol therapy until disease 
progression or other criteria for protocol discontinuation are met.
Study Visits and Study Discontinuation Criteria
Screening procedures and baseline radiographic tumor assessments will be performed within 28 days 
prior to the first dose of veliparib/placebo on C1D–2.  Study visits will be conducted on Day 1 and Day 8 
of the first and second cycle, then on Day 1 of each subsequent cycle.
Post-baseline tumor assessment will be conducted every 8 weeks from C1D1 (prior to the start of a new 
cycle) until radiographic progression.
Subjects with controlled disease (complete response [CR], partial response [PR], or stable disease [SD]) 
and with tolerable side effects may continue to receive protocol therapy until disease progression.
When the Investigator has determined that subject should discontinue protocol therapy, a Final Visit will 
be conducted.  All subjects will have one Follow-Up Visit approximately 30 days after the last dose of 
protocol therapy.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:
!
≥ 18 years of age;
!
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon or rectum;
!
At least 1 unresectable lesion on a CT scan that is measurable as defined by RECIST, Version 1.1;
!
ECOG performance score of 0 or 1;
!
Adequate hematologic, renal and hepatic function as follows:
o
Bone marrow:  Absolute Neutrophil count (ANC) ≥ 1,500/μL; Platelets ≥ 100,000/mm3; 
(independent of platelet transfusions within 3 months prior to starting protocol therapy); 
Hemoglobin ≥ 9.0 g/dL;
o
Renal function:  Serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥ 50 mL/min;
o
Hepatic function and enzymes:  Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) ≤ 2.5 × the upper limit of normal (ULN) of institution's normal range.  Subjects with liver 
metastases may have an AST and ALT of ≤ 5.0 × ULN;


Veliparib
M14-217 Protocol Amendment 2
EudraCT 2014-002866-65
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):  
o
Bilirubin:  ≤ 1.5 × the ULN of institution's normal range.
!
If female, subject must be postmenopausal for at least 1 year, surgically sterile (bilateral tubal 
ligation, bilateral oophorectomy or hysterectomy), or practicing at least one of the following methods 
of birth control until 90 days after the last dose of protocol therapy:
o
Total abstinence from sexual intercourse as the preferred life style of the subject; periodic 
abstinence is not acceptable;
o
Vasectomized partner(s);
o
Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior C1D–2 
(if the subject is currently using a hormonal contraceptive, she should also use a barrier method 
during the study and for 1 month after protocol therapy completion);
o
Intrauterine device (IUD);
o
Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with 
spermicidal jellies or creams).
!
If male, subject must be surgically sterile or practicing at least one of the following methods of 
contraception, from the initial protocol therapy administration until 90 days after the last dose of 
protocol therapy:
o
Partner(s) using IUD;
o
Partner(s) using hormonal contraceptives (oral, vaginal, parenteral or transdermal);
o
Subject and/or partner(s) using double-barrier method (condoms, contraceptive sponge, 
diaphragm, or vaginal ring with spermicidal jellies or creams);
o
Total abstinence from sexual intercourse as the preferred life style of the subject; periodic 
abstinence is not acceptable.
!
Subject must be capable of understanding and complying with parameters as outlined in the protocol 
and able to voluntarily sign and date an informed consent, approved by an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or 
study-specific procedures.
For Subjects Receiving Bevacizumab:
!
Blood pressure must be well controlled (< 160/90 mm Hg) on a stable regimen of anti-hypertensive 
therapy for at least 2 weeks.


Veliparib
M14-217 Protocol Amendment 2
EudraCT 2014-002866-65
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion:  
!
Prior anti-cancer treatment for metastatic colorectal cancer;
!
Prior exposure to PARP inhibitors;
!
The last course of adjuvant or neoadjuvant chemotherapy must have ended > 12 months prior to 
C1D–2;
!
Known Gilbert's Syndrome;
!
Prior radiotherapy to greater than 25% of bone marrow;
!
Prior radiotherapy ≤ 4 weeks of C1D–2;
!
Any type of major surgery ≤ 4 weeks of C1D–2;
!
Previous or concurrent malignancy except for adequately treated basal cell or squamous cell skin 
cancer, in situ cervical cancer, or other cancer for which the subject has been disease-free for 3 years;
!
Known hypersensitivity to irinotecan, 5-FU or leucovorin;
!
Clinically significant and uncontrolled major medical condition(s) including but not limited to:
o
Uncontrolled nausea/vomiting/diarrhea;
o
Active uncontrolled infection;
o
Symptomatic congestive heart failure (NYHA Class ≥ II);
o
Unstable angina pectoris or cardiac arrhythmia;
o
Psychiatric illness/social situation that would limit compliance with study requirements.
!
Predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated 
by baseline pattern of > 3 watery of soft stools daily.  Subjects with an ileostomy or colostomy may 
enter the study at the discretion of the Investigator;
!
Subject is pregnant or lactating;
!
Subject who requires parenteral nutrition, tube feeding or has evidence of partial bowel obstruction 
or perforation within 28 days prior to C1D–2;
!
Any medical condition, which in the opinion of the study Investigator, places the subject at an 
unacceptably high risk for toxicities.
!
Subject has received an investigational drug within the 28 days prior to Screening.
!
Any subjects will be excluded if prohibited from participation according to local laws or regulations.
For Subjects Receiving Bevacizumab:
!
Prior treatment with bevacizumab;
!
Known central nervous system metastases;
!
Significant history of bleeding events or GI perforation;
o
Subjects with a history of significant bleeding episodes (e.g., hemoptysis, upper or lower 
GI bleeding) within 6 months of C1D–2 are not eligible unless the source of bleeding has been 
resected;
o
Subjects with a history of GI perforation within 12 months of C1D–2 are not eligible;
!
Serious or non-healing wound, ulcer or bone fracture;
!
History of venous or arterial thromboembolism within 2 months of enrollment;
!
Known hypersensitivity to recombinant or murine antibodies.


Veliparib
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Investigational Product:
Veliparib (ABT-888) or Placebo
Dose:
200 mg twice a day (BID), Day –2 through Day 5 of each 14-day cycle
Mode of Administration:
Oral
Reference Therapy:
Irinotecan
Dose:
180 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
Intravenous (IV) over 90 minutes ± 30 minutes
Reference Therapy:
Leucovorin (Folinic Acid)
Dose:
400 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
IV over 90 minutes ± 30 minutes
Reference Therapy:
Fluorouracil (5-FU) bolus or saline bolus
Dose:
400 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
IV up to 15 minutes
Reference Therapy:
Fluorouracil (5-FU) infusion
Dose:
2400 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
IV over 46 hours ± 4 hours
Reference Therapy:
Bevacizumab (at the Investigator's discretion)
Dose:
5 mg/kg
Mode of Administration:
IV immediately preceding FOLFIRI
Duration of Treatment:  
Subjects with controlled disease (CR, PR, or SD per RECIST, Version 1.1) and with tolerable side effects 
may continue to receive protocol therapy until disease progression.
Pharmacokinetic:
Blood samples will be collected at designated time points throughout the study.
Pharmacodynamic:
Research to find biomarkers that may serve as surrogates for clinical endpoints in future veliparib studies 
or that may be predictive of veliparib activity will be conducted.  Serum, plasma, blood and tissue 
samples will be collected at designated time points throughout the study.
Statistical Methods:
For all statistical analyses, P values will be provided.  The date of randomization (enrollment) is defined 
as the date that the Interactive Response Technology (IRT) system issues a randomization number.
Sample Size:  A minimum of 70 PFS events was chosen to provide adequate precision in the hazard ratio 
estimate.  Assuming median PFS time of 9.4 months in the FOLFIRI ± bevacizumab arm and 
15.7 months in the veliparib plus FOLFIRI ± bevacizumab arm, based on a minimum of 70 PFS events, 
the expected 95% confidence interval for the estimated hazard ratio would be approximately 0.37 to 0.96.  
A total of 120 subjects will be enrolled into the study.  Assuming a total enrollment period of 12 months, 
it is anticipated that the study will complete by end of the 22nd month if the true median times for each 
treatment arm are as assumed above.


Veliparib
M14-217 Protocol Amendment 2
EudraCT 2014-002866-65
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Statistical Methods (Continued):
Efficacy:
Primary
Progression-Free Survival (PFS):  will be defined as the number of days from the date the subject is 
randomized to the date the subject experiences a disease progression event or to the date of death if 
disease progression is not reached.  The progression-free survival distribution will be estimated for each 
treatment group using Kaplan-Meier methodology and compared between the two treatment groups using 
a log-rank test stratified by the planned bevacizumab use.  A two-sided, stratified log-rank test P value 
will be provided.  Median PFS time will be estimated and a 95% confidence interval for the median PFS 
time will be presented for each treatment group.  A hazard ratio estimate and a 95% confidence interval 
will be obtained from a proportional hazards regression model.
Secondary
Overall Survival (OS):  Time to death for a given subject will be defined as the number of days from the 
day the subject is randomized to the date of the subject's death.  All events of death will be included, 
regardless of whether the event occurs while the subject is still taking study drug, or after the subject 
discontinues study drug.  If a subject has not died, then the data will be censored at the date when the 
subject is last known to be alive.  The distribution of overall survival will be estimated for each treatment 
group using Kaplan-Meier methodology and compared between the two treatment groups using a 
log-rank test stratified by the planned bevacizumab use.  Median OS time will be estimated and a 95% 
confidence interval for the median OS time will be presented for each treatment group.  A hazard ratio 
estimate and a 95% confidence interval will be obtained from a proportional hazards regression model.
Objective Response Rate (ORR):  (CR and PR) will be defined as the proportion of subjects with a 
complete or partial objective response based on RECIST, Version 1.1.  The objective response rate will 
be estimated and compared between the two treatment groups using a Cochran-Mantel-Haenszel test, 
stratifying by the planned bevacizumab use.  In addition, a 95% confidence interval will be constructed 
for the estimated proportions.
Safety:
Safety will be assessed by evaluating study drug exposure, adverse events, serious adverse events, all 
deaths, as well as changes in laboratory data and vital signs.  Subjects who are randomized but do not 
receive study drug (veliparib) or placebo will not be included in the analyses of safety.  Safety analysis 
results will be presented by treatment group.


Veliparib
M14-217 Protocol Amendment 2
EudraCT 2014-002866-65
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
5-FU
5-fluorouracil 
ADL
Activities of Daily Living 
AE
Adverse Event 
ALT
Alanine Aminotransferase 
ANC
Absolute Neutrophil Count 
aPTT
Activated Partial Thromboplastin Time 
AST
Aspartate Aminotransferase 
BID
Twice a Day 
BUN
Blood Urea Nitrogen 
C
Cycle
D
Day
CEA
Carcinoembryonic Antigen 
CNS
Central Nervous System 
CR
Complete Response 
CRF
Case Report Form
CT
Computed Tomography 
CTCAE
Common Terminology Criteria for Adverse Events 
CTEP
Cancer Therapy Evaluation Program 
CYPs
Cytochrome P450s 
DDI
Drug-drug Interactions 
DMC
Data Monitoring Committee 
DNA
Deoxyribonucleic acid (DNA)
ECOG
Eastern Cooperative Oncology Group 
eCRF
Electronic Case Report Form 
eGFR
Estimated Glomerular Filtration Rate
ECG
Electrocardiogram 
EDC
Electronic Data Capture
EMA
European Medicines Agency 
FOLFIRI
Irinotecan, Fluorouracil, and Leucovorin chemotherapy regimen
FOLFOX
Oxaliplatin, Fluorouracil, and Leucovorin chemotherapy regimen
GI
Gastrointestinal


Veliparib
M14-217 Protocol Amendment 2
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GCP
Good Clinical Practice 
GLP
Good Laboratory Practice 
hCG
Human Chorionic Gonadotropin 
ICH
International Conference on Harmonization 
IMC
Internal Monitoring Committee 
IEC
Independent Ethics Committee 
IIA
Investigator Information and Agreement 
IMP
Investigational Medicinal Product 
INR
International Normalized Ratio 
IRB
Institutional Review Board 
IRT
Interactive Response Technology
IUD
Intrauterine device 
IV
Intravenous 
LDH
Lactate dehydrogenase 
mCRC
Metastatic colorectal cancer 
MMR
Mismatch-Repair
MRI
Magnetic Resonance Imaging 
MSI
Microsatellite instability
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NSCLC
Non-Small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival 
PAR
Poly(ADP-ribose)
PARP
Poly(ADP-ribose)-polymerase 
PD
Pharmacodynamic
PG
Pharmacogenetic
PFS
Progression-Free Survival 
PK
Pharmacokinetic 
POR
Proof of Receipt 
PR
Partial Response 
PT
Prothrombin Time 
QTc
QT Interval Corrected for Heart Rate
RBC
Red Blood Cell 


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RECIST
Response Evaluation Criteria in Solid Tumors 
RPLS
Reversible Posterior Leukoencephalopathy Syndrome 
SAE
Serious Adverse Event 
SD
Stable disease 
SGOT
Serum Glutamic-Oxaloacetic Transaminase 
SGPT
Serum Glutamic-Pyruvic Transaminase 
SmPC
Summary of Product Characteristics 
SUSAR
Suspected Unexpected Serious Adverse Reactions 
TMZ
Temozolomide
ULN
Upper Limit of Normal 
WBC
White Blood Cell


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................2
1.2
Synopsis .....................................................................................................6
1.3
List of Abbreviations and Definition of Terms........................................12
2.0
Table of Contents...................................................................15
3.0
Introduction ...........................................................................20
3.1
Colorectal Cancer.....................................................................................20
3.2
FOLFIRI ..................................................................................................20
3.3
Bevacizumab............................................................................................21
3.4
Veliparib ..................................................................................................21
3.5
Rationale for Veliparib FOLFIRI Combination Therapy........................22
3.6
Veliparib Preclinical Toxicology.............................................................23
3.7
Pharmacokinetics and Pharmacodynamics..............................................24
3.8
Clinical Experience..................................................................................24
3.9
Benefits and Risks....................................................................................26
3.10
Differences Statement..............................................................................26
4.0
Study Objective......................................................................27
5.0
Investigational Plan...............................................................28
5.1
Overall Study Design and Plan:  Description ..........................................28
5.2
Selection of Study Population..................................................................30
5.2.1
Inclusion Criteria .....................................................................................30
5.2.2
Exclusion Criteria ....................................................................................33
5.2.3
Prior and Concomitant Therapy...............................................................35
5.3
Efficacy Pharmacokinetic, Pharmacodynamic, Pharmacogenetic 
and Safety Assessments/Variables...........................................................37
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................37
5.3.1.1
Study Procedures .....................................................................................43
5.3.2
Drug Concentration Measurements .........................................................50
5.3.2.1
Blood Samples for Pharmacokinetic Analysis.........................................50
5.3.2.2
Measurement Methods.............................................................................50
5.3.2.3
Blood Samples for Pharmacogenetic Analysis........................................51


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5.3.2.4
Blood Samples for Pharmacodynamic Analysis......................................51
5.3.3
Efficacy Variables....................................................................................52
5.3.3.1
Primary Variable......................................................................................53
5.3.3.2
Secondary Variables ................................................................................53
5.3.3.3
Tertiary Variables ....................................................................................53
5.3.4
Safety Variables.......................................................................................53
5.3.5
Pharmacokinetic Variables ......................................................................53
5.3.6
Pharmacogenetic Variables......................................................................54
5.3.7
Pharmacodynamic Variables....................................................................54
5.4
Removal (Discontinuation) of Subjects from Protocol Therapy
and Study Visits .......................................................................................55
5.4.1
Discontinuing Subjects from Protocol Therapy.......................................56
5.4.2
Discontinuing Subjects from Study Visits...............................................57
5.4.3
Final Visit.................................................................................................57
5.4.4
Follow-Up Visit .......................................................................................58
5.4.5
Timing and Collection of Survival and Post-Treatment Cancer 
Information ..............................................................................................58
5.4.6
Discontinuation of Entire Study...............................................................58
5.5
Treatments................................................................................................59
5.5.1
Protocol Therapy Administered...............................................................59
5.5.2
Toxicity Management and Protocol Therapy Dose Reductions or 
Delays ......................................................................................................63
5.5.3
Identity of Investigational Product...........................................................63
5.5.4
Standard of Care Medicinal Products ......................................................64
5.5.5
Packaging and Labeling...........................................................................64
5.5.6
Storage and Disposition ...........................................................................65
5.5.7
Method of Assigning Subjects to Treatment Groups...............................65
5.5.8
Selection and Timing of Dose for Each Subject......................................66
5.5.9
Blinding....................................................................................................66
5.5.10
Treatment Compliance.............................................................................66
5.5.11
Drug Accountability.................................................................................67
5.6
Discussion and Justification of Study Design..........................................68
5.6.1
Discussion of Study Design and Choice of Control Groups....................68


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5.6.2
Appropriateness of Measurements...........................................................69
5.6.3
Suitability of Subject Population .............................................................69
5.6.4
Selection of Doses in the Study ...............................................................69
6.0
Adverse Events.......................................................................69
6.1
Definitions................................................................................................70
6.1.1
Adverse Event..........................................................................................70
6.1.2
Serious Adverse Events ...........................................................................71
6.2
Adverse Events Expected Due to mCRC or Progression of mCRC........72
6.3
Adverse Events Expected Due to Study Related Endpoints....................72
6.3.1
Deaths ......................................................................................................72
6.3.2
Lack of Efficacy or Worsening of Disease..............................................73
6.4
Adverse Event Severity............................................................................73
6.5
Relationship to Study Drug......................................................................74
6.6
Adverse Event Collection Period.............................................................75
6.7
Adverse Event Reporting.........................................................................75
6.8
Pregnancy.................................................................................................77
7.0
Protocol Deviations................................................................78
8.0
Statistical Methods and Determination of Sample 
Size ..........................................................................................79
8.1
Statistical and Analytical Plans................................................................79
8.1.1
Baseline Characteristics...........................................................................79
8.1.1.1
Demographics ..........................................................................................80
8.1.1.2
Medical History .......................................................................................80
8.1.2
Efficacy Endpoints...................................................................................80
8.1.2.1
Primary Efficacy Endpoint ......................................................................80
8.1.2.2
Secondary Efficacy Endpoints.................................................................80
8.1.2.3
Tertiary Efficacy Endpoints.....................................................................81
8.1.3
Primary Analysis of Efficacy...................................................................81
8.1.4
Secondary Analysis of Efficacy...............................................................82
8.1.4.1
Overall Survival.......................................................................................82
8.1.4.2
Objective Response Rate .........................................................................82
8.1.4.3
Tertiary Analysis of Efficacy...................................................................82
8.1.4.3.1
ECOG Performance Status ......................................................................82


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8.1.5
Safety Assessments..................................................................................83
8.1.6
Statistical Analyses of Safety...................................................................83
8.1.6.1
Duration of Study Drug ...........................................................................83
8.1.6.2
Adverse Events ........................................................................................83
8.1.6.3
Serious Adverse Events ...........................................................................83
8.1.6.4
Deaths ......................................................................................................84
8.1.6.5
Longitudinal Analyses of Laboratory and Vital Signs Data....................84
8.1.6.6
Analyses of Laboratory Data Using NCI CTCAE...................................84
8.1.6.7
Analyses of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values...................................................................85
8.1.7
Interim Analysis.......................................................................................85
8.2
Determination of Sample Size .................................................................86
8.3
Randomization Methods ..........................................................................86
9.0
Ethics.......................................................................................87
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) .............................................................................................87
9.2
Ethical Conduct of the Study...................................................................88
9.3
Subject Information and Consent.............................................................88
10.0
Source Documents and Case Report Form 
Completion .............................................................................89
10.1
Source Documents ...................................................................................89
10.2
Case Report Forms...................................................................................89
11.0
Data Quality Assurance ........................................................90
12.0
Use of Information.................................................................90
13.0
Completion of the Study .......................................................91
14.0
Investigator's Agreement......................................................92
15.0
Reference List ........................................................................93
List of Tables
Table 1.
Cautionary Medications...........................................................................36
Table 2.
Excluded Medications..............................................................................36
Table 3.
Concomitant Medications/Therapies .......................................................37


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Table 4.
Study Assessments...................................................................................39
Table 5.
Schedule of Pharmacokinetic (PK) Assessments ....................................42
Table 6.
Schedule of Pharmacogenetic (PG) and Pharmacodynamic (PD) 
Assessments .............................................................................................42
Table 7.
Clinical Laboratory Tests.........................................................................48
Table 8.
Identity of Investigational Product...........................................................64
Table 9.
Standard of Care Medicinal Products ......................................................64
Table 10.
Study Drug Storage Conditions ...............................................................65
List of Figures
Figure 1.
Protocol Therapy Dosing Schedule Overview.........................................30
Figure 2.
Adverse Event Collection ........................................................................75
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator............................................95
Appendix B.
List of Protocol Signatories......................................................................97
Appendix C.
Adverse Events Expected Due to mCRC or Progression of mCRC........98
Appendix D.
RECIST Version 1.1 for Tumor Response (PFS)....................................99
Appendix E.
Guidelines for Toxicity Management and Dose Reductions or 
Delays for Protocol Therapy..................................................................106
Appendix F.
Dose Reductions and Delays for Veliparib Toxicity .............................107
Appendix G.
Dose Reductions and Delays for FOLFIRI Toxicity .............................108
Appendix H.
Dose Reductions and Delays Guidelines for Bevacizumab 
Toxicity..................................................................................................109
Appendix I.
Toxicity Management Guidelines for Protocol Therapy .......................110
Appendix J.
Protocol Amendment:  List of Changes.................................................118


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3.0
Introduction
3.1
Colorectal Cancer
Colorectal cancer is the third most common cancer in men and the second most common 
cancer in women with 746,000 and 614,000 cases respectively worldwide in 2012.1  
Metastatic colorectal cancer remains a largely incurable disease.  The majority of patients
faced with a diagnosis of metastatic colorectal cancer have either extensive liver disease 
or disease outside the liver, limiting their treatment options to chemotherapy.  Current 
chemotherapy treatment options for these patients include fluoropyrimidines, irinotecan, 
oxaliplatin, bevacizumab, cetuximab, panitumumab, ziv-afilbercept, and regorafenib 
administered in various combinations or as single agents.2  While the introduction of each 
of these regimens has resulted in incremental increases in patient survival, the 5-year 
survival rate for advanced colorectal cancer remains at only ~6%.3
3.2
FOLFIRI
Fluorouracil (5-FU) is commonly administered with leucovorin (folinic acid), which 
modulates 5-FU activity. Irinotecan is active in advanced colorectal cancer and was 
first approved by the FDA for patients with disease refractory to 5-FU/leucovorin.  Initial 
approval was based on a response rate of about 15% and subsequently confirmed with a 
randomized study demonstrating improved survival for patients refractory to 5-FU who 
were treated with irinotecan compared to best supportive care.4  Two combinations of 
irinotecan/5-FU/leucovorin were compared to 5-FU/leucovorin regimens, one with bolus 
5-FU/leucovorin and another with continuous infusion 5-FU (FOLFIRI).5,6  In both 
studies, the irinotecan-containing combinations conferred a survival advantage, leading to 
the indication of these regimens as standard front-line therapy for patients with metastatic 
colorectal cancer (mCRC).  The bolus 5-FU/leucovorin and irinotecan combination was 
once favored in the US, although it appears to be more toxic than the FOLFIRI regimen, 
and the general consensus is that FOLFIRI merits further testing in the US.  In Europe, 
FOLFOX and FOLFIRI have been compared to each other, used sequentially, in the 
management of patients with advanced colorectal cancer, and there does not appear to be 


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a significant difference in outcome based on the sequence of administration, although the 
toxicity profiles are dissimilar.7  The treatments have not been compared head-to-head in 
the US.
3.3
Bevacizumab
Bevacizumab (Avastin) is a recombinant humanized version of a murine anti-human 
VEGF monoclonal antibody that has been clinically evaluated both as a single agent and 
in combination with cytotoxic chemotherapy in multiple metastatic solid tumor types.  It 
is approved for use in the first-line setting for advanced colorectal cancer in combination 
with fluorouracil-based chemotherapy.  In a study comparing irinotecan/5-FU/leucovorin 
with irinotecan/5-FU/leucovorin plus bevacizumab in first-line mCRC, a survival 
advantage of more than four months was observed in bevacizumab-treated patients.8  In 
the BICC-C Phase 3 study of irinotecan plus infusional, bolus, or oral fluoropyrimidines 
in first-line metastatic CRC by Fuchs and colleagues, PFS and OS were improved in 
bevacizumab combination versus respective chemotherapy only arms.  For FOLFIRI, PFS 
improved from 7.6 to 11.2 months and OS from 23.1 to 28 months with the addition of 
bevacizumab.9  Bevacizumab does not appear to alter the toxicity profile of 
chemotherapy, although hypertension and proteinuria are commonly seen.  Approximately 
3.4% of patients receiving bevacizumab suffer arterial thrombotic events.  Although there 
have been modest improvements in PFS and OS as noted above, given the risks of adding 
bevacizumab to standard chemotherapy, there remain many countries where bevacizumab 
is not considered first-line SOC for mCRC.
3.4
Veliparib
Poly(ADP-ribose)-polymerase (PARP) 1 and 2 are nuclear enzymes that recognize 
deoxyribonucleic acid (DNA) damage and facilitate DNA repair.10,11  Inactive PARPs 1 
and 2 bind to damaged DNA, which leads to their auto-activation.  The resulting activated 
PARP enzymes then poly(ADP-ribosyl)ate many nuclear target proteins, including those 
that facilitate DNA repair of both single-stranded or double-stranded DNA breaks.  Thus, 
PARP inhibition will result in less efficient DNA repair following a cytotoxic insult.


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DNA-damaging agents including cytotoxic chemotherapy and radiation therapy, remain a 
mainstay of treatment for many patients with cancer.  Since cancer cells are genetically 
unstable, often exhibiting complex karyotypes that include large deletions, insertions, and 
unbalanced translocations of chromosomal material, these cells are more susceptible than 
normal tissues to cytotoxicity induced by DNA-damaging agents.12  Of these, deficiencies 
in mismatch repair or homologous recombination are associated with the largest number 
of malignancies.  These deficiencies render cells more dependent on PARP for DNA 
repair, and hence more sensitive to PARP inhibition.13  PARP enabled DNA repair may 
also compensate for the loss of other repair pathways.  Higher expression of PARP in 
cancer cells compared to normal cells has been linked to drug resistance and the overall 
ability of cancer cells to sustain genotoxic stress.14  PARP recognizes topoisomerase I 
cleavage complexes (Top1cc) that arise upon treatment with camptothecin and 
indenoisoquinoline anti-cancer compounds including Irinotecan.  Activated PARP, in 
turn, is required for subsequent recruitment of Tyrosyl-DNA phosphodiesterase 1 (TDP1), 
a key repair enzyme for trapped Top1cc, and downstream base-excision repair (BER) 
proteins.  Inhibition of PARP by veliparib prevents recruitment of these irinotecan 
damage repair enzymes, increases reliance on double-strand break generating nucleotide 
excision repair, and increases overall DNA-damage and cytotoxicity resulting from the 
chemotherapy.15  Veliparib is a potent oral PARP inhibitor that delays the repair of 
DNA-damage induced by chemotherapeutic agents, including alkylating agents, 
platinums, radiation, and topoisomerase inhibitors.  Nonclinical efficacy with veliparib in 
combination with these agents has been demonstrated across an array of tumor types, 
including melanoma, glioma, prostate, breast, and colon.
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the Investigator's Brochure.14
3.5
Rationale for Veliparib FOLFIRI Combination Therapy
Administration of veliparib in vitro or in vivo inhibits the formation of poly(ADP-ribose) 
(PAR) polymers.  When veliparib and DNA-damaging cytotoxic agents are 
coadministered, veliparib inhibits the repair of DNA.  In a variety of nonclinical tumor 


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models, including melanoma, breast, prostate, colon, and glioma, veliparib significantly 
enhanced the antitumor activity when dosed on a schedule that overlapped the 
administration of a DNA-damaging agent.  Significant inhibition of tumor PAR levels at 
doses similar to those with antitumor effect was observed, which is consistent with 
veliparib potentiation of DNA-damaging agents being mediated through mechanistic 
inhibition of PARP.  Specific to the context of damage induced by irinotecan, veliparib 
prevents PARP activation and subsequent recruitment of TDP1 and downstream BER 
enzymes required for repair without DNA double-strand break formation.  Addition of 
veliparib to irinotecan thus increases reliance on double-strand break generating 
nucleotide excision repair, and increases overall DNA-damage and cytotoxicity resulting 
from the chemotherapy.15  Therefore, patients receiving cytotoxic chemotherapy including 
irinotecan may benefit from the addition of a veliparib.
3.6
Veliparib Preclinical Toxicology
The toxicological profile of veliparib has been evaluated in nonclinical general toxicity 
studies that included single-dose (rats and mice), repeat-dose (duration of up to 6 months 
in rats and up to 9 months in dog), reproductive (embryofetal development in rat and 
rabbit), genetic (Ames, in vitro cytogenetics, in vivo micronucleus), phototoxicity 
(in vitro photosensitivity) and juvenile rat toxicity studies.  Primary nonclinical findings 
included effects on the central nervous system (CNS) (convulsions, tremors), 
hematopoietic system (bone marrow depletion and resultant decreased circulating white 
and red blood cells), reproductive system (male germ cell depletion, female reproductive 
tract tissues degeneration), and lymphoid tissues (lymphocyte depletion), with lesser 
effects on the gastrointestinal tract (single-cell necrosis) and cardiovascular system 
(10% QTc interval prolongation).  Convulsions and other CNS-related signs were 
considered exposure-dependent, and were generally self-limiting, ameliorated by dose 
reduction or cessation of dosing, or responsive to treatment.  All other findings were dose 
dependent and reversible upon discontinuation of veliparib administration.  Veliparib was 
also genotoxic (induced chromosomal aberrations in vitro and increased micronuclei 
formation in vivo) and was toxic to the developing fetus (increases in the incidence of 


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fetal external/visceral/skeletal malformations/variations) in rats and rabbits.  Veliparib 
demonstrated no phototoxic potential in the photosensitivity assay.  With the exception of 
CNS and cardiovascular effects, the toxicity of veliparib is generally consistent with the 
pharmacology of the compound.
3.7
Pharmacokinetics and Pharmacodynamics
A detailed discussion of the veliparib preclinical toxicology, metabolism, and 
pharmacology can be found in the Investigator's Brochure.14
3.8
Clinical Experience
Veliparib 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 veliparib in AbbVie sponsored studies as of 
24 March 2014.  Additionally, in the Cancer Therapy Evaluation Program (CTEP) 
sponsored studies of veliparib, approximately 1,687 adult subjects and 44 pediatric 
subjects have been exposed to veliparib as of 31 March 2014.
AbbVie sponsored studies included the evaluation of veliparib in combination with 
temozolomide, whole brain radiation therapy, concurrent radiation therapy and 
temozolomide, carboplatin and gemcitabine, carboplatin and paclitaxel, and FOLFIRI in 
Phase 1 and Phase 2 clinical studies.  The main toxicities associated with veliparib to date 
are mechanism based and are not clearly distinguished from those expected of the base 
regimens with which veliparib 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 1, open-label dose escalation study evaluating the safety and 
tolerability of veliparib in combination with modified bimonthly FOLFIRI.16  As of 
14 March 2014, 96 subjects had been enrolled, enrollment was complete, and 6 patients 
remained on study.  Although combining veliparib with standard FOLFIRI including a 
5-FU bolus (400 mg/m2) was not tolerated, veliparib was dose escalated from 10 mg to 


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300 mg BID using a modified FOLFIRI regimen omitting the bolus (irinotecan 
150 mg/m2, 5-FU 2400 mg/m2, leucovorin 400 mg/m2).  It is relevant to note that a 
CTEP-sponsored Phase 1 dose escalation study of veliparib in combination with 
FOLFOX independently reached the same conclusion that a 5-FU bolus is not tolerated 
with veliparib.17  After 67 patients, the FOLFIRI dose was modified to irinotecan 
180 mg/m2, 5-FU 2400 mg/m2 and a second dose escalation of veliparib starting at 
100 mg BID was conducted.  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.  
Veliparib 200 mg BID was tolerated in this higher irinotecan dose.  As doses exceeding 
veliparib 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 subjects, 9.8%), diarrhea (5 subjects, 5.4%), dehydration 
(5 subjects, 5.4%) and hypokalemia (5 subjects, 5.4%).  Two patients in the veliparib 
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 2 dose combination was determined to be veliparib 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 veliparib Investigator's 
Brochure.14


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3.9
Benefits and Risks
This study proposes to establish improved clinical outcomes for patients with metastatic 
colorectal cancer (mCRC) through the addition of veliparib to FOLFIRI chemotherapy.  
Preclinical data demonstrate that veliparib potentiates the anti-tumor activity of 
topoisomerase inhibitors (such as irinotecan), and data from early-phase studies 
(completed or preliminary) is consistent with these observations.  As described above, 
study subjects receiving veliparib with FOLFIRI have shown favorable, though not 
statistically significant, results for the endpoints of clinical benefit rate (response + stable 
disease) and progression-free survival.  The current study is the first study to test 
colorectal cancer subjects receiving veliparib for improved progression-free survival that 
has sufficient power to detect a clinically meaningful benefit.
Risks in this study include toxicity from the addition of veliparib to standard therapy.  
Preliminary safety data from a Phase 1 study of the proposed combination suggest low 
rates of additional toxicities, and do not compromise the delivery of FOLFIRI, provided 
the 5-FU bolus is not used.  Omission of the 5-FU bolus from FOLFIRI for subjects 
receiving veliparib deviates from standard of care, and may reduce the efficacy of 
chemotherapy.  Veliparib may increase the likelihood subjects experience adverse events 
associated with FOLFIRI treatment.  Standard clinical practices to manage the toxicity of 
FOLFIRI are well established.  Other potential risks of veliparib administration, identified 
in preclinical studies or based on pharmacological mechanism, but not confirmed in 
clinical studies must also be considered.  These risks include seizures, changes in 
testes/ovaries, toxicity to the developing fetus and secondary malignancies.
3.10
Differences Statement
There are differences in the study population and the underlying base chemotherapy 
regimen between this study and other ongoing studies.  This study is the first randomized, 
blinded, multicenter, Phase 2 study comparing veliparib in combination with FOLFIRI ± 
bevacizumab to placebo in combination with FOLFIRI ± bevacizumab in subjects with 
previously untreated metastatic colorectal cancer.  Other Phase 2 veliparib studies include:


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Study M10-440:  A randomized, Phase 2, double-blind, placebo-controlled study 
evaluating the efficacy of veliparib in combination with temozolomide versus 
temozolomide alone in subjects with metastatic melanoma.
Study M10-757:  A randomized, Phase 2, open-label study in subjects with ovarian cancer 
receiving veliparib in combination with temozolomide versus pegylated liposomal 
doxorubicin alone.
Study M10-897:  A randomized, Phase 2, double-blinded, placebo-controlled study in 
subjects with brain metastases from non-small cell lung cancer receiving veliparib and 
whole brain radiation therapy.
Study M10-898:  A randomized, Phase 2, double-blinded, placebo-controlled study in 
subjects with untreated metastatic or advanced non-small cell lung cancer receiving 
veliparib plus carboplatin and paclitaxel.
Study M12-895:  A randomized, Phase 2, double-blinded, placebo-controlled study in 
subjects with BRCA1 or BRCA2 mutation and metastatic breast cancer receiving 
veliparib plus carboplatin and paclitaxel.
4.0
Study Objective
The primary objectives of the study are to assess whether the addition of oral veliparib to 
FOLFIRI will improve progression-free survival (PFS) in subjects with previously 
untreated mCRC.  The secondary objectives of the study are to assess overall survival 
(OS), objective response rate (ORR), safety, and tolerability.  The tertiary objectives are 
to assess duration of response (DOR) and the effects on a patient's Eastern Cooperative 
Oncology Group (ECOG) performance status (PS).


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5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a randomized, blinded, Phase 2 multicenter study evaluating the efficacy and 
tolerability of veliparib plus FOLFIRI versus placebo plus FOLFIRI in subjects with 
previously untreated metastatic colorectal cancer.  At the discretion of the Investigator, 
subjects can also be treated with bevacizumab.
The study was designed to enroll approximately 120 subjects at approximately 60 study 
sites to meet scientific and regulatory objectives without enrolling an undue number of 
subjects in alignment with ethical considerations.  Therefore, if the target number of 
subjects has been enrolled, there is a possibility that additional subjects in screening will 
not be enrolled.
Subjects will be randomized to one of two protocol therapy groups as follows: 
a.
Veliparib plus FOLFIRI ± bevacizumab
b. Placebo plus FOLFIRI ± bevacizumab
Subjects will be stratified by the planned use of bevacizumab (planned bevacizumab use 
versus no planned use with bevacizumab) and regions of the world (North America versus 
rest of world).  Randomization will be conducted to ensure that at least 60 subjects are 
enrolled in both the "planned bevacizumab use" group and "no planned bevacizumab use" 
group for a total of ~120 subjects.  Subject randomization is detailed in Section 8.3.
Note that for the purposes of this protocol, FOLFIRI is used to describe both the standard 
regimen containing a 5-FU bolus that will be administered to subjects randomized to the 
placebo arm, and a modified regimen with a saline bolus that will be administered to 
subjects randomized to the veliparib arm.  One cycle of protocol therapy consists of 
14 days, defined as Day –2 through Day 12.  Dosing of oral veliparib/placebo will begin 
2 days prior to the start of FOLFIRI and will continue twice a day (BID) for a total of 
7 consecutive days.  At the discretion of the Investigator, bevacizumab (5 mg/kg) may be 


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administered intravenously immediately preceding FOLFIRI.  Subjects randomized to the 
veliparib arm will receive modified FOLFIRI as irinotecan 180 mg/m2 (90 minute 
infusion ± 30 minutes); leucovorin 400 mg/m2 (90 minute infusion ± 30 minutes); saline 
bolus (up to 15 minute infusion) immediately followed by 5-FU 2400 mg/m2 (46-hour 
continuous infusion ± 4 hours) starting on Day 1 of each 14-day cycle.  Subjects 
randomized to the placebo arm will receive standard FOLFIRI as irinotecan 180 mg/m2
(90 minute infusion ± 30 minutes); leucovorin 400 mg/m2 (90 minute infusion 
± 30 minutes); 5-FU bolus 400 mg/m2 (up to 15 minute infusion) immediately followed 
by 5-FU 2400 mg/m2 (46-hour continuous infusion ± 4 hours) on Day 1 of each 14-day 
cycle.  FOLFIRI is only to be given after veliparib/placebo dosing on cycle Day –2 and 
Day –1 are confirmed.  An overview of the protocol schedule constituting one treatment 
cycle is shown in Figure 1.  Additional details regarding dosing with veliparib/placebo, 
FOLFIRI and bevacizumab can be found in Section 5.5.
Guidelines for toxicity management and dose reductions or delays can be found in 
Appendix E, Appendix F, Appendix G, Appendix H, and Appendix I.
Screening procedures and baseline radiographic tumor assessments will be performed 
within 28 days prior to the first dose of veliparib/placebo on Cycle 1 Day –2 (C1D–2).  
Study visits will be conducted on Day 1 and Day 8 of the first and second cycle, then on 
Day 1 of each subsequent cycle.  Subjects will continue protocol therapy and attending 
study visits until they meet one of the defined discontinuation criteria found in 
Section 5.4.  When the Investigator has determined that a subject meets the criteria for 
discontinuation, a Final Visit will be conducted.  All subjects will have one Follow-Up 
Visit approximately 30 days after the last dose of protocol therapy.
Sites will begin collecting post-treatment and survival information 4 weeks after the last 
clinical assessment.  Post-treatment and survival information is detailed in Section 5.4.5.
Details regarding study visits and study procedures can be found in Section 5.3 and 
Section 5.4.


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Post-baseline radiographic tumor assessment will be conducted every 8 weeks from C1D1 
(prior to the start of a new cycle) until radiographic progression.  Radiographic tumor 
assessments will be evaluated using the Response Evaluation Criteria in Solid Tumors 
(RECIST), Version 1.1.18
Figure 1.
Protocol Therapy Dosing Schedule Overview
5.2
Selection of Study Population
The study population will consist of adult subjects with histologically or cytologically 
documented adenocarcinoma of the colon or rectum with metastatic disease, who have not 
received prior chemotherapy for their metastatic colorectal cancer.
5.2.1
Inclusion Criteria
1.
≥ 18 years of age;
2.
Histologically or cytologically confirmed metastatic adenocarcinoma of the colon 
or rectum;


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3.
At least 1 unresectable lesion on a CT scan that is measurable as defined by 
RECIST, Version 1.1;
4.
ECOG performance score of 0 or 1;
5.
Adequate hematologic, renal and hepatic function as follows:
●
Bone marrow:  Absolute Neutrophil Count (ANC) ≥ 1500/μL; 
Platelets ≥100,000/mm3; (independent of platelet transfusions within 3 months 
prior to starting protocol therapy); Hemoglobin ≥ 9.0 g/dL;
●
Renal function:  serum creatinine ≤ 2.0 mg/dL or calculated creatinine 
clearance ≥ 50 mL/min;
●
Hepatic function and enzymes:  aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤ 2.5 × the upper limit of normal (ULN) of 
institution's normal range.  Subjects with liver metastases may have an AST 
and ALT of ≤ 5.0 × ULN;
●
Bilirubin:  ≤ 1.5 × ULN of institution's normal range.
6.
If female, subject must be postmenopausal for at least 1 year, surgically sterile 
(bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or practicing at 
least one of the following methods of birth control until 90 days after the last dose 
of protocol therapy:
●
Total abstinence from sexual intercourse as the preferred life style of the 
subject; periodic abstinence is not acceptable;
●
Vasectomized partner(s);
●
Hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months 
prior C1D–2 (if the subject is currently using a hormonal contraceptive, she 
should also use a barrier method during the study and for 1 month after 
protocol therapy completion);
●
Intrauterine device (IUD);
●
Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal 
ring with spermicidal jellies or creams).


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7.
If male, subject must be surgically sterile or practicing at least one of the following 
methods of contraception, from the initial protocol therapy administration until 
90 days after the last dose of protocol therapy:
●
Partner(s) using IUD;
●
Partner(s) using hormonal contraceptives (oral, vaginal, parenteral or 
transdermal);
●
Subject and/or partner(s) using double-barrier method (condoms, contraceptive 
sponge, diaphragm, or vaginal ring with spermicidal jellies or creams);
●
Total abstinence from sexual intercourse as the preferred life style of the 
subject; periodic abstinence is not acceptable.
8.
Subject must be capable of understanding and complying with parameters as 
outlined in the protocol and able to voluntarily sign and date an informed consent, 
approved by an Independent Ethics Committee (IEC)/Institutional Review Board 
(IRB), prior to the initiation of any screening or study-specific procedures.
Criteria Only For Subjects Receiving Bevacizumab
9.
Blood pressure must be well controlled (< 160/90 mm Hg) on a stable regimen of 
anti-hypertensive therapy for at least two weeks.
Rationale for Inclusion Criteria
1 – 4
To select the appropriate subject population with sufficient disease severity 
for evaluation
5
For the safety of the subjects
6 – 7
The impact of veliparib on the unborn fetus is unknown; therefore, these 
criteria ensure that adequate precautions are taken to avoid pregnancy
8
In accordance with harmonized Good Clinical Practice (GCP)
9
For the safety of subjects that receive bevacizumab


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5.2.2
Exclusion Criteria
1.
Prior anti-cancer treatment for metastatic colorectal cancer;
2.
Prior exposure to PARP inhibitors;
3.
The last course of adjuvant or neoadjuvant chemotherapy must have ended 
> 12 months prior to C1D–2;
4.
Known Gilbert's Syndrome;
5.
Prior radiotherapy to greater than 25% of bone marrow;
6.
Prior radiotherapy ≤ 4 weeks of C1D–2;
7.
Any type of major surgery ≤ 4 weeks of C1D–2;
8.
Previous or concurrent malignancy except for adequately treated basal cell or 
squamous cell skin cancer, in situ cervical cancer, or other cancer for which the 
subject has been disease-free for 3 years;
9.
Known hypersensitivity to irinotecan, 5-FU or leucovorin;
10.
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);
●
Unstable angina pectoris or cardiac arrhythmia;
●
Psychiatric illness/social situation that would limit compliance with study 
requirements.
11.
Predisposing colonic or small bowel disorders in which the symptoms are 
uncontrolled as indicated by baseline pattern of > 3 watery of soft stools daily.  
Subjects with an ileostomy or colostomy may enter the study at the discretion of 
the Investigator;
12.
Subject is pregnant or lactating;


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13.
Subject who requires parenteral nutrition, tube feeding or has evidence of partial 
bowel obstruction or perforation within 28 days prior to C1D–2;
14.
Any medical condition, which in the opinion of the study Investigator, places the 
subject at an unacceptably high risk for toxicities;
15.
Subject has received an investigational drug within the 28 days prior to Screening;
16.
Any subjects will be excluded if prohibited from participation according to local 
laws or regulations.
Criteria Only For Subjects Receiving Bevacizumab:
17.
Prior treatment with bevacizumab;
18.
Known central nervous system metastases;
19.
Significant history of bleeding events or GI perforation;
●
Subjects with a history of significant bleeding episodes (e.g., hemoptysis, 
upper or lower GI bleeding) within 6 months of C1D–2 are not eligible unless 
the source of bleeding has been resected;
●
Subjects with a history of GI perforation within 12 months of C1D–2 are not 
eligible.
20.
Serious or non-healing wound, ulcer or bone fracture;
21.
History of venous or arterial thromboembolism within 2 months of enrollment;
22.
Known hypersensitivity to recombinant or murine antibodies.
Rationale for Exclusion Criteria
1 – 4, 7, 8, 11, 13, 16
To select the appropriate subject population with sufficient 
disease severity for evaluation
5, 6, 9, 10, 12, 14, 15
For the safety of the subjects
17 – 22
For the safety of subjects that receive bevacizumab


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5.2.3
Prior and Concomitant Therapy
Any medication, therapy, or vaccine (including over-the-counter or prescription 
medicines, vitamins and/or herbal supplements) that the subject is receiving beginning 
with the Screening Visit, receives during the study, and up to 30 days following the 
last dose of protocol therapy must be recorded along with the reason for use, date(s) of 
administration including start and end dates, and dosage information including dose, route 
and frequency.  Note:  Post-treatment cancer therapy information will be collected during 
survival (Section 5.4.5).
For purposes of this protocol, anti-cancer treatment, medication or therapy is defined as, 
but not limited to:  anti-cancer agents (cytotoxic chemotherapy, immunotherapy, biologic 
therapy and/or radiation therapy) and investigational agents.  An investigational agent is 
any drug or therapy not currently approved for use in humans.
For the purposes of study eligibility, subjects who have not received prior systemic 
chemotherapy after the diagnosis of metastatic colorectal cancer are considered 
"previously untreated."
General guidelines regarding cautionary, excluded, and permitted concomitant 
medications/therapies are summarized in Table 1, Table 2, and Table 3.
The locally approved product label or applicable Summary of Product Characteristics 
(SmPC) for irinotecan, leucovorin, and 5-FU should also be referenced for any 
concomitant therapy guidelines.
**Additional guidance for the use of concomitant medications is provided in the Toxicity 
Management Guidelines for Protocol Therapy (Appendix E, Appendix F, Appendix G, 
Appendix H, and Appendix I).**
The AbbVie Study Designated Physician identified in Section 6.7 should be contacted if 
there are any questions regarding prior therapy(ies) or concomitant medications/therapies.


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Table 1.
Cautionary Medications
Medication/Therapy
Comments
Therapies to Take 
Caution with When 
Administered with 
Irinotecan:
Strong CYP3A4 Inducers:  Anticonvulsants and other strong inducers:  
Exposure to irinotecan and its active metabolite SN-38 is substantially reduced 
in subjects concomitantly receiving the CYP3A4 enzyme-inducing 
anticonvulsants such as phenytoin, phenobarbital or carbamazepine.  
Consideration should be given to substituting non-enzyme inducing 
therapies at least 2 weeks prior to initiation of irinotecan therapy.
St. John's Wort:  Exposure to the active metabolite SN-38 is reduced in 
patients receiving concomitant St. John's Wort.  St. John's Wort should be 
discontinued at least 2 weeks prior to the first cycle of protocol therapy.
Strong CYP3A4 Inhibitors:  Discontinue at least 1-week prior to starting 
irinotecan therapy and do not use during irinotecan therapy.
Ketoconazole is a strong inhibitor of CYP3A4 enzymes.  Subjects receiving 
concomitant ketoconazole have increased exposure to irinotecan and its active 
metabolite SN-38.  Subjects should discontinue ketoconazole at least 1-week 
prior to starting protocol therapy.
Table 2.
Excluded Medications
Medication/Therapy
Comments
Anti-Cancer Treatment
Not permitted prior to enrollment and during protocol therapy; this includes 
hormonal therapy administered with the intent of using it as an anti-cancer 
therapy.
PARP Inhibitors
Not permitted prior to enrollment and during protocol therapy.
Alternate Therapy
Herbal remedies or non-prescription supplements with the intent of using 
them as an anti-cancer therapy are not permitted ≤ 2 weeks prior to C1D–2 
and during protocol therapy.
Ketoconazole
Not permitted during irinotecan therapy.
St. John's Wort
Not permitted during irinotecan therapy.


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Table 3.
Concomitant Medications/Therapies
Medication/Therapy
Comments
Premedication for Leucovorin
Refer to the locally approved product label or applicable SmPC
Premedication for Fluorouracil
Refer to the locally approved product label or applicable SmPC
Premedication for Irinotecan
Refer to the locally approved product label or applicable SmPC
Premedication for Bevacizumab
Refer to the locally approved product label or applicable SmPC
Supportive Care:
Permitted:  Best supportive care and treatment can be given as 
appropriate to each subject, including but not limited to 
anti-emetics, anti-diarrheal, antibiotics, steroids for adrenal failure, 
hormonal therapy administered for non-disease related conditions, 
blood and blood products, nutritional support, palliative treatment 
for pain, etc.
Growth Factors:
Permitted:  Biologic response modifiers administered for 
erythropoiesis (e.g., erythropoietin, darbepoetin alpha) may be 
administered during protocol therapy.  Granulocyte growth factors 
(e.g., G-CSF, GM-CSF, etc.) are to be administered according to the 
Investigator's standard practice and/or NCCN guidelines, 2014.  
Growth factors may be given with the intent to prevent dose 
reductions or delays.
Non-disease Related Surgery:
Non-disease related surgery during protocol therapy is permitted; 
however, the AbbVie Study Designated Physician must be 
contacted.  For patients receiving bevacizumab, refer to locally 
approved product information for specific guidelines regarding 
surgery.
Disease Related Surgery:
Disease related surgery during protocol therapy is permitted; 
however, the AbbVie Study Designated Physician must be 
contacted.  For subjects receiving bevacizumab, refer to locally 
approved product information for specific guidelines regarding 
surgery.
5.3
Efficacy Pharmacokinetic, Pharmacodynamic, 
Pharmacogenetic and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
The schedule of study activities are outlined in Table 4.  The schedule of 
pharmacokinetic, pharmacodynamics and pharmacogenetic assessments are presented in 


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Table 5 and Table 6.  The procedures outlined in Table 5 and Table 6 are discussed in 
detail in Section 5.3.2.


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Table 4.
Study Assessments
Activity*^
Screening
Cycle 1 Day –2
Cycle 1 Day 1
Cycle 1 Day 8
Cycle 2 Day 1
Cycle 2 Day 8
Day 1 of Each 
Cycle
Every 8 Weeks 
from C1D1^
Final Visita
30-Day 
Follow-Up Visitb
Survival Periodc
Informed Consentd
X
Medical and Cancer History
X
Physical Exam
Xe
Xe
X
X
X
X
Subject Weight
X
X
X
X
12-lead ECG
X
X
Vital Signs
X
X
X
X
X
X
X
Performance Status (ECOG)
X
X
X
X
X
Pregnancy Testf
X
X
Hematologyg
X
X
X
X
X
X
X
X
X
Chemistryg
X
X
X
X
X
X
X
X
X
Urinalysisg
X
Xh
Xh
Xh
Xh
Xh
Xh
aPTT/PT/INRg
X
CEA
X
Xi
Tumor Assessments
Xj
Xj
X
Randomizationk
X


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Table 4.
Study Assessments (Continued)
Activity*^
Screening
Cycle 1 Day –2
Cycle 1 Day 1
Cycle 1 Day 8
Cycle 2 Day 1
Cycle 2 Day 8
Day 1 of Each 
Cycle
Every 8 Weeks 
from C1D1^
Final Visita
30-Day 
Follow-Up Visitb
Survival Periodc
Dispense veliparib/placebol
X
X
X
X
Administer Veliparib/Placebo at the sitem
X
X
X
X
Administer Bevacizumabk
X
X
X
Administer FOLFIRIn
X
X
X
AE Assessmentso
X
X
X
X
X
X
X
X
X
Prior and Concomitant Therapy Assessments
X
X
X
X
X
X
X
X
X
Post-treatment Cancer Information
X
Date and Cause of Death
X
*
Refer to Table 5 and Table 6 for the schedule of PK, PG, and PD assessments.
^
Subjects who discontinue protocol therapy prior to reaching an event of disease progression are to continue attending study visits and radiographic assessments until 
progression.
For all study procedures:  At the discretion of the Investigator, additional monitoring can be done if clinically indicated.
Timing of Study Procedures:  Screening procedures must be performed within 28 days prior to C1D–2.  For procedures performed at Screening then repeated on C1D–2 prior to 
dosing, the later procedure(s) will serve as baseline for clinical assessment and must still meet all eligibility criteria.  Subsequent study visits may be performed 4 days surrounding 
(± 2 days) the scheduled visit date, with the exception of scheduled tumor assessments and laboratory tests.  Tumor assessments can be performed up to 4 days prior to a scheduled 
tumor assessment, but should be performed prior to administration of the next scheduled cycle of FOLFIRI.  Clinical laboratory tests must be performed up to 48 hours prior to 
dosing, not after dosing.


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Table 4.
Study Assessments (Continued)
a.
When an Investigator has determined that a subject should discontinue protocol therapy and attending study visits, a Final Visit will be conducted.
b.
All subjects will have one Follow-Up Visit approximately 30 days after the last dose of protocol therapy.  If a subject is discontinued from the study with an ongoing adverse 
event or an unresolved clinically significant laboratory result, the site will attempt to provide follow-up until a satisfactory clinical resolution of the laboratory results or 
adverse event is achieved.
c.
Sites will be collecting survival information and post-treatment cancer information beginning 4 weeks after the last study visit and continuing every 4 weeks for 1 year, then 
every 8 weeks for up to 2 additional years or until the endpoint of death.
d.
Must be performed prior to initiation of any screening or study specific procedures.
e.
Height is only measured at Screening.  Physical exam is not required on C1D–2 if one has been performed within the last 7 days.
f.
For women with potential childbearing status, serum pregnancy test will be done at Screening.  Urine pregnancy test will be done prior to dosing at C1D–2 unless the serum 
pregnancy test was collected within 7 days of C1D–2.  Subjects with non-childbearing status do not require pregnancy tests.
g.
All laboratory samples will be assessed using a central laboratory and these data will be used for all data analysis.  A local reference laboratory mayperform chemistry, 
hematology, coagulation, and urinalysis tests for immediate subject management (i.e., emergent situations); however, split or concurrent samples must be drawn and sent to 
the central laboratory for analysis.
h.
Urinalysis is required for all subjects at Screening.  Subsequent testing is then only required for those that are receiving bevacizumab.  For proteinuria of ≥ 2+:  Confirm total 
urine protein with a 24-hour urine collection or urine protein to creatinine (UPC) ratio.  Refer to Appendix I (Proteinuria) for additional guidance.
i.
A CEA blood test will only need to be repeated if it is elevated above ULN at baseline.
j.
Baseline tumor assessments must be conducted within 28 days prior to C1D–2.  Post-baseline tumor assessment will be conducted every 8 weeks from C1D1 until 
radiographic progression.  Scheduled tumor assessments will not be affected by delays in therapy and/or drug holidays.  Tumorassessments should be conducted prior to the 
start of the next scheduled cycle of FOLFIRI.  An unscheduled tumor assessment should be performed if the subject discontinues from the study for a reason other than 
radiographic progression, and no scan has been performed within the last 4 weeks.
k.
Bevacizumab use is optional.  Investigators must declare their planned use of bevacizumab at the time of randomization.
l.
Sufficient medication will be dispensed to cover the remaining cycle and pre-dosing for the subsequent cycle.
m.
On days that pre-dose PK and PD sampling is required (refer to Table 5 and Table 6), dosing will occur in the morning at the site to facilitate PK and PD sampling.  Instruct 
subjects not to take veliparib/placebo at home.
n.
FOLFIRI is to be given only after veliparib/placebo dosing on Day –2 and Day –1 of each cycle is confirmed.  Site pharmacy personnel will be unblinded and should prepare 
the bolus with 5-FU for subjects randomized to the placebo arm and without 5-FU for subjects randomized to the veliparib arm.
o.
See Section 6.6, Adverse Event Collection, for details.


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Table 5.
Schedule of Pharmacokinetic (PK) Assessments
Procedure
Visit 
Schedule
Before Drug 
Administration
After Veliparib 
AM Dose
Sampling Plan
Specimen Matrix
Veliparib PK 
Sampling
C1D–2
--
1, 2, 3 h
Blood →Plasma
Frozen (as per the study 
specific laboratory manual)
Veliparib PK 
Samplinga
C2D1 and 
C3D1
0 ha
--
Blood →Plasma
Frozen (as per the study 
specific laboratory manual)
a.
Before the administration of the morning dose of veliparib/placebo.  Veliparib/placebo dosing will occur in the 
morning at the site to facilitate PK sampling.  Instruct subjects not to take the morning dose of veliparib/placebo at 
home.
Table 6.
Schedule of Pharmacogenetic (PG) and Pharmacodynamic (PD) 
Assessments
Activity
Visit Schedule
Before Drug 
Administration
Sampling Plan
Specimen Matrix
Optional with Consent 
PG Blood Sampling*
Genetic (DNA)
C1D–2
Not applicable
Whole Blood
Frozen (as per the study 
specific laboratory manual)
Final Visit
PD Blood Sampling
Plasma Markersa,b
C1D–2, C2D1, Final 
Visit
Pre-dose**
At the time of the 
study visit
Blood →Plasma
Frozen (as per the study 
specific laboratory manual)
Serum Markersc
C1D–2, C2D1, Final 
Visit
Pre-dose**
At the time of the 
study visit
Blood →Serum
Frozen (as per the study 
specific laboratory manual)
Tissue Sample
Collection
Screeningd
Archived FFPE tissue blocks 
(Room Temperature or 
Refrigerated-FFPE)
MSI Testing Control 
Sample
C1D–2
N/A
Blood
Frozen –20°C or colder
* 
(Optional) only to be collected after additional informed consent is obtained.
**
Veliparib/placebo dosing will occur in the morning at the site to facilitate PD sampling.  Instruct subjects not to 
take the morning dose of veliparib/placebo at home.
a.
At C1D–2 and the Final Visit, 12 mL of blood for plasma markers will be collected.  At C2D1, it will be 6 mL of 
blood.
b.
Processing should be completed in less than 60 minutes of sample being drawn.
c.
Processing should be completed in less than 90 minutes of sample being drawn.
d.
Sites should make every effort to obtain archived, diagnostic tissue sample by the C3D1 study visit.


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5.3.1.1
Study Procedures
The study procedures outlined in Table 4 are discussed in detail in this section, with the 
exception of administering protocol therapy (Section 5.5), Final Visit (Section 5.4.3), 
30-day Safety Follow-Up Visit (Section 5.4.4), and Survival and Post-Treatment Cancer 
Information (Section 5.4.5).  All study data will be recorded on electronic case report 
forms (eCRFs).
For all study procedures:  The study procedures outlined in this protocol are 
recommendations based on routine safety assessments required during chemotherapy and 
veliparib administration.  At the discretion of the Investigator, additional monitoring can 
be done whenever clinically indicated.
Timing of Study Procedures
Screening procedures must be performed within 28 days prior to C1D–2.  For procedures 
performed at Screening then repeated on C1D–2 prior to dosing, the later procedure(s) 
will serve as baseline for clinical assessment and must still meet all eligibility criteria.  
Subsequent study visits may be performed 4 days surrounding (± 2 days) the scheduled 
visit date, with the exception of the following:
●
If the Screening physical examination is performed within 7 days of C1D–2, it 
is not required to repeat the exam on C1D–2 unless clinically indicated.
●
Tumor assessments can be performed up to 4 days prior to a scheduled tumor 
assessment, but should be performed prior to administration of the next 
scheduled cycle of FOLFIRI.
●
Clinical laboratory tests should be performed up to 48 hours prior to dosing.
Informed Consent
Signed informed consent will be obtained from the subject before any study procedures 
are undertaken or before any prohibited medications are withheld from the subject in 
order to participate in this study.


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A separate optional informed consent will be required for pharmacogenetic testing.  
Details about how informed consent will be obtained and documented are provided in 
Section 9.3.
In the event of pregnancy occurring in the partner of an enrolled subject, written informed 
consent for release of medical information from the partner must be obtained.  Details 
about how informed consent will be obtained and documented are provided in Section 6.8.
Subjects will be considered screen failures if the informed consent has been signed and a 
study specific procedure has been performed (e.g., central labs drawn), but subject does 
not randomize into the study.  The informed consent process for subjects will be repeated 
in the event the site obtains written permission from the AbbVie Study Designated 
Physician to re-screen a subject for the study.
Medical History
A complete medical history, including documentation of the following:
●
Clinically significant medical condition(s);
●
History of tobacco and alcohol use;
●
Surgical history;
●
Date subject was diagnosed with colorectal cancer and pathology information;
●
RAS status (if known);
●
BRAF status (if known);
●
Microsatellite instability (MSI) status (if known).
On C1D–2 any changes observed from the screening assessments, prior to dosing, will be 
recorded in the subject's medical history.  At each subsequent visit, the subject's medical 
history will be reviewed and any clinically significant changes from baseline will be 
recorded in the source documents and on the adverse event eCRF.


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Physical Examination and Body Weight
A physical examination will be performed per Table 4.  Clinically significant changes 
from baseline will be documented in the source documentation and eCRFs as adverse 
events.
Body weight will be measured only at the visits identified in Table 4.
Height will be measured at the Screening Visit only.  For height and weight assessments, 
the subject should not wear shoes.
Vital Signs
Vital signs will be performed per Table 4.  Vital sign determinations include sitting blood 
pressure, heart rate and body temperature.  If possible, blood pressure and heart rate 
measurements should not immediately follow scheduled blood collections.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed per Table 4.  A qualified physician will 
determine whether any findings outside of normal physiological variation are clinically 
significant (in consultation with a cardiologist if necessary).  The physician will document 
whether findings are clinically significant or not clinically significant on the tracing and 
sign and date the tracing.  The original annotated ECG tracing along with a photocopy of 
the tracing containing the physician's assessment will be retained in the subject's records 
at the study site.
ECOG Performance Status
The ECOG performance status will be assessed per Table 4 as follows:


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Grade
ECOG
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 all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours.
3
Capable of only 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.
Documentation of Non-Childbearing Status or Pregnancy Test
For each female subject, the Investigator will document non-childbearing status 
(surgically sterile or post-menopausal for at least 1 year) or potential childbearing status.  
Subjects with non-childbearing status do not require pregnancy tests.  For subjects of 
childbearing potential, a serum pregnancy test will be performed at Screening and the 
results must be available prior to the administration of the first dose of protocol therapy on 
C1D–2.  A urine pregnancy test should also be performed prior to dosing on C1D–2 if 
> 7 days since obtaining Screening serum test results.  The test results must be reviewed 
and determined to be negative prior to dosing.  A positive urine pregnancy test will be 
confirmed with a serum pregnancy test.  Pregnancy tests may also be repeated at the 
discretion of the Investigator at any time during the study.
Should a female study subject become pregnant or suspect she is pregnant while 
participating in this study, she should inform the Investigator immediately (Section 6.8).  
Subjects with confirmed pregnancy must immediately discontinue protocol therapy and 
must be discontinued from the study.


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Clinical Laboratory Tests
Laboratory samples will be collected per Table 4.  Specific laboratory tests are listed in 
Table 7.  Qualified medical staff at the site will review, initial and date all local and 
central laboratory results.  Any laboratory value outside the reference range that is 
considered clinically significant by the Investigator will be followed as appropriate.  
Clinically significant laboratory values will be recorded as adverse events if they meet the 
criteria as specified in Section 6.0.
All laboratory samples will be assessed using a central laboratory and these data will be 
used for all data analysis.  The central laboratory will provide instructions regarding the 
collection, processing, handling, and shipping of samples.  All clinical laboratory samples 
will be shipped to the central laboratory.
A local reference laboratory may perform chemistry, hematology, coagulation, and 
urinalysis tests for immediate subject management (i.e., emergent situations); however, 
split or concurrent samples must be drawn and sent to the central laboratory for analysis.  
The appropriate certifications will be collected for both the central and local laboratories 
as needed.
**If there is a discrepancy between the local and central labs, the site must enter the 
relevant local labs that were used for treatment decisions on the appropriate eCRF.**


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Table 7.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count (estimate not
acceptable)
Blood Urea Nitrogen (BUN)
Creatinine
Total bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Calcium
Inorganic phosphate
Uric acid
Total protein
Glucose
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate/CO2
Estimated Glomerular Filtration
Rate (eGFR)
Specific gravity
Ketones
pH
Protein*
Blood
Glucose
Tumor Marker
Carcinoembryonic antigen 
(CEA)**
Coagulation Tests
Serum Pregnancy Test
Prothrombin time (PT)
Activated partial thromboplastin 
time (aPTT)
International normalized ratio 
(INR)
Human Chorionic 
Gonadotropin (hCG)***
*
For proteinuria of ≥ 2+, confirm total urine protein with a 24-hour urine collection.
**
A CEA will only need to be repeated after screening if elevated above the ULN at baseline.
*** At Screening and at any time point in which pregnancy is suspected or following a positive urine pregnancy test.
Tumor Assessments (Radiologic)
A CT scan of all areas of metastatic disease (including the neck, chest, abdomen, and/or 
pelvis (where appropriate) using RECIST, Version 1.1 will be used in the evaluation of 
tumor responses.  If the subject is unable to undergo a CT scan with IV contrast due to 
allergy or renal insufficiency, a non-contrast CT may be performed.  Magnetic resonance 
imaging (MRI) can be conducted instead of CT scans in cases where local 
laws/requirements mandate or when an MRI would be a better tool for tumor assessments.  
Subjects are to continue monitoring by the same methods unless evidence of tumor 
metastasis warrants otherwise or a medical contraindication is noted.


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Baseline tumor assessments must be conducted within 28 days prior to C1D–2.  
Post-baseline tumor assessment will be conducted every 8 weeks from C1D1 until 
radiographic progression.  Scheduled tumor assessments will not be affected by delays in 
therapy and/or drug holidays.  Scheduled tumor assessments should be performed prior to 
the administration of the next cycle of FOLFIRI.  An unscheduled tumor assessment 
should be performed if the subject discontinues from the study for a reason other than 
radiographic progression, and no scan has been performed within the last 4 weeks.
For the purposes of this protocol, complete or partial responses do not need to be 
confirmed on a subsequent scan following initial documentation of the response.
AbbVie may require that sites electronically transfer copies of all CT or MRI scans used 
for radiographic tumor assessments.  Instructions regarding procedures for transferring 
scans will be provided in a separate manual.
Randomization and Subject Number Assignment
An IRT system will be utilized to register subjects on study.  The site will contact the IRT 
to obtain a screening (subject) number once the subject has signed informed consent and a 
study specific procedure has been performed (e.g., central labs drawn).  Once the 
screening number is assigned, if the subject is not randomized into the study, the reason 
for screen failure will be documented in the source and captured in the IRT system and 
documented in the eCRF.
Subjects who complete all screening procedures and meet the eligibility criteria can 
proceed to randomization.  The site will access the IRT and a unique randomization 
number will be provided.  During the randomization process, subjects will be randomized 
in a 1:1 ratio to either veliparib 200 mg BID plus FOLFIRI or placebo BID plus FOLFIRI 
(bevacizumab will be administered at the discretion of the Investigator).  
Note:  The use of bevacizumab must be known prior to randomization and when 
accessing the IRT for randomization.


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A bottle number randomization schedule and a subject randomization schedule will be 
generated by the Clinical Statistics Department at AbbVie prior to the start of the study.  
A copy of all randomization schedules will be kept by the Clinical Statistics Department 
at AbbVie and a copy will be forwarded to the IRT vendor.
5.3.2
Drug Concentration Measurements
5.3.2.1
Blood Samples for Pharmacokinetic Analysis
Veliparib Pharmacokinetic Specimen Collection
The date and time of each blood sample collection will be recorded.  The date and time of 
the veliparib/placebo dose on PK sampling days (refer to Table 5) and the date and time 
of the two doses of veliparib/placebo prior to PK sampling on C2D1 and C3D1 will be 
captured on the eCRF.  Blood samples (3 mL) will be collected by venipuncture into 
evacuated potassium (K2) EDTA tubes per Table 5.
Sufficient blood will be collected to produce approximately 1 mL of plasma for each 
sample.
Processing and Shipment of Pharmacokinetic Samples
All samples should be processed, labeled and shipped as outlined in the study specific 
laboratory manual.  An inventory of the samples being shipped will accompany the 
package.
5.3.2.2
Measurement Methods
Plasma concentrations of veliparib will be determined using a validated method under the 
supervision of the Drug Analysis Department at AbbVie.  Additionally, veliparib 
metabolite(s) concentrations in plasma samples may be determined using a non-validated 
or a validated assay.


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5.3.2.3
Blood Samples for Pharmacogenetic Analysis
Two 4 mL whole blood sample for DNA isolation will be collected from each subject who 
consents to provide a sample for pharmacogenetic analysis.  The procedure for obtaining 
and documenting informed consent is discussed in Section 9.3.  The first sample will be 
collected at C1D–2 and the second sample will be collected at the final visit.
The sample collection tubes will minimally be labeled with "PG-DNA blood," protocol 
number, subject number and visit.  Samples will be shipped frozen to AbbVie or a 
designated laboratory for DNA extraction and long-term storage.  Instructions for the 
preparation and shipment of pharmacogenetic samples will be provided in the lab manual.
AbbVie will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.  The samples will be retained while research on Veliparib (or 
drugs of this class) continues but no longer than 20 years.
5.3.2.4
Blood Samples for Pharmacodynamic Analysis
Pharmacodynamic correlative studies are exploratory in nature.  Serum, plasma and tissue 
specimens may be utilized to evaluate known and novel markers (nucleic acids, 
peptides/proteins and/or metabolites) of disease status.  PD variables will be further 
discussed in Section 5.3.7.
Blood Collection for Plasma Markers
Twelve (12) mL or 6 mL of blood will be collected pre-dose by venipuncture at 
timepoints outlined in Table 6 in conjunction with PK samples, if possible.  The 
collection, processing and storage should be performed as described in the study specific 
laboratory manual.  The complete process of centrifugation, transfer to cryovial and 
freezing should be accomplished in less than 1 hour from the time of blood draw.


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Blood Collection for Serum Markers
Approximately 5 mL of blood will be collected pre-dose by venipuncture at timepoints as 
outlined in Table 6.  The collection, processing and storage should be performed as 
described in the study specific laboratory manual.  The complete process of clot 
formation, centrifugation, transfer to cryovials and freezing should be accomplished in 
less than 90 minutes from the time of blood draw.
Archived Tissue Collection
Subjects must provide available archival tissue for analysis.  The most recent archived 
biopsy is preferred and should be obtained during screening if possible; however, every 
effort should be made to obtain the tissue sample by the C3D1 study visit.  While sending 
FFPE blocks is preferred, slides prepared by the local pathology laboratory are acceptable 
and should be prepared as described in the study specific laboratory manual.  Study 
specific biopsies are not required for subject participation.
Collection of MSI Testing Control Sample
One 4 mL whole blood sample for DNA isolation will be collected at C1D–2 from each 
subject.  The collection, processing and storage should be performed as described in the 
study specific laboratory manual.
Shipment of Pharmacodynamic Samples
All samples should be labeled and shipped as outlined in the study specific laboratory 
manual.  An inventory of the samples being shipped will accompany the package.
5.3.3
Efficacy Variables
Disease progression will be defined as clinical progression as determined by the 
Investigator, or radiographic progression of disease by RECIST, Version 1.1 
(Appendix D).18


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5.3.3.1
Primary Variable
The primary efficacy endpoint is progression-free survival.
5.3.3.2
Secondary Variables
Secondary efficacy endpoints are overall survival (OS) and objective response rate 
(ORR).
5.3.3.3
Tertiary Variables
The tertiary efficacy endpoints are duration of overall response (DOR) and Eastern 
Cooperative Oncology Group (ECOG) performance status.
5.3.4
Safety Variables
AbbVie will assess adverse events, laboratory data, and vital signs.  Adverse events will 
be assessed according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events NCI CTCAE Version 4.0.19  During the conduct of the study, the AbbVie 
medical and safety team will be monitoring subject laboratory results and serious adverse 
event data as it is reported.
The AbbVie Study Designated Physician and safety team will review individual patient 
safety data during planned interim analyses and aggregate safety data on a regular basis 
for continued safety assessment.
5.3.5
Pharmacokinetic Variables
A nonlinear mixed effect modeling analysis will be conducted to estimate the population 
pharmacokinetic parameters of veliparib such as apparent oral clearance (CL/F) and 
volume of distribution (V/F).
AbbVie or a designated laboratory will store the pharmacokinetic samples in a secure 
storage space with adequate measures to protect confidentiality.  To increase confidence 
in trends, remaining sample aliquots may be used to perform replicate tests, or sample 


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analysis at additional time points for tests currently identified in the protocol.  Upon 
completion of this research AbbVie or a designated laboratory will destroy the samples.
5.3.6
Pharmacogenetic Variables
DNA samples may be sequenced and data analyzed for genetic factors contributing to the 
disease or to the subject's response to veliparib (or other study treatment) in terms of 
pharmacokinetics, efficacy, tolerability, and safety.  Such genetic factors may include 
genes for drug metabolizing enzymes, drug transport proteins, genes within the target 
pathway, genes believed to be related to the disease or to drug response.  Some genes 
currently insufficiently characterized or unknown may be understood to be important at 
the time of analysis.  The samples may be analyzed as part of a multi-study assessment of 
genetic factors involved in the response to veliparib, drugs of this class, or the disease 
state.  The samples may also be used for the development of diagnostic tests related to 
veliparib, drugs of this class, or the disease state.  The results of pharmacogenetic analyses 
may not be reported with the study summary.
5.3.7
Pharmacodynamic Variables
Several putative biomarkers of efficacy and response may be evaluated in this protocol 
with the goal of exploring the relationship between tumor response and/or disease status.
Biospecimens collected may be evaluated for genetic lesions whether they occur by 
amplification, chromosomal loss and/or mutational/methylation with the intent of 
identifying potential associations with subject outcome or to better characterize the 
disease.  These characterizations may be included, but are not limited, characterization of 
gene methylation/mutational status or copy number changes of genes, particularly those 
involved in DNA repair pathways.  Additional analysis aimed at identifying underlying 
defects in the homologous recombination pathway, regardless of etiology, may be 
performed and associated with response.
Biospecimens may be evaluated for levels of biomarkers including nucleic acids, 
proteins/peptides and metabolites.  For example, protein analysis of relevant proteins, 


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including but not limited to, DNA repair proteins, such as ERCC1 and XPF, may be 
performed on tumor tissue obtained from each consented subject.
AbbVie (or people or companies working with AbbVie) will store and analyze the 
samples in a secure space with adequate measures to protect confidentiality.  Samples will 
be retained up to 20 years (or per local legal requirement) while research on veliparib (or 
drugs of this class) or colorectal cancer (or related conditions) continues.
5.4
Removal (Discontinuation) of Subjects from Protocol 
Therapy and Study Visits
Each subject also has the right to withdraw from the study (withdraw from protocol 
therapy and attending scheduled study visits) at any time.  In addition, the Investigator 
may discontinue a subject from the study at any time for any reason if the Investigator 
considers it necessary, including the occurrence of an adverse event or noncompliance 
with the protocol.
In the event a subject withdraws consent from participating in the study, stored 
pharmacodynamic samples will continue to be used for research and analysis.  In the 
event that a subject would like to withdraw consent for research of samples, the subject 
may request for samples to be withdrawn.  Once AbbVie receives the request, remaining 
samples will be destroyed unless the FDA requires AbbVie to keep the samples.  If the 
subject changes his/her consent, and the samples have already been tested, those results 
will still remain part of the overall research data.
When subject discontinuation from the study is planned without the subject reaching a 
protocol-defined endpoint, the Investigator will notify the individuals listed in Section 7.0
via telephone and/or email, as soon as possible (provided, in each case, subject care and 
safety are not compromised).  If not notified prior to study discontinuation, the AbbVie 
Study Designated Physician or designee may contact the site to discuss the reason for 
withdrawal from the study.


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The Investigator, or designee, must report when a subject discontinues protocol therapy 
and/or scheduled study visits in the IRT system.  After a subject discontinues protocol 
therapy and stops attending scheduled study visits they will be followed for survival and 
post-treatment cancer information for up to 3 years or until the end point of death.
5.4.1
Discontinuing Subjects from Protocol Therapy
Tumor Response
Subjects who achieve a CR, PR, or SD should continue on protocol therapy until 
intolerable toxicity, or if there is documented clinical or radiographic progression.  
Clinical data that supports colorectal progression will be collected on the appropriate 
eCRF.
Surgical Intervention
As a result of treatment, subjects may suspend protocol therapy to undergo surgical 
resection with curative intent for metastatic disease.  Subjects may then restart protocol 
therapy beginning with the next scheduled cycle provided they have recovered from 
surgery and the Investigator believes that continuing treatment would be in the best 
interests of the subject.  With respect to tumor measurements, subjects who undergo 
surgical resection must undergo radiographic assessment within 14 days of resuming 
protocol therapy.  This scan will serve as the new post-surgery baseline.  Target or 
non-target lesions existing before and remaining after surgery should continue to be 
evaluated using RECIST, Version 1.1.  Subjects can remain on study until there is clinical 
or radiographic disease progression (i.e., a new lesion) or the subject meets other 
discontinuation criteria.  Investigators should refer to locally approved product 
information guidelines before any surgical intervention.  Details regarding tumor response 
measurements can be found in Appendix D.
Additional Criterion for Discontinuation of Protocol Therapy
Subjects will discontinue protocol therapy if any of the following occur:


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●
The subject experiences unacceptable protocol therapy toxicity (refer to 
Appendix E, Appendix F, Appendix G, Appendix H, and Appendix I) or the 
Investigator believes it is otherwise in the best interest of the subject;
●
Subject is suspected to be pregnant; pregnancy is confirmed or begins 
breastfeeding during the treatment portion of the study;
●
The subject decides to withdraw consent for any reason;
●
Any other medical reason that AbbVie or the Investigator deems appropriate.
The Investigator, or designee, must report when a subject discontinues protocol therapy 
for any reason in the IRT.
5.4.2
Discontinuing Subjects from Study Visits
When subjects reach an event of disease progression, a Final Visit and 30-Day Safety 
Follow-Up Visit should be conducted.
Subjects who discontinue protocol therapy prior to reaching an event of disease 
progression should continue to receive radiographic assessments per Table 4 until 
documented clinical or radiographic disease progression is experienced, if possible.
The Investigator, or designee, must report when a subject stops attending scheduled study 
visits in the IRT.
5.4.3
Final Visit
When a subject discontinues protocol therapy, a Final Visit will be conducted (preferably 
prior to the initiation of another anti-cancer therapy).  However, these procedures should 
not interfere with the initiation of any new treatments or therapeutic modalities that the 
Investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of the protocol therapy, the subject will be treated in accordance with the Investigator's 
best clinical judgment.
At the Final Visit, the reason(s) for the discontinuation from the study will be recorded 
and assessments will be performed per Table 4.


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5.4.4
Follow-Up Visit
All subjects will have one Follow-Up Visit approximately 30 days after the last dose of 
protocol therapy.  If a subject is discontinued from the study with an ongoing adverse 
event or an unresolved clinically significant laboratory result, the site will attempt to 
provide follow-up until a satisfactory clinical resolution of the laboratory results or 
adverse event is achieved.
5.4.5
Timing and Collection of Survival and Post-Treatment 
Cancer Information
Subjects who discontinue protocol therapy will be followed for survival (the date and 
cause of death or last known alive date if not deceased) and post-treatment cancer 
information.  Sites will collect survival information and post-treatment cancer information 
beginning 4 weeks after the last clinical assessment and continuing every 4 weeks for 
1 year, then every 8 weeks for up to 2 additional years or until the endpoint of death.  
Survival and post-treatment cancer information will be collected in the electronic data 
capture (EDC) system.
Every effort should be made by study staff to follow each subject for survival and 
post-treatment cancer information.  In the event a subject no longer wants to be contacted, 
they must specifically withdraw consent from the collection of survival and post-treatment 
cancer information collection.  Study staff may use a public information source (such as 
county records) to obtain information about survival status only, as appropriate per local 
regulations.
5.4.6
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  


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Advance notice is not required by either party if the study is stopped due to safety 
concerns.
The following procedures for study discontinuation will be followed:
●
If the Sponsor has decided to prematurely discontinue the study, the Sponsor 
will promptly notify in writing each Investigator as well as regulatory 
authorities of the decision and give detailed reasons for the discontinuation.
●
Each Investigator must promptly notify the IRB/IEC and give detailed reasons 
for the discontinuation.
●
Each Investigator must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments such as replacement of 
protocol therapy, if applicable, by other appropriate regimens.
5.5
Treatments
5.5.1
Protocol Therapy Administered
Subjects will be randomized to one of the following protocol therapy groups:
●
Veliparib 200 mg PO BID Day –2 through Day 5 plus modified FOLFIRI 
(irinotecan IV 180 mg/m2; leucovorin IV 400 mg/m2; saline IV bolus; 5-FU IV 
2400 mg/m2) ± bevacizumab (5 mg/kg) administered on Day 1 of each 14-day 
cycle;
●
Placebo 200 mg PO BID Day –2 through Day 5 plus standard FOLFIRI 
(irinotecan IV 180 mg/m2; leucovorin IV 400 mg/m2; 5-FU IV 400 mg/m2
bolus; 5-FU IV 2400 mg/m2) ± bevacizumab (5 mg/kg) administered on Day 1 
of each 14-day cycle.
Dispensing Protocol Therapy
Randomized subjects will receive sufficient quantities of veliparib/placebo for Cycle 1 
Days –2 to 1 by dispensing on C1D–2.  Beginning with C1D1, subjects will receive 
veliparib/placebo for Days 1 – 5 of the current cycle and a separate bottle for Days –2 and 


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–1 of the following cycle.  This dispensing schedule will allow subjects to begin 
veliparib/placebo dosing prior to the start of the next FOLFIRI cycle without requiring a 
return to the investigative site prior to FOLFIRI administration.  The IRT will assign 
every bottle of study drug to be dispensed to a subject.  Prior to each scheduled drug 
dispensation visit, site personnel must contact IRT for the next bottle number assignment.  
Study medication cannot be dispensed without contacting the IRT.  AbbVie or designee 
will provide specific instructions on the use of IRT.
FOLFIRI and bevacizumab should be obtained commercially via the site pharmacy.  Site 
pharmacy personnel should prepare the bolus with 5-FU for subjects randomized to the 
placebo arm, or without 5-FU for subjects randomized to the veliparib arm.  Site 
pharmacy personnel are responsible for ensuring that the appearance of the bolus does not 
compromise the blind for the subject, Investigator, or other site staff.  Trained site 
personnel will administer FOLFIRI and bevacizumab (if the Investigator chooses to use 
bevacizumab) intravenously on Day 1 of each 14-day cycle.  Subjects will be supervised 
at the time of the infusion.
FOLFIRI and bevacizumab are to be given only after veliparib/placebo dosing on cycle 
Day –2 and Day –1 are confirmed.  If veliparib/placebo was not taken by the subject on 
Day –2 and Day –1, a new supply of veliparib is to be dispensed, and Day –2 and Day –1 
are to be repeated for that cycle.
Sites may calculate body surface area (BSA) per local treatment practice.  Bevacizumab 
and FOLFIRI doses should be calculated based on the weight measurement obtained at 
C1D1.  Subsequent bevacizumab and FOLFIRI doses must be recalculated if a subject's 
body weight increases or decreases by more than 10%.
On days that pre-dose PK and PD sampling is required (refer to Table 5 and Table 6), 
dosing of veliparib will occur in the morning at the clinic to facilitate PK and PD 
sampling.


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Administration of Veliparib/Placebo
Subjects will self-administer the morning dose of veliparib/placebo and the evening dose 
of veliparib/placebo approximately 12 hours after the morning dose with or without food 
in the same calendar day.
It is recommended that if a subject misses a scheduled dose of veliparib/placebo and less 
than 6 hours have passed since the scheduled dosing time, the dose should be immediately 
taken.  It is recommended that if more than 6 hours have passed since the scheduled 
dosing time, the subject should not take the missed dose but should wait for the next 
regularly scheduled dose.
If the subject vomits within 15 minutes of taking veliparib/placebo, 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.  The subject is to contact the 
Investigator if additional veliparib/placebo is needed to complete BID dosing through 
Day 5 of the cycle.
Subjects will be provided self-administration instructions and subject dosing cards to 
record the date and time the veliparib/placebo was administered.  Subjects will be 
instructed to store veliparib/placebo according to specific directions included in 
Section 5.5.6.  Subjects should return bottles of veliparib/placebo (empty, partially filled 
or full) to the study site prior to each cycle and at the Final Visit.
Administration of Irinotecan
For the purposes of this protocol, irinotecan 180 mg/m2 will be administered as a 
90 minute (± 30 minutes) IV infusion on Day 1 of each 14-day cycle.  Investigators 
should evaluate subjects for irinotecan treatment per the locally approved product label, 
local practice, or applicable SmPC.


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Administration of Leucovorin
For the purposes of this protocol, leucovorin 400 mg/m2 will be administered as a 
90 minute (± 30 minutes) IV infusion concurrent with irinotecan on Day 1 of each 14-day 
cycle.  Irinotecan and leucovorin may be administered sequentially in accordance with 
local practice.  Investigators should evaluate subjects for leucovorin treatment per the 
locally approved product label, local practice, or applicable SmPC.
Administration of Fluorouracil (5-FU) Bolus
For the purposes of this protocol, administration of a 5-FU bolus will be contingent on 
whether subjects are randomized to the veliparib or placebo arm.  For subjects 
randomized to the placebo arm, a 5-FU 400 mg/m2 bolus (up to 15 minutes) will be 
administered.  For subjects randomized to the veliparib arm, a saline bolus (up to 
15 minutes) will be administered.  Site pharmacy personnel will have access to the 
treatment arm assignment via the IRT system and should prepare the bolus accordingly.  
Investigators should evaluate subjects for 5-FU treatment per the locally approved product 
label, local practice, or applicable SmPC.
Administration of Fluorouracil (5-FU) Infusion
For the purposes of this protocol, 5-FU 2400 mg/m2 will be administered as a 46-hour 
(± 4 hours) IV infusion on Day 1 of each 14-day cycle.  Investigators should evaluate 
subjects for 5-FU treatment per the locally approved product label, local practice, or 
applicable SmPC.
Administration of Bevacizumab
At the discretion of the Investigator, bevacizumab may be administered at 5 mg/kg 
intravenously immediately preceding FOLFIRI on Day 1 of each 14-day cycle.  The 
initial dose of bevacizumab should be given over 90 minutes (± 30 minutes), second dose 
over 60 minutes (± 20 minutes), and all subsequent doses over 30 minutes (± 10 minutes) 
if prior infusions are tolerated without infusion associated adverse events.


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Order of Administration
Protocol therapy will be administered in the following order:  veliparib/placebo followed 
by FOLFIRI as irinotecan concurrent with leucovorin followed by a saline or 5-FU 
bolus followed by 5-FU infusion.  For the purposes of this protocol, veliparib/placebo 
should always be given first.
Irinotecan and leucovorin may be administered sequentially in accordance with local 
treatment practice.
At the Investigator's discretion, bevacizumab may be administered at 5 mg/kg 
intravenously after veliparib/placebo and immediately preceding FOLFIRI on Day 1 of a 
14-day cycle.
Dose Modifications for Obese Patients
There is no clearly documented adverse impact of treatment of obese subjects when 
dosing is performed according to actual body weight.  Therefore, all dosing is to be 
determined solely by the subject's actual weight without any modification.  This will 
eliminate the risk of calculation error and the possible introduction of variability in dose 
administration.  Investigators who are uncomfortable with administering chemotherapy 
dose based on actual body weight should not enroll obese subjects.
5.5.2
Toxicity Management and Protocol Therapy Dose 
Reductions or Delays
Specific guidelines for toxicity management and dose reductions or delays for protocol 
therapy are discussed in Appendix E (General Guidelines), Appendix F (Dose Reductions 
for Veliparib/Placebo), Appendix G (Dose Reductions for FOLFIRI), Appendix H (Dose 
Reductions for Bevacizumab) and Appendix I (Toxicity Management).
5.5.3
Identity of Investigational Product
Information regarding the veliparib and placebo formulation to be used in this study is 
presented in Table 8.


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Table 8.
Identity of Investigational Product
Study Drug
Dosage Form
Strength
Route of Administration
Manufacturer
Veliparib (ABT 888)
Capsule
50 mg
Oral
AbbVie
Placebo
Capsule
50 mg placebo
Oral
AbbVie
AbbVie will supply veliparib capsules and a matching placebo for veliparib.
5.5.4
Standard of Care Medicinal Products
Information regarding FOLFIRI and bevacizumab to be used in this study is presented in 
Table 9.
Table 9.
Standard of Care Medicinal Products
Study Drug
Dosage Form
Route of Administration
Bevacizumab
vial
intravenous
Irinotecan
vial
intravenous
Fluorouracil (5-FU)
vial
intravenous
Leucovorin (Folinic Acid)
vial
intravenous
FOLFIRI and bevacizumab should be obtained commercially via the site pharmacy.  Each 
site will be responsible for tracking the lot numbers for all FOLFIRI and bevacizumab 
dispensed.
5.5.5
Packaging and Labeling
Veliparib will be packaged in bottles containing 20 or 44 capsules of 50 mg active or 
placebo.  This will allow for the 2 or 5 days of administration with one additional dose to 
cover loss, spillage or replacement due to vomiting within 15 minutes.  Each bottle label 
will include all information as required by local regulations and must remain affixed to 
the bottle.  All blank spaces on the label will be completed by site staff prior to dispensing 
to the subject.


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5.5.6
Storage and Disposition
Veliparib or Placebo
Table 10.
Study Drug Storage Conditions
Study Drug
Country
Storage Conditions
Veliparib or placebo
All countries, except 
Australia/New Zealand
Store at 15°C to 25°C
(59°F to 77°F)
Australia/New Zealand
Store below 25°C
All clinical supplies provided by AbbVie must be stored in a secure place at the proper 
storage conditions as presented in Table 10, until they are dispensed for subject use or are 
returned to AbbVie.
Investigational products are for investigational use only and are to be used only within the 
context of this study.  The clinical supplies supplied for this study must be maintained 
under adequate security and stored under conditions specified on the label.  
Storage and Disposition of FOLFIRI and Bevacizumab
Irinotecan, Fluorouracil (5-FU), Leucovorin (Folinic Acid) and Bevacizumab should all 
be stored per locally approved label or SmPC in the provided cartons to protect from light.
5.5.7
Method of Assigning Subjects to Treatment Groups
All subjects in the study will be randomized using an IRT system.  Before the study is 
initiated, directions for the IRT system will be provided to each site.  Subject 
randomization will be stratified into 4 groups as described in Section 8.3.  The 
stratification factors used for the randomization should be the last values on or prior to the 
date of randomization and should be consistent with those on the eCRF.
During randomization, subjects within each of the stratification groups will be 
randomized in a 1:1 ratio to one of the following protocol therapy groups:
a.
Veliparib plus FOLFIRI ± bevacizumab


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b. Placebo plus FOLFIRI ± bevacizumab
5.5.8
Selection and Timing of Dose for Each Subject
All randomized subjects will receive 200 mg of veliparib/placebo orally BID on Day –2 
through Day 5 of each 14-day cycle.  No other doses or schedules of veliparib are being 
investigated in this study.
5.5.9
Blinding
The Investigator, his or her clinical and research staff, and subjects will remain blinded to 
each subject's treatment with veliparib/placebo throughout the course of the study.  Site 
pharmacy personnel will be unblinded throughout the study.  To monitor patient safety on 
an ongoing basis, AbbVie study personnel will remain unblinded throughout the study.
AbbVie must be notified before the blind is broken by the Investigator unless 
identification of the study drug is required for medical emergency, i.e., situation in which 
the knowledge of the specific blinded treatment will affect the immediate management of 
the subject's conditions (e.g., antidote is available).  AbbVie must then be notified within 
24 hours of the blind being broken.  The date and reason that the blind was broken must 
be recorded in the source documentation and eCRF, as applicable.
5.5.10
Treatment Compliance
The Investigator or his/her designated and qualified representatives will 
administer/dispense protocol therapy only to subjects enrolled in the study in accordance 
with the protocol.  The protocol therapy must not be used for reasons other than that 
described in the protocol.  Veliparib/placebo should be taken as directed by the 
Investigator.  FOLFIRI and bevacizumab will be administered intravenously by trained 
site personnel.
Unless otherwise directed by the Investigator, the subject will be considered compliant 
with all study therapy if at least 80% of the assigned dose of FOLFIRI, bevacizumab 


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(when used), and veliparib/placebo is taken during a cycle.  Compliance below 80% will 
require counseling of the subject by study site personnel.
Subjects will be instructed to return all veliparib/placebo bottles (empty, partially filled or 
full) to the study site personnel prior to each cycle and at the Final Visit.  The site staff 
will document the bottles returned and the number of capsules per bottle on the 
appropriate form.
Upon completion or termination of the study, all original bottles/cartons containing 
unused veliparib/placebo (empty containers will be defaced and discarded on site) will be 
returned to AbbVie according to AbbVie's instructions, or if pre-arranged between the 
sponsor and site, destruction of used and unused bottles will be performed at the site.
5.5.11
Drug Accountability
The Investigator or his/her designated representative agrees not to supply protocol therapy 
to any persons not enrolled in the study or not named as a subinvestigator listed on the 
FDA 1572 or Investigator Information and Agreement (IIA) form.
Veliparib/Placebo
Upon receipt of a shipment of veliparib/placebo, the representative at each site will 
1) open and inspect the shipment; 2) verify that the veliparib/placebo has been received 
intact, in the correct amounts and at the correct address; 3) sign and date the Proof of 
Receipt (POR) or similar documentation accompanying the shipment; 4) register the 
shipment as received via the IRT.  All veliparib/placebo must be retained in the 
designated secure area under proper storage conditions.  This will be documented by 
signing and dating the POR or similar document or via direct recording in the IRT.
An overall accountability of veliparib/placebo will be performed and verified by the site 
monitor throughout the study and at the study site closeout visit.  An accurate running 
inventory of veliparib/placebo will be maintained utilizing the IRT drug accountability 
module and, if required, according to your institutional policy and will include the lot 


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number, POR number(s), the bottle/kit numbers, and the date study drug was dispensed 
for each subject.
Upon completion or termination of the study, all original containers (empty or containing
unused veliparib/placebo) will be returned to AbbVie according to instructions from 
AbbVie or if pre-arranged between the sponsor and site, destruction of used and unused 
study drug in bottles will be performed at the site.
Standard of Care Medicinal Products
The site will record the dose of irinotecan, 5-FU, leucovorin, and bevacizumab given to 
each subject in the source documents and on the eCRF.  As the Investigator will obtain 
irinotecan, 5-FU, leucovorin, and bevacizumab commercially, site inventory and 
accountability of irinotecan, 5-FU, leucovorin, and bevacizumab will not be performed, 
and drug accountability forms will not be provided.  However, each site will be 
responsible for tracking the lot numbers for all irinotecan, 5-FU, leucovorin, and 
bevacizumab dispensed.
Site pharmacy personnel will document whether the bolus was prepared with or without 
5-FU for each subject.  It is the site pharmacy personnel's responsibility to ensure this 
documentation remains confidential and is not shared with any other site staff members.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The FOLFIRI combination is standard first-line treatment for previously untreated 
metastatic adenocarcinoma of the colon or rectum.  Veliparib may have a potential benefit 
for subjects with mCRC.  This randomized, blinded, placebo-controlled study will 
evaluate the treatment effect due to the addition of veliparib to FOLFIRI ± bevacizumab 
chemotherapy in subjects with previously untreated metastatic adenocarcinoma of the 
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5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.  The efficacy measurements in this study are standard and validated.
5.6.3
Suitability of Subject Population
Subjects with pathologically documented and previously untreated metastatic 
adenocarcinoma of the colon or rectum will be selected to participate in this study.  The 
proposed inclusion and exclusion criteria are anticipated to result in a study subject 
population representative of mCRC who receive systemic therapy according to current 
practice guidelines.2
5.6.4
Selection of Doses in the Study
The initial starting dose of 200 mg BID veliparib in this trial was derived from the results 
obtained in the Phase 1 dose escalation study (Study M10-977).  The maximum dose of 
veliparib/placebo for any subject in this study is 200 mg BID for 7 of 14 days per cycle.  
A Phase 1 dose escalation study evaluating veliparib in combination with FOLFIRI found 
that the 5-FU bolus is not tolerated; therefore, subjects randomized to the veliparib arm 
will receive modified FOLFIRI without a 5-FU bolus.17  For subjects randomized to the 
placebo arm, FOLFIRI will be given as per standard of care in first-line treatment for 
mCRC per NCCN guidelines, 2014.2  Should the investigator elect to treat with 
bevacizumab, it will be given as per standard of care in first-line treatment for mCRC as 
per NCCN guidelines, 2014.2
6.0
Adverse Events
The Investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The Investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 


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Investigator will provide an Other cause of the event.  For adverse events to be considered 
intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1
Definitions
6.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, meets protocol specific criteria (see Appendix E, Appendix F, 
Appendix G, Appendix H, and Appendix I regarding toxicity management) and/or if the 
Investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
was pre-planned prior to study entry, or performed for curative intent.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 


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earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
All protocol-related AEs must be collected from the signing of the study specific informed
consent until study drug administration.  In addition, adverse events with onset or 
worsening reported by a subject from the time that the first dose of study drug (veliparib 
or placebo) is administered until 30 days have elapsed following discontinuation of study 
drug administration will be considered as treatment-emergent adverse events.
6.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the SAE.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility, hospitalization for respite care, or 
hospitalization due solely to progression of the underlying 
cancer.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively 
minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Additionally, any elective or spontaneous abortion or 
stillbirth is considered an important medical event.  Examples 
of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form.
6.2
Adverse Events Expected Due to mCRC or Progression of 
mCRC
Events that are clearly consistent with the expected progression of mCRC, including but 
not limited to tumor pain, bowel obstructions, and constipation should be considered as 
expected.  A list of expected adverse events is presented in Appendix C of the protocol.  
These adverse events may occur alone or in various combinations and are considered 
expected adverse events in mCRC subjects.
6.3
Adverse Events Expected Due to Study Related Endpoints
6.3.1
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol 
specified adverse event reporting period (see Section 6.6) that are more likely related to 
disease progression will therefore be an expected adverse event and will not be subject to 
expedited reporting.


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Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be reported.  
The term "sudden death" should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without pre-existing 
heart disease, within 1 hour of the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the patient was last seen alive and stable.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be replaced 
by the established cause of death.
6.3.2
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease are also considered an expected outcome for this study and will not be 
subject to expedited reporting.
6.4
Adverse Event Severity
The study Investigator will rate the severity of each adverse event according to the 
National Cancer Institute Common Terminology Criteria for Adverse Events NCI 
CTCAE Version 4.0.19
For adverse events not captured by the NCI CTCAE Version 4.0, the Investigator will use 
the following definitions to rate the severity of each adverse event:
Mild
(Grade 1)
The adverse event is transient and easily tolerated by the subject.
Moderate
(Grade 2)
The adverse event causes the subject discomfort and interrupts the 
subject's usual activities.
Severe
(Grade 3 or 4)
The adverse event causes considerable interference with the subject's 
usual activities and may be incapacitating or life threatening.


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Death
(Grade 5)
The adverse event resulted in death of the subject.
If a reported adverse event increases in severity, the initial adverse event should be given 
an outcome date and a new adverse event should be reported to reflect the change in 
severity.
For all reported serious adverse events that increase in severity, the supplemental eCRFs 
also need to be updated and need to include the new AE serial number.
6.5
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug (for the purpose of this section, protocol therapy is 
considered veliparib/placebo and FOLFIRI ± bevacizumab, all assessed individually):
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the investigator for the serious 
adverse event.


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6.6
Adverse Event Collection Period
All protocol-related serious adverse events and nonserious adverse events must be 
collected from the signing of the study specific informed consent until study drug 
administration.
In addition, all adverse events reported from the time of study drug administration until 
30 days following discontinuation of study drug administration have elapsed will be 
collected, whether solicited or spontaneously reported by the subject.
Serious and nonserious adverse events occurring after the study specific informed consent 
is signed but prior to the initial dose of veliparib/placebo will be collected only if they are 
considered by the Investigator to be causally related to the study-required procedures.
Adverse event information will be collected as shown in Figure 2.
Figure 2.
Adverse Event Collection
Protocol-Related 
SAEs and 
Nonserious AEs*
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported
∀
∀
∀
∀
Consent 
Signed
Study 
Drug Start
Study Drug 
Stopped
30 Days 
After Study 
Drug Stopped
*
Only if considered by the Investigator to be causally related to study-required procedures.
6.7
Adverse Event Reporting
In the event of a serious adverse event, whether associated with protocol therapy or not, 
the Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being 
made aware of the serious adverse event by entering the serious adverse event data into 
the EDC system (RAVE®).  Serious adverse events that occur prior to the site having 
access to the RAVE® system or if RAVE® is not operable should be documented on the 
SAE Non-CRF forms and emailed (preferred route) or faxed to Clinical 


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Pharmacovigilance within 24 hours of the site being made aware of the serious adverse 
event.
Serious adverse events which are considered expected due to the underlying disease of 
mCRC as described in Appendix C would not be expedited as individual safety case 
reports to regulatory authorities.
Email to:
FAX to:
For safety concerns, contact the AbbVie Oncology Safety Management Team at:
For any subject safety concerns, please contact the AbbVie Study Designated Physician 
listed below:


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In emergency situations involving study subjects when the primary Study Designated 
Physician (SDP) is not available by phone, please contact the 24-hour AbbVie Medical 
Escalation Hotline where your call will be re-directed to a designated backup AbbVie 
SDP:
Phone:  
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure for veliparib or 
Summary of Product Characteristics (SmPC) for irinotecan, 5-FU, and leucovorin.
6.8
Pregnancy
In the event of a positive pregnancy test, subjects must immediately discontinue protocol 
therapy and must be discontinued from the study.  The Investigator must report the 
positive pregnancy test to the Study Designated Physician listed in protocol Section 6.7
within 1 working day of the site becoming aware of the pregnancy.
All subjects should be informed that contraceptive measures should be taken throughout 
the study and for 90 days after discontinuing protocol therapy.  Information regarding a 
pregnancy occurrence in a study subject and the outcome of the pregnancy will be 
collected.  The Investigator must follow the pregnancy to completion and provide an 
update to AbbVie after delivery.
Male subjects should be informed that contraceptive measures should be taken by their 
female partners.  If the subject's partner should become pregnant during the study, this 
should also be reported and data may be collected.  In the event of pregnancy occurring in 
the partner of an enrolled subject, written informed consent for release of medical 
information from the partner must be obtained prior to the collection of any pregnancy 
specific information and the pregnancy will be followed to outcome.


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Pregnancy in a study subject is not considered an adverse event.  However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to AbbVie within 24 hours of the 
site becoming aware of the event.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The Investigator is 
responsible for complying with all protocol requirements, and applicable global and local 
laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) after a 
subject has been enrolled, the Investigator is responsible for notifying Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) regulatory authorities (as applicable), 
and the following AbbVie contacts.  Such contact must be made as soon as possible to 
permit a review by AbbVie to determine the impact of the deviation on the subject and/or 
the study:
Primary Contact:
Alternate Contact (Primary):


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Alternate Contact (Secondary):
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
The data of randomization (enrollment) is defined as the data that the IRT issues a 
randomization number.
All subjects who are randomized will be included in the efficacy analyses.
All subjects who receive at least one dose of the study drug (veliparib or placebo) will be 
included in the safety analysis.
8.1.1
Baseline Characteristics
All baseline summary statistics and analyses will be based on characteristics prior to the 
initiation of study drug (or randomization for non-treated subjects).  Unless otherwise 
stated, baseline for a given variable will be defined as the last value for that variable 
obtained prior to the first dose of study drug.


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8.1.1.1
Demographics
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
means, standard deviation, minimum, maximum, and range.  Frequencies and percentages 
will be computed for the following parameters:  gender, race, planned bevacizumab use, 
geographical region, and ECOG performance status.
8.1.1.2
Medical History
Frequencies and percentages will be computed for each medical history parameter.
8.1.2
Efficacy Endpoints
8.1.2.1
Primary Efficacy Endpoint
The primary efficacy analysis will be a comparison of progression-free survival (PFS) 
between veliparib 200 mg BID plus FOLFIRI ± bevacizumab, and placebo for veliparib 
BID plus FOLFIRI ± bevacizumab.
For a given subject, PFS will be defined as the number of days from the date the subject 
was randomized to the date the subject experiences an event of disease progression or 
death, whichever occurs first.  All events of disease progression will be included, 
regardless of whether the event occurred while the subject was still taking study drug or 
had previously discontinued study drug.  Events of death will be included for subjects 
who had not experienced an event of disease progression, provided the death occurred 
within 8 weeks of the last evaluable disease progression assessment.  If the subject does 
not have an event of disease progression and the subject has not died as defined above, the 
subject's data will be censored at the date of the subject's last evaluable disease 
progression assessment.
8.1.2.2
Secondary Efficacy Endpoints
Secondary efficacy analyses comparing the effects of veliparib plus FOLFIRI ± 
bevacizumab and placebo plus FOLFIRI ± bevacizumab on the following set of endpoints 
will be performed:  overall survival (OS) and objective response rate (ORR).


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Time to death (overall survival) for a given subject will be defined as the number of days 
from the date the subject was randomized to the date of the subject's death.  All events of 
death will be included, regardless of whether the event occurred while the subject was still 
taking study drug or after the subject discontinued study drug.  If a subject has not died, 
the data will be censored at the date last known to be alive.
Objective response rate (ORR) is calculated as the proportion of subjects who have PR or 
CR based on assessment by RECIST, Version 1.1.  Subjects who receive local therapy 
(surgery, radiation, etc.) will be censored at the time of surgery from subsequent ORR 
assessments.
8.1.2.3
Tertiary Efficacy Endpoints
Tertiary efficacy analyses comparing the effects of veliparib plus FOLFIRI ± 
bevacizumab and placebo plus FOLFIRI ± bevacizumab on the following set of endpoints 
will be performed:  duration of overall response (DOR) and changes in ECOG 
performance status.
Duration of Overall Response (DOR) will be defined as the number of days from the day 
the criteria are met for CR or PR (whichever is recorded first) to the date that progressive 
disease PD is observed.  If a subject is still responding then the subject's data will be 
censored at date of the last available disease progression assessment.  For subjects who 
never experienced CR or PR, the subject's data will not be included in DOR analysis.
ECOG performance status is a scale from 0 to 4 collected at baseline, Day 1 of each cycle 
and final visit.
8.1.3
Primary Analysis of Efficacy
The progression-free survival distribution will be estimated for each treatment group 
using Kaplan-Meier methodology and compared between the two treatment groups using 
a log-rank test stratified by the planned bevacizumab use.  A two-sided, stratified log-rank 
test P value will be provided.  Median PFS time will be estimated and a 95% confidence 


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interval for the median PFS time will be presented for each treatment group.  A hazard 
ratio estimate and a 95% confidence interval will be obtained from a proportional hazards 
regression model.
8.1.4
Secondary Analysis of Efficacy
8.1.4.1
Overall Survival
The distribution of overall survival will be estimated for each treatment group using 
Kaplan-Meier methodology and compared between the two treatment groups using a 
log-rank test stratified by the planned bevacizumab use.  Median OS time will be 
estimated and a 95% confidence interval for the median OS time will be presented for 
each treatment group.  A hazard ratio estimate and a 95% confidence interval will be 
obtained from a proportional hazards regression model.
8.1.4.2
Objective Response Rate
The objective response rate will be estimated and compared between the two treatment 
groups using a Cochran-Mantel-Haenszel test, stratifying by the planned bevacizumab 
use.  In addition, a 95% confidence interval will be constructed for the estimated 
proportions.
8.1.4.3
Tertiary Analysis of Efficacy
8.1.4.3.1
ECOG Performance Status
Changes from baseline in ECOG performance status will be summarized using descriptive 
statistics for each scheduled post-baseline visit and for the final visit.  Subjects that do not 
have a baseline measurement or do not have any post-baseline measurements will not be 
included.  Changes from baseline to each visit will be compared between the 
two treatment groups using an analysis of covariance with treatment group as the factor 
and baseline value as a covariate.


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8.1.5
Safety Assessments
The safety of the study regimens will be assessed by evaluating study drug exposure, 
adverse events, serious adverse events, and all deaths, as well as changes in laboratory 
determinations and vital sign parameters.  Subjects who were randomized but did not 
receive study drug (veliparib or placebo) will not be included in the analyses of safety.
8.1.6
Statistical Analyses of Safety
8.1.6.1
Duration of Study Drug
A summary of the number of days and/or cycles subjects were exposed to study drug will 
be provided.
8.1.6.2
Adverse Events
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the day of the first dose of study drug (veliparib or placebo).  
Analyses will not include those that have an onset greater than 30 days after the last dose 
of study drug.
Treatment-emergent adverse events will be coded and summarized by system organ class 
and preferred term according to the Medical Dictionary for Regulatory Activities 
(MedDRA) adverse event coding dictionary.  The percentage of subjects experiencing an 
adverse event at a given NCI CTCAE version 4.0 grade, and relationship to study drug 
will be provided.  Comparisons of the percentages of subjects experiencing an adverse 
event between the veliparib and placebo study arms will be performed using Fisher's exact 
test.
8.1.6.3
Serious Adverse Events
Serious adverse events will be summarized using the same methods as adverse events 
described above in Section 8.1.6.2.


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8.1.6.4
Deaths
The number of subject deaths will be summarized 1) for deaths occurring while the 
subject was still receiving study drug in this study, 2) for deaths occurring off treatment 
within 30 days after the last dose of study drug, and 3) for all deaths in this study 
regardless of the number of days after the last dose of study drug.
8.1.6.5
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline will be analyzed for each scheduled post-baseline visit and for the 
final visit for blood chemistry and hematology parameters, as well as urinalysis and vital 
sign parameters.  If more than one measurement exists for a subject on a particular day, an 
arithmetic average will be calculated.  This average will be considered to be that subject's 
measurement for that day.  Post-baseline measurements more than 30 days after the last 
dose of randomized study drug will not be included.  Subjects that do not have a baseline 
measurement or do not have any post-baseline measurements will not be included.  
Comparisons of the differences in mean changes from baseline between the veliparib and 
placebo arms will be made using ANCOVA with treatment group as the factor and 
baseline as a covariate.
8.1.6.6
Analyses of Laboratory Data Using NCI CTCAE
Where applicable, blood chemistry and hematology determinations will be categorized 
according to NCI CTCAE version 4.0 grades, and shifts from baseline NCI CTCAE 
version 4.0 grades to maximum and final post-baseline grades will be assessed.  The 
baseline and final grades will be defined respectively as the grade of the last measurement 
collected prior to the first dose of study drug, and as the grade of the last post-baseline 
measurement collected no more than 30 days after the last dose of study drug.  If multiple 
values are available for a post-baseline measurement, then the value with the highest NCI 
CTCAE grade will be used in the assessment of shift.  Comparisons of the number of 
subjects experiencing a shift from baseline grades of 0 to 2 or no grade to maximum 
post-baseline grades of 3 to 4, and from baseline grades of 0 to 2 or no grade to final 
post-baseline grades of 3 to 4 between the veliparib and placebo arms will be performed 


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using Fisher's exact tests.  Additional analyses including all measurements collected, 
regardless of the number of days after the last dose of study drug, will be performed.
Detailed listings of data for subjects experiencing NCI CTCAE Grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug, will be included in these 
listings.
8.1.6.7
Analyses of Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values
Detailed listings of data for subjects experiencing potentially clinically significant vital 
sign values according to the AbbVie-defined criteria for vital sign values will be provided.  
All measurements collected, regardless of the number of days after the last dose of study 
drug, will be included in these listings.
8.1.7
Interim Analysis
To ensure subject safety and assess the efficacy of veliparib during the study, AbbVie will 
perform at least one efficacy and two safety interim analyses.  An Internal Monitoring 
Committee (IMC) will be formed to review the interim data and make recommendations 
to the conduct of the study.  A separate IMC agreement defines the roles and 
responsibilities of the IMC, including its membership, scope, timing of meetings, and 
communication plan.
The first safety interim analysis will occur at least 8 – 10 weeks after 20 subjects in the 
"planned bevacizumab use" group are randomized.  All subjects who have received at 
least 1 dose of protocol therapy prior to the database versioning date will be included in 
this analysis.  The main objective for this early interim assessment will be to evaluate the 
safety of veliparib when combined with bevacizumab and FOLFIRI, which was not tested 
during any previous veliparib trials.
A second interim analysis for both efficacy and safety will be conducted at least 8 –
10 weeks after 35 PFS events have occurred.  The Internal Monitoring Committee will 


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review efficacy data to determine the futility of the study.  A comprehensive review and 
assessment of the cumulative safety data will also be undertaken at the same time.  The 
main objective for this interim safety assessment will be to determine if the safety of 
veliparib in combination with FOLFIRI is sufficient to allow the on-study treatment to 
continue, or if a modification to the study should be made.
8.2
Determination of Sample Size
A minimum of 70 PFS events was chosen to provide adequate precision in the hazard 
ratio estimate.  Assuming median PFS time of 9.4 months in the FOLFIRI ± bevacizumab 
arm and 15.7 months in the veliparib plus FOLFIRI ± bevacizumab arm, based on a 
minimum of 70 PFS events, the expected 95% confidence interval for the estimated 
hazard ratio would be approximately 0.37 to 0.96.  A total of 120 subjects will be enrolled 
into the study.  Assuming a total enrollment period of 12 months, it is anticipated that the 
study will complete by end of the 22nd month if the true median times for each treatment 
arm are as assumed above.
8.3
Randomization Methods
An IRT system will be utilized to randomize subjects.  Before the study is initiated, 
directions for the IRT will be provided to each site.  The investigational site will contact 
the IRT on or prior the subject's C1D–2 visit and a unique randomization number will be 
provided.
Subject randomization will be stratified into 4 groups as follows:
Group
Strat Factor 1
Strat Factor 2
1
North America
Planned Bevacizumab Use
2
North America
No Planned Bevacizumab Use
3
Rest of World
Planned Bevacizumab Use
4
Rest of World
No Planned Bevacizumab Use


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During randomization, subjects within each of the 4 stratification groups will be 
randomized in a 1:1 ratio to either the veliparib 200 mg BID plus FOLFIRI group or the 
placebo BID plus FOLFIRI group.
The stratification factors used for the randomization should be the last values on or prior 
to the date of randomization and should be consistent with those on the eCRF.  
Randomization will be conducted to ensure that at least 60 subjects are enrolled in both 
the "planned bevacizumab use" group and "no planned bevacizumab use" group for a total 
of ~120 subjects.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 


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any additional reports required by local regulations) to the IEC/IRB of any changes that
affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record or Investigator binder per local legislation.  An entry must 
also be made in the subject's dated source documents to confirm that informed consent 
was obtained prior to any study-related procedures and that the subject received a signed 
copy.
Pharmacogenetic analysis will only be performed if the subject has voluntarily signed and 
dated a separate pharmacogenetic informed consent approved by an IRB/IEC, after the 
nature of the testing has been explained and the subject has had an opportunity to ask 
questions.  The separate pharmacogenetic informed consent must be signed before the 
pharmacogenetic testing is performed.  If the subject does not consent to the 
pharmacogenetic testing, it will not impact the subject's participation in the study.


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10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an EDC system called RAVE® provided by the technology vendor 
Medidata Solutions Incorporated, NY, USA.  The EDC system and the study specific 
electronic case report forms (eCRFs) will comply with Title 21 CFR Part 11.  The 
documentation related to the validation of the EDC system is available through the 
vendor, Medidata, while the validation of the study specific eCRFs will be conducted by 
AbbVie and will be maintained in the Trial Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The Investigator or an authorized member of the Investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 


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performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided. The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the study through a 
password-protected method of internet access.  Such access will be removed from 
Investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature and the results will not be suitable for clinical decision making 
or patient management.  Hence, neither the investigator, the subject, nor the subject's 
physician (if different from the investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic researchers will have no access to 
subject identifiers.  Individual results will not be reported to anyone not directly involved 
in this research other than for regulatory purposes.  Aggregate pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 


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conventions.  Pharmacogenetic information will be published or presented only in a way 
that does not identify any individual subject.
13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the Investigator and AbbVie.  The Investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The Investigator must retain any records related to the study according to local 
requirements.  If the Investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory Investigator from the Investigators who participate in the 
study.  Selection criteria for this Investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory Investigator for the study will review and sign the final study report in 
accordance with the European Medicines Agency (EMA) Guidance on Investigator's 
Signature for Study Reports.
The end-of-study is defined as the date of last subject's last survival follow-up contact.  
The sponsor may also end the study upon confirmation that the primary endpoint was 
statistically met.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for veliparib (ABT-888) 
and the product labeling for irinotecan, fluorouracil (5-FU), leucovorin, and 
bevacizumab.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
Randomized, Blinded, Multicenter, Phase 2 Study Comparing 
Veliparib Plus FOLFIRI ± Bevacizumab Versus Placebo Plus 
FOLFIRI ± Bevacizumab in Previously Untreated Metastatic 
Colorectal Cancer
Protocol Date:
16 July 2015
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
World Health Organization.  GLOBOCAN 2012:  Estimated Cancer Incidence, 
Mortality and Prevalence Worldwide in 2012.  Available from:  
http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.  Accessed on:  
2014 April 16.
2.
National Comprehensive Cancer Network.  NCCN Guidelines Version 3.  
2014, Colon Cancer.  Available from:  
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#colon.  
Accessed on:  2014 April 16.
3.
American Cancer Society.  What are the survival rates for colorectal cancer by 
stage?  Available from:  
http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-
cancer-survival-rates.  Accessed on:  2014 April 16.
4.
Cunningham D, Pyrhönen S, James RD, et al.  Randomised trial of irinotecan plus 
supportive care versus supportive care alone after fluorouracil failure for patients 
with metastatic colorectal cancer.  Lancet.  1998;352(9138):1413-8.
5.
Saltz LB, Cox JV, Blanke C, et al.  Irinotecan plus fluorouracil and leucovorin for 
metastatic colorectal cancer.  Irinotecan Study Group.  N Engl J Med.  
2000;343(13):905-14.
6.
Douillard JY, Cunningham D, Roth AD, et al.  Irinotecan combined with 
fluorouracil compared with fluorouracil alone as first-line treatment for metastatic 
colorectal cancer:  a multicentre randomised trial.  Lancet.  
2000;355(9209):1041-7.
7.
Tournigand C, André T, Achille E, et al.  FOLFIRI followed by FOLFOX6 or the 
reverse sequence in advanced colorectal cancer:  a randomized GERCOR study.  
J Clin Oncol.  2004;22(2):229-37.
8.
Mendelsohn J.  Targeting the epidermal growth factor receptor for cancer therapy.  
J Clin Oncol.  2002;20 (18 Suppl):1S-13S.


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9.
Fuchs CS, Marshall J, Mitchell E, et al.  Randomized, controlled trial of irinotecan 
plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic 
colorectal cancer:  results from the BICC-C Study.  J Clin Oncol.  
2007;25(30):4779-86.
10.
Chiarugi A.  Poly(ADP-ribose) polymerase:  killer or conspirator?  The 'suicide 
hypothesis' revisited.  Trends Pharmacol Sci.  2002; 23(3):122-9.
11.
Virág L, Szabó C.  The therapeutic potential of poly(ADP-ribose) polymerase 
inhibitors.  Pharmacol Rev.  2002;54(3):375-429.
12.
DePinho RA, Polyak K.  Cancer chromosomes in crisis.  Nat Genet.  
2004;36(9):932-4.
13.
Curtin NJ, Wang LZ, Yiakouvaki A, et al.  Novel poly(ADP-ribose) polymerase-1 
inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair 
deficient cells.  Clin Cancer Res.  2004;10(3):881-9.
14.
AbbVie.  ABT-888 Investigator's Brochure Edition 8.  12 June 2014.
15.
Das BB, Huang SY, Murai J, et al.  PARP1-TDP1 coupling for the repair of 
topoisomerase I-induced DNA damage.  Nucleic Acids Res.  2014;42(7):4435-49. 
16.
Berlin J, Ramanathan RK, Strickler JH, et al.  A phase 1 dose-escalation study of 
veliparib with bimonthly FOLFIRI in patients with advanced solid tumors.  J Clin 
Oncol.  2014;32 Suppl 5 (Abstr 2574).
17.
Pishvaian MJ, Wang H, Zhuan T, et al.  A phase I/II study of ABT-888 in 
combination with 5-fluorouracil (5-FU) and oxaliplatin (Ox) in patients with 
metastatic pancreatic cancer (MPC).  J Clin Oncol.  2013;31 Suppl 4 (Abstr 47).
18.
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in 
solid tumors:  revised RECIST guideline (version 1.1).  Eur J Cancer.  
2009;45(2):228-47.
19.
National Cancer Institute.  Common Terminology Criteria for Adverse Events 
(CTCAE), v4.0, NCI, NIH, DHHS.  May 28, 2009.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
Accessed on:  2014 April 16.


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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.


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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical
Clinical
GDSM
Statistics
Statistics
Clinical
Pharmacokinetics
Bioanalysis


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Appendix C.
Adverse Events Expected Due to mCRC or Progression of mCRC
Preferred Term (MedDRA Version 13.1)
Tumor pain
Bowel obstruction
Biliary obstruction/cholestasis
Fatigue
Abdominal pain
Abdominal pain upper
Abdominal pain lower
Anorexia
Nausea 
Diarrhea 
Constipation
Vomiting
Dyspnea
Pyrexia
Asthenia
Rectal haemorrhage
Abdominal distension
Proctalgia
Intestinal obstruction
Progression of metastatic colon cancer
Progression of metastatic rectal cancer
Metastases to lymph nodes
Metastases to liver
Metastatic pain
Cancer pain
Non-cardiac chest pain


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Appendix D.
RECIST Version 1.1 for Tumor Response (PFS)
Response criteria will be assessed using RECIST, Version 1.1.  Changes in the 
measurable lesions over the course of therapy must be evaluated using the criteria listed 
below.
Eligibility
Subjects with measurable disease at baseline can have objective tumor response evaluated 
by RECIST, Version 1.1.  Measurable disease is defined by the presence of at least 
one measurable lesion.  If the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should be confirmed by cytology/histology if possible.


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Measurability
Measurable Lesions
Lesions accurately measured in at least one dimension with a minimum 
size of: 
Longest diameter ≥ 10 mm (CT scan slice thickness no greater than 5 mm)
10 mm caliper measurement by clinical exam
Non-Measurable Lesions
All other lesions, including small lesions (longest diameter < 10 mm) as 
well as truly non-measurable lesions.  Lesions considered truly 
non-measurable include:  leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung and also abdominal masses that are not 
confirmed and followed by imaging techniques.
Measurable Malignant 
Lymph Nodes
To be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in 
follow-up, only the short axis will be measured and followed.
Non-Measurable 
Malignant Lymph Nodes
Pathological lymph nodes with ≥ 10 to < 15 mm short axis.
Special Considerations 
Regarding Lesion 
Measurability
Bone lesions
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by cross sectional imaging 
techniques such as MRI/CT can be considered as measurable lesions if the 
soft tissue component meets the definition of measurability described 
above.
Blastic bone lesions are non-measurable.
Cystic lesions
Lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor 
non-measurable) since they are, by definition, simple cysts.
'Cystic lesions' thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described 
above.
However, if non-cystic lesions are present in the same subject, these are 
preferred for selection as target lesions.
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or in an area 
subjected to other loco-regional therapy, are usually not considered 
measurable unless there has been demonstrated progression in the lesion.


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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers.  For 
the case of skin lesions, documentation by color photography including a ruler to estimate 
the size of the lesion is recommended.
Methods of Measurement
Conventional CT should be performed with cuts of 5 mm or less in slice thickness 
contiguously.  This applies to tumors of the chest and abdomen.  A scale should be 
incorporated into all radiographic measurements.  MRI can be performed if required by 
local law, but should have sponsor approval.
If prior to enrollment, it is known a subject is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT 
or MRI should be used to evaluate the subject at baseline and follow-up should be guided 
by the tumor type under investigation and the anatomic location of the disease.  For 
subjects who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI should be made based upon discussion 
with the AbbVie Study Designated Physician.
For accurate objective response evaluation, ultrasound (US) should not be used to 
measure tumor lesions.
The utilization of endoscopy and laparoscopy for objective tumor evaluation is not 
advised.  However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained.
Cytology and histology can be used to differentiate between partial response (PR) and 
complete response (CR) in rare cases.


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Baseline Documentation of "Target" and "Non-Target" Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements.  
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor.  Pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to 
the baseline sum.  The short axis of the node is the diameter normally used by radiologists 
to judge if a node is involved by solid tumor.  Nodal size is normally reported as 
two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane).  The smaller of these measures is the short axis.  For example, an 
abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis 
≥10 mm but < 15 mm) should be considered non-target lesions.  Nodes that have a 
short axis < 10 mm are considered non-pathological and should not be recorded or 
followed.
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD.  If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum.  The baseline sum LD will be used as reference 
by which to characterize the objective tumor response.


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All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence (stable, increasing or decreasing) or 
absence of each should be noted throughout follow-up.
Evaluation of Target Lesions
Complete Response (CR):
The disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters.
Non-Evaluable (NE):
To be exclusively used for subjects who have undergone surgical resection with curative 
intent who no longer have a measurable lesion.  Subjects who undergo surgical resection 
will resume protocol therapy and study visits until there is a new lesion (PD).
Progressive Disease (PD):
At least a 20% increase in the sum of the LD of target lesions, taking as reference the 
smallest sum LD recorded since the treatment started (baseline or after) or the appearance 
of one or more new lesions.  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD since the treatment started (baseline or after).


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Assessment of Target Lesions:
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the 'sum' of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm.  For PR, SD and PD, the actual short axis measurement of the nodes is 
to be included in the sum of target lesions.
All lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (< 5 mm).  
However, sometimes target lesions or lymph nodes become too small to measure.  If it is 
in the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present, but too small to 
measure, a default value of 5 mm should be assigned (as derived from the 5 mm CT slice 
thickness).  The measurement of these lesions is potentially non-reproducible; therefore 
providing this default value will prevent false responses or progression based upon 
measurement error.
Evaluation of Non-Target Lesions
Complete Response (CR):
The disappearance of all non-target lesions and normalization of tumor marker level.  All
lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits.
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.


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In this setting, to achieve 'unequivocal progression' on the basis of non-target disease, 
there must be an overall level of substantial worsening in non-target disease such that, 
even in the presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 'increase' in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare.
New Lesions
The appearance of new malignant lesions denotes disease progression.  While there are no 
specific criteria for the identification of new radiographic lesions, the findings of a new 
lesion should be unequivocal; i.e., not attributable to differences in scanning technique, 
timing of scanning, phase of contrast administration, change in imaging modality or 
finding thought to represent something other than tumor (e.g., some 'new' bone lesions 
may be simply healing or flare of pre-existing lesions).  A lesion identified on a follow-up 
study in an anatomical location that was not scanned at baseline is considered a new 
lesion and will indicate disease progression.  An example of this is the subject who has 
visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases.  The subject's brain metastases are considered evidence of progressive 
disease even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal (e.g., too small to measure), continued therapy and follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is a 
new lesion, then progression should be declared using the date of the initial scan.


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Appendix E.
Guidelines for Toxicity Management and Dose Reductions or 
Delays for Protocol Therapy
If a subject experiences adverse events that results in the dose modification (including 
dose delay, reduction, or discontinuation) of veliparib/placebo, FOLFIRI, or bevacizumab 
during a cycle, the subject will complete the planned activities of the cycle as scheduled 
per Table 4 (i.e., vital signs, labs, radiographic tumor assessment, etc.) until resuming 
protocol therapy.
If a dose interruption is needed, the subject will continue to have study visits as planned; 
however, PD and/or PK samples will not be collected during this period.  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.  The timing of dose resumption should be at the discretion of the Investigator; 
however, the primary contact listed in Section 8.0 should be contacted regarding the 
timing of PD and/or PK sample collection once subjects have resumed dosing.
Subjects can be treated with antibiotic therapy if they develop severe neutropenia.  A new 
cycle of treatment (i.e., Day –2 of the next cycle) may not begin until the ANC is 
≥1500/mm3, the platelet count is ≥ 100,000/mm3, and any treatment-related GI toxicity 
has resolved to ≤ Grade 1.  If the initiation of a new cycle, or therapy during a cycle is 
delayed for ≥ 4 weeks, Investigators should contact the Study Designated Physician 
regarding ongoing clinical benefit prior to resumption of protocol therapy.
Dose modifications should be based on laboratory values obtained as described in 
Section 4.3.1.1.  Interval counts (i.e., CBC's done on non-FOLFIRI days) are not 
determinants of dose reductions unless associated with other issues such as febrile 
neutropenia.
Dose reductions and delays for veliparib/placebo, FOLFIRI, and bevacizumab toxicity are 
described in Appendix F, Appendix G, Appendix H, and Appendix I.


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Appendix F.
Dose Reductions and Delays for Veliparib Toxicity
The following are guidelines for dose reduction, delay and discontinuation of veliparib:
●
For any Grade 3 or 4 toxicity attributable to veliparib and not FOLFIRI nor 
underlying disease.
●
Any event of seizure, regardless of grade or attribution, requires interruption of 
veliparib and discussion with the AbbVie Study Designated Physician 
regarding the decision to resume treatment.
Veliparib will be held until the toxicity(ies) recovery to ≤ Grade 1 or baseline grade if 
present at screening.  Upon resuming veliparib/placebo treatment, the dose is to be 
reduced one dose level as shown below.
If a subject begins veliparib/placebo on Day –2 but subsequently experiences an event 
requiring delay of the FOLFIRI dosing on Day 1, the subject is to stop veliparib/placebo 
dosing immediately.  Upon resolution of the event, the subject may restart the current 
cycle by repeating Day –2 and Day –1.  For such delays, a new veliparib supply will be 
dispensed to restart the cycle at Day –2.
For the purposes of this study, only three dose reductions of veliparib/placebo are 
allowed.  All dose reductions are permanent.  If a dose reduction is required beyond dose 
level 3, subjects 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 subjects continue to experience clinical benefit.
Veliparib Dose Reduction or Delay
Drug
Starting Dose
Level 1 Reduction
Level 2 Reduction
Level 3 Reduction
Veliparib/Placebo
200 mg BID
150 mg BID
100 mg BID
50 mg BID


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Appendix G.
Dose Reductions and Delays for FOLFIRI Toxicity
Dose modification for the current cycle and reduction for subsequent cycles should be 
carried out as shown below.  Dose adjustments of irinotecan and 5-FU infusion may be 
made independently based on the specific types of toxicities observed as discussed in 
Appendix 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 use, but continue veliparib/placebo, 5-FU, leucovorin and bevacizumab.  If a 
dose reduction is required beyond dose level 3 for 5-FU, discontinue all protocol therapy. 
Note:  The 5-FU bolus can only be skipped or discontinued.
FOLFIRI Dose Reductions
Drug*
Starting Dose
Dose Level –1
Dose Level –2
Dose Level –3
Irinotecan 
180 mg/m2
150 mg/m2
120 mg/m2
100 mg/m2
5-FU Infusion
2400 mg/m2
1920 mg/m2
1600 mg/m2
1360 mg/m2
5-FU Bolus
400 mg/m2
Discontinued
Discontinued
Discontinued
*
Leucovorin is always administered at 400 mg/m2 IV prior to the 5-FU infusion.  If an infusion of 5-FU needs to be 
skipped, leucovorin must also be skipped.


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Appendix H.
Dose Reductions and Delays Guidelines for Bevacizumab Toxicity
Bevacizumab is always administered at 5 mg/kg IV.  Bevacizumab may be skipped or 
discontinued, but the dose is not reduced.


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Appendix I.
Toxicity Management Guidelines for Protocol Therapy
Hematologic Toxicities:
The following dose modifications are recommended for the next treatment cycle based on 
unresolved toxicity experienced during a previous cycle (i.e., after Day 1 of any cycle):
●
Grade 2 neutropenia or thrombocytopenia, discontinue 5-FU bolus.  Reduce 
5-FU infusion and irinotecan one dose level for the next cycle.  For each 
subsequent cycle, may resume 5-FU infusion and irinotecan at the previous 
dose levels, provided ANC ≥ 1500/μL and platelets ≥ 100,000/mm3.
●
Grade 3 or 4 neutropenia or thrombocytopenia, suspend all protocol therapy.  
If counts recover to ANC ≥ 1500/μL and platelets ≥75,000/mm3 within 
4 weeks, resume protocol therapy with dose reductions as follows:  discontinue 
5-FU bolus and continue 5-FU infusion and irinotecan at one lower dose level. 
●
Febrile neutropenia (defined as ANC < 1000/μL and T ≥ 38.5°C), suspend all 
protocol therapy.  If fever resolves, and counts recover to ANC ≥ 1500/μL and 
platelets ≥ 75,000/mm3 within 4 weeks, resume protocol therapy with dose 
reductions as follows: discontinue 5-FU bolus and continue 5-FU infusion and 
irinotecan at one lower dose level.
●
Veliparib may exacerbate neutropenia or thrombocytopenia associated with 
FOLFIRI.  Investigators should consider reducing veliparib/placebo one dose 
level, as appropriate.  Subjects should not receive veliparib while 5-FU 
infusion and irinotecan are suspended.  Skipped doses are not to be made up.
●
No bevacizumab dose modifications will be made for hematologic toxicity.  
Subjects should not receive bevacizumab while 5-FU infusion and irinotecan 
are suspended.  Resume bevacizumab concurrently with FOLFIRI when 5-FU 
and irinotecan are skipped for hematologic toxicities.
Gastrointestinal Toxicities:
Diarrhea:  Lacrimation, rhinorrhea, miosis, diaphoresis, hot flashes, flushing, abdominal 
cramping, diarrhea, or other symptoms of early cholinergic syndrome may occur during or 
shortly after receiving irinotecan.  It is strongly suggested that Atropine, 0.25 – 1.0 mg IV 


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or SC be used at the time of irinotecan administration to prevent these symptoms.  
Additional antidiarrheal measures may be used at the discretion of the Investigator.  
Combination anticholinergic medications containing barbiturates or other agents 
(e.g., Donnatal) should not be used because these may affect irinotecan metabolism.  
Anticholinergics should be used with caution in patients with potential contraindications 
(e.g., obstructive uropathy, glaucoma, tachycardia, etc.).
Late diarrhea (e.g., developing more than 24 hours after irinotecan) should be managed 
with loperamide as described below.  
The following concomitant medications and/or dose modifications are based on toxicity 
experienced during a cycle (i.e., after Day 1 of any cycle):
Oral fluoroquinolone treatment should be initiated for any of the following:
●
Diarrhea persisting for more than 24 hours despite loperamide.
●
ANC < 500/μL (even in the absence of diarrhea or fever).
●
Fever with diarrhea (even in the absence of neutropenia).
●
Antibiotic therapy should also be initiated in patients who are hospitalized 
with prolonged diarrhea (even in the absence of neutropenia).
●
For Grade 2 diarrhea, discontinue 5-FU bolus. Reduce 5-FU infusion and 
irinotecan one dose level for the next cycle.  For each subsequent cycle, 
resume 5-FU infusion and irinotecan at the previous dose levels, provided 
diarrhea has fully resolved.
●
For Grade 3 or 4 diarrhea, suspend all protocol therapy.  If diarrhea resolves to 
≤Grade 2 within 4 weeks, resume protocol therapy with dose reductions as 
follows:  discontinue 5-FU bolus and continue 5-FU infusion and irinotecan at 
one lower dose level. 
●
No veliparib/placebo or bevacizumab dose reductions should be made for 
diarrhea.  Subjects should not receive veliparib or bevacizumab while 5-FU 
infusion and irinotecan are suspended.  Skipped doses are not to be made up.


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For symptoms of diarrhea and/or abdominal cramping that occur at any time during a 
treatment cycle with irinotecan, subjects will be instructed to begin taking loperamide.  
Loperamide should be started at the earliest sign of 1) a poorly formed or loose stool or 
2) the occurrence of 1 to 2 more bowel movements than usual in 1 day or 3) an increase in 
stool volume or liquidity.  Loperamide should be taken in the following manner:  4 mg at 
the first onset of diarrhea, then 2 mg every 2 hours around the clock until diarrhea-free for 
at least 12 hours.  Subjects may take loperamide 4 mg every 4 hours during the night.  The 
maximum daily dose of loperamide is 16 mg/day.  Subjects should be provided with
loperamide at the initial treatment visit so that they have sufficient supply on hand in case 
antidiarrheal support is required.  Additional antidiarrheal measures may be used at the 
discretion of the Investigator.  Subjects should be instructed to increase fluid intake to 
help maintain fluid and electrolyte balance during episodes of diarrhea.
Mucositis:  The following dose modifications are based the grade of mucositis seen on 
the day of treatment for any day after Day 1 in any cycle.
●
For Grade 2 mucositis, may discontinue 5-FU bolus.  Reduce 5-FU infusion 
and irinotecan one dose level for the next cycle.  For each subsequent cycle, 
may resume 5-FU infusion and irinotecan at the previous dose levels, provided 
mucositis has fully resolved.
●
For Grade 3 or 4 mucositis, suspend all protocol therapy.  If mucositis resolves 
to ≤Grade 2 within 4 weeks, resume protocol therapy with dose reductions as 
follows:  discontinue 5-FU bolus and continue 5-FU infusion and irinotecan at 
one lower dose level. 
●
No veliparib/placebo or bevacizumab dose reductions should be made for 
mucositis.  Subjects should not receive veliparib or bevacizumab while 5-FU 
infusion and irinotecan are suspended.  Skipped doses are not to be made up.
Nausea/Vomiting:  The following dose modifications are based on the grade of nausea 
and vomiting occurring during a cycle (i.e., after Day 1 in any cycle).


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●
For Grade 3 nausea or vomiting, reduce irinotecan one dose level for the next
cycle.  For each subsequent cycle, may continue irinotecan at previous dose 
level, provided nausea has resolved ≤Grade 2.
●
For Grade 4 nausea or vomiting, discontinue 5-FU bolus and continue 5-FU 
infusion and irinotecan at one lower dose level. These dose reductions for 
vomiting and/or nausea should be made only if they persist/occur despite 
two treatments with adequate (combination) antiemetic therapy.  The use of 
aprepitant is prohibited for those patients receiving FOLFIRI.
●
Veliparib may exacerbate nausea associated with FOLFIRI.  Investigators 
should consider reducing veliparib/placebo one dose level as appropriate.
●
No bevacizumab dose modifications will be made for diarrhea, mucositis, 
nausea, or vomiting.  Continue bevacizumab when 5-FU and irinotecan are 
skipped for these GI toxicities.
Pulmonary Toxicities
●
For ≥ Grade 3 cough, dyspnea, hypoxia, pneumonitis, or pulmonary infiltrates, 
skip bevacizumab until interstitial lung disease is ruled out.  Continue 
irinotecan and 5-FU/leucovorin.  Discontinue all protocol therapy if interstitial 
lung disease is confirmed.
●
No veliparib/placebo dose reductions should be made for pulmonary toxicities.
Hypertension
●
For hypertension controlled with medication (to < 160/90 mmHg):  Continue 
bevacizumab.
●
For persistent or symptomatic hypertension:  Skip bevacizumab.  If 
bevacizumab treatment is delayed for more than 4 weeks due to uncontrolled 
hypertension, discontinue bevacizumab.
●
Grade 4 hypertension:  Discontinue bevacizumab.  Patients who skip or 
discontinue bevacizumab due to hypertension may continue other protocol 
therapy.
●
No veliparib/placebo dose reductions should be made for hypertension.


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Reversible Posterior Leukoencephalopathy Syndrome (RPLS/PRES)
For signs and symptoms suggestive of RPLS (e.g., confusion, headache, seizures, cortical 
blindness) skip bevacizumab.  Suspected RPLS should be investigated with MRI.  If 
diagnosis of RPLS is confirmed, bevacizumab should be permanently discontinued.
If RPLS is ruled out via MRI, the decision on resuming bevacizumab should be based on 
the nature of the signs/symptoms.  For Grade 4 events with likely relationship to 
bevacizumab, discontinue bevacizumab; for Grade 3 events, bevacizumab may be 
resumed if toxicities completely resolve within 4 weeks.
Other protocol therapy may be continued at the discretion of the Investigator.
Cardiovascular Toxicities:
Subjects should be carefully monitored for evidence of thromboembolic disease during 
treatment.
Venous Thrombotic Events
●
For Grade 3 venous thrombosis or asymptomatic pulmonary embolism:  Skip 
bevacizumab.  If the planned duration of full-dose anticoagulation is 
< 2 weeks, bevacizumab should be held until the full-dose anticoagulation 
period is over.  If the planned duration of full-dose anticoagulation is 
> 2 weeks, bevacizumab may be resumed during the period of full-dose 
anticoagulation if all of the following criteria are met:
○
The patient must have an in-range INR (usually between 2 and 3) on a 
stable dose of warfarin or be on stable dose of low molecular weight 
heparin prior to restarting bevacizumab treatment;
○
The patient must not have pathological conditions that carry high risk of 
bleeding (e.g., tumor involving major vessels);
○
The patient must not have had hemorrhagic events while on study.
●
For Grade 4 or for recurrent/worsening venous thromboembolic events after 
resumption of bevacizumab:  Discontinue all protocol therapy.


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●
For symptomatic pulmonary embolism, subjects will discontinue all protocol 
therapy.
Arterial Thrombotic Events
●
For Grade 2 arterial thrombotic events not present at baseline or worsened 
since the initiation of protocol therapy, discontinue bevacizumab.  Subjects 
may continue other protocol therapy.
●
For Grade 3 cerebrovascular ischemia, and/or peripheral or visceral arterial 
ischemia, discontinue bevacizumab.  Subjects may continue other protocol 
therapy.
●
For Grade 3 cardiac ischemia/infarction, discontinue all protocol therapy.
●
For any Grade 4 arterial thrombotic event, including cerebrovascular ischemia, 
cardiac ischemia/infarction, peripheral or visceral arterial ischemia, 
discontinue all protocol therapy.
Left Ventricular Dysfunction
●
For Grade 3 LV dysfunction, discontinue bevacizumab.  Subjects may 
continue other protocol therapy.
●
For Grade 4 LV dysfunction, discontinue all protocol therapy.
Hemorrhage/Bleeding
●
For Grade 3 hemorrhage/bleeding, discontinue bevacizumab and skip other 
protocol therapy; once hemorrhage or bleeding resolves, other protocol therapy 
may be continued at the treating physician's discretion.
●
For Grade 4 hemorrhage/bleeding, discontinue all protocol therapy.
Proteinuria
●
For proteinuria of ≥ 2+:  Confirm total urine protein with a 24-hour urine 
collection or urine protein to creatinine (UPC) ratio.  For 2+ proteinuria, the 
scheduled dose of bevacizumab may be given while awaiting the results of the 
24-hour collection or UPC ratio.  For > 2+ proteinuria, skip bevacizumab 


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while awaiting results of the 24-hour urine collection or UPC ratio.  Other 
protocol therapy may be continued.
●
If proteinuria is ≥ 2 g/24 hours or UPC ratio ≥ 2.0, skip bevacizumab until 
urine protein recovers to < 2 g/24 hours or UPC < 2.0, continue other protocol 
treatment.  If bevacizumab is delayed more than 8 weeks due to proteinuria, 
discontinue bevacizumab.
●
If nephrotic syndrome (Grade 4 proteinuria) occurs, discontinue bevacizumab.
●
No veliparib/placebo dose reductions should be made for proteinuria.
Wound Dehiscence, GI Perforation, or Intra-Abdominal Fistula
●
For wound dehiscence requiring medical or surgical intervention:  Discontinue 
bevacizumab.
●
For any grade GI perforation, GI leak, or intra-abdominal fistula:  Discontinue 
bevacizumab.
Hypersensitivity and Infusion Reactions
Note that the NCI CTCAE defines these reactions differently:  "Cytokine release 
syndromes/acute infusion reactions are different from allergic/hypersensitivity reactions, 
although some of the manifestations are common to both AEs.  An acute infusion reaction 
may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other 
biological agents).  Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion."  
See the "Syndromes" section of the CTCAE version 4.0 for a complete list of signs and 
symptoms of "Cytokine release syndrome/acute infusion reaction;" and see the 
"Allergy/Immunology" section for a description of hypersensitivity.
Bevacizumab Dose Modifications for Infusion Reactions
The initial bevacizumab dose should be administered over a minimum of 90 minutes.  If 
no adverse reactions occur, the second dose should be administered over a minimum of 
60 minutes.  Again, if no adverse reactions occur, the third and subsequent doses should 


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be administered over a minimum of 30 minutes.  If infusion-related adverse reactions 
occur, subsequent infusions should be administered over the shortest period that is well 
tolerated.  Patients may receive premedication with diphenhydramine 25 to 50 mg 
intravenously or orally 30 minutes prior to bevacizumab if they have previously 
experienced mild infusion reactions.  Acetaminophen premedication may also be used.
Dose Modifications for Hypersensitivity Reactions
●
For Grade 1 hypersensitivity reactions (transient rash, drug fever < 38°C):  
Decrease the infusion rate by 50% until symptoms resolve, then resume at the 
initial planned rate.
●
For Grade 2 hypersensitivity reactions (urticaria, drug fever ≥ 38°C and/or 
asymptomatic bronchospasm):  Stop infusion.  Administer H1 and/or H2 
blockers, and/or steroids according to institutional policy.  Restart the infusion 
when symptoms resolve and pretreat before all subsequent doses.  Treat 
according to institutional policy.
●
For Grade 3 or Grade 4 hypersensitivity reactions:  Stop the infusion.  
Discontinue all protocol treatment and notify the Study Designated Physician.
Other Non-Hematologic Toxicities
●
For all other ≥ Grade 3 non-hematologic toxicities not described above, hold 
all protocol therapy and monitor toxicity at least weekly.  If toxicity resolves to 
≤ Grade 1 within 4 weeks, protocol therapy may be resumed.  Discontinue the 
5-FU bolus and continue with 5-FU infusion and irinotecan at one lower dose 
level.  Veliparib/placebo may be reduced at the discretion of the Investigator.


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Appendix J.
Protocol Amendment:  List of Changes
Specific Protocol Changes
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Section 1.2  Synopsis
Subsection Methodology:
Heading "Protocol Therapy"
Fifth and sixth sentence previously read:
Subjects randomized to the veliparib arm will receive modified FOLFIRI as irinotecan 
180 mg/m2 (90 minute infusion); leucovorin 400 mg/m2 (90 minute infusion); saline bolus 
(up to 15 minute infusion) immediately followed by 5-FU 2400 mg/m2 (46-hour 
continuous infusion) starting on Day 1 of each 14-day cycle.  Subjects randomized to the 
placebo arm will receive standard FOLFIRI as irinotecan (180 mg/m2); leucovorin 
400 mg/m2 (90 minute infusion); 5-FU bolus 400 mg/m2 (up to 15 minute infusion) 
immediately followed by 5-FU 2400 mg/m2 (46-hour continuous infusion) on Day 1 of 
each 14-day cycle.


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Has been changed to read:
Subjects randomized to the veliparib arm will receive modified FOLFIRI as irinotecan 
180 mg/m2 (90 minute infusion ± 30 minutes); leucovorin 400 mg/m2 (90 minute infusion 
± 30 minutes); saline bolus (up to 15 minute infusion) immediately followed by 5-FU 
2400 mg/m2 (46-hour continuous infusion ± 4 hours) starting on Day 1 of each 14-day 
cycle.  Subjects randomized to the placebo arm will receive standard FOLFIRI as 
irinotecan 180 mg/m2 (90 minute infusion ± 30 minutes); leucovorin 400 mg/m2
(90 minute infusion ± 30 minutes); 5-FU bolus 400 mg/m2 (up to 15 minute infusion) 
immediately followed by 5-FU 2400 mg/m2 (46-hour continuous infusion ± 4 hours) on 
Day 1 of each 14-day cycle.
Section 1.2  Synopsis
Subsection Diagnosis and Main Criteria for Inclusion/Exclusion:
Heading "Main Exclusion:"
Third bullet previously read:
The last course of adjuvant chemotherapy must have ended > 12 months prior to 
colorectal cancer recurrence;
Has been changed to read:
The last course of adjuvant or neoadjuvant chemotherapy must have ended > 12 months 
prior to C1D–2;
Section 1.2  Synopsis
Subsection Diagnosis and Main Criteria for Inclusion/Exclusion:
Heading "Main Exclusion:"
Tenth bullet, third sub-bullet previously read:
Symptomatic congestive heart failure;
Has been changed to read:
Symptomatic congestive heart failure (NYHA Class ≥ II);


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Section 1.2  Synopsis
Subsection Reference Therapy:
Previously read:
Reference Therapy:
Irinotecan
Dose:
180 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
Intravenous (IV) over 90 minutes
Reference Therapy:
Leucovorin (Folinic Acid)
Dose:
400 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
IV over 90 minutes
Reference Therapy:
Flourouracil (5-FU) bolus or saline bolus
Dose:
400 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
IV up to 15 minutes
Reference Therapy:
Flourouracil (5-FU) infusion
Dose:
2400 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
IV over 46 hours
Has been changed to read:
Reference Therapy:
Irinotecan
Dose:
180 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
Intravenous (IV) over 90 minutes ± 30 minutes
Reference Therapy:
Leucovorin (Folinic Acid)
Dose:
400 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
IV over 90 minutes ± 30 minutes
Reference Therapy:
Fluorouracil (5-FU) bolus or saline bolus
Dose:
400 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
IV up to 15 minutes 
Reference Therapy:
Fluorouracil (5-FU) infusion
Dose:
2400 mg/m2, Day 1 of each 14-day cycle
Mode of Administration:
IV over 46 hours ± 4 hours
Reference Therapy:
Bevacizumab (at the Investigator's discretion)
Dose:
5 mg/kg
Mode of Administration:
IV immediately preceding FOLFIRI


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Section 1.3  List of Abbreviations and Definition of Terms
"IDMC" previously read:
IDMC Independent Data Monitoring Committee
Has been changed to read:
IMC
Internal Monitoring Committee
Section 3.8  Clinical Experience
Third paragraph, tenth sentence previously read:
The most commonly reported treatment-emergent Grade 3 or 4 adverse events (rate 
> 10%) were neutropenia (44 subjects, 47.8%), nausea (35 subjects, 38.0%), diarrhea 
(31 subjects, 33.7%), fatigue (28 subjects, 30.4%), vomiting (25 subjects, 27.2%), anemia 
(22 subjects, 23.9%), alopecia (18 subjects, 19.6%), decreased appetite (14 subjects, 
15.2%), and stomatitis (11 subjects, 12.0%) and two patients in the veliparib 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).
Has been changed to read:
The most commonly reported treatment-emergent Grade 3 or 4 adverse events (rate > 5%) 
were neutropenia (33 subjects, 35.9%), anemia (9 subjects, 9.8%), diarrhea (5 subjects, 
5.4%), dehydration (5 subjects, 5.4%) and hypokalemia (5 subjects, 5.4%).  Two patients 
in the veliparib 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).
Section 5.1  Overall Study Design and Plan:  Description
Fifth paragraph, fifth and sixth sentence previously read:
Subjects randomized to the veliparib arm will receive modified FOLFIRI as irinotecan 
180 mg/m2 (90 minute infusion); leucovorin 400 mg/m2 (90 minute infusion); saline bolus 
(up to 15 minute infusion) immediately followed by 5-FU 2400 mg/m2 (46-hour 


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continuous infusion) starting on Day 1 of each 14-day cycle.  Subjects randomized to the 
placebo arm will receive standard FOLFIRI as irinotecan (180 mg/m 2); leucovorin 
400 mg/m2 (90 minute infusion); 5-FU bolus 400 mg/m2 (up to 15 minute infusion) 
immediately followed by 5-FU 2400 mg/m2 (46-hour continuous infusion) on Day 1 of 
each 14-day cycle.
Has been changed to read:
Subjects randomized to the veliparib arm will receive modified FOLFIRI as irinotecan 
180 mg/m2 (90 minute infusion ± 30 minutes); leucovorin 400 mg/m2 (90 minute infusion 
± 30 minutes); saline bolus (up to 15 minute infusion) immediately followed by 5-FU 
2400 mg/m2 (46-hour continuous infusion ± 4 hours) starting on Day 1 of each 14-day 
cycle.  Subjects randomized to the placebo arm will receive standard FOLFIRI as 
irinotecan 180 mg/m2 (90 minute infusion ± 30 minutes); leucovorin 400 mg/m2
(90 minute infusion ± 30 minutes); 5-FU bolus 400 mg/m2 (up to 15 minute infusion) 
immediately followed by 5-FU 2400 mg/m2 (46-hour continuous infusion ± 4 hours) on 
Day 1 of each 14-day cycle.
Section 5.1  Overall Study Design and Plan:  Description
Eighth paragraph, first sentence previously read:
Sites will begin collecting post-treatment and survival information 4 weeks after the 
Final Visit.  
Has been changed to read:
Sites will begin collecting post-treatment and survival information 4 weeks after the last 
clinical assessment.  


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Figure 1.  Protocol Therapy Dosing Schedule Overview
Previously read:
Has been changed to read:


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Section 5.2.2 Exclusion Criteria
Criterion 3 previously read:
The last course of adjuvant chemotherapy must have ended > 12 months prior to 
colorectal cancer recurrence;
Has been changed to read:
The last course of adjuvant or neoadjuvant chemotherapy must have ended > 12 months 
prior to C1D–2;
Section 5.2.2 Exclusion Criteria
Criterion 10, third bullet previously read:
Symptomatic congestive heart failure;
Has been changed to read:
Symptomatic congestive heart failure (NYHA Class ≥ II);
Section 5.2.2  Exclusion Criteria
Subsection Rationale for Exclusion Criteria
Previously read:
1 – 4, 8, 11, 13, 16
To select the appropriate subject population with sufficient 
disease severity for evaluation
5, 6, 9, 10, 12, 14, 15
For the safety of the subjects
17 – 22
For the safety of subjects that receive bevacizumab
Has been changed to read:
1 – 4, 7, 8, 11, 13, 16
To select the appropriate subject population with sufficient 
disease severity for evaluation
5, 6, 9, 10, 12, 14, 15
For the safety of the subjects
17 – 22
For the safety of subjects that receive bevacizumab


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Table 4.  Study Assessments
Activity*^ "Physical Exam" previously read:
Activity*^
Screening
Cycle 1 Day –2
Cycle 1 Day 1
Cycle 1 Day 8
Cycle 2 Day 1
Cycle 2 Day 8
Day 1 of Each 
Cycle
Every 8 Weeks
from C1D1^
Final Visita
30-Day 
Follow-Up Visitb
Survival Periodc
Physical Exam
Xe
Xe
Xe
X
X
X
X
Has been changed to read:
Activity*^
Screening
Cycle 1 Day –2
Cycle 1 Day 1
Cycle 1 Day 8
Cycle 2 Day 1
Cycle 2 Day 8
Day 1 of Each 
Cycle
Every 8 Weeks 
from C1D1^
Final Visita
30-Day 
Follow-Up Visitb
Survival Periodc
Physical Exam
Xe
Xe
X
X
X
X


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Table 4.  Study Assessments
Table note "e." previously read:
Physical exam not required, if performed within 7 days prior to C1D–2.  Height is only 
measured at Screening.
Has been changed to read:
Height is only measured at Screening.  Physical exam is not required on C1D–2 if one has 
been performed within the last 7 days.
Table 6.  Schedule of Pharmacogenetic (PG) and Pharmacodynamic (PD) 
Assessments
Activity "Tissue Sample Collection" previously read:
Activity
Visit Schedule
Before Drug 
Administration
Sampling Plan
Specimen Matrix
Tissue Sample 
Collection
Screeningb,d
Archived FFPE tissue blocks 
(Room Temperature or 
Refrigerated-FFPE)
Has been changed to read:
Activity
Visit Schedule
Before Drug 
Administration
Sampling Plan
Specimen Matrix
Tissue Sample 
Collection
Screeningd
Archived FFPE tissue blocks 
(Room Temperature or 
Refrigerated-FFPE)
Section 5.3.1.1  Study Procedures
Last paragraph, first sentence previously read:
For all study procedures:  The study procedures outlined in this protocol are 
recommendations based on routine safety assessments required during chemotherapy 
+ veliparib administration.


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Has been changed to read:
For all study procedures:  The study procedures outlined in this protocol are 
recommendations based on routine safety assessments required during chemotherapy and 
veliparib administration.
Section 5.3.1.1  Study Procedures
Subsection Medical History
Fifth, sixth and seventh bullet previously read:
●
RAS status;
●
BRAF status;
●
Microsatellite instability (MSI) status.
Has been changed to read:
●
RAS status (if known);
●
BRAF status (if known);
●
Microsatellite instability (MSI) status (if known).
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Third paragraph, first sentence previously read:
A local reference laboratory may perform chemistry, hematology, coagulation, and 
urinalysis tests for immediate subject management (i.e., emergent situations); however, 
split or concurrent samples must be drawn and sent to the central laboratory for analysis.  
Has been changed to read:
A local reference laboratory may perform chemistry, hematology, coagulation, and 
urinalysis tests for immediate subject management (i.e., emergent situations); however, 
split or concurrent samples must be drawn and sent to the central laboratory for analysis.  


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Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Last paragraph previously read:
**If there is a discrepancy between the local and central labs, the site must enter the 
relevant local labs that were used for eligibility or treatment decisions on the appropriate 
eCRF.**
Has been changed to read:
**If there is a discrepancy between the local and central labs, the site must enter the 
relevant local labs that were used for treatment decisions on the appropriate eCRF.**
Table 7.  Clinical Laboratory Tests
Column "Clinical Chemistry,""Inorganic phosphorus" previously read:
Inorganic phosphorus
Has been changed to read:
Inorganic phosphate
Table 7.  Clinical Laboratory Tests
Column "Clinical Chemistry,""Sodium Bicarbonate" previously read:
Sodium Bicarbonate
Has been changed to read:
Bicarbonate/CO2
Section 5.3.2.1  Blood Samples for Pharmacokinetic Analysis
Section Veliparib Pharmacokinetic Specimen Collection
First paragraph, first and second sentence previously read:
The date and time of sample collection and the date and time of the dose of veliparib will 
be captured on the eCRF. Blood samples (3 mL) will be collected by venipuncture 
intoevacuated potassium (K2) EDTA tubes per Table 5.


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Has been changed to read:
The date and time of each blood sample collection will be recorded.  The date and time of 
the veliparib/placebo dose on PK sampling days (refer to Table 5) and the date and time 
of the two doses of veliparib/placebo prior to PK sampling on C2D1 and C3D1 will be 
captured on the eCRF.
Section 5.3.2.2  Measurement Methods
Last sentence previously read:
Additionally, veliparib metabolite(s) concentrations in plasma samples may be determined 
using a non-GLP or a validated assay.
Has been changed to read:
Additionally, veliparib metabolite(s) concentrations in plasma samples may be determined 
using a non-validated or a validated assay.
Section 5.3.2.3  Blood Samples for Pharmacogenetic Analysis
Second paragraph, first sentence previously read:
The sample collection tubes will minimally be labeled with "PG-DNA," protocol number, 
subject number and visit.
Has been changed to read:
The sample collection tubes will minimally be labeled with "PG-DNA blood," protocol 
number, subject number and visit.  
Section 5.3.7  Pharmacodynamic Variables
Fourth paragraph previously read:
Samples collected during the course of this study may be banked and used in the future to 
investigate new scientific questions related to this study.  Additionally, the samples may 
be anonymized and used for diagnostic test development.  AbbVie (or a designated 
laboratory) will store the samples in a secure storage space with adequate measures to 


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protect confidentiality.  The samples will be retained while research on veliparib (or drugs 
of this class) continues for up to but no longer than 20 years.
Has been changed to read:
AbbVie (or people or companies working with AbbVie) will store and analyze the 
samples in a secure space with adequate measures to protect confidentiality.  Samples will 
be retained up to 20 years (or per local legal requirement) while research on veliparib (or 
drugs of this class) or colorectal cancer (or related conditions) continues.
Section 5.4  Removal (Discontinuation) of Subjects from Protocol Therapy and 
Study Visits
Second paragraph previously read:
Additionally, in the event a subject withdraws from the study, pharmacodynamic samples 
stored for long term biomarker research (no more than 20 years) will also be destroyed.  
In the event that destruction is not possible, they will no longer be linked to the subject.  If 
the subject changes his/her consent and the samples have already been tested, those results 
will still remain part of the overall research data.  In the event of a subject's death or loss 
of competence, the samples and data will continue to be part of AbbVie's research but will 
not be stored more than 20 years.
Has been changed to read:
In the event a subject withdraws consent from participating in the study, stored 
pharmacodynamic samples will continue to be used for research and analysis.  In the 
event that a subject would like to withdraw consent for research of samples, the subject 
may request for samples to be withdrawn.  Once AbbVie receives the request, remaining 
samples will be destroyed unless the FDA requires AbbVie to keep the samples.  If the 
subject changes his/her consent, and the samples have already been tested, those results 
will still remain part of the overall research data.


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Section 5.4.5  Timing and Collection of Survival and Post-Treatment Cancer 
Information
First paragraph, second sentence previously read:
Sites will collect survival information and post-treatment cancer information beginning 
4 weeks after the last study visit and continuing every 4 weeks for 1 year, then every 
8 weeks for up to 2 additional years or until the endpoint of death.
Has been changed to read:
Sites will collect survival information and post-treatment cancer information beginning 
4 weeks after the last clinical assessment and continuing every 4 weeks for 1 year, then 
every 8 weeks for up to 2 additional years or until the endpoint of death.
Section 5.5.1  Protocol Therapy Administered
Subsection Dispensing Protocol Therapy
Add:  new fourth paragraph
Sites may calculate body surface area (BSA) per local treatment practice.  Bevacizumab 
and FOLFIRI doses should be calculated based on the weight measurement obtained at 
C1D1.  Subsequent bevacizumab and FOLFIRI doses must be recalculated if a subject's 
body weight increases or decreases by more than 10%.
Section 5.5.1  Protocol Therapy Administered
Subsection Administration of Irinotecan
First sentence previously read:
For the purposes of this protocol, irinotecan 180 mg/m2 will be administered as a 
90 minute IV infusion on Day 1 of each 14-day cycle.
Has been changed to read:
For the purposes of this protocol, irinotecan 180 mg/m2 will be administered as a 
90 minute (± 30 minutes) IV infusion on Day 1 of each 14-day cycle.


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Section 5.5.1  Protocol Therapy Administered
Subsection Administration of Leucovorin
First sentence previously read:
For the purposes of this protocol, leucovorin 400 mg/m2 will be administered as a 
90 minute IV infusion concurrent with irinotecan on Day 1 of each 14-day cycle.  
Has been changed to read:
For the purposes of this protocol, leucovorin 400 mg/m2 will be administered as a 
90 minute (± 30 minutes) IV infusion concurrent with irinotecan on Day 1 of each 14-day 
cycle.  Irinotecan and leucovorin may be administered sequentially in accordance with 
local practice.
Section 5.5.1  Protocol Therapy Administered
Subsection Administration of Fluorouracil (5-FU) Infusion
First sentence previously read:
For the purposes of this protocol, 5-FU 2400 mg/m2 will be administered as a 46-hour IV 
infusion on Day 1 of each 14-day cycle.  
Has been changed to read:
For the purposes of this protocol, 5-FU 2400 mg/m2 will be administered as a 46-hour 
(± 4 hours) IV infusion on Day 1 of each 14-day cycle.  
Section 5.5.1  Protocol Therapy Administered
Subsection Administration of Bevacizumab
Last sentence previously read:
The initial dose of bevacizumab should be given over 90 minutes, second dose over 
60 minutes, and all subsequent doses over 30 minutes if prior infusions are tolerated 
without infusion associated adverse events.


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Has been changed to read:
The initial dose of bevacizumab should be given over 90 minutes (± 30 minutes), 
second dose over 60 minutes (± 20 minutes), and all subsequent doses over 30 minutes 
(± 10 minutes) if prior infusions are tolerated without infusion associated adverse events.
Section 5.5.1  Protocol Therapy Administered
Subsection Order of Administration
Add:  new second paragraph
Irinotecan and leucovorin may be administered sequentially in accordance with local 
treatment practice.
Section 5.5.9  Blinding
First paragraph, last sentence previously read:
To facilitate preplanned interim analyses of safety and efficacy data, AbbVie study 
personnel will remain unblinded throughout the study.
Has been changed to read:
To monitor patient safety on an ongoing basis, AbbVie study personnel will remain 
unblinded throughout the study.
Section 6.7  Adverse Event Reporting
First paragraph, last sentence previously read:
Serious adverse events that occur prior to the site having access to the RAVE® system or 
if RAVE® is not operable should use the SAE Non-CRF paper forms and send them to 
Clinical Pharmacovigilance within 24 hours of the site being made aware of the serious 
adverse event.
Has been changed to read:
Serious adverse events that occur prior to the site having access to the RAVE® system or 
if RAVE® is not operable should be documented on the SAE Non-CRF forms and emailed 


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(preferred route) or faxed to Clinical Pharmacovigilance within 24 hours of the site being 
made aware of the serious adverse event.
Section 6.7  Adverse Event Reporting
Fax and email information following second paragraph previously read:
FAX to:
Email to:
Has been changed to read:
Email to:
FAX to:
Section 6.7  Adverse Event Reporting
Fourth paragraph previously read:
For any subject safety concerns, please contact the AbbVie Study Designated Physician 
listed below:


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Has been changed to read:
Section 6.7  Adverse Event Reporting
Fifth paragraph previously read:
Should in case of subject safety concerns or medical emergencies the Primary Study 
Designated Physician be unavailable, please call the following central back-up number:
Has been changed to read:
In emergency situations involving study subjects when the primary Study Designated 
Physician (SDP) is not available by phone, please contact the 24-hour AbbVie Medical 
Escalation Hotline where your call will be re-directed to a designated backup AbbVie 
SDP:
Section 7.0  Protocol Deviations
First paragraph, first sentence previously read:
AbbVie does not allow intentional/prospective deviations from the protocol.
Has been changed to read:
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.


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Section 7.0  Protocol Deviations
"Primary Contact:" previously read:
Primary Contact:
Primary Contact:
Has been changed to read:
Primary Contact:


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Section 7.0  Protocol Deviations
"Alternate Contact (Secondary)" previously read:
Has been changed to read:
Section 8.1.7  Interim Analysis
Previously read:
To ensure subject safety and assess the efficacy of veliparib during the study, AbbVie will 
perform at least two efficacy and two safety interim analyses.
The two efficacy interim analyses will occur when approximately 25 and 50 PFS events 
are accrued.
The first safety interim analysis will occur approximately 2 weeks after 10 subjects 
stratified to the "planned bevacizumab use" group are randomized to the veliparib arm.  


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The second safety interim analysis will occur at the same time as the first efficacy interim 
analysis after approximately 107 subjects have completed the first cycle of protocol 
therapy.
Has been changed to read:
To ensure subject safety and assess the efficacy of veliparib during the study, AbbVie will 
perform at least one efficacy and two safety interim analyses.  An Internal Monitoring 
Committee (IMC) will be formed to review the interim data and make recommendations 
to the conduct of the study.  A separate IMC agreement defines the roles and 
responsibilities of the IMC, including its membership, scope, timing of meetings, and 
communication plan.
The first safety interim analysis will occur at least 8 – 10 weeks after 20 subjects in the 
"planned bevacizumab use" group are randomized.  All subjects who have received at 
least 1 dose of protocol therapy prior to the database versioning date will be included in 
this analysis.  The main objective for this early interim assessment will be to evaluate the 
safety of veliparib when combined with bevacizumab and FOLFIRI, which was not tested 
during any previous veliparib trials.
A second interim analysis for both efficacy and safety will be conducted at least 8 –
10 weeks after 35 PFS events have occurred.  The Internal Monitoring Committee will 
review efficacy data to determine the futility of the study.  A comprehensive review and 
assessment of the cumulative safety data will also be undertaken at the same time.  The 
main objective for this interim safety assessment will be to determine if the safety of 
veliparib in combination with FOLFIRI is sufficient to allow the on-study treatment to 
continue, or if a modification to the study should be made.


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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Clinical
GDSM
Statistics
Statistics
Clinical
Pharmacokinetics
Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
GDSM
Statistics
Statistics
Clinical
Pharmacokinetics
Bioanalysis
Appendix I.  Toxicity Management Guidelines for Protocol Therapy
Subsection Hematologic Toxicities:
First paragraph previously read:
The following dose modifications are based on toxicity experienced during a cycle 
(i.e., after Day 1 of any cycle):
Has been changed to read:
The following dose modifications are recommended for the next treatment cycle based on 
unresolved toxicity experienced during a previous cycle (i.e., after Day 1 of any cycle):


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Appendix I.  Toxicity Management Guidelines for Protocol Therapy
Subsection Gastrointestinal Toxicities:
Third paragraph previously read:
The following dose modifications are based on toxicity experienced during a cycle 
(i.e., after Day 1 of any cycle):
Has been changed to read:
The following concomitant medications and/or dose modifications are based on toxicity 
experienced during a cycle (i.e., after Day 1 of any cycle):
Appendix I.  Toxicity Management Guidelines for Protocol Therapy
Subsection Pulmonary Toxicities
First bullet, second sentence previously read:
Continue 5-FU.
Has been changed to read:
Continue irinotecan and 5-FU/leucovorin.
Appendix I.  Toxicity Management Guidelines for Protocol Therapy
Subsection Posterior Leukoencephalopathy Syndrome (RPLS)
Subsection title previously read:
Posterior Leukoencephalopathy Syndrome (RPLS)
Has been changed to read:
Reversible Posterior Leukoencephalopathy Syndrome (RPLS/PRES)



SAP_001.pdf: 
Veliparib
M14-217 – Statistical Analysis Plan
Version 1.0 – 23 February 2017
1
1.0
Title Page
Statistical Analysis Plan
Study M14-217
Randomized, Blinded, Multicenter, Phase 2 Study 
Comparing Veliparib Plus FOLFIRI ± Bevacizumab 
Versus Placebo Plus FOLFIRI ± Bevacizumab in 
Previously Untreated Metastatic Colorectal Cancer
Date:  23 February 2017
/$5


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M14-217 – Statistical Analysis Plan
Version 1.0 – 23 February 2017
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................4
4.0
Study Objectives, Design and Procedures............................4
4.1
Objectives .............................................................................................. 4
4.2
Design Diagram ..................................................................................... 4
4.3
Sample Size............................................................................................ 7
4.4
Interim Analysis..................................................................................... 7
5.0
Analysis Populations .............................................................7
5.1
Definition for Analysis Populations ........................................................ 7
5.2
Variables Used for Stratification of Randomization ................................ 8
6.0
Analysis Conventions ............................................................8
7.0
Demographics, Baseline Characteristics, Medical 
History, Previous/Concomitant Medications and 
Prior Oncology Therapies................................................... 12
7.1
Demographic and Baseline Characteristics ........................................... 12
7.2
Medical History.................................................................................... 13
7.3
Prior and Concomitant Medications and Prior Oncology Therapies ...... 14
8.0
Subjects Disposition ............................................................ 14
9.0
Study Therapy Exposure and Compliance ........................ 14
9.1
Exposure to Study Therapy................................................................... 14
9.1.1
Dose Reductions, Interruptions and Delays........................................... 15
9.2
Compliance .......................................................................................... 16
10.0
Efficacy Analysis .................................................................17
10.1
General Considerations......................................................................... 17
10.2
Primary Efficacy Analysis.................................................................... 17
10.3
Secondary Efficacy Analyses ............................................................... 18
10.3.1
Overall Survival ................................................................................... 18
10.3.2
Objective Response Rate ...................................................................... 19
10.4
Tertiary Efficacy Analyses ................................................................... 19
10.4.1
Duration of Overall Response............................................................... 19


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3
10.4.2
ECOG Performance Status ................................................................... 20
10.5
Additional Efficacy Analyses ............................................................... 20
11.0
Safety Analysis.....................................................................21
11.1
General Considerations......................................................................... 21
11.2
Analysis of Adverse Events.................................................................. 22
11.3
Deaths.................................................................................................. 25
11.4
Analysis of Laboratory and Vital Signs Data ........................................ 26
11.5
Analyses of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values................................................................ 27
List of Tables
Table 1.
Time Windows for Visit-Wise Analysis (ECOG, Laboratory, and 
Vital Signs) .......................................................................................... 12
List of Figures
Figure 1.
Protocol Therapy Dosing Schedule Overview......................................... 6


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3.0
Introduction
This statistical analysis plan (SAP) describes the full statistical analyses for veliparib 
(ABT-888) Protocol M14-217 dated 16 July 2015.  It will provide details of statistical 
methods and describe analysis conventions to guide the statistical programming work. 
Unless noted otherwise, all analyses will be performed using SAS version 9.4 (SAS 
Institute Inc., Cary, NC 27513) under the UNIX operating system. 
4.0
Study Objectives, Design and Procedures
4.1
Objectives
Primary Objective:
The primary objective of the study is to assess whether the addition of oral veliparib to 
FOLFIRI will improve progression-free survival (PFS) in subjects with previously 
untreated metastatic colorectal cancer (mCRC). 
Secondary Objectives: 
The secondary objectives of the study are to assess overall survival (OS), objective 
response rate (ORR), safety, and tolerability. 
Tertiary Objectives: 
The tertiary objectives are to assess duration of response (DOR) and the effects on a 
patient's Eastern Cooperative Oncology Group (ECOG) performance status.
4.2
Design Diagram
This is a randomized, blinded, Phase 2 multicenter study evaluating the efficacy and 
tolerability of veliparib plus FOLFIRI versus placebo plus FOLFIRI in subjects with 
previously untreated metastatic colorectal cancer.  At the discretion of the Investigator, 
subjects can also be treated with bevacizumab.


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The study was designed to enroll approximately 120 subjects at approximately 60 study 
sites.  Subjects will be stratified by the planned use of bevacizumab (planned 
bevacizumab use versus no planned use with bevacizumab) and regions of the world 
(North America versus rest of world).  Within each stratification group, subjects will be 
randomized in a 1:1 ratio to one of two protocol therapy groups as follows: 
a.
Veliparib plus FOLFIRI ± bevacizumab
b. Placebo plus FOLFIRI ± bevacizumab
Enrollment will be gated to ensure that at least 60 subjects are enrolled in both the 
"planned bevacizumab use" group and "no planned bevacizumab use" group for a total of 
~120 subjects. 
Dosing Schedule Overview
One cycle of protocol therapy consists of 14 days, defined as Day –2 through Day 12.  
Dosing of oral veliparib/placebo will begin 2 days prior to the start of FOLFIRI and will 
continue twice a day (BID) for a total of 7 consecutive days.  At the discretion of the 
Investigator, bevacizumab (5 mg/kg) may be administered intravenously immediately 
preceding FOLFIRI.  FOLFIRI (irinotecan, leucovorin, 5-FU bolus (saline bolus for 
subjects randomized to the veliparib arm), 5-FU) will be administered starting on Day 1 of 
each 14-day cycle.  FOLFIRI is only to be given after veliparib/placebo dosing on cycle 
Day –2 and Day –1 are confirmed.  An overview of the protocol schedule constituting 
one treatment cycle is shown in Figure 1.  Additional details regarding dosing with 
veliparib/placebo, FOLFIRI and bevacizumab can be found in Section 5.5 of the Protocol.


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Figure 1.
Protocol Therapy Dosing Schedule Overview
Visit Schedule Overview
Screening procedures and baseline radiographic tumor assessments will be performed 
within 28 days prior to the first dose of veliparib/placebo on Cycle 1 Day –2 (C1D–2).  
Study visits will be conducted on Day 1 and Day 8 of the first and second cycle, then on 
Day 1 of each subsequent cycle.  Subjects will continue protocol therapy and attending 
study visits until they meet one of the defined discontinuation criteria found in Section 5.4 
of the Protocol.  When the Investigator has determined that a subject meets the criteria for 
discontinuation, a Final Visit will be conducted.  All subjects will have one Follow-Up 
Visit approximately 30 days after the last dose of protocol therapy.  Sites will begin 
collecting post-treatment and survival information 4 weeks after the Final Visit. 
Post-baseline radiographic tumor assessment will be conducted every 8 weeks from C1D1 
(prior to the start of a new cycle) until radiographic progression.  Radiographic tumor 
assessments will be evaluated using the Response Evaluation Criteria in Solid Tumors 
(RECIST), Version 1.1. 


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4.3
Sample Size
A minimum of 70 PFS events was chosen to provide adequate precision in the hazard 
ratio estimate.  Assuming median PFS times of 9.4 months in the FOLFIRI ± 
bevacizumab arm and 15.7 months in the veliparib plus FOLFIRI ± bevacizumab arm, 
based on a minimum of 70 PFS events, the expected 95% confidence interval for the 
estimated hazard ratio would be approximately 0.37 to 0.96.  A total of 120 subjects will 
be enrolled into the study.  Assuming a total enrollment period of 12 months, it is 
anticipated that the study will complete by end of the 22nd month if the true median times 
for each treatment arm are as assumed above.
4.4
Interim Analysis
To ensure subject safety and assess the efficacy of veliparib during the study, AbbVie 
performed one efficacy/futility analysis and two safety interim analyses.  An Internal 
Monitoring Committee (IMC) was formed to review the interim data and make 
recommendations to the study team regarding the conduct of the study.  A separate IMC 
agreement defines the roles and responsibilities of the IMC, including its membership, 
scope, timing of meetings, and communication plan.
The first safety interim was planned to occur at least 8 – 10 weeks after 20 subjects in the 
"planned bevacizumab use" group are randomized.  A second interim analysis for both 
efficacy and safety was planned to be conducted at least 8 – 10 weeks after 35 PFS events 
have occurred. 
The first IMC meeting reviewed safety data on August 31, 2015, and the second IMC 
meeting reviewed safety and efficacy data on May 16, 2016.  The IMC recommended 
continuing the study after both of the IMC meetings.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
Two study populations will be analyzed, defined as follows:


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●
Intent-To-Treat (ITT) population – all subjects who were randomized by IRT.  
The data from ITT population will be analyzed by the treatment group 
assignment given at the time of randomization, even if the subject takes the 
incorrect drugs that do not match the assigned treatment, or does not receive 
any treatment, or does not follow the protocol until completion.
●
As Treated (AST) population – all subjects who were randomized by IRT and 
took at least 1 dose of study drug (veliparib/placebo).  The data from AST 
population will be analyzed by the actual treatment that subject received.
5.2
Variables Used for Stratification of Randomization
Subject randomization will be stratified by Region (North America vs. Rest of World) and 
Planned Bevacizumab Use (Planned Bevacizumab Use vs. No Planned Bevacizumab Use) 
into 4 strata as follows:
Group
Strat Factor 1
Strat Factor 2
1
North America
Planned Bevacizumab Use
2
North America
No Planned Bevacizumab Use
3
Rest of World
Planned Bevacizumab Use
4
Rest of World
No Planned Bevacizumab Use
During randomization, subjects within each of the 4 strata were randomized in a 1:1 ratio 
to either the veliparib plus FOLFIRI group or the placebo plus FOLFIRI group.
6.0
Analysis Conventions
General Considerations
Due to the proof-of-concept nature of the study, all of the analyses will be conducted in an 
estimation fashion.  Ninety-five percent confidence intervals will be presented and 
P-values will be not provided.  The date of randomization is defined as the date that the 
IRT issues a randomization number.


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All randomized subjects will be included in the efficacy analyses.  All subjects who 
receive at least one dose of the study drug (veliparib/placebo) will be included in the 
safety analysis.
Definition of Study Drug
Unless otherwise specified, the study drug in this document refers to veliparib/placebo.
Definition of Study Therapy
Unless otherwise specified, the study therapy in this document refers to all protocol 
allowed therapies including veliparib/placebo, bevacizumab, ironotecan, leucovorin, and 
5-FU infusion/saline bolus.
Stratification Factor for Efficacy Analyses
Planned bevacizumab use (planned bevacizumab use versus no planned bevacizumab use) 
will be used in all stratified analyses of the efficacy endpoints.  The stratification factor 
value under which the subject is randomized by the IRT will be used in the efficacy 
analyses.
Dealing with Multiple Values on the Same Day
In cases where multiple values are collected on the same day (including baseline visit and 
post-baseline visits), the maximum grade value will be selected as the value for that day 
for the shift analysis of lab parameters; the arithmetic average will be calculated and used 
as the value for that day for the change from baseline in performance status (ECOG), 
laboratory, and vital signs parameters.
Definition of Baseline
Unless otherwise specified, the baseline is defined as the last non-missing observation 
collected on or prior to the date of the first dose of study drug for treated subjects (or the 
date of randomization for non-treated subjects).


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Dealing with Surgical Intervention
As a result of treatment, subjects may suspend protocol therapy to undergo surgical 
resection with curative intent for metastatic disease.  Subjects may then restart protocol 
therapy beginning with the next scheduled cycle provided they have recovered from 
surgery.  With respect to tumor measurements, the first post-surgery radiographic 
assessment will serve as the new post-surgery baseline.  Target or non-target lesions 
existing before and remaining after surgery should continue to be evaluated using 
RECIST, Version 1.1.  Details regarding tumor response measurements can be found in 
Protocol Appendix D.
Definition of Final Visit
For ECOG, laboratory and vital signs variables, Final Visit is defined as the last non-
missing observation collected within 30 days following the last dose of study drug 
(veliparib/placebo).  All post-baseline assessments collected more than 30 days after the 
last dose of study drug (veliparib/placebo) will not be included in the analyses of 
laboratory and vital signs variables.
Definition of Cycle X Rx Day 
Cycle X Rx Day 1 for each cycle during the treatment period (1 cycle is defined as a 
minimum of 14 days) is defined as 2 days prior to the first dose day of Fluorouracil 
Infusion in each cycle.  Cycle X Rx Day is defined as days relative to Cycle X Rx Day 1 
of each cycle.  Cycle X Rx Day is a negative (positive) value when the time point of 
interest is prior to (after) Cycle X Rx Day 1.  The day before Cycle X Rx Day 1 is 
therefore Cycle X Rx Day –1 and there is no Cycle X Rx Day 0.  After treatment of 
veliparib/placebo is over, nominal Cycle X Rx Day 1 is generated as 14 days from the last 
Cycle X Rx Day 1. 


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Definition of Analysis Windows
All time points and corresponding time windows are defined for each cycle based on 
Cycle X Rx Day 1 to obtain number of days relative to the Cycle X Rx Day 1 of each 
cycle.
For visit-wise longitudinal analyses such as change from baseline to all post-baseline 
assessments in ECOG, laboratory, and vital signs values, the time windows specified in 
Table 1 describe how the data will be assigned to the protocol specified visits.  Analysis 
time windows are constructed using the following algorithm:
●
Determine the nominal Cycle X Rx Day for each scheduled visit.
●
Determine the window around a specific nominal Cycle X Rx Day as in 
Table 1.
●
If more than one assessment is included in a time window, the assessment 
closest to the nominal day should be used.  If there are two observations 
equally distant to the nominal day, the later one will be used in analyses.
The data will only be analyzed for visits that have at least 5 subjects' observation for 
either of treatment group.


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Table 1.
Time Windows for Visit-Wise Analysis (ECOG, Laboratory, and 
Vital Signs)
Protocol Defined 
Study Visit
Cycle X
Rx Day
Nominal Cycle 
Rx Rx Day**
Time Window
(Cycle X Rx Day 
Range)*
Time Window
(Cycle X Rx Day 
Range)***
Cycle 1 Day –2
Cycle 1 Rx Day 1
Baseline
Baseline
Baseline
Cycle 1 Day 1
Cycle 1 Rx Day 3
3
[2, 6]
[2, 9]
Cycle 1 Day 8*
Cycle 1 Rx Day 10
10
[7, 13]
Cycle 2 Day 1
Cycle 2 Rx Day 3
3
[–1, 6]
[–5, 9]
Cycle 2 Day 8*
Cycle 2 Rx Day 10
10
[7, 13]
Cycle 3 Day 1
Cycle 3 Rx Day 3
3
[–1, 9]
[–5 ,9]
Cycle X Day 1
Cycle X Rx Day 3
3
[–5, 9]
[–5, 9]
Final Visit
Final Visit
See Final Visit
See Final Visit
See Final Visit
*
For Chemistry, Hematology and Urinalysis only.
**
For ECOG, nominal Cycle Rx Day 1 will be generated as 14 days from Day 1 of the last cycle after treatment is 
over.
*** For ECOG and Vital Signs.
7.0
Demographics, Baseline Characteristics, Medical 
History, Previous/Concomitant Medications and 
Prior Oncology Therapies
The ITT population will be used in the analyses of demographic, baseline characteristics, 
medical history, and previous/concomitant medication and prior oncology therapies.  For 
the safety interims, all analyses will also be performed on the ITT population subset for  
planned bevacizumab use.
7.1
Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized:
●
Country 
●
Geographical Region [North America, Rest of World]
●
Planned Bevacizumab Use (as randomized) [planned bevacizumab use, not 
planned bevacizumab use]


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●
Bevacizumab Use (actual) [bevacizumab received, bevacizumab not received]
●
Race
●
Gender
●
Age (continuous and by categories [< 65 versus ≥ 65])
●
Height
●
Weight
●
Smoking history (current smoker versus never smoked versus past smoker)
●
ECOG
The number of subjects with missing information will also be summarized.
Categorical data will be summarized by numbers and percentages in each category.  
Continuous data will be summarized by mean, standard deviation, median, minimum and 
maximum values.
The Fisher's exact test will be used for testing homogeneity between the two treatment 
groups for the categorical demographic and baseline characteristics data.  The missing 
information of categorical data will not be included in the test.  An ANOVA model with 
treatment group as the factor will be used for testing homogeneity between the 
two treatment groups for the continuous demographic and baseline characteristics data.
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The number and percentage of subjects with a particular 
condition/diagnosis will be summarized for each treatment group.  Subjects reporting
more than one condition/diagnosis within a body system will be counted only once for 
that body system.  There will be no statistical comparison for the medical history between 
the two treatment groups.


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7.3
Prior and Concomitant Medications and Prior Oncology 
Therapies
The number and percentage of subjects who took at least one dose of medication other 
than study drug will be summarized by the generic name coded by WHO dictionary.  This 
analysis will be performed for prior and concomitant medications separately.  The number 
and percentage of subjects who have prior oncology therapies will be summarized by 
regimen names.  There will be no statistical comparison for the prior and concomitant 
medications and prior oncology therapies between the two treatment groups.
8.0
Subjects Disposition
Analyses for the subject disposition will be performed on the ITT population.  
The screen failure reasons will be summarized for the screen failure subjects.  The number 
of randomized subjects and the number of treated subjects will be summarized by country 
and investigator for each treatment group respectively.
The number and percentage of subjects who discontinue study and all study treatment (all 
protocol therapy) will be summarized for each treatment group.  All reasons and primary 
reason (per eCRF) for discontinuation of study and each treatment (veliparib/placebo, 
bevacizumab, irinotecan, leucovorin, fluorouracil bolus or fluorouracil infusion) given by 
each subject will be included in the summary.  There will be no statistical comparison for 
the subject disposition.
9.0
Study Therapy Exposure and Compliance
9.1
Exposure to Study Therapy
Analyses for the study therapy exposure will be performed on the AST population.  The 
number of cycles that subjects are exposed to veliparib/placebo, bevacizumab, irinotecan, 
leucovorin, and 5-FU infusion/saline bolus will be summarized. 
In addition, the following will be summarized for veliparib/placebo:


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Duration of study drug exposure is defined as the total number of days a subject 
received study drug.  
Average dosed days per cycle of study drug is defined as the total number of days a 
subject received study drug divided by the number of cycles that the subject is exposed to 
study drug.  
Descriptive statistics (mean, standard deviation, median, and range) will be used to 
summarize duration and average dosed days per cycle of study drug.  An ANOVA model 
will be used for the comparisons of duration and average dosed days per cycle of exposure 
between the two treatment groups.  In addition, the number and percentage of subjects 
exposed to study drug will be summarized for each of the following 35-day duration 
intervals.
●
1 to 35 days
●
36 to 70 days
●
71 to 105 days
●
106 to 140 days
●
141 to 175 days
●
176 to 210 days
●
211 to 245 days
●
> 245 days
9.1.1
Dose Reductions, Interruptions and Delays
The numbers and percentages of subjects having dose reductions, interruptions, or delays 
will be summarized for each treatment group.
Dose Reductions
If a subject has any dose reduction from the previous dose of veliparib/placebo, 
Irinotecan, or 5-FU Infusion, this subject will be considered as having experienced a dose 


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reduction of the respective drug.  Dose reductions of Leucovorin, bevacizumab and the 
5-FU/Saline Bolus are not allowed. 
Dose Interruptions
Dose interruptions are defined for veliparib/placebo only, and are considered within each 
cycle.  Each instance that a subject skips one or more consecutive days of dosing will be 
counted as a single dose interruption.  Multiple instances of skipped dosing days are 
counted as multiple dose interruptions.  Alternatively, a subject will be considered as 
having a dose interruption if the subject does not achieve the required 7 days of dosing 
without skipping any consecutive days. 
Dose Delays
If the difference between dose dates of two consecutive doses of veliparib/placebo, 
Irinotecan, 5-FU infusion or 5-FU bolus, or bevacizumab, is more than 21 days, the 
subject will be considered as having experienced a dose delay.
9.2
Compliance
Analyses for the compliance of study drug will be performed on the AST population.  
Unless otherwise directed by the Investigator, the subject will be considered compliant 
with all study therapy if at least 80% of the assigned dose of veliparib/placebo is taken 
during a cycle.  The number and percentage of subjects will be summarized by treatment 
group for (1) at least 80% compliant based on investigator opinion for every cycle, (2) at 
least 80% compliant based on investigator opinion for all but one cycle, (3) less than 80% 
compliant based on investigator opinion for more than one cycle.  There will be no 
statistical comparison for this analysis.
In addition, the compliance based on investigator opinion for each subject during the 
whole course of study will be provided in the listing.


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10.0
Efficacy Analysis
10.1
General Considerations
Due to the proof-of-concept nature of the study, all of the analyses will be conducted in an 
estimation fashion.  Ninety-five percent confidence intervals will be presented and 
P-values will be not provided.  
Efficacy analyses will be performed on ITT population.  The date of randomization is 
defined as the date when the randomization number is issued by IRT.
The 'Event Cutoff' date for the PFS, DOR, and OS endpoints is December 31, 2016, 
defined by the data cleaning cutoff for the database lock after 70 events of disease 
progression or death have occurred in both treatment arms combined.  It is the censoring 
date for both the PFS, DOR and OS endpoints for the subjects who have not had an event 
prior to that day.
Statistical analyses will be performed using SAS version 9.4 under the UNIX operating 
system.
10.2
Primary Efficacy Analysis
The primary efficacy analysis will be a comparison of progression-free survival (PFS) 
between the two treatment groups.
For a given subject, PFS will be defined as the number of days from the date the subject 
was randomized to the first date the subject experiences an event of disease progression 
(as determined by the investigator) or to the date of death (all causes of mortality) if 
disease progression is not reached.  All events of disease progression (as determined by 
investigators) occurring on or before the "Event Cutoff" date will be included, regardless 
of whether the event occurred while the subject was still taking study drug or had 
previously discontinued study drug.  However, if a disease progression event occurred 
immediately after that subject missed two or more scheduled consecutive disease 
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after the last evaluable disease progression assessment), the subject will be censored at the 
last radiographic disease progression assessment prior to the disease progression event.  
All events of death occurring on or before the "Event Cutoff" date will be included for 
subjects who had not experienced disease progression provided the death occurred within 
8 weeks of the last evaluable disease progression assessment.  For those subjects who take 
other non-protocol anti-cancer therapies after discontinuation of the study drug prior to 
disease progression, the primary efficacy endpoint of PFS will be censored at the date of 
subject's initiation of other anti-cancer therapies.  If the subject does not have an event of 
disease progression nor has the subject died as described above, the subject's data will be 
censored at the date of the subject's last evaluable radiographic disease progression 
assessment.  If the randomized subject did not have any post-baseline disease progression 
assessment, the subject's data will be censored on the date of randomization.
The distribution of PFS will be estimated for each treatment group using Kaplan-Meier 
methodology.  Median PFS time will be estimated and 95% confidence interval for the 
estimated median PFS time will be presented for each treatment group.  The Cox 
Proportional Hazard Model will be used to estimate the hazard ratio and 95% confidence 
interval comparing the two treatment groups, stratified by planned bevacizumab use 
(planned use versus no planned use). 
10.3
Secondary Efficacy Analyses
Secondary efficacy analyses comparing the effects of veliparib plus FOLFIRI and placebo 
plus FOLFIRI on the following set of endpoints will be performed:  overall survival (OS) 
and objective response rate (ORR).
10.3.1
Overall Survival 
Time to death (overall survival) for a given subject will be defined as the number of days 
from the date that the subject was randomized to the date of the subject's death.  All 
events of death will be included, regardless of whether the event occurred while the 
subject was still taking study drug, or after the subject discontinued study drug.  If a 


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subject has not died on or before the "Event Cutoff" date, the data will be censored at the 
date when the subject was last known to be alive (survival follow-up and study visit, etc.).
The distribution of OS will be estimated for each treatment group using Kaplan-Meier 
methodology.  Median survival time will be estimated and 95% confidence interval for 
the estimated median survival time will be presented for each treatment group.  The Cox 
Proportional Hazard Model will be used to estimate the hazard ratio and 95% confidence 
interval comparing the two treatment groups, stratified by planned bevacizumab use 
(planned use versus no planned use).
10.3.2
Objective Response Rate
Objective response rate (ORR) is defined as the proportion of subjects with complete 
response (CR) or partial response (PR) per RECIST (version 1.1).  For subjects who 
underwent surgery, ORR is not evaluated after surgery.
The ORR will be estimated within each group and 95% confidence intervals will be 
constructed based on the exact binomial distribution.  The Mantel-Haenszel method will 
be used to calculate the difference in proportions between the two groups, stratified by 
planned bevacizumab use (planned use versus no planned use), along with the 95% 
confidence interval of the difference.  All subjects who were randomized regardless of 
whether they have any post-baseline disease progression assessment will be included in 
the analysis.
10.4
Tertiary Efficacy Analyses
Tertiary efficacy analyses comparing the effects of veliparib plus FOLFIRI and placebo 
plus FOLFIRI on the following set of endpoints will be performed:  duration of overall 
response (DOR) and changes in ECOG performance status. 
10.4.1
Duration of Overall Response 
The duration of overall response for a given subject will be defined as the number of days 
from the day the criteria are met for CR or PR (whichever is recorded first) to the date that 


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PD is objectively documented by investigators.  If a subject is still responding on or 
before the "Event Cutoff" date then the subject's data will be censored at date of the last 
available disease progression assessment on or before the "Event Cutoff."  For subjects 
who never experienced CR or PR, the subject's data will not be included.
If the ORR is at least 30% for both treatment groups combined, the distribution of the 
duration of overall response will be estimated for each treatment group using 
Kaplan-Meier methodology.  Median duration of overall response with the corresponding 
95% CI will be provided from Kaplan-Meier estimation for each treatment group.  The 
Cox Proportional Hazard Model will be used to estimate the hazard ratio and 
95% confidence interval comparing the two treatment groups, stratified by planned 
bevacizumab use (planned use versus no planned use).  If the ORR is not at least 30% for 
both treatment groups combined, only the Kaplan-Meier estimates will be summarized in 
a descriptive fashion.
10.4.2
ECOG Performance Status
ECOG performance status is a scale from 0 to 4 collected at baseline, Day 1 of each cycle 
and final visit.  All subjects who do not have baseline measurement or any post-baseline 
measurements will not be included in ECOG analyses.  ECOG at the scheduled post-
baseline visits will be obtained according to the visit window as in Table 1.  Descriptive 
statistics will be presented for baseline and each scheduled post-baseline visit (as defined 
in Table 1) of ECOG by treatment group.  Mean change (95% CI) from baseline to each 
scheduled post-baseline visit within each treatment group and the mean difference in 
change (95% CI) from baseline to each scheduled post-baseline visit between the 
two treatment groups will be obtained from the ANCOVA model with treatment group as 
the factor and baseline ECOG as a covariate.
10.5
Additional Efficacy Analyses
In addition to the stratified log-rank test for the primary and secondary efficacy endpoints, 
the following analyses may be performed for the comparison of PFS, OS, and ORR 
between the two treatment groups.


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●
Un-stratified log-rank test and the Cox proportional hazards model for PFS, 
OS.
●
Modified PFS endpoint to examine sensitivity to different censoring methods, 
described in detail below. 
●
Modified efficacy endpoint OS to censor at the date of subject's initiation of 
other post anti-cancer therapies.
●
Subgroup analysis by smoking history, gender, region, baseline ECOG, etc.
Sensitivity Analysis for PFS Endpoint
In addition to the Primary PFS analysis, modified PFS analyses will be performed to 
examine the sensitivity to various censoring methods.  A summary of these are in the 
following table.
Name for Analysis
Type of Censoring
Primary
Mod1
Mod2
Mod3
Mod4
Mod5
First Post-Treatment Anti-Cancer Therapy
Yes
No
Yes
Yes
Yes
No
56 day death window
Yes
Yes
No
Yes
Yes
No
Blind Break
No
No
No
Yes
No
No
Missing Scans
Yes
No
No
No
No
No
Yes means censor; No means do not censor.
Apply this to censor PFS and DOR; ORR will be evaluated only up to the censoring time defined by the above 
censoring rules.
Note that ORR and DoR are also impacted by surgery.
11.0
Safety Analysis
11.1
General Considerations
Safety analyses will be performed on AST population, as well as on the AST population 
with actual bevacizumab use.  For the visit wise safety analyses, the analysis visit widow 
as described in Table 1 will be used to align the data.  Only P values ≤ 0.100 when 
rounded to three digits will be presented.


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11.2
Analysis of Adverse Events
Analyses of adverse events will include only "treatment-emergent" events.  
"Treatment-emergent adverse events" are defined as any adverse events that first occur on 
or after the date of first dosing with veliparib/placebo and with an onset date no more than 
30 days after the last dose of veliparib/placebo.  Treatment-emergent adverse events will 
be summarized by preferred terms (PTs) within a System and Organ Class (SOCs) 
according to the version of the MedDRA adverse event coding dictionary at the time of 
the database lock.  The SOCs will be presented in alphabetical order and the PTs will be 
presented in alphabetical order within each SOC.   
Comparisons of the rates of subjects experiencing an adverse event between the 
two treatment groups will be performed using Fisher's exact test, as applicable. 
Adverse Event Overview
An overview of adverse events will be presented for each treatment arm consisting of the 
number and percentage of subjects experiencing at least one event for the following 
adverse event categories:
●
Any treatment-emergent adverse event
●
Any treatment-emergent adverse event that is rated by the investigator as a 
reasonable possibility of being related to each of:  veliparib, irinotecan, 
fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, and bevacizumab
●
Any treatment-emergent NCI terminology grade 3, grade 4, or grade 5 adverse 
event
●
Any treatment-emergent NCI terminology grade 3 or grade 4
●
Any treatment-emergent serious adverse event
●
Any treatment-emergent adverse event leading to discontinuation of each of:  
veliparib, irinotecan, fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, 
and bevacizumab


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●
Any treatment-emergent adverse event leading to discontinuation of each of: 
veliparib, irinotecan, fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, 
and bevacizumab due to disease progression
●
Any treatment-emergent adverse event leading to discontinuation of each of: 
veliparib, irinotecan, fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, 
and bevacizumab not due to disease progression
●
Any treatment-emergent adverse event leading to interruption of each of: 
veliparib, irinotecan, fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, 
and bevacizumab 
●
Any treatment-emergent adverse event leading to dose reduction of each of: 
veliparib, irinotecan, and fluorouracil (5-FU) infusion
●
Any treatment-emergent adverse event of special interest
●
Any treatment-emergent adverse event leading to death
●
All deaths.
Adverse Event by SOC and PT
In addition to the AE categories listed under Adverse Event Overview, the numbers and 
percentages of subjects experiencing treatment-emergent adverse events will be 
summarized by treatment group for the following adverse event categories:
●
Any treatment-emergent adverse event with number broken down by 
maximum NCI terminology grade
●
Any treatment-emergent adverse event with number broken down by 
maximum relationship to each of:  veliparib, irinotecan, fluorouracil (5-FU) 
infusion, fluorouracil (5-FU) bolus, and bevacizumab.
●
Any treatment-emergent adverse event that is rated by the investigator as a 
reasonable possibility of being related to each of:  veliparib, irinotecan, 
fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, and bevacizumab, by 
the investigator (Reasonable Possibility Related) with NCI terminology 
grade 3, grade 4, or grade 5 adverse event
●
Any treatment-emergent adverse event that is rated by the investigator as a 
reasonable possibility of being related to each of:  veliparib, irinotecan, 


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fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, and bevacizumab by 
the investigator (Reasonable Possibility Related) with NCI terminology 
grade 3 or grade 4 adverse event
●
Any treatment-emergent serious adverse event with number broken down by 
maximum NCI terminology grade
●
Any treatment-emergent serious adverse event with number broken down by 
maximum relationship to veliparib, irinotecan, fluorouracil (5-FU) infusion, 
fluorouracil (5-FU) bolus, and bevacizumab.
●
Any treatment-emergent serious adverse event that is rated by the investigator 
as a reasonable possibility of being related to each of veliparib, irinotecan, 
fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, and bevacizumab, by 
the investigator (Reasonable Possibility Related)
●
Any treatment-emergent NCI terminology grade 3, grade 4, or grade 5 serious 
adverse event
●
Any treatment-emergent adverse event that is rated by the investigator as a 
reasonable possibility of being related to each of veliparib, irinotecan, 
fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, and bevacizumab by 
the investigator (Reasonable Possibility Related) with NCI terminology 
grade 3, grade 4, or grade 5 serious adverse event
●
Any treatment-emergent NCI terminology grade 3 or grade 4 serious adverse 
event
●
Any treatment-emergent adverse event that is rated by the investigator as a 
reasonable possibility of being related to each of veliparib, irinotecan, 
fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, and bevacizumab by 
the investigator (Reasonable Possibility Related) with NCI terminology 
grade 3 or grade 4 serious adverse event
●
Any treatment-emergent adverse event leading to interruption of veliparib, 
irinotecan, fluorouracil (5-FU) infusion, fluorouracil (5-FU) bolus, or 
bevacizumab
●
Any treatment-emergent adverse event leading to dose reduction of veliparib, 
irinotecan, or 5-FU infusion


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●
Any treatment-emergent adverse event leading to death that is rated by the 
investigator as a reasonable possibility of being related to veliparib by the 
investigator (Reasonable Possibility Related)
For all adverse event summaries, the number and percentage of subjects experiencing 
treatment-emergent adverse events will be tabulated according to SOC and PT for each 
treatment arm.  Subjects reporting more than one AE for a given PT will only be counted 
once for that term.  Subjects reporting more than one adverse event within an SOC will 
only be counted once for that SOC.  Subjects reporting more than one AE will only be 
counted once in the overall total. 
Adverse Event by Frequency
The number and percentage of subjects experiencing treatment-emergent adverse events 
and treatment-emergent serious adverse events will be tabulated according to preferred 
term and sorted by overall frequency.  Percentages will be compared within the two pair-
wise comparisons using Fisher's exact tests.  Only P values ≤ 0.100 when rounded to 
three digits will be presented.
Adverse Event of Special Interest
Treatment-emergent AEs and serious AEs of special interest based on SMQ or PMQ 
broad searches may be summarized.
11.3
Deaths
The number of subject deaths will be summarized (1) for deaths occurring while the 
subject was still receiving study drug in this study, (2) for deaths occurring off treatment 
within 30 days after the last dose of study drug, and (3) for all deaths in this study 
regardless of the number of days after the last dose of study drug.  Listings of deaths 
occurring within 30 days after the last dose of study drug, and deaths occurring after 
30 days after the last dose of study drug will be provided.  There will be no statistical 
comparison for above analyses.


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11.4
Analysis of Laboratory and Vital Signs Data
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline are analyzed for each scheduled post-baseline visit and Final Visit 
(defined as in Table 1) for hematology variables, chemistry variables, vital signs variables 
including diastolic/systolic blood pressure, heart rate, and body temperature.  
Post-baseline visits more than 30 days after the last dose of study drug will not be 
included.  Subjects that do not have a baseline visit or do not have any post-baseline visits 
will not be included.  The data will be analyzed at visits with at least 5 subjects overall for 
each treatment group.
Descriptive statistics will be presented for baseline, each scheduled post-baseline, and 
Final Visit by each treatment group.  The comparison between the two treatment groups in 
mean change from baseline to each scheduled post-baseline visit and to Final Visit will be 
performed using the ANOVA model with treatment group as the factor.
Analyses of Laboratory Data Using NCI CTCAE
Following categorization of laboratory variable values by NCI CTCAE version 4.0 
grades, shift tables from baseline to maximum post-baseline and Final Visit terminology 
grade will be assessed.  Post-baseline visits more than 30 days after the last dose of study 
drug will not be included.
The tables will contain a cross-tabulation of number and percentage of categorized 
baseline grades versus maximum post-baseline/Final Visit grades.  The categories in the 
cross-tabulation include terminology grades 0 to 4 and missing value.  All treated subjects 
will be included in the cross tabulation regardless whether baseline or post baseline 
measurements are collected.
The number and percentage of subjects experiencing a shift from a baseline terminology 
grade of 0 to grade 2 to a maximum post-baseline grade of 3 to grade 4, and from a 
baseline grade of 0 to grade 2 to a Final Visit grade of 3 to grade 4 will be summarized 
and compared between the two treatment groups using Fisher's exact test.  All treated 


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subjects with baseline terminology grade of 0 to grade 2 and post baseline grades will be 
included in this analysis.
Listings of the applicable NCI CTC criteria and detailed listings of data for subjects with 
measurements (regardless of the number of days after the last dose of study drug) meeting 
the NCI CTC grade 3 to grade 4 criteria will be presented.
11.5
Analyses of Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values
Vital signs values will be assessed for potential clinical significance through the 
application of criteria developed at AbbVie as detailed in the table below.
Systolic Blood Pressure
> 150 mmHg and > 20 mmHg higher than baseline 
< 70 mmHg and a decrease of ≥ 30 mmHg from baseline
Diastolic Blood Pressure
> 100 mmHg and higher than baseline
< 50 mmHg and a decrease of ≥ 20 mmHg from baseline
Pulse Rate
> 120 bpm and an increase of ≥ 30 bpm from baseline
< 50 bpm and a decrease of ≥ 30 bpm from baseline
Temperature
≥ 38.9°C
≤ 35.6°C
The number and percentage of subjects with post baseline values meeting Criteria for 
Potentially Clinically Significant Vital Signs values will be summarized.  A subject who 
has at least one post-baseline measurement will be included in the summary.  If a subject 
does not have any vital sign measurements at baseline, but has a post-baseline 
measurement which meets the above criteria for blood pressure and pulse rate, this subject 
is considered as meeting the potentially clinically significant vital signs values for the 
measurement.  If a subject has both baseline and post-baseline measurements, the post-
baseline value must also be more extreme than the baseline values for blood pressures and 
pulse rates.  A separate listing will be provided that presents all of the subjects and values 
meeting the criteria.  The comparisons of the rates of subjects meeting the above criteria 
between the two treatment groups will be performed using Fisher's exact test.


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