Conditions: Metastatic Breast Cancer
Keywords: PARP Inhibitor Veliparib BRCA1 BRCA2 HER2-negative Locally recurrent Breast Cancer Metastatic Breast Cancer ABT-888 Genetic breast cancer Paclitaxel BRCA Mutation PARP Carboplatin BROCADE3
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 513
Healthy volunteers: no

Brief summary:
The primary objective of the study is to assess the progression-free survival (PFS) of veliparib in combination with carboplatin and paclitaxel (C/P) compared to placebo plus C/P in participants with a Breast Cancer Gene 1 or 2 (BRCA1; BRCA2) mutation in Human Epidermal Growth Factor Receptor 2 (HER2)-negative metastatic or locally advanced unresectable breast cancer. The secondary objectives of the study are to assess overall survival (OS), clinical benefit rate (CBR) through the end of Week 24, objective response rate (ORR) and PFS on subsequent therapy (PFS2) in participants treated with veliparib in combination with C/P versus placebo in combination with C/P.

Detailed description:
This is a Phase 3, randomized, double-blind, multinational, multicenter study to evaluate the efficacy and tolerability of veliparib in combination with C/P compared to placebo in combination with C/P in participants with a BRCA1 or BRCA2 mutation, as documented by the Sponsor core laboratory, with HER2-negative metastatic or locally advanced unresectable breast cancer who received no more than 2 prior lines of cytotoxic therapy for metastatic disease. For the purposes of eligibility, HER2-negative status was based on the most recent tumor biopsy. Participants were randomized in a 2:1 ratio, with a total of approximately 500 participants planned to be randomized. Veliparib 120 mg/placebo twice a day (BID) was dosed Days -2 through 5 with carboplatin target area under the concentration-time curve (AUC) 6 administered on Day 1 and paclitaxel 80 mg/m2 administered weekly on Days 1, 8, and 15 of each 21-day cycle.

Safety and efficacy data through the prespecified primary analysis cutoff date of 05 April 2019 are included in the interim analysis.

Arms:
arm 1: Placebo capsules for veliparib (120 mg) administered by mouth twice daily (BID) on Days -2 through 5 of a 21-day cycle. Carboplatin administered intravenously over approximately 15 to 30 minutes at AUC 6 mg/ml/min immediately following paclitaxel infusion on Day 1 of every cycle. Paclitaxel administered intravenously over approximately 1 hour at a dose of 80 mg/m² on Days 1, 8, and 15 of every cycle. arm 2: Veliparib capsules (120 mg) administered by mouth twice daily (BID) on Days -2 through 5 of a 21-day cycle. Carboplatin administered intravenously over approximately 15 to 30 minutes at AUC 6 mg/ml/min immediately following paclitaxel infusion on Day 1 of every cycle. Paclitaxel administered intravenously over approximately 1 hour at a dose of 80 mg/m² on Days 1, 8, and 15 of every cycle.

Interventions: intervention 1: Veliparib Placebo intervention 2: Veliparib intervention 3: Carboplatin intervention 4: Paclitaxel
Intervention descriptions: intervention 1: Supplied as 40 mg, 50 mg, or 100 mg capsules for oral administration twice daily (BID) on Days -2 through 5 of a 21-day cycle. intervention 2: Supplied as 40 mg, 50 mg, or 100 mg capsules for oral administration twice daily (BID) on Days -2 through 5 of a 21-day cycle. intervention 3: Administered intravenously over approximately 15 to 30 minutes at an area under the curve (AUC) of 6 mg/mL/min immediately following paclitaxel infusion on Day 1 of every cycle. The duration of carboplatin infusion may be lengthened according to institutional guidelines. intervention 4: Administered by intravenous infusion over approximately 1 hour at a dose of 80 mg/m² of body-surface area (BSA) on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel is to be infused prior to carboplatin on Day 1. Dosing of veliparib/placebo is to be completed before the carboplatin or paclitaxel infusions.

Protocol document:
Prot_000.pdf: 
Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
1
1.0
Title Page
Clinical Study Protocol M12-914
A Phase 3 Randomized, Placebo-Controlled Trial of 
Carboplatin and Paclitaxel With or Without the PARP 
Inhibitor Veliparib (ABT-888) in HER2-Negative 
Metastatic or Locally Advanced Unresectable 
BRCA-Associated Breast Cancer
Incorporating Administrative Changes 1, 2, 3, and 4
and Amendments 1, 2, 3, and 4
AbbVie Investigational
  Product:
Veliparib (ABT-888)
Date:
23 July 2020
Development Phase:
3
Study Design:
A Phase 3 Randomized, Placebo-Controlled Trial of 
Carboplatin and Paclitaxel with or without the PARP 
Inhibitor Veliparib (ABT-888) in HER2-Negative 
Metastatic or Locally Advanced Unresectable 
BRCA-Associated Breast Cancer
EudraCT Number:
2014-000345-70
Investigator:
Multicenter Trial:  Investigator information is on file at 
AbbVie.
Sponsor:
AbbVie*
NCT02163694




Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date 
Original
17 March 2014
Amendment 1
12 June 2014
Amendment 2
11 February 2015
Administrative Change 1
24 July 2015
Administrative Change 2
16 October 2015
Amendment 3
17 June 2016
Administrative Change 3
29 September 2016
Administrative Change 4
07 November 2017
The purpose of this amendment is to:
●
Add benefits and risks evaluation information and updated study procedures in 
the context of the ongoing COVID-19 pandemic (Section 3.5, Section 5.3.1.1, 
Section 5.4.1, Section 5.7, Section 6.1.6, Section 9.2, and Section 9.3).
Rationale:  To confirm that the current pandemic situation does not change 
the benefit risk of study participation as COVID-19 related risks are not 
expected to differ substantially between trial participants and the broader 
population of subjects being treated for metastatic breast cancer, as well as 
allow for procedure modification in response to the COVID-19 pandemic 
(including local labs, study drug shipment from sites to patients, subject 
withdrawal, Adverse Event reporting and consent procedures).
●
Introduce the option of off-site phone visits every other cycle for subjects who 
have been receiving single-agent veliparib/placebo at a stable dose without 
adjustment for multiple cycles without uncontrolled adverse events, and to add 
table of assessments for these visits (Section 5.1, Section 5.3.1.1 and 
Appendix F).
Rationale: To add flexibility, with appropriate guidance, for subjects on study
long term, while maintaining standard of care safety monitoring and tumor 
assessments.


Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
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●
Remove references to Blinded/Unblinded TA MD and study teams throughout 
protocol.
Rationale:  Primary site monitors, investigators and subjects continue to be 
blinded to treatment assignment until disease progression, after which 
unblinding to determine eligibility for crossover can be requested. However, 
the sponsor was unblinded to treatment assignment at the time of the primary 
analysis (03 June 2019). Therefore, a separate unblinded Study management 
team within AbbVie is no longer responsible for study conduct and data 
monitoring for subjects who crossover to open-label veliparib.
●
Include language to indicate that AbbVie may remove the requirements for 
sites to send clinical laboratory samples to the central laboratory and radiology 
scans to the central reviewer, or discontinue the requirements for central 
review at any time during the course of the study (Section 5.3.1.1).
Rationale: Local laboratory evaluations and local review of radiology scans 
can support safety monitoring and tumor assessment evaluation.  AbbVie may 
discontinue the requirements for the central laboratory and central radiology 
review, as the primary analysis has been completely.
●
Update tumor assessment schedule from every 9 weeks to allow every 
12 weeks (or at longer intervals not to exceed 24 weeks per the investigator's 
discretion) from the prior scan (Section 5.3.1.1).
Rationale:  To modify the tumor assessment schedule after completion of the 
primary analysis in order to allow the Investigators to follow standard of care 
for patients with disease control for several years and limit cumulative 
radiation exposure and associated risks.
●
Update IDMC review language according to current expectations 
(Section 5.3.5 and Section 8.1.8).
Rationale:  As primary analysis has occurred, no additional IDMC reviews 
will occur.
●
Update the guidelines on when chemotherapy can begin based on hematologic 
blood counts (Section 5.7.1.1).
Rationale:  The update aligns with other study guidance within the program 
for other veliparib studies, for which the primary analysis has been completed 


Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
5
and the safety profile of veliparib in combination with carboplatin and 
paclitaxel was acceptable.
●
Add language on the reporting of myelodysplastic syndrome, acute myeloid 
leukemia, or any secondary primary malignancy (Section 6.1.5).
Rationale: To clarify the time period of reporting of specific adverse events of 
special interest which may have a delayed onset.
●
Modify the Table of Study Procedures for Post Treatment Phase and for 
patients that are considered on study, off drug (Appendix E).
Rationale: To simplify procedures required for subjects who discontinue 
therapy without progressive disease (i.e., subjects who are on study, off drug), 
requiring only those procedures needed for safety monitoring and tumor 
assessment.  Also, to ensure that survival follow-up is the same for all subjects 
who have discontinued therapy, and to remove the requirement of tumor 
assessment at Final Visit in subjects without a tumor assessment within 
4 weeks as these were infrequently required and of lower priority after the 
primary analysis.
●
Clarify the timing/conduct of additional OS analyses before the final OS 
analysis, if needed (Section 8.1.3).
Rationale:  Allow for additional interim analyses of study data if requested by 
regulatory agencies or otherwise warranted.
●
Change duration of response (DOR) from secondary to tertiary endpoint 
(Section 5.3.3 and Section 8.1).
Rationale: To align with most recent version of Statistical Analysis Plan 
which was finalized prior to primary analysis.
●
Include updates from Administrative Changes 3 and 4 throughout the protocol.
●
Update contacts for safety reporting related questions or concerns and protocol 
deviations (Section 6.1.6 and Section 7.0).
●
Correct grammatical errors and inconsistencies throughout the protocol.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix M.


Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
6
1.2
Synopsis
AbbVie
Protocol Number:  M12-914
Name of Study Drug:  Veliparib (ABT-888)
Phase of Development:  Phase 3
Name of Active Ingredient:  Not applicable 
Date of Protocol Synopsis:  23 July 2020
Protocol Title:  A Phase 3 Randomized Placebo-Controlled Trial of Carboplatin and Paclitaxel With or 
Without the PARP Inhibitor Veliparib (ABT-888) in HER2-Negative Metastatic or Locally Advanced 
Unresectable BRCA-Associated Breast Cancer
Objectives:  The primary endpoint is to assess the progression-free survival (PFS) of veliparib in 
combination with carboplatin (C) and paclitaxel (P) compared to placebo with C/P in subjects with a 
BRCA1 and/or BRCA2 Mutation and HER2-Negative Metastatic or Locally Advanced Unresectable 
Breast Cancer.
The secondary objectives of the study are to assess overall survival (OS), clinical benefit rate (CBR), 
objective response rate (ORR), and PFS2 in subjects treated with veliparib in combination with C/P 
versus subjects treated with placebo with C/P.  The tertiary objectives are to assess duration of overall 
response (DOR), change in ECOG performance status, and change in Quality of Life (QoL).
Study Sites:  Multicenter; Approximately 200
Study Population:  Men and women ≥ 18 years of age with HER2-negative metastatic or locally 
advanced unresectable breast cancer and clinically significant (suspected deleterious or deleterious) 
BRCA1 and/or BRCA2 germline mutation.  Patients with bone-only disease and/or hormone receptor 
positive (ER and/or PR) disease should be deemed appropriate candidates for combination chemotherapy.
Number of Subjects to be Enrolled:  Approximately 500
Methodology:
This is a Phase 3, randomized, double-blinded study to evaluate the efficacy and tolerability of veliparib 
in combination with C/P compared to placebo plus C/P in subjects with BRCA1 or BRCA2 germline 
mutation and with HER2-negative metastatic or locally advanced unresectable breast cancer who have 
received no more than 2 prior lines of cytotoxic therapy for metastatic disease.
Veliparib/placebo will be dosed in combination with carboplatin AUC 6 with weekly paclitaxel 
(80 mg/m2), on a 21-day cycle.  Subject randomization will be in a 2:1 ratio to veliparib/C/P or 
placebo/C/P and stratified by estrogen receptor (ER) and/or progesterone receptor (PgR) positive versus 
ER/PgR negative, prior platinum therapy (yes versus no), and CNS metastases (yes versus no).
Subjects with BRCA1/BRCA2 mutation per local lab testing and who meet the remaining eligibility 
criteria may be randomized.  Patients who meet NCCN guidelines for BRCA1/BRCA2 testing are eligible 
for testing during the screening period.  BRCA mutation status will be documented for all subjects by the 
central laboratory (Myriad).
Subjects who discontinue carboplatin and paclitaxel and who have not progressed will continue 
veliparib/placebo as a single agent at the recommended Phase 2 single agent dose.  Subjects will continue 
dosing until they meet the defined treatment discontinuation criteria.  Subjects who discontinue 
carboplatin, paclitaxel, and veliparib/placebo for reasons other than progression should remain on study.  
At the time PD is documented according to RECIST 1.1, subjects randomized to placebo may be eligible 
to crossover to unblinded veliparib monotherapy.


Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
7
Methodology (Continued):
Tumor assessments (CT scan or MRI of the full chest, abdomen, pelvis and brain MRI or contrast CT) 
were performed at screening and then every 9 weeks from C1D-2 until tumor progression to determine 
the extent of tumor burden per RECIST 1.1.  Following the primary analysis and implementation of 
Protocol Amendment 4, the tumor assessment interval may be increased to every 12 weeks from last scan 
until tumor progression. At the investigator's discretion, the interval between scans may be longer than 
every 12 weeks for subjects who have durable disease control but must not exceed 24 weeks.  Post-
baseline brain MRI or contrast CT is only required in subjects with CNS lesions at baseline; in all other 
subjects, CNS imaging will be obtained as clinically indicated based upon symptoms indicative of CNS 
disease. Refer to Section 5.3.1.1 and Appendix C, Appendix D, and Appendix E for additional tumor 
assessment schedule details, including details for subjects on open-label crossover veliparib.
In addition to being reviewed by the investigator and/or site staff, radiographic scans will be sent to a 
central imaging center for review.  Subjects who discontinue study treatment prior to disease progression 
should remain on study and continue to undergo a modified schedule of assessments until disease 
progression per RECIST 1.1.  For these subjects who meet study treatment discontinuation criteria and 
who have not progressed (such as subjects who initiate another anti-cancer therapy), tumor assessment 
data per RECIST 1.1 will continue to be collected to document tumor status and the date of progression.  
Post treatment information (including dates and response to subsequent therapies) and survival 
information will be collected every two months beginning on the date the subject has discontinued study 
therapy until the endpoint of death, the subject is lost to follow-up or until the study termination by 
AbbVie.
QoL assessment via the EORTC QLQ-C30/BR23 and EQ-5D-5L questionnaires will be collected on 
C1D-2 pre-dose, Day 1 of Cycle 2 and every other cycle thereafter beginning with Cycle 4 (C6, C8, etc.), 
Final Visit, and 30-Day Follow-Up Visit.  Subjects who crossover to the unblinded veliparib 
monotherapy arm will continue to have QoL assessments performed as per this schedule (Day 1 of the 
first and second cycle of unblinded monotherapy and every other cycle thereafter beginning with Cycle 4 
until 2nd disease progression or until they meet the defined study treatment discontinuation criteria and at 
the Final Visit and 30-Day Follow-Up Visit).  Pain assessment via the BPI-SF will be collected at every 
cycle.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Men and women ≥ 18 years of age.
2.
Histologically or cytologically confirmed breast cancer that is either locally advanced or metastatic. 
!
Locally advanced breast cancer must not be primarily amenable to surgical resection or radiation 
with curative intent.
!
Patients with bone-only disease and/or hormone receptor positive disease should be deemed by 
the investigator as appropriate candidates for combination chemotherapy.


Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
8
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
3.
Suspected deleterious or deleterious BRCA1 and/or BRCA2 germline mutation.
The investigator should ensure that the testing is consistent with local guidelines, and clinical 
practice, and that the test uses either 1) direct DNA sequencing/multiplex ligation-dependent probe 
amplification (MLPA) or 2) a well-characterized methodology previously validated by sequencing, 
such as that used to assess founder mutations.  If testing has been performed prior to Study M12-914, 
subjects may be enrolled but must be re-tested by the Sponsor core laboratory for documentation of 
BRCA1 or BRCA2 germline mutations.
Subjects with BRCA variants of uncertain significance or polymorphisms in BRCA1 or BRCA2 will 
not be eligible for the study.
4.
Breast cancer must be HER2-negative, defined as IHC 0 – 1+ OR HER2-neu negative according to 
ASCO-CAP guideline recommendations.
5.
Measurable or non-measurable (but radiologically evaluable) disease per RECIST version 1.1 on 
computed tomography (CT) scan (within 28 days of randomization) with at least one lesion outside 
previously irradiated areas.
6.
ECOG Performance status of 0 to 2.
7.
Subject is able to swallow and retain oral medication and does not have uncontrolled emesis.
8.
Adequate hematologic, renal, and hepatic function as follows (within 28 days of randomization):
!
Bone Marrow:  Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 × 109/L); Platelets 
≥100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.5 g/dL (5.89 mmol/L);
!
Renal Function:  Serum creatinine ≤ 1.5 × upper limit of normal (ULN) range OR creatinine 
clearance ≥ 50 mL/min/1.73 m2 (according to local assessment method) for subjects with 
creatinine levels above institutional normal;
!
Hepatic Function:  Aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal; alanine 
transaminase (ALT) ≤ 2.5 × upper limit of normal; bilirubin ≤ 1.5 × the ULN range.  For 
subjects with liver metastases, AST < 5 × ULN range; ALT < 5 × ULN range.  Subjects with 
Gilbert's Syndrome may have a bilirubin ≥ 1.5 × the ULN range if no evidence of biliary 
obstruction exists;
!
Activated Partial Thromboplastin Time (APTT) must be ≤ 1.5 × the ULN range and 
international normalized ratio (INR) < 1.5.  Subjects on anticoagulant therapy will have an 
appropriate APTT and INR as determined by the investigator.
9.
Women of childbearing potential and men must agree to use adequate contraception (one of the 
following listed below) prior to study entry, for the duration of study participation, and for 6 months 
following completion of therapy.  Women of childbearing potential must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test prior to randomization.  To be 
considered of non-childbearing potential, postmenopausal women must be amenorrheic for at least 
12 months or subjects must be surgically sterile.
!
Total abstinence from sexual intercourse (abstinence is only acceptable as a contraceptive 
method if it is established as the subject's preferred and usual lifestyle);
!
Vasectomized male subjects or vasectomized partner of female subjects;


Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
9
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
Double-barrier method (condoms, contraceptive sponge, diaphragm, or vaginal ring with 
spermicidal jellies or cream); or
!
Intra-Uterine Device (IUD).
!
Additionally, male subjects (including those who are vasectomized) whose partners are pregnant 
or might be pregnant must agree to use condoms and refrain from sperm donation for the 
duration of the study and for 6 months following completion of therapy.
10. Capable of understanding and complying with parameters as outlined in the protocol and able to sign 
and date the informed consent, approved by an Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB), prior to initiation of any screening or study-specific procedures.
Main Exclusion:
Subjects who meet any of the following exclusion criteria are not eligible:
1.
Received anticancer agent(s) or an investigational agent within 21 days prior to C1D-2 or 
radiotherapy within 28 days prior to C1D-2.
!
Prior treatment with palliative local breast or bone lesion radiation (other than pelvis) can occur, 
if administered at least 14 days prior to C1D-2.
!
Anticancer hormonal therapy must be stopped 7 days before starting C1D-2.
!
Anti-cancer therapy should not be initiated by the site during the screening period, as a 21-day 
interval would be needed from the last dose and would lead to additional delays in therapy and 
potential exclusion of the subject.
2.
Received more than 2 prior lines of cytotoxic chemotherapy (e.g., gemcitabine, doxorubicin, 
capecitabine) for metastatic disease.*
!
Regimens received in the adjuvant/neoadjuvant setting or for locally advanced breast cancer 
within the past 6 months will also be considered toward the maximum of 2 prior lines of 
therapy.  Adjuvant/neoadjuvant chemotherapy for one cancer event will count as one prior line 
of therapy, if received within the past 6 months.
!
Previous treatments with hormonal therapy (tamoxifen, aromatase inhibitors) and signal 
transduction agents (e.g., erlotinib, gefitinib, everolimus, bevacizumab) are allowed and are not 
counted towards the prior line of therapy.
3.
Progressed or recurred within 12 months of completing platinum therapy or received > 1 prior line of 
platinum therapy for breast cancer in any setting (adjuvant, neoadjuvant or metastatic).
4.
Subjects experiencing a significant adverse effect or toxicity (Grade 3 or Grade 4) causally attributed 
to previous anticancer treatment that has not recovered to at least Grade 2.
5.
Prior therapy with PARP inhibitors.*
6.
Prior taxane therapy administered for the treatment of metastatic breast cancer with the below 
exceptions.*
!
Prior taxane therapy for metastatic breast cancer is allowed if the patient received ≤ 1 full cycle 
(i.e., therapy discontinued within 4 weeks for subjects receiving weekly paclitaxel or Abraxane; 
therapy discontinued within 3 weeks for subjects receiving paclitaxel or docetaxel every 
3 weeks) in the absence of progression or if taxane therapy for metastatic disease was 
> 12 months prior to C1D-2.


Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
!
Use of taxanes as adjuvant therapy or to treat locally advanced disease is permitted, if given 
more than 6 months prior to C1D-2.
7.
Subjects with active brain metastases or leptomeningeal disease.
!
Subjects should have a brain MRI within 28 days of randomization to confirm the absence of 
CNS metastases.  Contrast CT is acceptable for subjects who are unable to undergo a brain MRI.
!
Subjects with known brain metastases must have clinically controlled neurologic symptoms and 
have received previous adequate treatment, defined as surgical excision and/or radiation therapy 
with stable neurologic function and no evidence of Central Nervous System (CNS) disease 
progression as determined by comparing a computed tomography (CT) scan or magnetic 
resonance imaging (MRI) scan performed during screening to a prior scan performed at least 
4 weeks earlier and provided that the subject is asymptomatic, has no evidence of cavitation or 
hemorrhage, and does not require corticosteroids (must have discontinued steroids for 
management of neurological symptoms at least 3 months prior to study drug administration).
8.
A history of uncontrolled seizure disorder; including focal or generalized seizure within the past year.
9.
Pre-existing neuropathy in excess of Grade 1 (except focal neuropathy such as brachial plexopathy or 
carpal tunnel syndrome).
10. Major surgery within 3 weeks of randomization.
11. Known history of allergic reaction to cremophor-paclitaxel, carboplatin, Azo-Colourant Tartrazine 
(also known as FD&C Yellow 5 or E102), Azo-Colourant Orange Yellow-S (also known as FD&C 
Yellow 6 or E110) or known contraindications to any study supplied drug.
12. Clinically significant uncontrolled condition(s):
!
Active infection;
!
Symptomatic congestive heart failure;
!
Unstable angina pectoris or cardiac arrhythmia;
!
Myocardial infarction within last 6 months;
!
Known active hepatitis B or hepatitis C with abnormal liver function tests or organ dysfunction;
!
Uncontrolled hypertension (sustained systolic blood pressure > 150 mmHg or diastolic pressure 
> 100 mmHg despite optimal medical management);
!
Psychiatric illness/social situations that would limit compliance with study requirements; or
!
Any medical condition that, in the opinion of the investigator, places the subject at an 
unacceptably high risk for toxicities.
13. A previous or concurrent cancer that is distinct in primary site or histology from breast cancer, except 
cervical carcinoma in situ, non-melanoma carcinoma of the skin, or in situ carcinoma of the bladder 
or another in situ cancer that is considered cured by the Investigator.  Any cancer curatively treated 
greater than 3 years prior to entry is permitted.  For these subjects, metastases must be histologically 
or cytologically confirmed to be breast cancer.
14. Pregnant or breastfeeding.
*Note:
For prior chemotherapy, treatment for 1 full cycle or less will not be considered as prior therapy 
unless the patient experienced progression of disease while on that therapy.


Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
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Investigational Product:
Veliparib or Placebo
Dose:
120 mg BID Days –2 through 5 of 21-day cycle in combination with 
carboplatin and paclitaxel
Mode of Administration:
Oral
Reference Therapy:
Carboplatin
Dose:
AUC 6 Day 1 of 21-day cycle
Mode of Administration:
Intravenously (IV)
Reference Therapy:
Paclitaxel
Dose:
80 mg/m2 on Days 1, 8, 15 of 21-day cycle
Mode of Administration:
Intravenously (IV)
Investigational Product:
Veliparib or Placebo
Dose:
Starting dose of 300 mg BID Days 1 through 21 of 21-day cycle as 
single agent therapy, if tolerated, escalation to 400 mg BID will be 
allowed
Mode of Administration:
Oral
Interim Analyses:
To ensure subject safety, an IDMC reviewed unblinded safety data 
(which included all subjects enrolled in the study) when approximately 
60 subjects met at least one of the following criteria:
!
Received 6 cycles of treatment
!
Reached an event of disease progression
!
Discontinued the study due to toxicity/adverse events
Subsequent IDMC reviews of unblinded safety data prior to the primary 
analysis were carried out based on IDMC recommendations. No 
additional reviews by the IDMC will occur since the Sponsor 
management team was unblinded after completing the primary analysis.
Criteria for Evaluation:
Progression-free Survival (PFS):  will be evaluated according to progression per RECIST (version 1.1) 
and survival information (death).  Radiologic tumor response and disease progression will be assessed by 
CT scan utilizing RECIST (version 1.1).  Assessments were be performed at Screening, at 9-week 
intervals (from C1D-2) thereafter until disease progression. Following the primary analysis and 
implementation of Protocol Amendment 4 the tumor assessment interval may be increased to every 
12 weeks from last scan until tumor progression; at investigator discretion, the interval between scans 
may be longer than 12 weeks but must not exceed 24 weeks.
Clinical benefit rate (CBR), Objective Response Rate (ORR) and Duration of Overall Response 
(DOR):  will be evaluated according to progression per RECIST (version 1.1).  Radiologic tumor 
response and disease progression will be assessed by CT scan utilizing RECIST (version 1.1).  
Assessments were be performed at Screening, at 9-week intervals (from C1D-2) thereafter. Following 
the primary analysis and implementation of Protocol Amendment 4, the tumor assessment interval may 
be increased to every 12 weeks from last scan until tumor progression; at investigator discretion, the 
interval between scans may be longer than 12 weeks but must not exceed 24 weeks.


Veliparib
M12-914 Protocol Amendment 4
EudraCT 2014-000345-70
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Criteria for Evaluation (Continued):
Overall Survival (OS):  will be evaluated according to survival information and post treatment 
information (including therapy, dates of therapy and response) collected at two month intervals beginning 
on the date the subject is registered off study and until the endpoint of death, the subject is lost to 
follow-up or until the study termination by AbbVie.
PFS2:  will be evaluated according to survival information and post treatment information (includes 
dates of therapy and response per RECIST 1.1) collected at two-month intervals.
Statistical Methods:  Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a two-sided P value ≤ 0.05 when rounded.
Sample Size Determination:
Assuming the true hazard ratio for PFS in favor of the veliparib + C/P group is 0.69, a total of 344 PFS 
events will be needed for the study to have 90% power at 2-sided α level of 0.05 to detect a statistically 
significant treatment effect for the veliparib + C/P group using the log-rank test for progression free 
survival.  A total of approximately 500 subjects will be enrolled into the study.
Efficacy (Primary and Secondary Endpoints):
The analysis of the primary endpoint and secondary endpoints will include only the subjects who have 
been documented to have suspected deleterious or deleterious mutations by the Sponsor core lab.  The 
primary and secondary analyses will be based upon the investigator's assessment of response and disease 
progression per RECIST 1.1.  Sensitivity analyses of PFS, ORR, and CBR based on radiological and 
clinical assessment by the Central Imaging Center will be conducted.
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 disease progression, or to the date of death (all causes of 
mortality) if disease progression is not reached.
Clinical Benefit Rate (CBR):  will be defined as the progression-free rate at 24 weeks from the 
Kaplan-Meier curve for time to progression (defined as from the date of randomization to the date of 
disease progression).
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.
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).  All subjects who have had at 
least one measurable lesion at baseline will be included in the ORR calculation.
PFS2:  will be defined as the number of days from the day the subject is randomized to the date that the 
subject has disease progression or death of any cause on the subsequent therapy, whichever occurs first.
Safety:  Safety will be assessed by evaluating study drug exposure, adverse events, serious adverse 
events, all deaths, as well as changes in laboratory determinations and vital sign parameters.  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.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ADP
Adenosine Diphosphate
AE
Adverse Event
AI
Aromatase Inhibitor
ALT
Alanine Transaminase
ANC
Absolute Neutrophil Count
ANCOVA
Analysis of Covariance
APTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
BC
Breast Cancer
BCNU
Trade name for Carmustine
BID
Twice a Day
BSA
Body Surface Area
BPI-SF
Brief Pain Inventory – Short Form
BRCA
Breast Cancer Gene
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CBR
Clinical Benefit Rate
CFR
Code of Federal Regulations
CMH
Cochran-Mantel-Haenszel
CLIA
Clinical Laboratory Improvement Amendments
CNS
Central Nervous System
CPT
Cell Preparation Tube
CR
Complete Response
CRF or eCRF
Case Report Form or Electronic Case Report Form
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
Computed Tomography
CTC
Circulating Tumor Cells
CTEP
Cancer Therapy Evaluation Program
CV
Cardiovascular


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CYP
Cytochrome P450
DLT
Dose-Limiting Toxicity 
DNA
Deoxyribonucleic Acid
EC
Effective Concentration
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EDTA
Edetic Acid (ethylenediaminetetraacetic acid)
ELISA
Enzyme-linked Immunosorbent Assay
EMA
European Medicines Agency
EORTC
European Organization for Research and Treatment of Cancer
ESMO
European Society for Medical Oncology
ER
Estrogen Receptor
EU
European Union
FDA
U.S. Food and Drug Administration
FFPE
Formalin fixed, paraffin embedded
FISH
Fluorescence in situ hybridization
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GFR
Glomerular Filtration Rate
GM-CSF
Granulocyte Macrophage Colony Stimulating Factor
GOG
Gynecologic Oncology Group
HE
Hematoxylin and Eosin
HER2
Human Epidermal Growth Factor Receptor 2
IC
Informed Consent
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IDMS
Isotope Dilution Mass Spectroscopy
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
Intent To Treat


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IUD
Intra-Uterine Device
IV
Intravenously
IVRS/IWRS
Interactive Voice Response System/Interactive Web Response System
LDH
Lactate Dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
MLPA
Multiplex Ligation Dependent Probe Amplification
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NCCN
National Comprehensive Cancer Network
NCI CTCAE 
National Cancer Institute Common Terminology Criteria For Adverse 
Events
NCI CTEP
National Cancer Institute Cancer Therapy Evaluation Program
NE
Not Evaluable
NSCLC
Non-small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
PAR
Poly(ADP-ribose)
PARP
Poly(ADP-ribose)-Polymerase
PCP
Pneumocystis carinii Pneumonia
PD
Pharmacodynamic
PD
Progressive Disease
PFS
Progression-Free Survival
PG
Pharmacogenetic
PgR
Progesterone Receptor
PK
Pharmacokinetic
PO
Oral Route of Administration
POR
Proof of Receipt 
PR
Partial Response
PRO
Patient Reported Outcome
QA
Quality Assurance
QC
Quality Control
QD
Once Daily


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QoL
Quality of Life
q PCR
Quantitative Polymerase Chain Reaction
QTc
QT interval corrected for heart rate
RBC
Red Blood Cell
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SD
Stable Disease
SERM
Selective Estrogen Receptor Modulator
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
SOD
Sum of Diameter
TA MD
Therapeutic Area Medical Director
TNBC
Triple-Negative Breast Cancer
ULN
Upper Limit of Normal 
U.S.
United States 
US
Ultrasound
WBC
White Blood Cell
Definition of Terms
AUC
Area under the concentration-time curve
AUC∞
Area under the concentration-time curve from time zero to infinity
Cmax
Maximum observed concentration
Tmax
Time to maximum observed plasma concentration


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................6
1.3
List of Abbreviations and Definition of Terms........................................13
2.0
Table of Contents...................................................................17
3.0
Introduction ...........................................................................23
3.1
Breast Cancer...........................................................................................23
3.2
Carboplatin and Paclitaxel .......................................................................25
3.3
Poly(ADP-ribose)-Polymerase (PARP) Mechanism of Action...............27
3.4
Veliparib ..................................................................................................27
3.4.1
Preclinical Experience..............................................................................28
3.4.1.1
Pharmacokinetics/Pharmacodynamics.....................................................29
3.4.1.2
Toxicology ...............................................................................................30
3.4.2
Clinical Experience..................................................................................30
3.5
Benefits and Risks....................................................................................33
3.6
Differences Statement..............................................................................35
4.0
Study Objectives....................................................................35
5.0
Investigational Plan...............................................................36
5.1
Overall Study Design and Plan:  Description ..........................................36
5.2
Selection of Study Population..................................................................40
5.2.1
Inclusion Criteria .....................................................................................40
5.2.2
Exclusion Criteria ....................................................................................43
5.2.3
Prior and Concomitant Therapy...............................................................46
5.2.3.1
Prior Therapy ...........................................................................................47
5.2.3.2
Concomitant Therapy...............................................................................47
5.3
Efficacy Pharmacokinetic, Biomarker, Exploratory Research and 
Safety Assessments/Variables..................................................................50
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................50
5.3.1.1
Study Procedures .....................................................................................52
5.3.1.2
Collection and Handling of Biomarker and Exploratory Research 
Samples....................................................................................................69


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5.3.2
Drug Concentration Measurements .........................................................71
5.3.2.1
Collection of Samples for Analysis .........................................................71
5.3.2.2
Handling/Processing of Samples .............................................................72
5.3.2.3
Disposition of Samples ............................................................................72
5.3.2.4
Measurement Methods.............................................................................72
5.3.3
Efficacy Variables....................................................................................73
5.3.4
RECIST (Version 1.1) for Tumor Response............................................73
5.3.4.1
Definition of Disease Progression............................................................80
5.3.5
Safety Variables.......................................................................................81
5.3.6
Pharmacokinetic Variables ......................................................................82
5.3.7
Exploratory Research Variables ..............................................................82
5.3.8
Biomarker Variables ................................................................................82
5.4
Removal of Subjects from Therapy or Assessment.................................83
5.4.1
Discontinuation of Individual Subjects....................................................83
5.4.1.1
Discontinuation of Blinded Study Treatment (Veliparib/Placebo + 
Carboplatin + Paclitaxel) .........................................................................86
5.4.2
Discontinuation of Entire Study...............................................................86
5.5
Treatments................................................................................................87
5.5.1
Treatments Administered.........................................................................87
5.5.2
Identity of Investigational Product...........................................................90
5.5.2.1
Packaging and Labeling...........................................................................91
5.5.2.2
Storage and Disposition of Study Drug ...................................................91
5.5.3
Method of Assigning Subjects to Treatment Groups...............................92
5.5.4
Selection and Timing of Dose for Each Subject......................................93
5.5.5
Blinding....................................................................................................93
5.5.5.1
Blinding of Investigational Product.........................................................94
5.5.6
Treatment Compliance.............................................................................94
5.5.7
Drug Accountability.................................................................................95
5.6
Discussion and Justification of Study Design..........................................96
5.6.1
Discussion of Study Design and Choice of Control Groups....................96
5.6.2
Appropriateness of Measurements...........................................................97
5.6.3
Suitability of Subject Population .............................................................97
5.6.4
Selection of Doses in the Study ...............................................................97


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5.7
Dose Reductions or Delays......................................................................98
5.7.1.1
Carboplatin + Paclitaxel Dose Reduction and Delays .............................99
5.7.1.2
Veliparib or Placebo Dose Reductions and Delays in Combination 
with Carboplatin + Paclitaxel.................................................................107
5.7.1.3
Blinded Veliparib/Placebo and Unblinded Veliparib Monotherapy 
Dose Reductions and Delays..................................................................108
5.7.1.4
Allergic Reaction/Hypersensitivity........................................................110
6.0
Complaints ...........................................................................110
6.1
Medical Complaints...............................................................................111
6.1.1
Definitions..............................................................................................111
6.1.1.1
Adverse Event........................................................................................111
6.1.1.2
Serious Adverse Events .........................................................................112
6.1.2
Adverse Event Severity..........................................................................113
6.1.2.1
Adverse Events Expected Due to Breast Cancer or Progression of 
Breast Cancer.........................................................................................114
6.1.3
Adverse Events Expected Due to Study Related Endpoints..................114
6.1.3.1
Deaths ....................................................................................................114
6.1.3.2
Lack of Efficacy or Worsening of Disease ............................................115
6.1.4
Relationship to Study Drug....................................................................115
6.1.5
Adverse Event Collection Period...........................................................116
6.1.6
Adverse Event Reporting.......................................................................117
6.1.7
Pregnancy...............................................................................................119
6.1.8
Toxicity Management ............................................................................119
6.2
Product Complaint .................................................................................120
6.2.1
Definition ...............................................................................................120
6.2.2
Reporting................................................................................................120
7.0
Protocol Deviations..............................................................121
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................122
8.1
Statistical and Analytical Plans..............................................................123
8.1.1
Baseline Characteristics.........................................................................123
8.1.1.1
Demographics ........................................................................................123
8.1.1.2
Medical Histories...................................................................................123


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8.1.2
Efficacy Endpoints.................................................................................124
8.1.2.1
Primary Efficacy Endpoint ....................................................................124
8.1.2.2
Secondary Efficacy Endpoints...............................................................124
8.1.2.3
Tertiary Efficacy Endpoints...................................................................125
8.1.3
Timing of Efficacy Analyses and Safety Evaluations ...........................126
8.1.4
Primary Analysis of Efficacy.................................................................126
8.1.5
Secondary Analyses of Efficacy ............................................................127
8.1.5.1
Overall Survival.....................................................................................127
8.1.5.2
Clinical Benefit Rate..............................................................................127
8.1.5.3
Objective Response Rate .......................................................................127
8.1.5.4
PFS2.......................................................................................................128
8.1.6
Tertiary Analyses of Efficacy ................................................................128
8.1.6.1
Duration of Overall Response................................................................128
8.1.6.2
Patient Reported Outcomes (PRO) ........................................................128
8.1.6.3
Performance Status ................................................................................129
8.1.7
Additional Efficacy Analyses ................................................................130
8.1.8
Interim Analysis.....................................................................................131
8.1.9
Safety Assessments................................................................................131
8.1.10
Statistical Analyses of Safety.................................................................132
8.1.10.1
Duration of Study Treatment .................................................................132
8.1.10.2
Adverse Events ......................................................................................132
8.1.10.3
Serious Adverse Events .........................................................................132
8.1.10.4
Deaths ....................................................................................................132
8.1.10.5
Longitudinal Analyses of Laboratory and Vital Signs Data..................133
8.1.10.6
Analyses of Laboratory Data Using NCI CTCAE.................................133
8.1.10.7
Analyses of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values.................................................................134
8.1.10.8
Multiplicity Adjustments .......................................................................134
8.1.10.9
Censoring Dates for Subjects that had the Prematurely Blind 
Broken....................................................................................................134
8.2
Determination of Sample Size ...............................................................135
8.3
Randomization Methods ........................................................................136
9.0
Ethics.....................................................................................136


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9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................136
9.2
Ethical Conduct of the Study .................................................................137
9.3
Subject Information and Consent...........................................................137
10.0
Source Documents and Case Report Form 
Completion ...........................................................................139
10.1
Source Documents .................................................................................139
10.2
Case Report Forms.................................................................................139
11.0
Data Quality Assurance ......................................................140
12.0
Use of Information...............................................................141
12.1
Publication .............................................................................................142
13.0
Completion of the Study .....................................................142
14.0
Investigator's Agreement....................................................144
15.0
Reference List ......................................................................145
List of Tables
Table 1.
Treatment Schema for Each Cycle...........................................................37
Table 2.
Schedule Biomarker and Exploratory Research Assessments 
(Blinded Study Treatment) ......................................................................51
Table 3.
Schedule of Pharmacokinetic Assessments (Blinded Study 
Treatment)................................................................................................51
Table 4.
Clinical Laboratory Tests.........................................................................57
Table 5.
Identity of Investigational Products.........................................................90
Table 6.
Study Drug Storage Conditions ...............................................................92
Table 7.
Dose Levels for Veliparib/Placebo + Carboplatin/Paclitaxel ..................99
Table 8.
Blinded Study Treatment (Veliparib/Placebo + Carboplatin + 
Paclitaxel) Dose Reduction and Delays for Hematologic 
Toxicities on Day 1................................................................................101
Table 9.
Blinded Study Treatment (Veliparib/Placebo + Carboplatin + 
Paclitaxel) Dose Reduction and Delays for Hematologic 
Toxicities on Day 8 or 15.......................................................................103
Table 10.
Blinded Study Treatment (Veliparib/Placebo + Carboplatin + 
Paclitaxel) Dose Reduction and Delays for Other Toxicities ................105


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Table 11.
Blinded Veliparib/Placebo and Unblinded Veliparib Monotherapy 
Dose Levels............................................................................................110
List of Figures
Figure 1.
Veliparib in Combination with Carboplatin in the MX-1 Breast 
Carcinoma Xenograft Model in SCID Mice............................................29
Figure 2.
Adverse Event Collection ......................................................................117
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................150
Appendix B.
List of Protocol Signatories....................................................................152
Appendix C.
Study Activities for Blinded Study Treatment (Veliparib/Placebo 
+ Paclitaxel + Carboplatin)....................................................................153
Appendix D.
Study Activities for Unblinded Veliparib Monotherapy 
(Crossover Treatment) ...........................................................................156
Appendix E.
Study Activities for Post Treatment Phase ............................................158
Appendix F.
Study Activities for Blinded or Unblinded Study Treatment Phone 
Visit........................................................................................................159
Appendix G.
EORTC QLQ-C30 .................................................................................160
Appendix H.
EORTC QLQ - BR23.............................................................................162
Appendix I.
EQ-5D 5L Health Questionnaire ...........................................................164
Appendix J.
Brief Pain Inventory – Short Form ........................................................167
Appendix K.
ASCO-CAP HER2 Test Guideline Recommendations .........................169
Appendix L.
General Chemotherapy Guidelines ........................................................170
Appendix M.
Protocol Amendment:  List of Changes.................................................171


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3.0
Introduction
3.1
Breast Cancer
Breast cancer (BC) is diagnosed in over 1.3 million women worldwide each year and 
accounts for over 500,000 deaths, making it the leading cause of cancer-related death in 
women.  Internationally, the incidence of breast cancer varies dramatically with North 
America, Australia, and Northern and Western Europe having the highest incidence and 
Eastern Europe having intermediate levels.1  In the United States (US) and Europe, breast 
cancer is the most common cancer in women, with over 180,000 new cases in the US and 
332,000 new cases in the countries of the European Union (EU-27) in 2008.2,3  Although 
the number of agents approved for the treatment of advanced breast cancer continues to 
increase, overall survival has changed relatively little and median survival remains 
unchanged, in the range of 2 to 3 years from initial diagnosis of metastatic disease.
With the development of gene expression array technology, the heterogeneity of breast 
cancer has become clearer and the identification of novel cancer subtypes has 
reinvigorated the search for more specific and effective therapies.  Additionally, 
identification of genetic characteristics has helped in identifying risk factors.  One of these 
genetic characteristics includes mutations or alterations in the breast cancer susceptibility 
genes, BRCA1 and BRCA2.  It is estimated that at least 5% of breast cancer cases result 
from inherited mutations or alterations in BRCA1 and BRCA.2,4  Furthermore, women with 
these mutations have a lifetime risk of 40% to 85% of developing breast cancer.5  Males 
with BRCA2 mutations also carry an increased risk of breast cancer.  Malignancies with 
deficiencies in homologous repair, such as BRCA1- and BRCA2 deficient tumors, are 
more susceptible to cytotoxicity induced by DNA damaging agents and are more 
dependent on PARP for DNA repair than normal cells.  This explains why BRCA1/2
mutated cells, which are defective in homologous recombination, are selectively more 
sensitive to a PARP inhibitor than wild-type cells.6,7
Hierarchical clustering of genomic expression data from breast cancer specimens has 
demonstrated several distinct tumor subgroups with unique expression profiles, including 


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a HER2-positive subgroup, an estrogen receptor (ER)-positive subgroup, and a subgroup 
termed "basal-like" or "triple-negative."  A common feature of tumors in the basal-like 
subgroup is the lack of expression of ER, PgR, and HER2, resulting in the description 
"triple-negative breast cancer" (TNBC).  Although not all triple-negative breast cancers 
are basal-like, the classification of triple-negative tumors based on immunohistochemical 
staining is a clinically useful surrogate for the majority of basal-like breast cancer.  The 
majority of breast cancers with germline BRCA1 mutations are of the triple-negative 
phenotype, and chemotherapy is the only current treatment option for these patients.8  
Little progress has been made in identifying specific molecular pathways associated with 
TNBC that may be effectively targeted for therapeutic purposes and, consequently, this is 
an area of active research.9,10  There is particular interest in the role of PARP inhibitors as 
well as alkylating agents and platinum-based chemotherapy as treatment for 
BRCA-associated TNBC.
In contrast to the BRCA1 carcinomas that often have the basal cell phenotype, the BRCA2
carcinomas are more similar to sporadic breast cancer and tend to be ER- and 
PgR-positive.  Treatment of hormone receptor-positive (HR+) breast cancer often 
involves sequencing of successive lines of endocrine therapy with either aromatase 
inhibitors (AI) or the selective estrogen receptor modulator (SERM) tamoxifen.  In 
addition, exemestane with everolimus has demonstrated benefit in endocrine refractory 
patients.  However, up to one-third of subjects are primarily resistant to endocrine therapy 
and most subjects who initially respond to endocrine therapy will eventually become 
resistant.  Therefore, the vast majority of HR+ advanced breast cancer subjects will 
receive chemotherapy during the course of their disease.
A minority of BRCA-deficient tumors also express HER2 receptors (approximately 3%).11  
The development of HER2-directed targeted therapy has changed the natural history of 
this subtype of breast cancer.  Adjuvant therapy with trastuzumab has consistently shown 
up to 50% reductions in risk of recurrence compared to non-trastuzumab–based therapy.12  
In metastatic HER2 positive breast cancer, trastuzumab therapy results in improved 
survival when used in combination with paclitaxel chemotherapy compared to paclitaxel 


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alone.13  Pertuzumab, a monoclonal antibody that inhibits the ligand-dependent 
dimerization of HER2 and its downstream signaling, was recently approved for the 
treatment of first-line HER2-positive metastatic BC and has become a standard first-line 
therapy.  An antibody drug conjugate, ado-trastuzumab emtansine, has also recently 
demonstrated an increase in PFS and OS in women with HER2-positive metastatic breast 
cancer who had progressed following trastuzumab and taxane chemotherapy.  Despite 
these important advances, many patients eventually progress, and additional treatment 
options are needed for HER2-refractory patients.
3.2
Carboplatin and Paclitaxel
Carboplatin is a commonly used platinum compound that acts by producing interstrand 
deoxyribonucleic acid (DNA) cross-links and, thus, interrupting cell division.  It is 
approved by the Food Drug Administration (FDA) for the treatment of ovarian cancer and 
by the European Medicines Agency (EMA) for ovarian cancer of epithelial origin and 
small cell lung carcinoma.  It is also used for the treatment of non-small cell lung cancer 
(NSCLC), head and neck cancer, endometrial cancer, metastatic seminoma, and more 
recently in breast cancer, with reported response rates of 20% to 50% in previously 
untreated patients with metastatic breast cancer.14  Carboplatin is eliminated by renal 
excretion and the clearance is related to the glomerular filtration rate (GFR).  Therefore, it 
is dosed on the basis of GFR and the target area under the concentration versus time curve 
(AUC).  Myelosuppression is the dose limiting toxicity of carboplatin and is dose 
dependent.  Anemia may be cumulative and require transfusion support with prolonged 
therapy.  Anaphylactic-like reactions to carboplatin have been reported and may occur 
within minutes of carboplatin administration.  The risk of allergic reactions is increased in 
patients previously exposed to platinum therapy.  Other toxicities include nausea, 
vomiting, renal toxicity, and neurotoxicity.
Paclitaxel promotes the assembly of microtubule formation and stabilizes them by 
preventing depolymerization.  It is insoluble in water and, therefore, is formulated in 
cremophor.  Paclitaxel is approved by the FDA for the treatment of breast cancer and is 
widely used in the adjuvant and metastatic setting.  It is also approved by the FDA for the 


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treatment of ovarian cancer, NSCLC, and Kaposi's sarcoma.  It is administered as an 
intravenous (IV) infusion and can be used either on a 3-weekly schedule or a weekly 
schedule.  Main toxicities associated with the use of paclitaxel are myelosuppression and 
neuropathy.  Hypersensitivity reactions requiring treatment have occurred in 2% to 4% of 
patients receiving paclitaxel in clinical trials; thus, patients should be pretreated with 
corticosteroids, diphenhydramine, and H2 antagonists.
Emerging data suggest that BRCA1/2-mutated tumors may be more sensitive to DNA 
damaging agents, including carboplatin.  Specifically, two studies by Bryski et al are 
relevant to the use of platinum agents for BRCA-associated breast cancer.  The first was a 
small prospective trial of single-agent neoadjuvant cisplatin in patients with BRCA1- and 
BRCA2-associated breast cancer and demonstrated a high pathologic complete response 
rate (9 of 10 patients; 90%).15  The data were recently updated to include 25 patients in 
the expanded cohort, and it was found that the pathological complete response rate to be 
72%.16  The second study evaluated a cohort of 12 patients from the first study in 
comparison to retrospective data in patients with BRCA1-associated breast cancer who 
were treated with non-platinum regimens.  The pathological complete response rate across 
all regimens was 24% in the 102 patients with BRCA-deficient breast cancer; in contrast, 
the pathological complete response rate in the cisplatin-treated cohort was 83% (10 of 
12 patients; 95% CI = 54% – 96%) and was far lower in the other aggregated regimens 
(14 of 90 patients; 16%, CI = 9% – 25%).17  The results from the TNT trial in metastatic 
or recurrent locally advanced triple negative breast cancer indicated greater sensitivity to 
carboplatin than docetaxel in germline BRCA mutation carriers (68% [17/25; 95%CI
46.5 – 85.1] versus 33.3% [6/18, 95%CI 13.3 – 59.0] p = 0.03).18  Thus, the use of 
platinum-based regimens may be particularly appealing in this population.
The combination of carboplatin and paclitaxel is widely used for the treatment of patients 
with advanced NSCLC, ovarian cancer, and other solid tumors.  Paclitaxel in combination 
with carboplatin is also highly active in breast cancer, with response rates of 
approximately 39% to 62% in first-line metastatic breast cancer.14  Notably, data suggest 
that the administration of carboplatin in combination with paclitaxel results in less 


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thrombocytopenia than is expected from the use of carboplatin alone.19  Because of the 
increased sensitivity of BRCA-mutated tumors to DNA-damaging agents such as 
carboplatin, and the activity and potential platelet-sparing effects of paclitaxel, the 
combination of carboplatin and paclitaxel may have particular utility in patients with 
BRCA-mutated tumors.
3.3
Poly(ADP-ribose)-Polymerase (PARP) Mechanism of Action
Poly(ADP-ribose)-polymerase (PARP) is a nuclear enzyme that recognizes 
deoxyribonucleic acid (DNA) damage and facilitates DNA repair.20,21  Inactive PARPs 1 
and 2 bind to damaged DNA, which leads to their auto-activation.  The resulting activated 
PARP then poly(ADP-ribosyl)ates 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 DNA damage insult.
DNA-damaging agents, including cytotoxic chemotherapy and radiation therapy, remain a 
mainstay of treatment for many subjects with cancer.  Since cancer cells are genetically 
unstable, often exhibiting complex karyotypes that include large deletions, insertions, and 
unbalanced translocations of chromosomal fragment, these cells are more susceptible than 
normal tissues to cytotoxicity induced by DNA-damaging agents.22  Of these, deficiencies 
in mismatch repair and homologous recombination are associated with the largest number 
of malignancies.  These deficiencies render cells more dependent on PARP for DNA 
repair and, hence, are more prone to cytotoxicity induced by PARP inhibition.23  In 
particular, tumor cells with BRCA1 or BRCA2 deficiencies are exquisitely sensitive to 
PARP inhibition, even in the absence of any other insults.6,24
3.4
Veliparib
Veliparib is a potent inhibitor of PARP-1 and PARP-2.  When DNA-damaging cytotoxic 
agents are coadministered, veliparib inhibits the repair of DNA damage induced by these 
cytotoxic agents.  In addition, veliparib demonstrates single agent activity in tumors 
defective in DNA damage repair, such as BRCA1- and BRCA2-mutated tumors.  A 


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detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the Investigator's Brochure.38
3.4.1
Preclinical Experience
Veliparib is a novel small molecule that is a potent inhibitor of both PARP-1 and PARP-2 
with Kis of 5 nM and 3 nM, respectively.  In cells under oxidative stress, veliparib inhibits 
the PARP induced formation of poly(ADP-ribose) (PAR) with an EC50 of 2.4 nM.  
Consistent with the conclusion of mechanism-based efficacy, significant inhibition of 
PAR levels was observed with doses of veliparib capable of delivering significant 
antitumor efficacy in preclinical models.
Veliparib has been shown to enhance the efficacy of the combination of carboplatin and 
paclitaxel in several xenograft tumor models.  As a single agent, carboplatin produces a 
dose-dependent tumor growth inhibition in the MX-1 breast carcinoma xenograft model.  
Veliparib administered at 50 and 100 mg/kg/day in combination with carboplatin given at 
50 mg/kg/day (intraperitoneally [IP], QD Days 18, 25, 32) and with paclitaxel given at 
10 mg/kg/day (IV, QD Days 18, 25, 32) also regressed tumor volumes, whereas veliparib 
alone or carboplatin + paclitaxel did not (Figure 1).


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Figure 1.
Veliparib in Combination with Carboplatin in the MX-1 Breast 
Carcinoma Xenograft Model in SCID Mice
3.4.1.1
Pharmacokinetics/Pharmacodynamics
Preliminary clinical pharmacokinetic (PK) data available from 6 studies indicate that 
exposure of veliparib is approximately dose-proportional over 10 through 500 mg BID 
dose range.  The absorption of veliparib after oral dosing is relatively fast where veliparib 
plasma concentrations peak at approximately 1 to 2 hours after dosing across dose levels.  
The terminal half-life of veliparib is about 6 hours, with minimal accumulation following 
multiple BID dosing.  Food does not have a significant effect on veliparib bioavailability.  
The mean total urinary recovery of veliparib (as parent compound and M8 metabolite) is 
86%, which indicates that renal excretion is an important pathway in veliparib 
elimination.
Potential drug-drug interactions (DDI) of veliparib are being evaluated in veliparib 
combination studies.  Veliparib is not a potent inhibitor, nor an inducer, of the major 
human cytochrome P450s (CYPs), suggesting a minimal potential for DDIs at the 
anticipated therapeutic concentrations.


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In Phase 0 Study A10-161, substantial inhibition of PARP activity was observed in tumor 
biopsies collected 3 to 6 hours after dosing in all 3 subjects who received a single dose of 
25 mg veliparib (92%, 95%, and 100%).  Complete inhibition of PARP activity in 
PBMCs, maintained through 24 hours after dosing, was achieved in 3 of the subjects who 
received 50 mg veliparib.  For the 50 mg dose group, PARP activity inhibition in tumor 
biopsies averaged 75% 3 to 6 hours after dosing (N = 3) and averaged 74% 24 hours after 
dosing (N = 3).  Therefore, both 25 mg and 50 mg veliparib were found to be biologically 
active.
3.4.1.2
Toxicology
The toxicological profile of veliparib has been characterized in general toxicology studies 
of up to 6 months' duration in rats and 9 months' duration in dogs, in genotoxic studies 
(Ames assay, in vitro cytogenetics assay, in vivo micronucleus study), and in embryofetal 
development studies.  The primary target organs of veliparib exposure are the central 
nervous system (convulsions and other CNS-related signs), the hematologic system 
(decreased red and white blood cells), the bone marrow (hypocellularity), the lymphoid 
tissues (lymphocyte depletion), and the male (germ cell depletion) and the female 
(corpora lutea decrease and minimal degeneration of granulosa cells in follicles) 
reproductive tissues, with lesser effects on the cardiovascular system (10% QTc 
prolongation) and the gastrointestinal tract (single cell necrosis).  Convulsions and other 
CNS-related signs were considered exposure-dependent and were generally self-limiting, 
ameliorated by dose reduction or cessation of dosing, or respondent to treatment.  All 
other findings were dose-dependent and reversible upon discontinuation of veliparib 
administration.  Veliparib was genotoxic (induced chromosomal aberrations in vitro and 
increased micronuclei formation in vivo) and was toxic to the developing fetus (increased 
incidence of fetal, visceral, skeletal malformations and/or variations).
3.4.2
Clinical Experience
In combination with cytotoxic chemotherapy, the mechanism of action of PARP inhibitors 
is to block repair of DNA that has been damaged by the cytotoxic agent, such as 


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carboplatin.  By a similar mechanism, PARP inhibitors may potentiate the toxicities of 
cytotoxic chemotherapies.  Thus, each veliparib combination regimen will have a unique 
set of toxicities that is predominately similar to that anticipated for the backbone regimen, 
and also, a unique recommended Phase 2 dose.  Due to this, multiple Phase 1 studies of 
veliparib in combination with various chemotherapeutic agents are being conducted.
The combination of veliparib with carboplatin and paclitaxel has been investigated in 
ongoing Phase 1 studies conducted in collaboration with the NCI CTEP.  In CTEP 
Study 7967 the maximum dose administered in subjects with advanced or metastatic solid 
tumors was veliparib 120 mg BID for 7 days in addition to carboplatin AUC 6 and 
paclitaxel 200 mg/m2 administered on Day 3 of a 21-day cycle with 2 out of 6 subjects 
developing protocol-defined dose limiting toxicities (DLTs) at this dose.  The first DLT 
was grade 3 nausea lasting more than 48 hours after standard anti-emetic therapy; this 
event resolved with additional treatment.  The second DLT was grade 3 febrile 
neutropenia in a subject who previously received multiple cycles of dacarbazine (an 
alkylating agent which may cause cumulative bone marrow damage).  Both of these DLTs 
were reversible and manageable and did not lead to study treatment discontinuation due to 
toxicity.  Both febrile neutropenia and nausea are known toxicities of
carboplatin + paclitaxel therapy and are known to resolve after standard therapies such as 
G-CSF, antibiotic therapy, anti-emetics, and well-defined dose reductions.  Preliminary 
data from CTEP 7967 indicate that 8 out of 14 subjects with metastatic breast cancer had 
confirmed responses (3 CR, 5 PR).25  In CTEP Study 8620, veliparib was escalated 
beginning at 50 mg PO BID to a maximum of 200 mg PO BID in combination with 
carboplatin (AUC 2) and weekly paclitaxel (80 mg/m2) in subjects with advanced solid 
tumors, and the study is currently enrolling the expansion cohort of 6 to 12 patients with 
TNBC at the MTD (150 mg BID).  Dose-limiting toxicities included thrombocytopenia 
(veliparib 150 mg BID) and febrile neutropenia (veliparib 200 mg BID).25  In a 
subsequent analysis of preliminary data in refractory triple negative breast cancer subjects 
receiving veliparib in combination with carboplatin and paclitaxel on either a q-3week 
regimen (CTEP 7967) or a weekly regimen (CTEP 8620), an objective response rate of 
50% was observed with the weekly regimen (2 CR, 3 PR, n = 10) and an objective 


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response rate of 55% was observed with the q-3week regimen (2 CR, 4 PR).25  In the 
ongoing randomized, placebo-controlled Study M12-895 Phase 2 study, numerical 
increases in PFS and OS and increased ORR were observed with the addition of veliparib 
to carboplatin and paclitaxel compared to placebo with carboplatin and paclitaxel in 
patients with BRCA-mutated advanced breast cancer, supporting further evaluation in a 
larger Phase 3 trial.
Study GOG 9923 is an ongoing Phase 1 dose escalation study evaluating the safety and 
MTD of the combination of carboplatin (AUC 6, q-3week), paclitaxel (175 mg/m2
q-3weeks or 80 mg/m2 weekly), bevacizumab (15 mg/kg, q-3week, initiated in Cycle 2) 
with escalating doses of veliparib on both an intermittent and continuous schedule in 
subjects with newly diagnosed ovarian cancer.  Intermittent veliparib treatment is given 
for the first week of each cycle.  Preliminary safety data communicated by the investigator 
indicate Grade 3 febrile neutropenia and Grade 4 thrombocytopenia were DLT's in 
Cycle 1 at a dose of veliparib 300 mg PO BID (intermittent schedule) with carboplatin 
AUC 6 and paclitaxel 175 mg/m2 q-3week, with no DLTs observed in the 200 mg BID or 
250 mg BID cohorts.  For subjects receiving intermittent veliparib in combination with 
carboplatin AUC 6 and weekly paclitaxel 80 mg/m2, no DLTs were observed at the 
100 mg, 150 mg, and 200 mg BID dose levels; at both the 250 mg BID and 300 mg BID 
dose levels, 1 of 6 subjects experienced a DLT (Grade 4 thrombocytopenia).
Study Rationale
The therapeutic potential of PARP inhibitors was suggested by two clinical trials 
evaluating PARP inhibition in breast cancer and one clinical trial in ovarian cancer.  In 
subjects with metastatic breast cancer, the addition of a PARP inhibitor (veliparib) to 
carboplatin resulted in responses in subjects with deleterious germline mutations in 
BRCA1/2, with an objective response rate of 54% (14/26), with four complete responses.  
A single-arm trial evaluated a PARP inhibitor in metastatic breast cancer subjects with 
BRCA1/2 mutations and demonstrated single-agent activity, with an ORR of 38% in 
heavily pretreated subjects.26  A similar trial in BRCA1/2 mutation carriers with metastatic 
ovarian cancer showed a response rate of 33%.27  Together, these results validate the 


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proof of concept that PARP inhibition is an attractive therapeutic target in breast and other 
cancers.
Therapeutic potential in breast cancer has also been observed with veliparib in 
combination with carboplatin + paclitaxel.  In Study CTEP 7967, the combination of 
veliparib with carboplatin + paclitaxel was well tolerated with a similar incidence of most 
toxicities, including hematological toxicities to the Eastern Cooperative Oncology Group 
(ECOG) carboplatin + paclitaxel study.28  Preliminary data from this study indicate that 
8 out of 14 subjects with metastatic breast cancer had responses (3 CR, 5 PR).28  In a 
subsequent analysis of preliminary data in refractory triple negative breast cancer subjects 
receiving veliparib in combination with carboplatin and paclitaxel on either a q-3week 
regimen (Study CTEP 7967) or a weekly regimen (carboplatin AUC 2, paclitaxel 
80 mg/m2; Study CTEP 8620), an objective response rate of 50% was observed with the 
weekly regimen (2 CR, 3 PR, n = 10) and an objective response rate of 55% was observed 
with the q-3week regimen (2 CR, 4 PR).30  The I-SPY 2 adaptive Phase 2 study explored 
5 experimental agents (neratinib, veliparib, granitumumab, AMG 386, and MK-2206) in 
combination with weekly paclitaxel administration (+ trastuzumab if indicated) for 
12 weeks followed by standard 4 cycles of Adriamycin/cyclophosphamide given every 
3 weeks in the neoadjuvant setting.  Results reported for Study I-SPY 2 on 
13 December 2013 at the San Antonio Breast Cancer Symposium showed an increase of 
26% in the pCR rate in subjects with triple negative breast cancer that had veliparib and 
carboplatin added to standard of care (SoC) [pCR of 52% for veliparib + carboplatin + 
SoC versus 26% for SoC].
3.5
Benefits and Risks
This study proposes to establish improved clinical outcomes for patients with 
HER2-negative metastatic or locally advanced unresectable breast cancer with a suspected 
deleterious/deleterious germline mutation of BRCA1 or BRCA2 through the addition of 
veliparib to therapy with carboplatin and paclitaxel.  Preclinical data demonstrate that 
veliparib potentiates the anti-tumor activity of platinums, and data from early-phase 
clinical studies (completed or preliminary) are consistent with these observations.


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Veliparib in combination with carboplatin and paclitaxel has been investigated in three 
Phase 1 studies, an adaptive Phase 2 study, and two randomized blinded Phase 2 studies.  
Of these studies, preliminary efficacy data is available from the Phase 1 study conducted 
in advanced solid tumors (Study CTEP 7967) with durable responses observed in breast 
cancer (5 PR, 3 CR, n = 14), non-small cell lung cancer (4 PR, 1 CR with an additional 
PR in a patient with SCLC, n = 16), and other advanced solid tumors (gastric, head and 
neck, melanoma, urothelial).  The most common treatment-emergent serious adverse 
event in studies with veliparib in combination with carboplatin and paclitaxel has been 
neutropenia (4.5% of subjects) and the most common treatment-emergent adverse events 
(> 30% of subjects) have been neutropenia, leucopenia, fatigue, thrombocytopenia, 
nausea, anemia, and peripheral sensory neuropathy.  These events have been similar in 
severity and nature to that anticipated for the backbone regimen of carboplatin/paclitaxel 
alone.
Gastrointestinal toxicities such as nausea and vomiting are the most common toxicities 
with veliparib single-agent therapy and have occurred in some subjects following a single 
dose.  Antiemetics may be used as per standard of care for nausea during the course of the 
study.  Anemia and decreased lymphocyte count have been observed in clinical studies 
with continuously dosed single agent PARP inhibitors, including veliparib.
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.
In summary, veliparib is an orally available PARP inhibitor that has been shown to 
significantly potentiate the effects of carboplatin/paclitaxel in multiple preclinical models 
of tumor progression.  Anti-tumor activities also were observed in early clinical studies.  
Potential risks, as identified above, will be minimized by careful patient selection and 
monitoring.  The potential clinical benefit and the mitigation of potential risks to 
metastatic breast cancer patients support the evaluation of veliparib in combination with 
carboplatin and paclitaxel in this Phase 3 study.


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The benefits and risks of study participation have been evaluated in the context of the 
ongoing COVID-19 pandemic. No data are available to characterize the risk of 
participation in this trial specific to COVID-19. COVID-19-related risks are not expected 
to differ substantially between trial participants and the broader population of individuals 
receiving treatment for advanced breast cancer. In consideration of the life-threatening 
nature of the disease under study, the benefit/risk balance for participation in this trial is 
not changed.
3.6
Differences Statement
This is the first randomized, Phase 3 study of veliparib in HER2-negative metastatic or 
locally advanced unresectable breast cancer in patients with clinically significant 
(suspected deleterious or deleterious) germline mutation of BRCA1 or BRCA2.
4.0
Study Objectives
The primary objective of the study is to assess the PFS of veliparib in combination with 
carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in subjects 
with a BRCA1 or BRCA2 mutation in HER2-negative metastatic or locally advanced 
unresectable breast cancer.
The secondary objectives of the study are to assess overall survival (OS), clinical benefit 
rate (CBR) through the end of Week 24, objective response rate (ORR) and PFS2 in 
subjects treated with veliparib in combination with carboplatin and paclitaxel versus 
placebo in combination with carboplatin and paclitaxel.
The tertiary objectives are to assess ECOG performance status, QoL, duration of overall 
response, and exploratory correlative endpoints.


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5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3 randomized, double-blind, multinational, multicenter study to evaluate 
the efficacy and tolerability of veliparib in combination with carboplatin and paclitaxel 
compared to placebo plus carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 
mutation as documented by the Sponsor core laboratory with HER2-negative metastatic or 
locally advanced unresectable breast cancer who have received no more than two prior 
lines of DNA-damaging cytotoxic therapy for metastatic disease.  For the purposes of 
eligibility, HER2-negativity status will be based on the most recent tumor biopsy.  
Approximately 200 research sites will participate.  Subjects will be randomized in a 
2:1 ratio to one of the two treatment arms with a total of approximately 500 subjects 
randomized.  Veliparib 120 mg/placebo BID will be dosed Days –2 through 5 with 
carboplatin AUC 6 administered on Day 1 and Paclitaxel 80 mg/m2 administered weekly 
on Days 1, 8 and 15 of each 21-day cycle.
Subject randomization will be stratified by estrogen receptor (ER) and/or progesterone 
receptor (PgR) positive versus ER/PgR negative, prior platinum therapy (yes versus no), 
and CNS metastases (yes versus no).  Tumors with any detectable (≥ 1%) expression of 
ER and/or PgR by IHC are considered hormone-receptor positive.  Tumors with no 
detectable expression of ER and PgR are considered hormone receptor negative or 
endocrine non-responsive.  For subjects with heterogeneity between primary tumor and 
metastases, the biopsy most proximal to C1D-2 will be used for the purposes of 
stratification.  For subjects with de novo Stage IV disease, the receptor status of the 
primary tumor will be used for the purposes of stratification.
Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel)
Dosing of oral veliparib/placebo will begin 2 days prior to the start of the 
carboplatin/paclitaxel infusion on C1D-2 and will continue twice a day (BID) through 
C1D5 (7 consecutive days).  All subjects will receive carboplatin and paclitaxel IV 
infusion of Day 1.  In addition, subjects receive paclitaxel IV infusion on Days 8 and 15.  


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Carboplatin and paclitaxel are to be given only after veliparib/placebo dosing on Day –2 
and Day –1 are confirmed.
Table 1.
Treatment Schema for Each Cycle
Week 1
Days
–2
–1
1
2
3
4
5
Veliparib/Placebo
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Paclitaxel
Once
Carboplatin
Once
Week 2
6
7
8
9
10
11
12
Veliparib/Placebo
Paclitaxel
Once
Carboplatin
Week 3
13
14
15
16
17
18
19
Veliparib/Placebo
Paclitaxel
Once
Carboplatin
Subjects will continue to receive veliparib/placebo in combination with 
carboplatin/paclitaxel until unacceptable toxicity occurs or radiographic progression 
occurs.  Subjects who experience toxicities due to carboplatin/paclitaxel or veliparib may 
require a delay in dosing or dose modification as described in Section 5.7.
Subjects who discontinue carboplatin and paclitaxel and who have not progressed will 
receive single-agent, blinded veliparib/placebo starting at 300 mg BID.  If the subject 
tolerates 300 mg BID for 2 weeks, veliparib/placebo may be increased to 400 mg BID at 
the investigator's discretion.  Dosing with veliparib/placebo will begin on Day 1 and 
continue through Day 21 of a 21-day cycle.  For subjects who have been receiving single-
agent veliparib/placebo at a stable dose without adjustment for multiple cycles and who 
have no ongoing study drug related uncontrolled AEs (Adverse Events), it is possible to 


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alternate on-site visits and phone visits every other cycle. At a minimum, these subjects 
should have an on-site visit every other cycle. If an on-site visit is not possible for 
2 consecutive cycles, or if the subject is not on a stable dose or has ongoing study drug-
related uncontrolled AEs but wishes to alternate on-site and phone visits every other 
cycle, the plan for the subject's visits should be discussed with the AbbVie TA MD (see 
Section 7.0 for contact information).  Subjects will continue to follow the schedule of 
assessments as outlined in Appendix C and Appendix F.
Subjects who have discontinued blinded study treatment due to unmanageable toxicity or 
for reasons other than progression will remain on study, off drug and follow a reduced 
schedule of study assessments which will include tumor assessments per RECIST 1.1 and 
survival status assessments, until disease progression as outlined in Appendix E.
Once a subject discontinues blinded study treatment (including subjects that discontinued 
treatment due to unmanageable toxicity or for reasons other than progression), a Final 
Visit will be conducted.  All subjects will have a 30-Day Follow-Up Visit approximately 
30 days after the last dose of study treatment.  Follow-Up Visit procedures should be 
completed prior to starting any new anti-cancer therapy.  Subjects who have progressed 
on blinded study treatment may be eligible for unblinded veliparib monotherapy treatment 
as described below. 
Optional Unblinded Veliparib Monotherapy Treatment (Crossover)
Subjects will be eligible to receive unblinded veliparib monotherapy treatment upon 
confirmation of the following:
●
Documented disease progression in EDC per RECIST 1.1; 
Note:  Discussion with the AbbVie TA MD (see Section 7.0 for contact 
information) may be needed prior to unblinding and crossover to verify that 
criteria for unequivocal PD are met.
●
Confirmation subject was receiving placebo during blinded portion of the 
study;


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Transition to crossover treatment should occur within approximately 60 days following a 
confirmed event of progressive disease.  Transitions that occur after 60 days should be 
discussed with the AbbVie TA MD. 
Unblinded veliparib monotherapy will start at 300 mg BID on Cycle 1 Day 1.  If the 
subject tolerates 300 mg BID for approximately 2 weeks, veliparib may be increased to 
400 mg BID at the investigator's discretion.  For subjects who have been receiving 
veliparib monotherapy at a stable dose without adjustment for multiple cycles and who 
have no ongoing study drug related uncontrolled AEs, it is possible to alternate on-site 
visits and phone visits every other cycle. At a minimum, subjects should have an on-site 
visit every other cycle. If an on-site visit is not possible for 2 consecutive cycles, or if the 
subject is not on a stable dose or has ongoing study drug-related uncontrolled AEs but 
wishes to alternate on-site and phone visits every other cycle, the plan for the subject's 
visits should be discussed with the AbbVie TA MD (see Section 7.0 for contact 
information). Subjects will follow the schedule of assessments as outlined in Appendix D
and Appendix F. Subjects will continue on unblinded study treatment until a second 
disease progression event or unacceptable toxicity occurs.  
Subjects who have discontinued unblinded study treatment due to unmanageable toxicity 
or for reasons other than progression will remain on study, off drug and follow a reduced 
schedule of study assessments, which will include tumor assessments per RECIST 1.1 and 
survival status until disease progression as outlined in Appendix E.
Once a subject discontinues the unblinded study treatment (including subjects that 
discontinued treatment due to unmanageable toxicity or for reasons other than 
progression), a Final Visit will be conducted.  All subjects will have a 30-Day Follow-Up 
Visit approximately 30 days after the last dose of study treatment.  Follow-Up Visit 
procedures should be completed prior to starting any new anti-cancer therapy.  


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Survival and Post Blinded and Unblinded Study Treatment Information
Once a subject meets study treatment discontinuation criteria, subjects will be followed 
for survival and post study treatment information as outlined in Section 5.3.1.1 will be 
collected every two months (unless requested by sponsor more frequently to support data 
analysis) beginning on the date the subject is discontinued from therapy.  All randomized 
subjects should be followed for disease progression (PFS) and for the second progression 
(PFS2), until the endpoint of death (OS), until the subject has become lost to follow-up or 
until study termination by AbbVie.
5.2
Selection of Study Population
5.2.1
Inclusion Criteria
Subjects will be adult men and women with HER2-negative metastatic or locally 
advanced unresectable breast cancer and a documented deleterious or suspected 
deleterious BRCA1 or BRCA2 germline mutation.
Subjects must meet all of the following inclusion criteria to be eligible:
1.
≥ 18 years of age.
2.
Histologically or cytologically confirmed breast cancer that is either locally 
advanced or metastatic. 
●
Locally advanced breast cancer must not be primarily amenable to surgical 
resection or radiation with curative intent.
●
Patients with bone-only disease and/or hormone receptor positive disease 
should be deemed by the investigator as appropriate candidates for 
combination chemotherapy.
3.
Suspected deleterious or deleterious BRCA1 or BRCA2 germline mutation.
The investigator should ensure that the testing is consistent with local guidelines, 
and clinical practice, and that the test uses either 1) direct DNA 
sequencing/multiplex ligation-dependent probe amplification (MLPA) or 2) a 


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well-characterized methodology previously validated by sequencing, such as that 
used to assess founder mutations.  If testing has been performed prior to 
Study M12-914, subjects may be enrolled but must be re-tested by the Sponsor 
core laboratory for documentation of BRCA1 or BRCA2 germline mutations.  
Subjects with BRCA variants of uncertain significance or polymorphisms in 
BRCA1 or BRCA2 will not be eligible for the study.
4.
Breast cancer must be HER2-negative defined as IHC 0 – 1+ OR HER2-neu 
negative according to ASCO-CAP41 guideline recommendations (Appendix K).
5.
Measurable or non-measurable (but radiologically evaluable) disease per RECIST 
(version 1.1) on CT scan (within 28 days of randomization) with at least one lesion 
outside previously irradiated areas.
6.
ECOG performance status of 0 to 2.
7.
Subject is able to swallow and retain oral medication and does not have 
uncontrolled emesis.
8.
Adequate hematologic, renal, and hepatic function as follows (within 28 days of 
randomization):
●
Bone Marrow:  Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 × 109/L); 
Platelets ≥ 100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.5 g/dL 
(5.89 mmol/L);
●
Renal Function:  Serum creatinine ≤ 1.5 × upper limit of normal (ULN) range 
OR creatinine clearance ≥ 50 mL/min/1.73 m2 (according to local assessment 
method) for subjects with creatinine levels above institutional normal;
●
Hepatic Function:  AST ≤ 2.5 × upper limit of normal; ALT ≤ 2.5 × upper 
limit of normal, bilirubin ≤ 1.5 × the ULN range.  For subjects with liver 
metastases, AST < 5 × ULN range; ALT < 5 × ULN range.  Subjects with 
Gilbert's syndrome may have a bilirubin ≥ 1.5 × the ULN range, if no evidence 
of biliary obstruction exists;
●
Activated Partial Thromboplastin Time (APTT) must be ≤ 1.5 × the ULN 
range and INR < 1.5.  Subjects on anticoagulant therapy will have an 
appropriate APTT and INR as determined by the investigator.


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9.
Women of childbearing potential and men must agree to use adequate 
contraception (one of the following listed below) prior to study entry, for the 
duration of study participation, and for 6 months following completion of therapy.  
If male, subjects and subject's female partner(s) of childbearing potential should 
practice at least one of the following methods of birth control.  Women of 
childbearing potential must have a negative serum pregnancy test at screening and 
a negative urine pregnancy test prior to randomization (within 24 hours).  To be 
considered of non-childbearing potential, postmenopausal women must be 
amenorrheic for at least 12 months or subjects must be surgically sterile.
●
Total abstinence from sexual intercourse (abstinence is only acceptable as a 
contraceptive method if it is established as the subject's preferred and usual 
lifestyle);
●
Vasectomized male subjects or vasectomized partner of female subjects;
●
Double-barrier method (condoms, contraceptive sponge, diaphragm, or vaginal 
ring with spermicidal jellies or cream); or
●
Intra-Uterine Device (IUD).
●
Additionally, male subjects (including those who are vasectomized) whose 
partners are pregnant or might be pregnant must agree to use condoms and 
refrain from sperm donation for the duration of the study and for 6 months 
following completion of therapy.
10.
Capable of understanding and complying with parameters as outlined in the 
protocol and able to sign and date the informed consent, approved by an IEC/IRB, 
prior to initiation of any screening or study-specific procedures.
Rationale for Inclusion Criteria
(1 – 7)  To select the appropriate subject population with sufficient disease severity for 
evaluation.
(8)  For the safety of the subjects.


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(9)  The impact of veliparib, carboplatin, and paclitaxel on the unborn fetus is unknown; 
therefore, these criteria ensure that adequate precautions are taken to avoid pregnancy.
(10)  In accordance with harmonized Good Clinical Practice (GCP).
5.2.2
Exclusion Criteria
Subjects who meet any of the following exclusion criteria are not eligible:
1.
Received anticancer agent(s) or an investigational agent within 21 days prior to 
C1D-2 or radiotherapy within 28 days prior to C1D-2.
●
Prior treatment with palliative local breast or bone lesion radiation (other than 
pelvis) can occur, if administered at least 14 days prior to C1D-2.
●
Anticancer hormonal therapy must be stopped 7 days before starting C1D-2.
●
Anticancer therapy should not be initiated by the site during the screening 
period, as a 21-day interval would be needed from the last dose and would lead
to additional delays in therapy and potential exclusion of the subject.
2.
Received more than 2 prior lines of cytotoxic chemotherapy (e.g., gemcitabine, 
doxorubicin, capecitabine) for metastatic disease.*
●
Regimens received in the adjuvant/neoadjuvant setting or for locally advanced 
breast cancer within the past 6 months will also be considered toward the 
maximum of 2 prior lines of therapy.  Adjuvant/neoadjuvant chemotherapy for 
one cancer event will count as one prior line of therapy, if received within the 
past 6 months.
●
Previous treatments with hormonal therapy (tamoxifen, aromatase inhibitors) 
and signal transduction agents (e.g., erlotinib, gefitinib, everolimus, 
bevacizumab) are allowed and are not counted towards the prior line of 
therapy if not given in combination with cytotoxic chemotherapy.
3.
Progressed or recurred within 12 months of completing platinum therapy or 
received > 1 prior line of platinum therapy for breast cancer in any setting 
(adjuvant, neoadjuvant or metastatic).


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4.
Subjects experiencing a significant adverse effect or toxicity (Grade 3 or Grade 4), 
causally attributed to previous anticancer treatment that has not recovered to at 
least Grade 2.
5.
Prior therapy with PARP inhibitors.*
6.
Prior taxane therapy administered for the treatment of metastatic breast cancer with 
the below exceptions.*
●
Prior taxane therapy for metastatic breast cancer is allowed if the patient 
received ≤ 1 full cycle (i.e., therapy discontinued within 4 weeks for subjects 
receiving weekly paclitaxel or Abraxane; therapy discontinued within 3 weeks 
for subjects receiving paclitaxel or docetaxel every 3 weeks) in the absence of 
progression or if taxane therapy for metastatic disease was > 12 months prior 
to C1D-2.
●
Use of taxanes as adjuvant therapy or to treat locally advanced disease is 
permitted, if given more than 6 months prior to C1D-2.
7.
Subjects with active brain metastases or leptomeningeal disease.
●
Subjects should have a brain MRI within 28 days of randomization to confirm 
the absence of CNS metastases.  Contrast CT is acceptable for subjects who 
are unable to undergo a brain MRI.
●
Subjects with known brain metastases must have clinically controlled 
neurologic symptoms and have received previous adequate treatment, defined 
as surgical excision and/or radiation therapy with stable neurologic function 
and no evidence of Central Nervous System (CNS) disease progression as 
determined by comparing a computed tomography (CT) scan or magnetic 
resonance imaging (MRI) scan performed during screening to a prior scan 
performed at least 4 weeks earlier and provided that the subject is 
asymptomatic, has no evidence of cavitation or hemorrhage, and does not 
require corticosteroids (must have discontinued steroids for management of 
neurological symptoms at least 3 months prior to study drug administration).
8.
A history of uncontrolled seizure disorder, including focal or generalized seizure 
within the past year.


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9.
Pre-existing neuropathy from any cause in excess of Grade 1 (except focal 
neuropathy such as brachial plexopathy or carpal tunnel syndrome).
10.
Major surgery within 3 weeks of randomization.
11.
Known history of allergic reaction to cremophor/paclitaxel, carboplatin, 
Azo-Colourant Tartrazine (also known as FD&C Yellow 5 or E102), Azo-
Colourant Orange Yellow-S (also known as FD&C Yellow 6 or E110) or known 
contraindications to any study supplied drugs.
12.
Clinically significant uncontrolled condition(s) including, but not limited to:
●
Active infection;
●
Symptomatic congestive heart failure;
●
Unstable angina pectoris or cardiac arrhythmia;
●
Myocardial infarction within last 6 months;
●
Known active hepatitis B or hepatitis C with abnormal liver function tests or 
organ dysfunction;
●
Uncontrolled hypertension (sustained systolic blood pressure > 150 mmHg or 
diastolic pressure > 100 mmHg despite optimal medical management);
●
Psychiatric illness/social situations that would limit compliance with study 
requirements; or
●
Any medical condition that, in the opinion of the investigator, places the 
subject at an unacceptably high risk for toxicities.
13.
A previous or concurrent cancer that is distinct in primary site or histology from 
breast cancer, except cervical carcinoma in situ, non-melanoma carcinoma of the 
skin, or in situ carcinoma of the bladder or another in situ cancer that is considered 
cured by the Investigator.  Any cancer curatively treated more than 3 years prior to 
entry is permitted.  For these subjects, metastases must be histologically or 
cytologically confirmed to be breast cancer.  
14.
Pregnant or breastfeeding.


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*
Note: For prior chemotherapy, treatment for 1 full cycle or less will not be 
considered as prior therapy unless the patient experienced progression of 
disease while on that therapy.
Rationale for Exclusion Criteria
(1 – 12)  For the safety of the subjects.
(13)  To select the appropriate subject population with sufficient disease severity for 
evaluation.
(14)  The impact of veliparib and carboplatin or paclitaxel on pregnancies or breastfeeding 
is unknown.
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the subject is receiving at Screening, receives 
during the study, and up to 30 days following the last dose of study treatment must be 
recorded in source documents and the eCRFs.  The reason for use, dates of administration 
(including start and end dates), and dosage information (including dose and frequency) 
must be recorded.
For the purposes of this protocol, antitumor treatment may be defined as, but is not 
limited to, anticancer agents (cytotoxic chemotherapy, hormonal therapy, immunotherapy, 
biologic therapy), radiotherapy, and investigational agents.  An investigational agent is 
any drug or therapy not currently approved for use in humans.
The AbbVie TA MD identified in Section 6.1.6 should be contacted if there are any 
questions regarding prior or concomitant therapy(ies).


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5.2.3.1
Prior Therapy
Anticancer Agents:
Subject must have received no more than two prior lines of cytotoxic 
therapy for metastatic breast cancer.  
Regimens received in the adjuvant/neoadjuvant setting or for locally 
advanced disease within the past 6 months will also be considered 
towards the maximum of two prior lines of therapy.  If received within 
the past 6 months, adjuvant/neoadjuvant chemotherapy for one cancer 
event will count as one prior line of therapy.
Prior therapy with biologic agents including vaccines and 
immunostimulants are allowed.
Prior therapy with signal transduction agents such as EGFR/HER2-direct 
agents (e.g., erlotinib, gefitinib, bevacizumab) are allowed and will not 
count toward prior lines of therapy if not given in combination with 
cytotoxic chemotherapy.
Anticancer hormonal therapy is not permitted within 7 days prior to 
C1D-2 or during the study.
Radiation:
Prior treatment with radiation is allowed as long as the last treatment was 
at least 28 days prior to C1D-2.  Prior treatment with palliative local 
breast or bone lesion radiation (other than pelvis) is allowed if the last 
treatment was at least 14 days prior to C1D-2.
5.2.3.2
Concomitant Therapy
The locally approved product label, institutional guidelines, local practice, or applicable 
Summary of Product Characteristics (SmPC) for carboplatin, and paclitaxel should be 
referenced for any concomitant therapy guidelines.
Premedication:
To reduce the severity of hypersensitivity reactions due to treatment with 
paclitaxel, please manage according to institutional guidelines, the locally 
approved product label, local practice, or applicable SmPC 
(i.e., premedication with corticosteroids, diphenhydramine, and H2
antagonists).


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Anticancer Agents:
Anticancer agents (including anticancer hormonal agents such as tamoxifen or 
aromatase inhibitors) are not permitted during the treatment portion of the 
study.  All subjects will receive carboplatin + paclitaxel with 
veliparib/placebo during the treatment portion of the study.  A subject 
receiving maintenance GnRH antagonists for ovarian suppression prior to the 
screening period may be allowed to remain on therapy.  This should be 
discussed with the AbbVie TA MD.
The locally approved carboplatin and paclitaxel product labels or SmPCs 
should be referenced to determine if there are any contraindications associated 
with concomitant medications (e.g., yellow fever vaccine, phenytoin, etc.).  
Caution must be exercised when a subject receives concomitant treatment 
with carboplatin and aminoglycosides due to increased renal and/or audiologic 
toxicity.  The metabolism of paclitaxel is catalyzed by cytochrome P450 
isoenzymes CYP2C8 and CYP3A4.  Caution should be exercised when 
paclitaxel is concomitantly administered with known substrates 
(e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, 
simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, 
indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, 
saquinavir, and telithromycin), and inducers (e.g., rifampin and 
carbamazepine) of CYP3A4.  Caution should also be exercised when 
paclitaxel is concomitantly administered with known substrates (e.g., 
repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers 
(e.g., rifampin) of CYP2C8.


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Supportive Care:
Best supportive care and treatment will be given as appropriate to each subject 
(antiemetics, antibiotics, transfusions, nutritional support, non-radiation 
palliative treatment for pain) according to institutional guidelines or American 
Society of Clinical Oncology (ASCO) guidelines.
Bisphosphonate therapy for the treatment of osteoporosis and bisphosphonate 
or denosumab therapy for the management of bone metastases is allowed as 
per standard of care.  Bisphosphonate therapy intended for an anti-cancer 
effect is not allowed during the study.  If bisphosphonates or denosumab are 
initiated after randomization, the reason for its use must be clearly 
documented.  When possible, initiation of bisphosphonates or denosumab 
should be avoided during Cycle 1.
ASCO guidelines recommend a two drug combination of palonosetron 
and dexamethasone for moderately emetogenic therapies, such as 
carboplatin.  If palonosetron is not available, any of the first generation 
5-HT3 receptor antagonists may be used, preferably ondansetron or 
granisetron.  ASCO dosing guidelines are as follows:
!
Palonosetron 0.25 g IV OR 0.50 mg oral, Day 1 only
!
Dexamethasone 8 mg (IV or oral), Days 1 to 3
Aprepitant is not recommended, though clinicians may consider its use.  
If clinicians opt to use aprepitant, dosing guidelines are as follows:
!
Aprepitant:  125 mg Day 1, 80 mg Day 2 and Day 3
!
5-HT3 receptor antagonist dosing
!
Dexamethasone:  12 mg on Day 1 only.31
Growth Factors:
Biologic response modifiers administered for erythropoiesis 
(e.g., erythropoietin, darbepoetin alpha) and colony stimulating factors 
(e.g., G-CSF, GM-CSF, etc.) may be administered as supportive care or to 
maintain dose intensity or to avoid dose delays according to standard practice, 
institutional or clinical practice guidelines (e.g., ASCO, ESMO).  In the case 
of a dose modification in the treatment regimen due to WBC discrepancies 
growth factors (G-CSF) can be used to correct these discrepancies before a 
second dose modification.
Radiation:
Palliative radiotherapy is only allowed during the study treatment period for a 
symptomatic bone lesion present at baseline and for which no radiographic 
progression is visible on radiographic assessments.  If a patient requires 
radiation therapy to a new lesion, that new lesion would, per RECIST 1.1, 
qualify as progressive disease.
Subjects should not be randomized with the intent to receive local therapy for 
breast cancer (i.e., not initially a locally advanced patient appropriate for 
neoadjuvant therapy or other therapy with curative intent).  If a subject 
becomes a candidate for local treatment with radiation therapy, this should be 
discussed with the AbbVie TA MD and should be consistent with standard or 
institutional guidelines (a subject with multiple metastases is unlikely to 
benefit from local therapy).


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Surgery:
If the subject requires surgery during the study, timing of the procedure, study 
drug interruption, and resuming the study drug needs to be discussed with 
AbbVie TA MD.  Any diagnostic, therapeutic or surgical procedure 
performed during the study period should be recorded including the dates, 
description of the procedure(s), and any clinical findings.
As a precautionary measure, it is recommended, but not strictly required, that 
if subjects require placement of a central venous access device (CVAD), that 
procedure should be done 7 days prior to first study treatment start.
Subjects should not be randomized with the intent to receive local therapy for 
breast cancer (i.e., not initially a locally advanced patient appropriate for 
neoadjuvant therapy or other therapy with curative intent).  If a subject 
becomes a candidate for surgical resection, this should be discussed with the 
AbbVie TA MD and should be consistent with standard or institutional 
guidelines (a subject with multiple metastases is unlikely to benefit from local 
therapy).
Alternate Therapy
No anti-cancer medicine/herbal (e.g., Chinese medicine/herbals) remedies 
may be taken concurrently with veliparib (a 14-day washout period must be 
documented).
5.3
Efficacy Pharmacokinetic, Biomarker, Exploratory Research 
and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
A schedule of study activities is presented in Appendix C, Appendix D, Appendix E, and 
Appendix F.  Biomarker and Exploratory Research assessments will be performed as 
summarized in Table 2.  Pharmacokinetic (PK) assessments will be performed as 
summarized in Table 3.


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Table 2.
Schedule Biomarker and Exploratory Research Assessments 
(Blinded Study Treatment)
Procedure
Visit Schedule
Before Drug 
Administration
Sampling Plan
Specimen Matrix
PD Blood Sampling
Plasma Markersa,b
C1D-2, C3D1
Pre-dose
Blood →Plasma
Frozen –70°C or colder
Final Visit
At the time of the clinic visit
BRCA Sequencing:  
Bridging Sample 
C1D-2
Pre-dose
Blood 
Frozen –20°C or colder
Optional with Consent 
Pretreatment Tissue 
Biopsy
C1D-2
Pre-dose
Formalin fixed, paraffin 
embedded (FFPE) 
tissue blocks 
or FFPE slides ambient
Optional with Consent 
Post treatment Tissue 
Biopsy
Final Visit
At the time of clinic visit
Formalin fixed, paraffin 
embedded (FFPE) 
tissue blocks 
or FFPE slides ambient
Optional with Consent 
PG Blood Sampling 
Genetic (DNA)
C1D-2
Pre-dose
Blood 
Frozen –20°C or colder
a.
An additional sample may be collected at the time of study treatment discontinuation due to unmanageable toxicity.
b.
Based on a discussion between AbbVie and the investigator, samples for an individual subject may be collected at 
an alternate time point.
Note:
PD/PG sample collection will not be collected during unblinded veliparib monotherapy treatment.  The post-
treatment tissue biopsy can be collected after the subject completes blinded study treatment.
Table 3.
Schedule of Pharmacokinetic Assessments (Blinded Study 
Treatment)
Procedure
Visit 
Schedule
Before Drug 
Administration
After Veliparib 
AM Dose
Sampling Plan
Specimen Matrix
Veliparib/placebo 
PK Samplinga
C1D1
0 ha
1, 3 h
Blood →Plasma
Frozen –20°C or colder
Veliparib/placebo 
PK Samplinga
C2D1
0 ha
--
Blood →Plasma
Frozen –20°C or colder
a.
Before the administration of the morning dose of veliparib/placebo, which should be dosed in the clinic prior to 
carboplatin + paclitaxel on C1D1 and C2D1.
The date and time of the sample collection and the date and time of the last two doses of veliparib/placebo will be 
captured on the eCRF.
Note:
PK samples will not be collected during unblinded veliparib monotherapy treatment.


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5.3.1.1
Study Procedures
The study procedures outlined in Appendix C, Appendix D, Appendix E, and Appendix F
are discussed in detail in this section, with the exception of the monitoring of treatment 
compliance (Section 5.5.6) and the collection of concomitant medication (Section 5.2.3) 
and adverse event information (Section 6.1).  All study data will be recorded within the 
EDC system.
For procedures performed at Screening and repeated, the later procedure performed prior 
to dosing will serve as a baseline for clinical assessment.  Subsequent study procedures 
(excluding labs) should be performed within four (4) days surrounding the scheduled 
study visit date.
Study visits may be impacted by changes in local regulations due to the COVID-19 
pandemic.  Every effort should be made to ensure the safety of subjects and site staff, 
while maintaining the integrity of the study.  If visits cannot be conducted as outlined per 
the protocol due to travel restrictions or other pandemic-related reasons, the site should 
contact the Sponsor for further guidance.
Informed Consent
Signed informed consent will be obtained from the subject or the subject's legally 
acceptable representative in order to participate in this study.  The IRB/IEC-approved 
informed consent must be signed and dated by each subject prior to undergoing any study 
procedures or before any prohibited medications are withheld from the subject in order for 
the subject to participate in this study.  Informed consent will be required for the optional 
exploratory research.  Details about how informed consent will be obtained and 
documented are provided in Section 9.3.
Subjects will be considered screen failures if the informed consent has been signed and 
after a study-specific procedure has been done (e.g., central laboratories drawn), but the 
subject does not meet eligibility criteria.  The reason for screen failure will be documented 
in the source document and will be captured in the eCRF.


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Medical History
The following information will be collected during the Screening Visit:
●
Complete medical history, including documentation of any clinically 
significant medical condition;
●
History of tobacco and alcohol use;
●
Presence and severity of any symptoms/conditions associated with metastatic 
breast cancer; and
●
Detailed oncology history, including:
○
Previous testing for BRCA1/BRCA2 germline testing and results of tumor 
profiling/molecular markers (if applicable)
○
Date of primary cancer diagnosis;
○
Pathology (histology or cytology) of primary tumor
○
Surgical history;
○
Anticancer and radiation treatments administered (including dates and type 
of modality);
○
Metastasis information (including the location and histological markers), if 
applicable.
On C1D-2 any changes from the screening assessments, observed 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.
Physical Examination
A complete physical examination (PE), including height, will be performed at Screening.  
A symptom-directed PE, including weight, will be performed at all other visits, unless 
indicated otherwise.  Height will be measured at Screening only.  For height and weight 
assessments, the subject should not wear shoes.  If the Screening PE is performed within 
7 days of C1D-2, PE is not required on C1D-2, unless clinically indicated.  Clinically 
significant changes from baseline will be documented in the source documentation and 


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eCRF as adverse events.  Physical exams should include clinical evaluation for 
progression with subsequent confirmation by CT.
12-lead Electrocardiogram (ECG)
A resting 12 lead ECG will be performed at the Screening Visit within 28 days of C1D-2 
(prior to the first dose of veliparib/placebo to document the baseline status of the subject) 
C1D1 and at each blinded and unblinded study treatment Final Visit if not performed 
within the last 4 weeks.  The C1D1 ECG must be obtained one hour after dosing with 
veliparib/placebo and prior to the paclitaxel or carboplatin infusions.  For subjects in the 
crossover treatment, the C1D1 ECG must be obtained one hour after dosing with 
veliparib.  A qualified physician will sign and date the ECGs, determine whether any 
findings outside normal physiological variation are clinically significant (in consultation 
with a cardiologist if necessary), and document this on the ECG report.  The original ECG 
tracing or copy with physician's assessment will be retained in the subject's records at the 
study site.
Vital Signs
Vital sign determinations of heart rate, sitting blood pressure, and body temperature will 
be measured at all visits, unless indicated otherwise.  If possible, blood pressure and heart 
rate measurements should not take place immediately after scheduled blood collections.
Pregnancy Test (In Women of Childbearing Potential)
For female subjects of childbearing potential, a serum pregnancy test will be done at 
screening and a urine pregnancy test will be done prior to randomization (within 
24 hours).  A serum pregnancy test can be performed at C1D-2 and analyzed locally prior 
to randomization.  If a serum pregnancy test is performed on C1D-2, a urine pregnancy 
test does not need to be completed.  Pregnancy tests may also be repeated during the study 
according country requirements.  Subjects considered not of childbearing potential must 
be documented as being surgically sterile or postmenopausal (amenorrheic for at least 
12 months).


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If pregnancy results are equivocal (e.g., false positive due to B-hCG being a tumor 
marker) in subjects with evidence to support lack of pregnancy (e.g., surgically sterile), 
the results should be discussed with the AbbVie TA MD and the investigator's 
interpretation along with supporting information documented in the source documents.
The C1D-2 urine pregnancy test results must be reviewed and determined to be negative 
prior to randomization.  If the urine pregnancy test is positive at C1D-2, it should be 
confirmed by a serum pregnancy test and dosing should be delayed.
For female subjects of childbearing potential, who have prolonged interruption of therapy 
(> 3 months), a pregnancy test (urine or serum) must be performed and confirmed to be 
negative prior resuming therapy.  In situations of suspected pregnancy, pregnancy testing 
will be performed as soon as possible.  In addition, pregnancy testing may be repeated at 
the discretion of the investigator and according to country requirements at any time during 
the study.
Clinical Laboratory Tests
All subjects will undergo the laboratory assessments outlined in Table 4.
All laboratory samples will be assessed using a certified central laboratory and these data 
will be used for all data analysis.  The central laboratory will provide instructions 
regarding the collection, processing, and shipping of samples.  All laboratory samples will 
be shipped to the central laboratory.
A certified local reference laboratory may perform complete blood count (CBC) and 
chemistry tests prior to dosing in each cycle to allow for immediate subject management; 
however, split or concurrent samples will be drawn and sent to the central laboratory for 
analysis.  When necessary, local labs can be split and used to determine subject eligibility 
upon discussion with the AbbVie TA MD.  The appropriate certifications will be collected 
from both the central and local laboratories, as needed.


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Due to travel restrictions and other changes in local regulations in cases of state of 
emergency or pandemic or other special situations that prevent the site from collecting a 
Central Laboratory sample, if possible, sites should arrange for subjects to have laboratory 
work done at a local lab, hospital, or other facility.  Local lab results should be obtained 
along with reference ranges and kept within the subjects' source documentation.  Local lab 
results should be reviewed by the investigator as soon as possible.
If laboratory samples cannot be obtained per the protocol, the site should discuss with the 
AbbVie TA MD prior to continuing dosing.
AbbVie may discontinue the requirement for concurrent samples to be sent to the central 
laboratory, and require instead local laboratory results only at protocol-specified 
timepoints, at any time during the course of the study.
Samples for chemistry, hematology, and urinalysis will be collected at all visits, unless 
otherwise indicated, as detailed below.  For Screening labs performed greater than 7 days 
prior to C1D-2, hematology/chemistry should be split at C1D-2 (with a 24 hour window) 
and local labs reviewed prior to dosing.  For Day 1 visits of each cycle after Cycle 1, 
study samples for central laboratory analysis may be performed within 72 hours prior to 
dosing.  For visits conducted by phone as outlined in Appendix F, lab tests do not need to 
be performed and are to be collected at a minimum at the on-site visits (every other cycle).  
For Day 8 and Day 15 visits (during blinded study treatment), study samples for central 
laboratory analysis may be performed within 24 hours from the scheduled day.  There is 
no visit window for C1D-2 as any sample prior to randomization is still considered to be 
screening.  A qualified (e.g., certification or accreditation) local laboratory may be used to 
perform laboratory analyses for treatment decisions and should be entered into EDC, but 
this cannot replace the central laboratory analysis on a protocol defined visit.
●
Urinalysis samples will be collected at Screening, C1D-2 and at each blinded 
and unblinded study treatment Final Visit.
●
APTT/INR will be collected at Screening.


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●
BRCA1 and BRCA2 germline mutation testing will be collected on all subjects 
by the Sponsor core laboratory.
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 the investigator 
considers clinically significant will be followed, as appropriate.  Clinically significant 
laboratory values will be recorded as adverse events if they meet the criteria as specified 
in Section 6.1.
Table 4.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands (if indicated)
Lymphocytes
Monocytes
Basophils (if indicated)
Eosinophils (if indicated)
Platelet count (estimate not
acceptable)
Mean corpuscular volume
Mean corpuscular hemoglobin
concentration
RBC distribution width
Sodium
Potassium 
Chloride
Bicarbonate
Blood Urea Nitrogen (BUN)
Serum creatinine
Glucose
Calcium
Inorganic phosphorus
Magnesium
Total protein
Albumin
Total bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic
transaminase (SGOT/AST)
Alkaline phosphatase
Uric acid
Lactate dehydrogenase (LDH)
Serum or urine β-HCG*
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Coagulation
Special Chemistry
Activated partial thromboplastin
time (APTT)*
International normalized ratio 
(INR)*
BRCA1 and BRCA2 germline 
mutation**
*
Collected at Screening.  Serum or urine β-HCG will also be collected prior to randomization (within 24 hours).
**
Collected prior to C1D-2.


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BRCA1/BRCA2 Testing
BRCA1 and BRCA2 Germline Mutation Testing
The diagnosis of a suspected deleterious or deleterious BRCA1 or BRCA2 mutation must 
be documented prior to randomization and genetic risk assessment and counseling should 
proceed per NCCN guidelines or the standard policy of the institution.  A copy of the 
results (including non-Sponsor testing) will be needed for the site study file.  Subjects 
with BRCA variants of uncertain significance or polymorphisms in BRCA1 or BRCA2 will 
not be eligible for the study.
Documentation of BRCA mutation status must occur by one of the following mechanisms 
prior to randomization:
●
Previous diagnosis of a BRCA1 or BRCA2 mutation.
If the diagnostic testing for BRCA1/BRCA2 was not conducted by the Sponsor 
core laboratory, the investigator should ensure that the testing and 
classification is consistent with local guidelines and clinical practice and that 
the test employs either 1) direct DNA sequencing/MLPA or 2) a 
well-characterized methodology previously validated by sequencing, such as 
that used to assess founder mutations.  These subjects must also undergo 
Sponsor core laboratory BRCA gene sequencing during Screening or on
C1D–2.
Subjects with local labs indicating a suspected deleterious or deleterious 
mutation and who meet all of the eligibility criteria may be randomized prior 
to receiving results from the Sponsor core laboratory.
●
Subjects considered high risk for carrying a BRCA1/BRCA2 mutation are 
eligible for Sponsor core BRCA testing.  Subjects may be considered high risk 
if they meet one of the following criteria (per the most current NCCN 
guidelines):32
○
Individual from a family with a known deleterious BRCA1/BRCA2 gene 
mutation;
○
Personal history of breast cancer and one or more of the following:
●
Diagnosed at age ≤ 45;


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●
Diagnosed at age ≤ 50 with:
○
An additional breast cancer primary (i.e., bilateral disease or two or 
more clearly separate ipsilateral primary tumors);
○
≥ 1 close blood relative with breast cancer at any age;
○
≥ 1 close relative with pancreatic cancer;
○
≥ 1 relative with prostate cancer (Gleason score ≥ 7);
○
An unknown or limited family history; 
●
Diagnosed at age ≤ 60 with a triple negative breast cancer;
●
Diagnosed at any age with:
○
≥ 1 close blood relative with breast cancer diagnosed at age ≤ 50;
○
≥ 2 close blood relatives with breast cancer at any age;
○
≥ 1 close blood relative with ovarian carcinoma;
○
≥ 2 close blood relatives with pancreatic cancer and/or prostate 
cancer (Gleason score ≥ 7) at any age;
○
A close male blood relative with breast cancer;
○
For an individual of ethnicity associated with higher mutation 
frequency (e.g., Ashkenazi Jewish) no additional family history 
may be required; 
○
Personal history of epithelial ovarian/fallopian tube/primary peritoneal 
cancer;
○
Personal history of male breast cancer;
○
Personal history of prostate cancer (Gleason score ≥ 7) at any age with 
≥1 close blood relative with breast and/or ovarian cancer and/or pancreatic 
cancer or prostate cancer (Gleason score ≥ 7) at any age;
○
Personal history of pancreatic cancer with ≥ 1 close blood relative with 
breast and/or ovarian cancer and/or pancreatic cancer or prostate cancer 
(Gleason score ≥ 7) at any age.
Note:  Patients who pre-qualify with one or more of these criteria will be eligible to screen 
for BRCA1/BRCA2 mutation by the Sponsor core laboratory.  These subjects may be 
eligible for randomization upon receipt of documentation of a suspected deleterious or 


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deleterious germline BRCA1/BRCA2 mutation by the Sponsor core laboratory.  Germline 
mutation testing obtained greater than 28 days prior to Cycle 1 Day –2 will not preclude a 
subject from randomization.
BRCA Bridging Sample
In order to permit future bridging studies to other potential BRCA assays, in addition to 
the sample collected for the Sponsor core laboratory BRCA test, two tubes of blood must 
be obtained from all subjects per Table 2 to be tested at a future date.
Tumor Assessments (Radiologic)
Appropriate diagnostic CT assessments using modified RECIST version 1.133 for solid 
tumor response will be used in the evaluation of cases, as appropriate.  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 if the disease, especially potentially measurable 
lesions as present, can be appropriately evaluated.  Magnetic resonance imaging (MRI) 
may replace the CT imaging in cases where local laws or requirements mandate, but 
should have sponsor or central imaging center approval prior to performing the MRI.
Axial plane CT scans of the full chest, abdomen, pelvis (or MRI), and brain MRI or 
contrast CT to determine the extent of tumor burden were performed for all tumor 
assessments at Screening (within 28 days of randomization), and every 9 weeks from 
C1D-2 (tumor assessments could be conducted 5 days prior or 5 days following the 
scheduled assessment) until progression. For subjects in the blinded treatment period, 
following the primary analysis and implementation of Protocol Amendment 4, the tumor 
assessment interval may be increased to every 12 weeks from last scan (tumor 
assessments may be conducted 10 business days prior or 10 business days following the 
scheduled assessment). At the investigator's discretion, the interval between scans may be 
longer than every 12 weeks for subjects who have durable disease control but must not 
exceed 24 weeks.


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For subjects on open-label crossover veliparib, tumor assessments will be conducted 
every 9 weeks (± 5 business days) from C1D1.  Following the primary analysis and 
implementation of Protocol Amendment 4, if a crossover subject has disease control after 
6 scans while following the 9 week scan interval schedule, the tumor assessment 
frequency can be increased to every 12 weeks (± 10 business days) from the last scan. At 
the investigator's discretion, the interval between scans may be longer than every 
12 weeks for subjects who have durable disease control, but must not exceed 24 weeks.
Subjects who have discontinued study treatment due to unmanageable toxicity or reasons 
other than progression will remain on study but off drug and continue to complete 
scheduled tumor assessments until unequivocal progression per RECIST 1.1 is 
documented as per Appendix E.
Scheduled tumor assessments will not be affected by delays in therapy and/or drug 
holidays.  Subjects will continue to be monitored by the same diagnostic method 
throughout the study, unless evidence of tumor metastasis warrants otherwise.
Post baseline brain MRI or contrast CT is only required in subjects with CNS lesions at 
baseline; in all other subjects, CNS imaging will be obtained as clinically indicated based 
upon symptoms indicative of CNS disease.  Coronal or sagittal plane imaging may be 
acquired for paraspinal findings and other lesions that may be better appreciated in that 
plane.  Measurements should only be performed on axial imaging and lesions followed in 
non-axial planes should be assessed qualitatively only.
Baseline full body bone scan is required for study entry.  Subsequent bone scans will be 
performed, as clinically indicated or per the institution's standard of care.  A new bone 
lesion requires detection of new area of lysis, cortical destruction, or increasing soft tissue 
component.  New bone scan lesions will not be considered as PD, unless confirmed as 
increasing destruction/lytic on CT/MRI.  Increasing sclerosis will not be considered PD.  
New lesions or increasing sclerosis of existing bone lesions (flare) must be evaluated by 
CT/MRI.


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Subject treatment management will be based on the tumor assessment review by the local 
investigator and/or site staff.  If the investigator's assessment of progression is equivocal, 
the subject should remain on study until subsequent assessment demonstrates unequivocal 
PD per RECIST 1.1 is documented.  
In addition to being reviewed by the investigator and/or site staff, radiology scans will be 
sent to a central imaging center (PAREXEL Informatics) within 1 week during the course 
of the study and in cases of suspected PD, within 2 days of collection for review.  The 
central imaging center will provide instructions regarding the preparation and shipment of 
the images.  Imaging sent to the central imaging center should also include any 
unscheduled bone scan, PET-FDG or X-ray acquired by the sites for study purposes.  
Radiology scans will be assessed by the central imaging center according to RECIST 
(version 1.1) as outlined in Section 5.3.4.1.  Interpretations from the central imaging 
center will not be sent to the site.  It is recommended that subjects remain on study until 
the investigator and/or site staff receives notification from AbbVie that the assessment of 
PD has been completed.  AbbVie may discontinue the requirement for radiology scans to 
be sent to the central imaging center or the requirement for completing central reviews at 
any time during the course of the study.
ECOG Performance Status
ECOG performance status will be assessed as outlined in Appendix C, Appendix D, 
Appendix E, and Appendix F.


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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.
Patient Reported Outcomes (PRO) Questionnaires
To assess the subject's health-related quality of life and symptoms, the EORTC QLQ C30, 
the EORTC BR23, and the European Quality of Life-5 Dimensions (EQ 5D 5L) 
(Appendix G, Appendix H and Appendix I, respectively) will be administered pre-dose at, 
C1D-2, C1D1 (unblinded veliparib monotherapy treatment only), every other cycle 
thereafter beginning with Cycle 2 (C2, C4, C6, etc.), each blinded and unblinded study 
treatment Final Visit and at each blinded and unblinded study treatment 30-Day Follow-
Up Visit.  In addition, to assess pain more specifically, the Brief Pain Inventory Short 
Form (BPI-SF) questionnaire (Appendix J) will be administered pre-dose at C1D-2, C1D1 
(unblinded veliparib monotherapy treatment only), Day 1 of every cycle, each blinded and 
unblinded study treatment Final Visit and each blinded and unblinded study treatment 
Follow-Up Visit.  To minimize response bias, all PRO questionnaires will be administered 
before subjects are informed of their tumor assessment.  Subjects must complete the 
questionnaires on paper forms, which are then entered into EDC by the investigator or 
designee.  The Investigator or a designee will need to check the form returned by the 
subject for completeness before the subject leaves the clinic.  For subjects who are eligible 
to alternate on-site visits and phone visits, the PRO questionnaires should still be 
completed at the phone visits.  PRO questionnaires to be completed for the cycle during 
which the phone visit occurs should be provided to the subject by the investigator or 


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designee during the preceding on-site visit, so these can be completed at home as outlined 
in the schedule of assessments in Appendix F.
The EORTC QLQ-C30 is a 30-item questionnaire that consists of a global health 
status/QoL scale, a financial difficulties scale, five functional scales (cognitive 
functioning, social functioning, physical functioning, emotional functioning, and role 
functioning), and eight symptom scales/items (fatigue, insomnia, appetite loss, pain, 
constipation, diarrhea, dyspnea, and nausea and vomiting).  The EORTC BR-23 is a breast 
cancer–specific questionnaire and is meant for use complementary to the generic EORTC 
QLQ-C30 for patients with different disease stages and treatment modalities.34  It 
comprises of 23 items divided in four functioning scales (body image, sexual functioning, 
sexual satisfaction, and future perspective) and four symptom scales (side effects of 
systemic therapy, breast symptoms, arm symptoms, and upset by hair loss).  The 
questionnaire has been validated in an international study.
The EuroQol 5 Dimensions 5 Level (EQ-5D 5L)35 is a generic preference instrument that 
has been validated in numerous populations.  The EQ-5D 5L is composed of 5 questions 
and a visual analog scale (VAS) assessing overall health that can be converted into a 
single health status or "utility" score for use in an economic evaluation to adjust life-years 
gained by the subject's health-related quality of life.
The Brief Pain Inventory-Short Form (BPI-SF), originally developed to assess cancer 
related pain in clinical trials, is one of the most widely used measurement tools for 
assessing clinical pain.39  The BPI-SF allows patients to rate the severity of their pain and 
the degree to which their pain interferes with common dimensions of feeling and function.
Due to the COVID-19 pandemic and any local restrictions, sites may administer PRO 
questionnaires over the phone as needed.  Sites may read the PRO questions and response 
options to the subject and record the subject's responses.  Sites may send the 
questionnaires (email or hard copy) to the subjects to allow them to read/understand the 
questions and responses when the subject is providing responses over the phone.  The date 


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and time of PRO data collection should be recorded along with who collected the 
information.
Randomization and Subject Number Assignment
The site will contact the IVRS/IWRS to obtain a screening (subject) number once the 
subject has signed the informed consent and a study-specific procedure has been 
performed (i.e., 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 document and will be captured in the eCRF.
Subjects who complete all Screening procedures and meet the eligibility criteria in 
Section 5.2 and none of the exclusion criteria in Section 5.2.2 will proceed to 
randomization.
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 IVRS/IWRS vendor.
Dispensing Study Drug
The IVRS/IWRS will assign bottles of veliparib or placebo and vials of carboplatin and 
paclitaxel that are supplied by AbbVie to be dispensed to a subject during the study from 
the available supply at the site.  Prior to each scheduled drug dispensation visit (per 
Appendix C and Appendix D), site personnel must contact the IVRS/IWRS for the bottle 
number assignments no more than 5 days before Day 1 of each cycle.  Study medication 
cannot be dispensed unless the IVRS/IWRS is contacted.  AbbVie or the designee will 
provide specific instructions on the use of the IVRS/IWRS.
Subjects will be provided with self-administration instructions and subject dosing cards.  
Subjects will be instructed to store veliparib or placebo according to specific directions 
included in Section 5.5.2.2.  Subjects should return bottles of veliparib or placebo (empty, 


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partially filled, or full) to the study site prior to each cycle and each blinded and unblinded 
study treatment Final Visit.
Depending on local regulations due to the COVID-19 pandemic, provision of study drug 
for direct-to-patient (DTP) and direct-frompatient (DFP) transfer will be available upon 
request.  AbbVie has contracted with third party vendors for sites to ship study drug DTP 
and DFP.  Sites will be able to use the third party vendor and/or another local courier for 
drug shipment, as needed.  If necessary, notify AbbVie if DTP and/or DFP shipping will 
be used. 
Sites will be responsible to:
●
Meet IRB/IEC reporting requirements and submit the booking form (which 
will be provided to site by the courier) to the local IRB/IEC, as applicable.
●
Submit the booking form at least 72 business hours before the drug needs to be 
picked up, or as per the requirements of the courier.
●
Discuss the DTP and DFP process with the subject including:
○
Obtain consent to provide delivery information to the courier and 
document this in the source.
○
Obtain results of required safety procedures before registering subject 
dispensation of study drug in IRT.
○
Confirm the subject will be available to accept delivery.
○
Confirm the subject will maintain the drug containers, as well as any 
unused drug for return to site.
●
Follow up with the subject after shipment is received.
●
Retain documentation of the shipment for IP accountability and monitoring.
Blinded Study Treatment
Subjects will receive sufficient quantities of veliparib/placebo for 7 days of administration 
in each 21-day cycle.  Subjects should start treatment with veliparib/placebo within 
approximately 48 hours of randomization.  At C1D-2, subjects will be given 


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veliparib/placebo for dosing through Day –1.  At C1D1, subjects will be given 
veliparib/placebo for dosing through Day 5 and additional study drug for Cycle 2 Days –2 
and –1.  For subsequent cycles, subjects will receive veliparib/placebo for Days 1 – 5 of 
the current cycle and a separate bottle for Days –2 and –1 of the following cycle.  This 
dispensing schedule will allow subjects to begin veliparib/placebo dosing prior to 
receiving carboplatin and paclitaxel infusions without requiring a return to the 
investigative site on Day –2.
Trained site personnel will administer the carboplatin + paclitaxel intravenously on Day 1 
and paclitaxel on Days 8 and 15 of each 21-day cycle.  Subjects will be supervised at the 
time of the infusion. 
If carboplatin or paclitaxel is obtained commercially via the site pharmacy, the site will be 
responsible for tracking the lot numbers for all carboplatin and paclitaxel dispensed and 
include the information in the trial master file (TMF).
On Day 1, subjects on blinded single-agent veliparib/placebo will be given study drug for 
dosing through Day 21.
For subjects who are eligible to alternate on-site visits and phone visits every other cycle, 
during the on-site visits, the investigator or designee should dispense blinded study drug 
via IRT and subject dosing cards for 2 consecutive cycles, as outlined in the schedule of 
assessments in Appendix F.
Unblinded Study Treatment
Subjects will receive sufficient quantities of unblinded veliparib for 21 days of 
administration in 21-day cycle.  At C1D1, subjects will be given unblinded veliparib for 
dosing through Day 21.  For subsequent cycles, subjects will receive unblinded veliparib 
monotherapy for Days 1 – 21 of the current cycle.
For subjects who are eligible to alternate on-site visits and phone visits every other cycle, 
during the on-site visits, the investigator or designee should dispense unblinded study 


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drug via IRT and subject dosing cards for 2 consecutive cycles, as outlined in the schedule 
of assessments in Appendix F.
Post-Progression/Survival Follow-Up Information
Once a subject meets study treatment discontinuation criteria, subjects will continue to be 
followed during the Post Treatment Follow-Up Phase for survival (i.e., the date and cause 
of death) and post-therapy information, including date of progression to the first post-
study therapy.  These data will be collected on the appropriate eCRF at 2 month intervals 
(or as requested by Sponsor to support data analysis), beginning on the date the subject 
discontinued from study therapy until the endpoint of death, the subject has become lost-
to follow-up, or AbbVie terminates the study.
The following will be collected for post-therapy information:
●
Name(s) of post-therapy regimens;
●
Post-therapy dates of initiation and completion;
●
Date of progression on the first post-study therapy (PFS2);
●
Response to subsequent therapies and reason for discontinuation.
The investigator must report the withdrawal to the IVRS/IWRS system within 3 days of 
the subject's discontinuation.  Following entry into the Post Treatment Follow-Up Phase, 
the subject will be treated in accordance with the investigator's best clinical judgment. 
Subjects who have discontinued study treatment due to unmanageable toxicity or reasons 
other than progression will remain on study, off drug and continue to be followed for 
survival and post-treatment therapy information at 2 months intervals (or as requested by 
Sponsor to support data analysis) as outlined in the schedule of assessments in 
Appendix E.
Subjects who wish to withdraw specifically from survival follow-up must have the request 
documented in the subject's medical record and signed by the investigator.  If the subject 
withdraws from the Post Treatment Follow-Up, the study staff may use public 


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information source (such as county records) to obtain information about survival status 
only per local regulations, as appropriate.
5.3.1.2
Collection and Handling of Biomarker and Exploratory 
Research Samples
Blood and tissue samples will be collected for biomarker and optional exploratory 
research.  Subjects may still participate in the main study even if they decide not to 
participate in optional exploratory research.
All biomarker and exploratory research samples should be labeled and shipped as outlined 
in the study-specific laboratory manual.  AbbVie (or people or companies working with 
AbbVie) will store the biomarker and exploratory research 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), this disease and related conditions 
continues, but for no longer than 20 years after study completion.  The procedure for 
obtaining and documenting informed consent for exploratory research samples is 
discussed in Section 9.3.
Biomarker Samples
Plasma and blood for BRCA bridging will be collected at time points as outlined in 
Table 2 and may be utilized to evaluate known and/or novel markers (nucleic acids, 
peptides/proteins and/or metabolites) of disease status, related conditions or to evaluate 
the association with pharmacokinetics, safety or efficacy.  The biomarker rationale will be 
discussed in the Biomarker Research Variables Section (Section 5.3.8).
Collection of Optional Exploratory Research Samples
Pharmacogenetic Sample (Optional) for Exploratory Research
One 4-mL whole blood sample for DNA isolation will be collected at C1D-2 (during the 
blinded study portion) from each subject who consents to provide samples for exploratory 
research.  If the sample is not collected at C1D-2, the sample may be collected at any time 


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throughout the study.  PG samples will not be collected during unblinded veliparib 
monotherapy treatment.
Pretreatment Tissue Biopsy-Archived or Fresh Tissue Biopsy for Exploratory 
Research (Optional)
If available, fixed samples from most recent pathological analysis will be collected from 
subjects (with consent) at C1D-2.  Only one of the following forms of pre-treatment 
tumor tissue (archived tissue or fresh biopsy) is required:
●
Pretreatment Biopsy-Archived
●
Fresh Tumor Tissue Biopsy
The most recent archived biopsy is preferred and should be obtained during Screening if 
possible.  If no archived material is available, a fresh biopsy may be collected from 
subjects who consent according to Institutional procedures for subjects.  If a fresh biopsy 
is collected, it should be fixed in formalin and embedded in paraffin according to 
Institutional procedures.  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.  Tumor samples should be stored according to Institutional 
procedures until shipment to AbbVie or an AbbVie-designated contract research 
organization (CRO).
Included with each shipment should be a copy of the pathology report with all subject-
identifying information redacted and completed shipment inventory form.  Tissue slides 
will be shipped in slide boxes.  Slide boxes should be packaged using suitable shipping 
materials and sent to AbbVie at ambient temperature.
Post Treatment Tumor Biopsy for Exploratory Research (Optional)
An optional post treatment tumor tissue biopsy should be collected at the blinded study 
treatment Final Visit.  Institutional procedures should be followed to fix and embed the 
collected biopsy in paraffin.  While tissue blocks are preferred, slides prepared by the 


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local pathology lab are acceptable and should be prepared as described in the subject 
specific laboratory manual.
Included with each shipment should be a copy of the pathology report with all subject-
identifying information redacted and completed shipment inventory form.  Tissue slides 
will be shipped in slide boxes.  Slide boxes should be packaged using suitable shipping 
materials and sent to AbbVie at ambient temperature.
5.3.2
Drug Concentration Measurements
Pharmacokinetic variables are discussed in Section 5.3.6.
5.3.2.1
Collection of Samples for Analysis
Blood samples for determination of plasma concentration of veliparib will be collected at 
time points as outlined in Table 3.  The date and time of sample collection and the date 
and time of the last 2 doses of veliparib will be captured on the eCRF.  Approximately 
3 mL of blood will be collected by venipuncture into one 3-mL potassium (K2) EDTA 
(purple cap) tube in conjunction with clinical lab blood draws (if possible).  Sufficient 
blood will be collected to produce approximately 1 mL of plasma for each sample.  The 
date and time of collection for each sample will be recorded.  Plasma should be 
transferred into one 2 mL Greiner tube.
If an indwelling catheter of any type is used, approximately 3 mL volume of blood must 
be collected and discarded prior to collection of the veliparib sample.  The use of 
indwelling catheter for the collection of pharmacokinetic samples is discouraged unless it 
is absolutely necessary.
Samples should not be collected when subjects are on a dose interruption.


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5.3.2.2
Handling/Processing of Samples
The complete process of centrifugation, transfer to polypropylene tubes, and freezing 
should be accomplished within 120 minutes from blood draw.  The processing of 
pharmacokinetic samples should be performed, as described below:
●
Collect the blood sample in a 3-mL EDTA (purple top) tube.
●
Immediately invert the collection tubes 8 to 10 times.
●
Within 60 minutes from blood draw, centrifuge sample at 1100 to 1300 × g for 
10 minutes at 2° to 8°C.  If a refrigerated centrifuge is not available, samples 
can be centrifuged under room temperature conditions.
●
Transfer plasma into an appropriately labeled (drug name, type of sample, 
protocol number, subject number, treatment cycle and day, and the planned 
time of sample collection relative to dosing, and the sample collection date) 
screw-capped polypropylene tube and freeze at –20°C or colder.
●
Plasma samples must be frozen upright at –20°C or colder within 2 hours after 
collection and must remain frozen until shipped frozen to the central 
laboratory.  Samples should not be allowed to thaw prior to arrival at the 
central laboratory.
5.3.2.3
Disposition of Samples
Samples and inventory sheet should be batch shipped frozen to a designated laboratory on 
dry ice sufficient for 3 days.  Samples should not be allowed to thaw prior to arrival at the 
designated laboratory.  Shipment information will be provided in the laboratory manual.
5.3.2.4
Measurement Methods
Plasma concentrations of veliparib will be determined under the supervision of the Drug 
Analysis Department at AbbVie.


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5.3.3
Efficacy Variables
The primary efficacy endpoint will be PFS.  The secondary efficacy endpoints will be OS, 
CBR, ORR, and PFS2.  The tertiary endpoints will include DOR, change in ECOG 
performance status, and change in QoL indices.
5.3.4
RECIST (Version 1.1) for Tumor Response
Response criteria will be assessed using RECIST (version 1.1).  Changes in the target and 
non-target lesions over the course of therapy must be evaluated using the criteria listed 
below.
Eligibility
Subjects with measurable or non-measurable (but radiologically evaluable) disease with at 
least one lesion outside previously irradiated areas 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 (target) lesion in at least one site which has not 
received prior radiotherapy.  Lesions that have been previously irradiated will be 
considered non-target lesions.  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, lymphangitis 
cutis/pulmonis, and 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
Bone lesions are considered non-target/non-measurable lesions.
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 
measurable lesions if they meet the definition of measurability described 
above.  However, if noncystic lesions are present in the same patient, 
these are preferred for selection as target lesions.
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area will be considered 
non-target lesions.


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All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and not more than 28 days prior to randomization.
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.  In 
the case of skin lesions, documentation by color photography including a ruler to estimate 
the size of the lesion is recommended.  All measurements should be taken using calipers 
and recorded in metric notation, if clinically assessed.  When lesions can be evaluated by 
both clinical exam and imaging, imaging evaluation should be undertaken, since it is more 
objective and may also be reviewed at the end of the study.
Methods of Measurement
Conventional CT should be performed with contiguous axial cuts of 5 mm or less in slice 
thickness for tumors of the chest, abdomen and pelvis.  A scale should be incorporated 
into all radiographic measurements.  MRI can be performed if required by local law, but 
must have sponsor/central imaging center approval.  Non-axial slices may be of value in 
the interpretation of paraspinal lesions findings and other lesions that are better 
appreciated in non-axial planes.  Lesions followed on non-axial imaging should be 
assessed qualitatively (i.e., as CR, Non-CR/Non-PD, unequivocal PD, unequivocal new, 
NE).  Lesions only visible on non-axial imaging are not considered suitable as target 
lesions.
For accurate objective response evaluation, ultrasound or bone scan 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.


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Cytology and histology can be used to differentiate between benign and malignant fluid 
collections in cases of new and/or enlarging pleural effusion and/or ascites in which the 
response will be based on other target or non-target lesions.  New effusions or ascites 
should be considered unknown until cytology confirms whether they are benign or 
malignant.  If cytology is available and suggesting malignancy, the data must be entered 
into the eCRF and will be considered in the determination of progression.  While fluid 
collections are present, the response determination cannot be considered CR.
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.  Tumor lesions situated in a previously irradiated area or in an 
area subjected to other loco-regional therapy are considered non-target lesions.
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 (no more than 2 may be 
selected), 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 whether a node is involved by solid 
tumor.  Nodal size is normally reported as 2 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 diameters (SOD) for all target lesions will be calculated and reported as the 
baseline sum SOD.  If lymph nodes are to be included in the sum, then, as noted above, 


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only the short axis is added into the sum.  The baseline SOD will be used as reference by 
which to characterize the objective tumor response.
All other lesions (or sites of disease), including pathological lymph nodes, CNS 
metastases and skin lesions, should be identified as non-target lesions and should also be 
recorded at Baseline.  Measurements of these lesions are not required, but the presence 
(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.
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest SOD 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 SOD 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 radiologist believes that the lesion is 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.
If interventions occur during the study that affect disease burden, such as surgery, the 
lesion(s) affected will typically be considered non-evaluable (NE) from that point forward 
and subsequent time points will be either NE or PD (if evidence of progression is 
available).
Evaluation of Non-Target Lesions
Complete Response (CR)
The disappearance of all non-target lesions.  All lymph nodes must be non-pathological in 
size (< 10 mm short axis).


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Non-CR/Non-PD
Persistence of one or more non-target lesion(s).
Progressive Disease (PD)
Unequivocal progression of existing non-target lesions.
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, therefore, will 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 
possibly representing 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.
If a new lesion is equivocal (e.g., too small to measure), continued therapy and follow-up 
evaluation will clarify whether it truly represents 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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Calculating Final Response:
Response of Combined Lesion Type
Target Lesion
Non-Target Lesion
Unequivocal New 
Lesion*
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not evaluated
No
PR
SD
Non-PD or not evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
*
Equivocal new lesions will not allow for CR but will otherwise not impact the overall response.
Calculating Final Response for Non-Measurable Disease:
Non-Target Lesion
New Lesion
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/Non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
5.3.4.1
Definition of Disease Progression
Disease progression will be defined as progression of disease by RECIST (version 1.1).
If the subject experiences symptomatic deterioration and clinical progression is 
determined by the investigator, every effort will be made to document radiographic or 
clinical evidence of progression for analysis of the primary endpoint, even after 
discontinuation of treatment.  Thus, all randomized subjects should be followed for 
disease progression and for the second progression (PFS2), death, or withdrawal of 
consent for follow up until PD.


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Clinical data that support progression will be collected and submitted for central review, 
including the following:
●
Data on palliative radiotherapy and/or surgery/resection while on study, 
including specific location, date and results, as applicable;
●
Biopsy or cytology, including reason, date and pathology result (additional 
assessment eCRF);
●
Redacted reports on any lesions on off-protocol modalities, such as x-ray or 
FDG-PET, including specific locations, dates and status; redacted reports 
should only include data on imaging not submitted for review;
●
Skin lesion reports (using the study approved form) will be provided by 
investigative sites for any lesions assessed by physical exam.
Clinical data provided to the central independent reviewers (additional assessment eCRF 
and Lesions Assessed by Physical Exam form) will not include information on images 
submitted for central review or information indicative of the site's assessment of tumor 
status (PD).
5.3.5
Safety Variables
AbbVie will assess adverse events, laboratory data, and vital signs throughout the study.  
Adverse events will be assessed according to NCI CTCAE version 4.0 Published:  
May 28, 2009 (v4.03:  June 14, 2010).
During the conduct of the study, the AbbVie medical and safety team will be monitoring 
subject laboratory results, adverse event and serious adverse event data, as it is reported.  
Medically significant changes in vital signs and ECGs will be reviewed, as available.
An IDMC reviewed unblinded safety data intermittently prior to the primary analysis.  No 
additional reviews by the IDMC will occur since the Sponsor management team was 
unblinded after completing the primary analysis.
Please refer to Section 8.1.8 for further details pertaining to the IDMC review.


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5.3.6
Pharmacokinetic Variables
Collection and shipment of PK samples is discussed in Section 5.3.2.
Values for compartmental pharmacokinetic parameters of veliparib such as rate of 
absorption (Ka), apparent volume of distribution (V/F) and oral clearance (CL/F) may be 
estimated using a nonlinear mixed-effect population modeling approach with NONMEM 
software and reported in a separate pharmacokinetic report.  Additional analyses may be 
performed, if useful in the interpretation of the data.
AbbVie or a designated laboratory will store the PK 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 analysis may 
be performed 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.
5.3.7
Exploratory Research Variables
Optional blood and tissue samples may be collected to conduct exploratory investigations 
into known and novel biomarkers.  The types of biomarkers to be analyzed may include, 
but are not limited to, nucleic acids, proteins, lipids or metabolites.  The samples may be 
analyzed as part of a multi-study assessment of factors influencing the subjects' response 
to the study drug (or drugs of the same or similar class) or the development and 
progression of the subjects' disease or related conditions.  The samples may also be used 
to develop new diagnostic tests, therapies, research methods or technologies.  The results 
from these analyses are exploratory in nature and may not be included with the study 
report.  Samples will be collected to conduct exploratory analyses to investigate 
biomarkers.
5.3.8
Biomarker 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.


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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.
Biospecimens may be evaluated for levels of biomarkers including nucleic acids, 
proteins/peptides and metabolites.  For example, protein analysis of relevant proteins, 
including but not limited to, DNA repair proteins, such as ERCC1 and XPF, may be 
performed on tumor tissue obtained from each consented subject.
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 
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.
BRCA Bridging Sample
In order to permit future bridging studies, additional samples will be collected to allow 
testing using additional assays to assess assay performance compared to other potential 
BRCA assays to be tested in the future.
5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Subjects will receive therapy until disease progression according to Section 5.3.4, 
RECIST 1.1, unmanageable toxicity (per discussion with the AbbVie TA MD), or they 
meet the study treatment discontinuation criteria as outlined below.  Subjects who 
discontinue therapy for reasons other than disease progression will continue to be 
followed as per a modified scheduled of assessments per Appendix E.


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Each subject has the right to withdraw from study treatment at any time.  In addition, the 
investigator may discontinue a subject from the study treatment at any time for any reason 
if the investigator considers it necessary, including the occurrence of an adverse event or 
noncompliance with the protocol.  Each subject will discontinue study treatment, if any of 
the following occur:
●
The subject experiences disease progression as defined by RECIST 
(version 1.1).
●
Clinically significant deterioration of the subject's medical status, as 
determined by the investigator.  
●
The investigator believes it is in the best interest of the subject;
●
The subject requires alternative anticancer agents for primary or metastatic 
disease;
●
The subject becomes pregnant or begins breastfeeding during the treatment 
portion of the study;
●
The subject or subject's legally acceptable representative decides to withdraw 
consent for any reason; or
●
Any other medical reason that AbbVie or the investigator deems appropriate.
Criteria for study discontinuation include:
●
The subject experiences unequivocal disease progression as defined by 
RECIST (version 1.1) on blinded therapy and does not meet criteria for 
proceeding to the unblinded portion of the study, or experiences unequivocal 
disease progression as defined by RECIST (version 1.1) on unblinded therapy;
●
The subject becomes pregnant or begins breastfeeding during the treatment 
portion of the study; or
●
The subject or subject's legally acceptable representative decides to withdraw 
consent for any reason.


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In cases of state of emergency or pandemic situations, if subjects withdraw consent from 
study treatment, they should be considered as on study, off drug and follow the schedule 
of assessments per Appendix E, if the subject consents to continued follow up.
When a subject discontinues either the blinded or unblinded study treatment, a Final Visit 
will be conducted.  During a Final Visit, the reasons for the discontinuation from the 
study treatment will be recorded and a physical examination, vital signs measurement, 
laboratory analyses, performance status, ECG (if not performed within the last 4 weeks), 
QoL assessment, collection of unused study drug, and an assessment of adverse events 
will be performed.  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.  
All subjects will have a 30-Day Follow-Up Visit approximately 30 days after the last dose 
of study treatment.  Follow-Up Visits should not precede a Final Visit.  Subjects starting 
any new cancer therapy within 30 days after the last dose of study treatment should 
complete the 1 month follow-up assessments in advance of starting any anti-cancer 
therapy.  Assessments performed within the 7 days prior to the 30-Day Follow-up Visit do 
not need to be repeated, unless further study treatment was administered or a test result 
was abnormal.  The 30-Day Follow-Up Visit does not need to be performed for subjects 
who have had a Final Visit conducted ≥ 30 days after the last dose of study treatment.
When a subject discontinuation is planned without the subject reaching a protocol-defined 
endpoint, the investigator will notify the AbbVie TA MD or the clinical team 
representative (Section 6.1.6) via telephone, as soon as possible (provided, in each case, 
subject care and safety are not compromised).  If not notified prior to discontinuation, the 
AbbVie TA MD may contact the site to discuss the reason for withdrawal from the study.
If a subject is discontinued from study treatment 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.


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In the event that a subject becomes pregnant during the study, the administration of study 
treatment to that subject must be discontinued immediately.  The site must report the 
pregnancy by telephone within 24 hours to one of the AbbVie representatives listed in 
Section 7.0.  Discontinued subjects will not be replaced.
5.4.1.1
Discontinuation of Blinded Study Treatment 
(Veliparib/Placebo + Carboplatin + Paclitaxel)
Subjects will receive veliparib/placebo + carboplatin + paclitaxel until reaching a protocol 
defined event of disease progression or they experience unmanageable toxicity.  Dose 
reductions of carboplatin and paclitaxel will occur on the basis of the toxicity observed 
and may result in discontinuation of either agent (e.g., discontinuation of paclitaxel for 
neurotoxicity).  The subject may continue on therapy with the remaining agent in 
combination with veliparib/placebo.  Discontinuation of carboplatin and paclitaxel in the 
absence of toxicity requiring dose modification should be discussed with the AbbVie TA 
MD.  Subjects who discontinue carboplatin and paclitaxel and who have not progressed 
will receive blinded veliparib/placebo as a single agent starting at 300 mg BID.
Carboplatin and paclitaxel administration will continue after veliparib/placebo has been 
discontinued.
5.4.2
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 or her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped for reasons of safety.  
If AbbVie terminates the study for safety reasons, AbbVie will immediately notify the 
investigator by telephone and subsequently provide written instructions for study 
termination.


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The following procedures for discontinuation must be followed:
●
If the Sponsor has decided to prematurely discontinue the study, the Sponsor 
will promptly notify in writing the investigator, as well as regulatory 
authorities of the decision and give detailed reasons for the discontinuation;
●
The investigator must promptly notify the IRB/IEC and give detailed reasons 
for the discontinuation; and
●
The investigator must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments, such as replacement of 
the treatment regimen by other appropriate regimens, if applicable.
5.5
Treatments
5.5.1
Treatments Administered
Subjects will be randomized in a 2:1 ratio to receive one of the following blinded 
treatments:
●
Veliparib + Carboplatin and Paclitaxel
●
Placebo + Carboplatin and Paclitaxel
General chemotherapy guidelines are found in Appendix L.
Veliparib/Placebo
Subjects will self-administer veliparib/placebo twice daily (with the morning and the 
evening doses approximately 8 – 12 hours apart) with or without food in the same 
calendar day for Days –2 through 5 of the 21-day cycle during the blinded study treatment 
portion.  Dosing of veliparib/placebo on Day 1 of every cycle should be done before 
carboplatin + paclitaxel infusion.
Subjects who discontinue chemotherapy will self-administer veliparib/placebo twice daily 
(with the morning and the evening doses approximately 8 – 12 hours apart) with or 
without food in the same calendar day for Days 1 through 21 of the 21-day cycle.


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Subjects in the unblinded veliparib monotherapy treatment will self-administer twice daily 
(with the morning and the evening doses approximately 8 – 12 hours apart) with or 
without food in the same calendar day for Days 1 through 21 of the 21-day cycle.
If the subject vomits within 15 minutes of taking veliparib/placebo, another dose should 
be administered.  It is recommended that if a subject misses a scheduled dose of veliparib 
and less than 6 hours have passed since the scheduled dosing time, the dose should be 
taken immediately.  It is recommended that if more than 6 hours have passed since the 
scheduled dosing time, the subject should not take the missed dose, but should wait and 
take the next regularly scheduled dose.
Paclitaxel
All subjects should be pretreated with corticosteroids, diphenhydramine, and H2
antagonists according to institutional guidelines, the locally approved product label, local 
practice, or applicable SmPC.
Paclitaxel will be administered intravenously over approximately 1 hour at a dose of 
80 mg/m2 on Day 1, 8 and 15 of every cycle.  Paclitaxel will be infused prior to 
carboplatin on Day 1.  Dosing of veliparib/placebo should always be done before the 
carboplatin or paclitaxel infusion.
If needed per dose modifications guidelines, it is recommended that growth factors (i.e., 
filgrastim, peg-filgrastim) dosed according to institutional standard will be administered 
daily subcutaneously starting 24 – 72 hours after the last dose of carboplatin/paclitaxel or 
after last dose of weekly paclitaxel.  Pegfilgrastim should not be used for subjects 
receiving Day 15 paclitaxel as they do not have a 2-week chemotherapy-free interval.
Carboplatin
Carboplatin will be administered intravenously over approximately 15 to 30 minutes at 
(AUC 6 mg/mL/min) immediately following paclitaxel infusion on Day 1 of every cycle.  
The duration of carboplatin infusion may be lengthened according to institutional 


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guidelines.  Dosing of veliparib/placebo should always be done before the carboplatin or 
paclitaxel infusion.
Maximum carboplatin dose will be capped as follows:
Carboplatin dose (mg) = target AUC (mg/mL/min) × (150 mL/min)
●
For a target AUC = 6, the maximum dose is 6 × 150 = 900 mg
●
For a target AUC = 5, the maximum dose is 5 × 150 = 750 mg*
●
For a target AUC = 4, the maximum dose is 4 × 150 = 600 mg*
*
Only for subjects who have had dose modifications.
Serum creatinine as provided by the central laboratory is based upon the IDMS method.  
Use of the central laboratory creatinine result for the calculation of estimated GFR and the 
Calvert formula for carboplatin dosing is strongly encouraged, with the maximum 
carboplatin dose capped as above.  If the central laboratory value of plasma creatinine is 
not available at the time of carboplatin dose calculation, the local value may be used.
Similarly, when the GFR is estimated using isotopic/EDTA clearance, maximum 
carboplatin dosing should be based upon standard guidelines and institutional practices 
(e.g., AUC – 1).  In subjects with a low serum creatinine (less than 0.7 mg/dl), the 
creatinine clearance should be estimated using a minimum value of 0.7 mg/dl.
eGFR determined according to local practice will be capped at a maximum of 
125 mL/min/1.73m2.  If a subject experiences toxicity that would lead to dose reduction of 
carboplatin to an AUC of < 4, carboplatin will be discontinued.  Note that carboplatin 
dose will be recalculated if the subject has a weight change of greater than or equal to 
10% from baseline; adjustments for weight change of < 10% are allowed per institutional 
guidance.  In the absence of renal toxicity greater than or equal to CTCAE Grade 2 (serum 
creatinine > 1.5 × ULN) or toxicity requiring dose modification, the dose of carboplatin 
will not need to be recalculated for subsequent cycles, but will be subject to dose 
modification for toxicity as noted in the protocol.


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If needed per dose modifications guidelines, it is recommended that growth factors (i.e., 
filgrastim, peg-filgrastim) dosed according to institutional standard will be administered 
daily subcutaneously starting 24 – 72 hours after the last dose of carboplatin/paclitaxel or 
after last dose of weekly paclitaxel.
5.5.2
Identity of Investigational Product
Information about veliparib, placebo, carboplatin, and paclitaxel formulations to be used 
in this study is presented in Table 5.
Table 5.
Identity of Investigational Products
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
Veliparib 
(ABT-888)
Capsule
40 mg active
50 mg active
100 mg active
Oral
AbbVie
Veliparib 
(ABT-888) 
Placebo
Capsule
40 mg placebo
50 mg placebo
100 mg placebo
Oral
AbbVie
Carboplatin 
(commercially 
available)*
Vial*
150 mg /15 mL 
aqueous solution*
450 mg/45 mL 
aqueous solution*
Intravenously
Generic 
manufacturer
Paclitaxel 
(commercially 
available)*
Vial*
100 mg/16.7 mL 
non-aqueous 
solution*
Intravenously
Generic 
manufacturer
*
Carboplatin and paclitaxel formulations may vary based on the source.
AbbVie will supply veliparib capsules and a matching placebo for veliparib.  Veliparib 
will be tested for stability and relabeled and/or replaced as necessary.  Instructions for 
relabeling supplies will be provided by AbbVie.  Carboplatin and paclitaxel will either be 
obtained commercially by the site or AbbVie will supply carboplatin and paclitaxel to 
sites depending on local regulations and availability of supplies.


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5.5.2.1
Packaging and Labeling
Veliparib and placebo will be packaged in bottles containing the required number of 
capsules of 40 mg active, 50 mg active or 100 mg active or placebo.  Each bottle label 
will include all information, as required by local regulations and must remain affixed to 
the bottle.  The site staff must complete all blank spaces on the label prior to dispensing 
drug to the subject.
If carboplatin and/or paclitaxel are provided by AbbVie, the label will include all 
information as required by local regulations and must remain affixed to the primary and 
secondary packaging material.  The site staff must complete all blank spaces on the label 
prior to dispensing drug to the subject.
AbbVie will provide the study site with detailed instructions and training for the handling 
of study supplies.
5.5.2.2
Storage and Disposition of Study Drug
All clinical supplies provided by AbbVie must be stored in a secure place at the proper 
storage conditions as presented in Table 6, 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.  If 
pre-arranged between AbbVie and the site, destruction of used and unused study drug will 
be performed at the site.


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Table 6.
Study Drug Storage Conditions
Study Drug
Country**
Storage Conditions
Veliparib or placebo
All countries, except 
Australia
Store at 15° to 25°C (59° to 77°F).
Australia
Store below 25°C.
Carboplatin
All countries, except 
Australia
Store at 15° to 25°C (59° to 77°F).  Protect from 
light.
Australia
Store below 25°C.  Protect from light.
Paclitaxel
All countries, except 
Australia
Store at 15° to 25°C (59° to 77°F).  Protect from 
light.
Australia
Store below 25°C.  Protect from light.
**
Study drug must be stored according to the labeled storage conditions or local labeling instructions.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects in study will be randomized to the blinded portion of the study by an 
IVRS/IWRS.  Before the study is initiated, each site will be provided with directions for 
the IVRS/IWRS.  The site will contact the IVRS/IWRS to obtain a Screening (subject) 
number once the subject has signed the informed consent and a study-specific procedure 
has been performed (i.e., 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 document and in the eCRF.
Subjects who complete all Screening procedures and meet the inclusion criteria in 
Section 5.2, and none of the exclusion criteria in Section 5.2.2 will proceed to 
randomization.  The site should access the system on or within 2 days prior to the 
subject's C1D-2 visit to randomize the subject.
The IVRS/IWRS will randomize subjects in a 2:1 ratio, between the veliparib 
BID + carboplatin + paclitaxel arm and the placebo BID + carboplatin + paclitaxel arm.  
Subject randomization will be stratified by estrogen receptor (ER) and/or progesterone
receptor (PgR) positive versus ER/PgR negative, prior platinum therapy (yes versus no), 
and CNS metastases (yes versus no).  Tumors with any detectable (≥ 1%) expression of 


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ER and/or PgR by IHC are considered hormone-receptor positive.  Tumors with no 
detectable expression of ER and PgR are considered hormone receptor negative or 
endocrine non-responsive.  For subjects with heterogeneity between primary tumor and 
metastases, the biopsy most proximal to C1D-2 will be used for the purposes of 
stratification.  For subjects with de novo Stage IV disease, the receptor status of the 
primary tumor will be used for the purposes of stratification.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects will be randomized into 1 of 2 treatment arms.
Subjects will self-administer veliparib/placebo twice daily (with the morning and the 
evening doses approximately 8 – 12 hours apart) with or without food in the same 
calendar day.
Subjects will return to the site on Day 1 of each cycle to have carboplatin and paclitaxel 
administered intravenously.  In addition subjects will return to the site on Days 8 and 15 
of each cycle to have paclitaxel administered intravenously.
5.5.5
Blinding
This is a double-blind study.  AbbVie, the investigator, the study site personnel, and the 
subject will remain blinded to each subject's treatment with veliparib/placebo until 
progression of disease.  Subjects who discontinue study treatment because of disease 
progression as defined by Section 5.3.4 have the option to be unblinded to determine 
eligibility for unblinded veliparib monotherapy (crossover).  Following progression of 
disease, a separate unblinded study team was responsible for study conduct and data 
monitoring for subjects who crossed over to veliparib monotherapy. 
After completion of the primary analysis the sponsor was unblinded to treatment 
assignment. A separate unblinded study team is no longer responsible for study conduct 
and data monitoring for subjects who crossover to veliparib monotherapy.  Primary site 
monitors, investigators and subjects continue to be blinded to treatment assignment until 


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disease progression, after which unblinding to determine eligibility for crossover can be 
requested.
5.5.5.1
Blinding of Investigational Product
The IVRS/IWRS will provide access to blinded subject treatment information for an 
individual during the double-blind period.  The AbbVie TA MD (listed in Section 6.1.6) 
must be notified before the blind is broken 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 conveyed to AbbVie and 
recorded on the appropriate eCRF.  In the event the AbbVie Clinical Project Team should 
break the blind, the reason will be documented in a note to study file and on the 
appropriate eCRF.
5.5.6
Treatment Compliance
The investigator or his or her designated and qualified representatives will administer and 
dispense veliparib/placebo, carboplatin, and paclitaxel only to subjects enrolled in the 
study in accordance with the protocol.  Veliparib, placebo, carboplatin, and paclitaxel 
must not be used for reasons other than those described in the protocol.
Veliparib/placebo should be taken as directed by the investigator.
Carboplatin and paclitaxel will be administered intravenously by trained 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 each blinded and unblinded 
study treatment Final Visit.  The study site personnel will document the bottles/cartons of 
veliparib/placebo returned and the number of capsules per bottle/carton on the appropriate 
form.  The bottles/cartons will be retained until the site monitor performs accountability 


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of veliparib/placebo, carboplatin (when supplied by AbbVie), and paclitaxel (when 
supplied by AbbVie).
The study coordinator will document subject study drug administration details on the 
appropriate eCRF.  If the number of capsules taken and the number of capsules returned 
do not add up to the number of capsules dispensed, an explanation will be provided.
Unless otherwise directed by the investigator at the site, a subject will be considered 
compliant with veliparib/placebo if 80% of the assigned dose is taken during a cycle.  
Compliance below 80% will require counseling of the subject by study site personnel.
5.5.7
Drug Accountability
Upon receipt of a shipment, the representative at each site will 1) open and inspect the 
shipment; 2) verify that the veliparib, placebo, carboplatin, and paclitaxel 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; and 
4) register the shipment as received via the IVRS/IWRS.  All study drugs 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 
IVRS/IWRS.
An overall accountability of veliparib, placebo, carboplatin, and paclitaxel supplied by 
AbbVie will be performed and verified by the site monitor via IWRS throughout the study 
and at the study site closeout visit.  An accurate running inventory of veliparib, placebo, 
carboplatin, and paclitaxel supplied by AbbVie will be kept by the site in the IWRS and 
will include the lot number, POR numbers, the bottle/carton numbers, and the date 
veliparib, placebo, carboplatin, and paclitaxel were dispensed for each subject.
Upon completion or termination of the study, all original bottles/cartons containing 
unused veliparib, placebo, carboplatin, paclitaxel (empty containers will be defaced and 
discarded on site) will be returned to AbbVie according to AbbVie's instructions, or if 


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pre-arranged between the sponsor and site, destruction of used and unused veliparib, 
placebo, carboplatin, and paclitaxel in bottles/cartons will be performed at the site.
The investigator or his or her designated representative agrees not to supply veliparib, 
placebo, carboplatin, or paclitaxel to any persons not enrolled in the study or not named as 
a sub-investigator listed on the FDA 1572 or IIA form.
The site will record the bottle number and dose of veliparib, placebo and the bottle/carton 
number and dose of carboplatin and paclitaxel given to each subject in the source 
documents and on the eCRF.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This is a Phase 3, randomized, double-blind study to evaluate the efficacy and tolerability 
of veliparib in combination with carboplatin + paclitaxel compared to an active, placebo 
controlled arm of carboplatin + paclitaxel in subjects with HER2-negative locally 
advanced unresectable or metastatic BRCA-Associated breast cancer.  The choice of the 
control group allowed for a blinded assessment of the contribution of veliparib to the 
safety and efficacy of the backbone regimen of carboplatin + paclitaxel.  In addition to 
paclitaxel being an approved agent for breast cancer, emerging data indicate enhanced 
sensitivity of BRCA mutated cells to platinums; thus, there is potential for increased 
activity of this regimen in this population.
The randomization will be 2:1.  Randomization will be stratified by estrogen receptor 
(ER) and/or progesterone receptor (PgR) positive versus ER/PgR negative, prior platinum 
therapy (yes versus no), and CNS metastases (yes versus no).  Tumors with any detectable
(≥ 1%) expression of ER and/or PgR by IHC are considered hormone-receptor positive.  
Tumors with no detectable expression of ER and PgR are considered hormone receptor 
negative or endocrine non-responsive.


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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
Documented BRCA1 or BRCA2 mutation carriers with histologically (or cytologically) 
confirmed HER2-negative locally advanced unresectable or metastatic breast cancer will 
be enrolled into the study.  Subjects must have had no more than two prior 
DNA-damaging cytotoxic chemotherapy agents for metastatic disease.  Subjects must 
have measurable or non-measurable (but radiologically evaluable) disease as defined by 
modified RECIST (version 1.1).
5.6.4
Selection of Doses in the Study
The combination of veliparib with carboplatin and paclitaxel has been investigated in 
ongoing Phase 1 studies conducted in collaboration with the NCI CTEP.  CTEP 7967 
enrolled subjects who are chemotherapy-naive as well as subjects who received previous 
DNA damaging chemotherapy including platinum compounds.  In this study, the 
maximum dose administered is veliparib 120 mg BID for 7 days in addition to carboplatin 
AUC 6 and paclitaxel 200 mg/m2 administered on Day 3 of a 21-day cycle (regimen based 
upon standard of care for non-small cell lung cancer).  Chemotherapy is administered on 
the third day of veliparib treatment to ensure steady state levels of veliparib (and thus 
maximal inhibition of PARP for given dose) at the start of chemotherapy treatment.  
Toxicities were as expected with carboplatin and paclitaxel chemotherapy, including 
neutropenia, thrombocytopenia, and peripheral neuropathy.29  Weekly paclitaxel is 
standard therapy for breast cancer. The safety and tolerability of veliparib in combination 
with paclitaxel and carboplatin has been evaluated in study GOG 9923; current dose 
levels for intermittent veliparib are 300 mg BID with both q-3week carboplatin/paclitaxel 
(1/7 DLT at 300 mg BID, febrile neutropenia) and weekly carboplatin/paclitaxel (1/6 DLT 
at 250 mg BID; G4 thrombocytopenia), further supporting the tolerability of the 120 mg 
BID dose.  The proposed study will allow subjects who discontinue chemotherapy to 


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continue with single agent veliparib starting at 300 mg BID and if tolerated, escalate to 
400 mg BID administered continuously.  This dose has been selected based upon the 
recommended Phase 2 dose (CTEP 8282) and additional safety and efficacy data in 
Phase 2 studies in BRCA-mutation carriers with breast cancer (CTEP 8264) or ovarian 
cancer (GOG 280), in which durable responses were observed to single agent therapy.
The maximum dose of veliparib for any subject under this protocol is 120 mg BID in 
combination with carboplatin and paclitaxel and 400 mg BID as monotherapy.
5.7
Dose Reductions or Delays
The intention is for veliparib/placebo to be administered concurrently with carboplatin + 
paclitaxel.  Thus, if a delay in any component of the regimen is required for any reason, 
all drugs within the regimen should be delayed until the subject is eligible to receive all 
drugs.  All toxicities, with the exception of anemia, alopecia, and non-treatment related 
clinically insignificant laboratory abnormalities, should be resolved to Grade 1 or lower or 
to baseline if Grade 2 is present at the time of study entry prior to initiation of a new cycle 
of therapy.  Neuropathy should be resolved to Grade 1 or lower to initiate a new cycle of 
therapy, unless paclitaxel has been previously discontinued.
If chemotherapy must be withheld because of hematological toxicity, CBC should be 
obtained at least weekly until the counts reach the lower limits for treatment as outlined.  
The AbbVie TA MD is to be contacted for subjects who require cycle delays of > 28 days 
due to toxicity.
Study drug interruptions for events that are clearly not related to the study drug, 
e.g., underlying cancer, planned surgical procedures, or acute viral illnesses, do not 
necessitate a dose reduction.  The timing of dose resumption should be at the 
investigator's discretion.  
Dose reduction for fatigue will only be done if the fatigue is deemed to be study 
drug-related in the investigator's opinion.


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In the case of delays, interruptions or study treatment discontinuation, tumor assessments 
should have continued at intervals of 9 weeks from C1D-2.  Following the primary 
analysis and implementation of Protocol Amendment 4, the tumor assessment interval 
may be increased to every 12 weeks (or not to exceed 24 weeks for subjects with durable 
disease control, at investigator discretion) from last scan.
Due to the COVID-19 pandemic, temporary study drug interruption may occur.  The
AbbVie TA MD is to be contacted for subjects who require cycle interruptions of 
> 28 days.
5.7.1.1
Carboplatin + Paclitaxel Dose Reduction and Delays
If a dose reduction or delay is required for carboplatin and/or paclitaxel, the investigator 
should follow procedures according to institutional guidelines, the locally approved 
product label, local practice, or applicable SmPC.  The dose levels and guidelines for dose 
modifications based on prior studies with veliparib, carboplatin, and paclitaxel appear in 
Table 7, Table 8, Table 9, and Table 10, respectively.
Table 7.
Dose Levels for Veliparib/Placebo + Carboplatin/Paclitaxel
Dose Level
Carboplatin
Paclitaxel*
Veliparib/Placebo
Starting Dose Level
AUC 6
80 mg/m2
120 mg BID
Dose Level –1
AUC 5
70 mg/m2
80 mg BID
Dose Level –2
AUC 4
60 mg/m2
40 mg BID
*
Discontinuation of the Day 15 paclitaxel infusion for hematological toxicities (per Table 8) will be considered a 
dose reduction and will be maintained in subsequent cycles.
It is recommended that treatment on Day 1 of each cycle proceeds only if ANC is 
≥1500 cells/mm3 and the platelet count is ≥ 100,000/mm3. Recommended dose 
modifications/delays based on hematologic toxicities on Day 1 are outlined in Table 8. 
For subjects with an ANC of 1000 – 1499/mm3 or platelet count 75,000 – 99,999/mm3 on 
Day 1, dosing may continue without modification or delay until recovery, at investigator 
discretion, if drug-related toxicity has been ruled out.  If ANC is below 1000/mm3 or the 
platelet count is below 75,000/mm3, treatment should be delayed until recovery.


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For subjects receiving paclitaxel on the second and third week of the cycle, ANC must be 
≥ 1000/mm3 and platelets ≥ 75,000/mm3 on Day 8 and Day 15 of the cycle.  If counts are 
lower than this, treatment for that day will be omitted with reassessment of hematological 
counts 1 week later.  Dose reductions as outlined in the tables will be used in the 
following cycle.  Within a given cycle, if the Day 8 dose is omitted and the counts recover
by Day 15, the Day 15 dose may be given.  If the ANC and platelet counts have not 
recovered sufficiently for the Day 15 paclitaxel infusion to be administered, therapy may 
be resumed with the subsequent cycle once the hematological counts have recovered (the 
intent is to maintain a 21-day cycle).
Carboplatin and paclitaxel are to be delayed if veliparib/placebo was not taken by the 
subject on Day –2 and Day –1.  In such a case, a new supply of veliparib/placebo is to be 
dispensed, and Day –2 and Day –1 are to be repeated for that cycle.
For any Grade 3 or 4 toxicities not mentioned in Table 8, Table 9 and Table 10 treatment 
will be withheld until the patient recovers to Grade 1 or baseline, and the dose of the 
drug(s) most likely to have caused the toxicity will be reduced.  Re-escalation of therapy 
on combination chemotherapy is not permitted.


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Table 8.
Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel) Dose Reduction and Delays for 
Hematologic Toxicities on Day 1
Adverse Event
Dose Reduction/Delay for Weekly Paclitaxel Dosing
Paclitaxel
Carboplatin
Veliparib or Placebo
Hematological toxicity 
attributable to any or all 
treatment
ANC 1000 – 1499/mm3
and/or Platelets 75000 – 99999/mm3
Resume at the same dose 
level after recovery.
Resume at the same dose 
level after recovery.
Resume at the same dose 
level after recovery.
For repeated occurrences or delays > 2 weeks, consider reducing paclitaxel, 
carboplatin or veliparib/placebo by one dose level.
ANC < 1000/mm3
First Occurrence
Reduce paclitaxel by 
one dose level after 
recovery.
Reduce carboplatin 
one dose level and it is 
recommended to use 
G-CSF.
Resume at the same dose 
level after recovery.
Second Occurrence
Discontinue Day 15 
paclitaxel.b
Resume at the same dose 
level after recovery.
Platelets 25000 –
74999/mm3
First Occurrence
Resume at the same dose 
level after recovery.
Reduce carboplatin by 
one dose level.
Second Occurrence
Resume at the same dose 
level after recovery.
Reduce carboplatin by 
one dose level.
ANC < 1000/mm3 AND 
Platelets 25000 –
74999/mm3
First Occurrence
Reduce paclitaxel by 
one dose level after 
recovery.
Reduce carboplatin by 
one dose level and it is 
recommended to use 
G-CSF.
Second Occurrence
Discontinue Day 15 
paclitaxel.b
Reduce carboplatin by 
one dose level.


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Table 8.
Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel) Dose Reduction and Delays for 
Hematologic Toxicities on Day 1 (Continued)
Adverse Event
Dose Reduction/Delay for Weekly Paclitaxel Dosing
Paclitaxel
Carboplatin
Veliparib or Placebo
Hematological toxicity 
attributable to any or all 
treatment (continued)
ANC < 500/mm3 for 
≥7 days
Hold until recovery to 
ANC ≥ 1500/mm3.  
Reduce paclitaxel by 
one dose level.  It is 
recommended to use 
G-CSF.
Reduce carboplatin by 
one dose level.
Resume at the same dose 
level after recovery.
Febrile neutropenia (ANC 
≤ 1000/mm3 with 
temperature of > 38.5°Ca)
First Occurrence
Hold until recovery to 
ANC ≥ 1500/mm3.  
Reduce paclitaxel by 
one dose level.  It is 
recommended to use 
G-CSF.
Resume at the same dose 
level after recovery.
Resume at the same dose 
level after recovery.
Second Occurrence
Hold until recovery to 
ANC ≥ 1500/mm3.  
Discontinue Day 15 
paclitaxel.b  It is 
recommended to use 
G-CSF.
Reduce carboplatin by 
one dose level.
Resume at the same dose 
level after recovery.
Anemiaa
No reduction or delay.
No reduction or delay.
No reduction or delay.
a.
For clinically significant anemia consider treatment with erythrocyte growth factor and RBC transfusion according to local institutional guidelines.
b.
For subjects who have already discontinued Day 15 paclitaxel, reduce paclitaxel by one additional dose level.
Note:
If needed per dose modifications guidelines, it is recommended that growth factors (i.e., filgrastim, peg-filgrastim) dosed according to institutional standard will be 
administered daily subcutaneously starting 24 – 72 hours after the last dose of carboplatin/paclitaxel or after last dose of weekly paclitaxel.  Pegfilgrastim should not be 
used for subjects receiving Day 15 paclitaxel as they do not have a 2-week chemotherapy-free interval.


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Table 9.
Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel) Dose Reduction and Delays for 
Hematologic Toxicities on Day 8 or 15
Adverse Event
Dose Reduction/Delay for Weekly Paclitaxel Dosing
Paclitaxel
Carboplatin
Veliparib or Placebo
Hematological toxicity 
attributable to any or all 
treatment
ANC 500 – 999/mm3 and 
Platelets
50,000 – 74,999/mm3
Resume at the same dose 
level after recovery.
Resume at the same dose 
level after recovery.
Resume at the same dose 
level after recovery.
ANC <500/mm3
First Occurrence
Resume at the same dose 
level after recovery.
Reduce carboplatin by 
one dose level and it is 
recommended to use 
G-CSF with next cycle.
Resume at the same dose 
level after recovery.
Second Occurrence
Discontinue Day 15 
paclitaxel.b
Resume at the same dose 
level after recovery.
Platelets  <50,000/mm3
First Occurrence
Resume at the same dose 
level after recovery.
Reduce carboplatin by 
one dose level with the 
next cycle.
Second Occurrence
Discontinue Day 15 
paclitaxel.b
Reduce carboplatin an 
additional dose level with 
the next cycle.
ANC < 500/mm3 AND 
Platelets < 50,000/mm3
First Occurrence
Resume at the same dose 
level after recovery.
Reduce carboplatin by 
one dose level and it is 
recommended to use 
G-CSF with the next 
cycle.
Second Occurrence
Discontinue Day 15 
paclitaxel.b
Reduce carboplatin by 
one dose level.


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Table 9.
Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel) Dose Reduction and Delays for 
Hematologic Toxicities on Day 8 or 15 (Continued)
Adverse Event
Dose Reduction/Delay for Weekly Paclitaxel Dosing
Paclitaxel
Carboplatin
Veliparib or Placebo
Hematological toxicity 
attributable to any or all 
treatment (continued)
ANC < 500/mm3 for 
≥7 days
Hold until recovery.  
Reduce paclitaxel by 
one dose level.  It is 
recommended to use 
G-CSF.
Hold until recovery.  
Reduce carboplatin by 
one dose level.
Resume at the same dose 
level after recovery.
Febrile neutropenia (ANC 
≤ 1000/mm3 with 
temperature of > 38.5°Ca)
Hold until recovery.  
Reduce paclitaxel by 
one dose level.  It is 
recommended to use 
G-CSF.
Resume at the same dose 
level after recovery.
Resume at the same dose 
level after recovery.
Anemiaa
No reduction or delay.
No reduction or delay.
No reduction or delay.
a.
For clinically significant anemia consider treatment with erythrocyte growth factor and RBC transfusion according to local institutional guidelines.
b.
For subjects who have already discontinued Day 15 paclitaxel, reduce paclitaxel by one additional dose level.
Note:
If needed per dose modification guidelines, it is recommended that growth factors (i.e., filgrastim, peg-filgastrim) dosed according to institutional standard will be 
administered daily subcutaneously starting 24 – 72 hours after the last dose of carboplatin/paclitaxel or after last dose of weekly paclitaxel.  Pegfilgrastim should not be 
used for subjects receiving Day 15 paclitaxel as they do not have a 2-week chemotherapy-free interval.


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Table 10.
Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel) Dose Reduction and Delays for 
Other Toxicities
Dose Reduction/Delay
Adverse Event
Paclitaxel
Carboplatin
Veliparib or Placebo
Hepatic Toxicitya
Grade 3 or greater AST 
(SGOT), ALT (SGPT), Total 
Bilirubin, or Alkaline 
Phosphatase 
Hold until recovery to Grade 1 
or baseline.  Reduce by one dose 
level.
Hold until recovery to Grade 1 
or baseline.  Resume at previous 
dose.
Hold until recovered to Grade 1 
or baseline.  Resume at previous 
dose.
Total Bilirubin > 5 × ULN or 
AST or ALT > 10 × ULN
Discontinue
Hold until AST/ALT < 3 × 
ULN.  Resume at previous dose.
Hold until AST/ALT < 3 × 
ULN.  Resume at previous dose.
Non-hematologic Grade 3 or 4 
toxicity attributable to any or all 
treatment
Grade 3 or 4 nausea/vomiting 
despite optimal antiemetic 
treatmentb
Hold until nausea/vomiting have 
resolved to ≤ Grade 1.  Reduce 
by one dose level.
Hold until nausea/vomiting have 
resolved to ≤ Grade 1.  Resume 
at 1 dose level below current 
dose level.
Hold until nausea/vomiting have 
resolved to ≤ Grade 1.  Resume 
at previous dose.
≥ Grade 2 stomatitis
Hold until stomatitis has 
resolved to ≤ Grade 1.  Reduce 
by one dose level.
Hold until stomatitis has 
resolved to ≤ Grade 1.  Reduce 
by one dose level.
Hold until stomatitis has 
resolved to ≤ Grade 1.  Resume 
at previous dose.
≥ Grade 2 neuropathyc
Hold until recovery to Grade 1 
or less.  Reduce dose by 
one dose level.  If peripheral 
neuropathy fails to recover to 
Grade 1 within 3 weeks, 
paclitaxel should be 
discontinued.
Resume at the same dose level 
after recovery.
Resume at the same dose level 
after recovery.
Toxicity attributable to veliparib 
and not carboplatin or paclitaxel, 
nor underlying disease
Any Grade 3 or 4 toxicity
Resume at the same dose level 
after recovery to ≤ Grade 1 or to 
baseline.  
Resume at the same dose level 
after recovery to ≤ Grade 1 or to 
baseline.
Hold until recovery to ≤ Grade 1 
or to baseline.  After recovery, 
reduce by one dose level.
Any other Grade 3 or 4 toxicity 
not attributable to underlying 
disease
Hold until recovery to ≤ Grade 1 or to baseline and reduce the dose of the drug(s) most likely to have 
caused the toxicity by one dose level.


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Table 10.
Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel) Dose Reduction and Delays for 
Other Toxicities (Continued)
a.
A subject will be allowed a maximum of 2 dose reductions.  If a third reduction is required, the subject should discontinue paclitaxel.  If paclitaxel is withheld because of 
hepatic toxicity, carboplatin should also be withheld and administered when the paclitaxel is resumed.  If paclitaxel is withheld, hepatic values must recover to ≤ Grade 1 
within 3 weeks or paclitaxel will be discontinued.
b.
Prophylactic anti-emetic therapy (e.g., aprepitant, ondansetron, palonosetron, dexamethasone) should be administered to all subjects per institutional guidelines; specific 
agents are at the discretion of the treating physician.
c.
Dose reductions of paclitaxel for Grade 1 neuropathy will also be allowed, per the investigator's standard practice.  For neurologic toxicity, the subject will be allowed a 
maximum of 2 dose reductions.  If a third dose reduction is required, the subject should discontinue paclitaxel.  If the subject continues to receive carboplatin, veliparib may 
also be continued.


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5.7.1.2
Veliparib or Placebo Dose Reductions and Delays in 
Combination with Carboplatin + Paclitaxel
The following are guidelines for dose reduction, delay, and discontinuation of 
veliparib/placebo in combination with carboplatin and paclitaxel.  Dose reductions are 
outlined below and subjects will continue to follow the schedule of assessments as 
outlined in Appendix C.
1.
For any subject who experiences Grade 3/4 toxicity which is not attributable to 
carboplatin/paclitaxel or the underlying disease, the veliparib/placebo dose is to be 
held until the toxicity resolves to Grade 1 or lower or to baseline if Grade 2 is 
present at the time of study entry.  Upon resuming veliparib/placebo treatment, the 
dose is to be reduced one dose level.  Any dose reduction below 40 mg BID is to 
result in veliparib/placebo discontinuation.
2.
Carboplatin and/or paclitaxel administration will continue after veliparib/placebo 
has been discontinued.
3.
Veliparib/placebo administration will continue after carboplatin and paclitaxel 
discontinuation (Section 5.7.1.3).  Subjects who discontinue carboplatin and 
paclitaxel due to toxicity and protocol-defined dose modifications and who have 
not progressed will receive single-agent, blinded veliparib/placebo starting at 
300 mg BID.  The treatment plan for subjects who experience a robust and durable 
response (such as a confirmed CR following 10 or more cycles of therapy) and for 
whom the investigator considers the potential risks of continued cytotoxic 
chemotherapy outweigh the benefits should be discussed with the AbbVie TA MD 
prior to initiating single-agent blinded veliparib/placebo.
4.
If a subject begins veliparib/placebo on Day –2, but subsequently experiences an 
event requiring the delay of the carboplatin/paclitaxel 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.


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5.
For any ≥ Grade 2 event of seizure attributed to veliparib/placebo, 
veliparib/placebo is to be interrupted, brain CT or MRI obtained, and the event 
should be discussed with the AbbVie TA MD.
5.7.1.3
Blinded Veliparib/Placebo and Unblinded Veliparib 
Monotherapy Dose Reductions and Delays
Subjects who discontinue carboplatin and paclitaxel and who have not progressed may 
receive single-agent, blinded veliparib/placebo starting at 300 mg BID.  Subjects will 
continue to follow the schedule of assessments as outlined in Appendix C.  In addition, 
subjects who progressed while on placebo may crossover to unblinded veliparib 
monotherapy and will follow the schedule of assessment as outlined in Appendix D.  If 
veliparib was discontinued previously in combination with carboplatin and paclitaxel, the 
subject can resume veliparib/placebo monotherapy dosing if symptoms resolve to 
≤ Grade 1.  If veliparib/placebo monotherapy is initiated, the starting dose should be 
300 mg BID for 2 weeks followed by an increase to 400 mg BID, if well tolerated.
The following are guidelines for dose reductions, delays and discontinuation of blinded 
veliparib/placebo or unblinded veliparib monotherapy.  Dose reductions are outlined in 
Table 11.
It is recommended that treatment on Day 1 of each cycle proceeds only if ANC is 
≥1500 cells/mm3 and the platelet count is ≥ 100,000/mm3.  Dosing may continue in 
subjects with ANC and/or platelet counts ranges of ANC of 1000 – 1499/mm3 or platelet 
count 75,000 – 99,999/mm3 without modification at investigator discretion if drug-related 
toxicity has been ruled out.
For any subject who experiences Grade 3 or 4 toxicity despite optimal supportive care and 
the toxicity is not attributable to underlying disease, the veliparib/placebo dose will be 
held until the toxicity resolves to Grade 1 or lower or to baseline if Grade 2 is present at 
the time of study entry.


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The dose of veliparib/placebo will be reduced by one dose level for subjects experiencing 
the following toxicities if attributed to veliparib/placebo:
Hematological toxicities:
●
Grade 3 or 4 neutropenia persisting ≥ 7 days
●
Grade 3 or 4 ANC with fever (ANC < 1.0 × 109/L, fever ≥ 38.5°C)
●
Grade 3 or 4 thrombocytopenia
Non-hematological toxicities
●
Any CTCAE ≥ Grade 3 toxicity that represents at least 2 grade increase from 
baseline with the following clarifications
○
Excludes nausea, vomiting, diarrhea, and tumor pain that have not received 
optimal treatment with antiemetics, antidiarrheals, or analgesics.
○
A rise in creatinine to Grade 3, only if not corrected to Grade 1 or baseline 
within 24 hours with IV fluids.
○
Metabolic toxicities, only if not corrected to Grade 2 or less within 
24 hours (such as glucose changes, hypokalemia, hypomagnesemia, 
hyperuricemia, hypophosphatemia, and hyponatremia).  Grade 4 metabolic 
toxicities that are symptomatic will result in dose reduction regardless of 
duration or ability to correct.
○
For any > Grade 2 event of seizure attributed to veliparib/placebo, 
veliparib/placebo is to be interrupted, brain CT or MRI obtained, and the 
event should be discussed with the AbbVie TA MD.
Re-escalation may be permitted on the veliparib monotherapy arm only if toxicity 
resolved to Grade 1 or lower and can be maintained with optimal supportive care.  This 
should be discussed with the appropriate AbbVie TA MD.


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Table 11.
Blinded Veliparib/Placebo and Unblinded Veliparib Monotherapy 
Dose Levels
Dose Level
Veliparib
Starting Dose Level
300 mg BID (if unable to 
escalate dose due to toxicity by 
C1D15 then continue current 
dose) 
400 mg BID (if acceptable 
toxicity then escalate dose on 
C1D15)
Dose Level –1
200 mg BID
300 mg BID
Dose Level –2
150 mg BID
200 mg BID
5.7.1.4
Allergic Reaction/Hypersensitivity
Paclitaxel:
Severe reactions, such as hypotension requiring treatment, dyspnea requiring 
bronchodilators, angioedema, or generalized urticaria, require immediate discontinuation 
of paclitaxel and aggressive symptomatic therapy.  Subjects who have developed severe 
hypersensitivity reactions should not be rechallenged with paclitaxel.
Carboplatin:
Severe reactions, such as hypotension requiring treatment, dyspnea requiring 
bronchodilators, angioedema, or generalized urticaria, require immediate discontinuation 
of carboplatin and aggressive symptomatic therapy.  Subjects who have developed 
hypersensitivity reactions may undergo desensitization per institutional protocol as 
determined by the investigator.  This should be discussed with the AbbVie TA MD.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.


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Complaints associated with any component of this investigational product must be 
reported to the Sponsor.  For adverse events, please refer to Sections 6.1 through 6.1.8.  
For product complaints, please refer to Section 6.2.
6.1
Medical Complaints
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 treatment, and any action(s) taken.  For serious and nonserious 
adverse events considered as having "no reasonable possibility" of being associated with 
study treatment, the investigator will provide an Other cause of the event.  For adverse 
events to be considered intermittent, the events must be of similar nature and severity.  
Adverse events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
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.  
Laboratory abnormalities and changes in vital signs are considered to be adverse events 


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only if they result in discontinuation from the study, necessitate therapeutic medical 
intervention, [meets protocol specific criteria (see Section 6.1.8 regarding toxicity 
management)] and/or if the Investigator considers them to be adverse events.
An elective surgery/procedure will not be considered an adverse event if the 
surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre planned prior to study entry or is due to an improvement 
in the underlying disease.  However, if the pre-existing condition deteriorates 
unexpectedly during the study (e.g., surgery performed earlier than planned), then the 
deterioration of the condition for which the elective surgery/procedure is being done will 
be considered an adverse event.
6.1.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie, as
appropriate, as a serious adverse event (SAE) within 24 hours of the site being made 
aware of the serious adverse event.
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.


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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).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
Examples of such events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug 
dependency or drug abuse.  A toxicity is deemed "clinically 
significant" on the basis of the investigator's medical 
judgment.  Additionally, any elective or spontaneous abortion 
or stillbirth is considered an important medical event.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.2
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).36
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.


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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.
Death (Grade 5)
The adverse event resulted in death of the subject (severe).
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 CRFs 
also need to be updated and need to include the new AE serial number.
6.1.2.1
Adverse Events Expected Due to Breast Cancer or 
Progression of Breast Cancer
Adverse events that may be expected from primary breast cancers or progression of breast 
cancer include skin erythema, skin edema, skin erosion, non-cardiac chest pain, 
metastases to bone, metastases to brain, metastases to central nervous system, metastases 
to liver, and tumor pain.
These events may occur alone or in various combinations and are considered expected 
adverse events in breast cancer subjects.
6.1.3
Adverse Events Expected Due to Study Related Endpoints
6.1.3.1
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol 
specified adverse event collection period (Section 6.1.5) that are more likely related to 
disease progression will therefore be an expected adverse event and will not be an 
expedited report.


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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.
6.1.3.2
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.  If there is any uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event.
6.1.4
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study treatment:  For the purpose of this section, study treatment is 
considered veliparib or placebo, carboplatin and or paclitaxel.
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 treatment will be considered "associated."  Events assessed as having 
no reasonable possibility of being related to study drug will be considered "not 


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associated."  In addition, when the investigator has not reported 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 treatment 
is given, an Other cause of event must be provided by the investigator for the serious 
adverse event.
6.1.5
Adverse Event Collection Period
All protocol-related serious and nonserious adverse events must be collected from the 
signing of the study specific informed consent until study treatment administration. 
In addition, all adverse events reported from the time of study treatment administration 
until 30 days following discontinuation of study treatment 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, carboplatin or paclitaxel will be 
collected only if they are considered by the Investigator to be causally related to study 
required procedures.
Adverse event information will be collected as shown in Figure 2.


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Figure 2.
Adverse Event Collection
*
Only if considered by the Investigator to be causally related to study-required procedures.
**
Adverse events of myelodysplastic syndrome, acute myeloid leukemia or any second primary malignancy should 
be reported throughout the entire duration of follow-up phase even if the onset is > 30 days following 
discontinuation of study treatment.
6.1.6
Adverse Event Reporting
In the event of a serious adverse event, whether related to AbbVie study medication or 
not, the Investigator will notify AbbVie 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 Electronic Data Capture (EDC) system.  Serious adverse events that 
occur prior to the site having access to the RAVE® system, or if RAVE is not operable, 
should be faxed to AbbVie Clinical Pharmacovigilance within 24 hours of being made 
aware of the serious adverse event.
FAX to:  +1 (847)-938-0660 or
Email to:  PPDINDPharmacovigilance@abbvie.com
For safety reporting related questions or concerns, contact the Oncology Safety Team at:




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COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol and above.  If a subject has a confirmed or suspected COVID-19 infection, the 
investigator should contact the AbbVie TA MD before reintroducing study drug.
6.1.7
Pregnancy
As there is a potential risk of birth or early development defects with study treatment(s), 
subjects will consent to avoid pregnancy and/or breastfeeding for a minimum of 6 months 
(or longer per local labels of carboplatin and paclitaxel, if applicable) following 
completion of therapy.  Pregnancy in a study subject must be reported to AbbVie within 
24 hours of the site becoming aware of the pregnancy.  Subjects who become pregnant 
during the study must be discontinued (Section 5.4.1).  Information regarding a pregnancy 
occurrence in a study subject and the outcome of the pregnancy will be collected within 
the EDC system.  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.
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.
6.1.8
Toxicity Management
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the Investigator.  The table of clinical 
toxicity grades modified from the NCI CTCAE Version 4.0 Published:  May 28, 2009 
(v4.03:  June 14, 2010) (available on the CTEP home page http://ctep.info.nih.gov) is to 


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be used in the grading of adverse events and laboratory abnormalities that are reported as 
adverse events, each of which will be followed to satisfactory clinical resolution.
A drug-related toxicity is an adverse event or laboratory value outside of the reference 
range that is judged by the Investigator or AbbVie as a "reasonable possibility" to be 
related to the study treatment (Section 6.1.1.1).
A toxicity is deemed "clinically significant" on the basis of the investigator's medical 
judgment.
All adverse events will be followed to a satisfactory conclusion.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint related to the biologic or drug component of the 
product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.


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Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol eligibility 
criteria.  The principal 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 principal 
investigator is responsible for notifying Independent Ethics Committee (IEC)/Independent 
Review Board (IRB) regulatory authorities (as applicable), and his or her assigned clinical 
monitor or the following AbbVie representatives:




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the impact of any discrepancies between results from the local laboratory and from the 
Sponsor core laboratory.
All subjects who receive at least one dose of the study treatment (veliparib or placebo) 
will be included in the safety analysis.  
Comparisons will be performed between the two treatments as assigned by the IVRS/IWR 
(veliparib 120 mg BID + carboplatin + paclitaxel versus placebo BID + carboplatin 
+ paclitaxel).
8.1
Statistical and Analytical Plans
8.1.1
Baseline Characteristics
All baseline summary statistics and analyses will be based on characteristics prior to the 
initiation of study treatment (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 treatment.
Baseline characteristic data will be summarized for all subjects who are randomized to 
veliparib 120 mg BID + carboplatin + paclitaxel and placebo BID + carboplatin + 
paclitaxel.
8.1.1.1
Demographics
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
means, standard deviation, and range.  Frequencies and percentages will be computed for 
the following parameters:  gender, race, BRCA1, BRCA2, ER/PgR status, number and 
sites of metastases, prior platinum therapy (yes versus no), CNS metastases (yes versus 
no), and baseline ECOG performance status.
8.1.1.2
Medical Histories
Frequencies and percentages will be computed for each medical history parameter.


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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 120 mg BID + carboplatin + paclitaxel and placebo BID + carboplatin 
+ paclitaxel.
For a given subject, time to PFS will be defined as the number of days from the date the 
subject was randomized to the date the subject experiences disease progression (as 
determined by the investigators), or death, whichever occurs first (all causes of mortality).  
All events of disease progression will be included, regardless of whether the event 
occurred while the subject was still taking study treatment or had previously discontinued 
study treatment.  Events of death will be included for subjects who had not experienced an 
event of disease progression, provided the death occurred within 9 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.  Every 
effort should be made to document radiographic progression for analysis of the primary 
endpoint, even after discontinuation of treatment or initiation of subsequent anti-cancer 
therapy.
8.1.2.2
Secondary Efficacy Endpoints
Secondary efficacy analyses comparing the effects of veliparib 120 mg BID + carboplatin 
+ paclitaxel and placebo + carboplatin + paclitaxel on the following set of endpoints will 
be performed:  overall survival (OS), clinical benefit rate (CBR) through the end of 
Week 24, objective response rate (ORR) and progression-free survival on subsequent 
therapy (PFS2).
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 


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taking study treatment or after the subject discontinued study treatment. If a subject has 
not died, the data will be censored at the date last known to be alive.
Clinical Benefit Rate (CBR) is defined as the progression-free rate at 24 weeks from the 
Kaplan-Meier curve for time to progression (defined as from the date of randomization to 
the date of disease progression as determined by the investigators).
Objective Response Rate (ORR) is calculated as the proportion of subjects who have PR 
or CR based on assessment by the investigators.  All subjects who have had at least 
one measurable lesion at baseline will be included in the ORR calculation.
Progression Free Survival 2 (PFS2) will be defined as the number of days from the day 
the subject is randomized to the date that the subject has disease progression or death of 
any cause on the subsequent therapy, whichever occurs first.  If the subject does not have 
an event of PFS2 (as determined by the Investigator), the subject's data will be censored at 
the subject's last known date of follow-up.
8.1.2.3
Tertiary Efficacy Endpoints
In addition to the primary and secondary efficacy analyses, tertiary efficacy analyses will 
be performed comparing the effects of veliparib 120 mg BID + carboplatin + paclitaxel 
versus placebo + carboplatin + paclitaxel on duration of response (DOR), quality of life, 
and performance status.
Duration of response will be defined as the number of days from the day that the criteria 
are met for CR or PR, whichever is recorded first, to the date that progressive disease is 
documented.  If a subject's response is ongoing at the analysis cutoff date then the subjects 
data will be censored at the date of the last disease progression assessment performed 
prior to the cutoff.  Subjects who never experience a confirmed PR or CR will not be 
included in the analysis.


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8.1.3
Timing of Efficacy Analyses and Safety Evaluations
When the 344th PFS (determined by the investigators) event occurs, there will be a final 
review of the eCRF data.  When the data are reviewed for completeness and all data 
management quality assurance (QA) and quality control (QC) procedures are performed, 
the randomization schedule will be released and clinical database data will be extracted 
for documentation and statistical analyses of the efficacy and safety data.
The data cutoff date for the primary PFS analyses will be specified in the statistical 
analysis plan (SAP) prior to database lock.  All imaging related efficacy analyses (PFS, 
CBR, ORR, DOR) will include data up to the cutoff date.
OS will be analyzed at the time of 'Primary PFS Analysis' as an interim analysis.  The Lan 
DeMets alpha spending function with an O'Brien-Fleming boundary will be used to 
ensure that the one-sided false positive rate will be 0.025 or less for overall survival.  If 
OS is not statistically significant at the interim analysis, a 'Final OS Analysis' will be 
performed after observing approximately 357 death events.  Additional OS analyses may 
be performed before the 'Final OS analysis,' if requested by regulatory agencies or 
otherwise warranted.  For each additional interim analysis of OS, a small amount of alpha 
(0.00001) will be spent.
The clinical study report (CSR) will summarize the results from the above analyses.
8.1.4
Primary Analysis of Efficacy
The distribution of PFS (PFS as determined by the investigators, as detailed in 
Section 5.3.3) will be estimated for each treatment group using Kaplan-Meier 
methodology and compared between veliparib 120 mg BID + carboplatin + paclitaxel and 
placebo + carboplatin + paclitaxel treatment groups using the log-rank test, stratified by 
ER and/or PgR positive versus ER/PgR negative and prior platinum therapy (yes versus 
no).


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8.1.5
Secondary Analyses of Efficacy
If the veliparib treatment group is not statistically significantly better than the placebo 
treatment group for the primary endpoint of PFS, then none of the secondary endpoints 
will be tested and statistical significance will not be declared for any secondary endpoints 
regardless of the observed P values.  P values for secondary efficacy analyses will be 
subject to multiple comparison adjustments using the fixed sequence testing method, with 
analyses performed in the following order:  OS, CBR, ORR, and PFS2.
8.1.5.1
Overall Survival
The distribution of overall survival will be estimated for each treatment group using 
Kaplan-Meier methodology and compared between veliparib 120 mg BID + carboplatin 
+ paclitaxel and placebo  + carboplatin + paclitaxel using the log-rank test, stratified by 
ER and/or PgR positive versus ER/PgR negative and prior platinum therapy (yes versus 
no).
8.1.5.2
Clinical Benefit Rate
Clinical benefit rate (CR, PR, SD or Non-CR/Non-PD) at Week 24 will be defined as the 
progression-free rate at 24 weeks from the Kaplan-Meier curve for time to progression 
(defined as from the date of randomization to the date of disease progression as 
determined by investigators).  A test statistic based on Kaplan-Meier estimates of the 
progression-free probability at 24 weeks and the estimated variance will be constructed to 
test the null hypothesis that the clinical benefit rate at Week 24 for the two treatment 
groups are the same.
8.1.5.3
Objective Response Rate
The objective response rate (CR and PR) will be computed for all subjects with 
measurable disease at baseline.  The proportion of subjects with a complete or partial 
objective response based on the RECIST (version 1.1) criteria in Section 5.3.3 will be 
estimated for each treatment group and compared between veliparib 120 mg BID + 
carboplatin + paclitaxel and placebo BID + carboplatin + paclitaxel using CMH test, 


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stratified by ER/PgR positive versus ER/PgR negative and prior platinum therapy (yes 
versus no).
8.1.5.4
PFS2
The distribution of PFS2 will be estimated for each treatment group using Kaplan-Meier 
methodology and compared between veliparib 120 mg BID + carboplatin + paclitaxel and 
placebo + carboplatin + paclitaxel treatment groups using the log-rank test, stratified by 
ER and/or PgR positive versus ER/PgR negative and prior platinum therapy (yes versus 
no).
8.1.6
Tertiary Analyses of Efficacy
8.1.6.1
Duration of Overall Response
The distribution of the duration of overall response for responders (CR or PR) will be 
estimated for each treatment group using Kaplan-Meier methodology.
8.1.6.2
Patient Reported Outcomes (PRO)
The EORTC scoring manual will be used to transform the raw scores into the domain 
scores (global heath, functional scales, symptom scales/items).  The EQ-5D manual and 
the published weights will be used to convert the individual items to the utility scores.  
The BPI-SF user guide will be used to convert the raw responses to pain severity and pain 
interference scores.  
Descriptive statistics will be used to summarize the individual item and scored 
domain/sub-scale QoL and pain scores at each scheduled assessment time point.  Change 
from baseline in the domain scores at the time of each assessment will be summarized.  
Subjects with a baseline score and at least one post baseline score during the treatment 
period will be included in the change from baseline analyses.
The PRO variables will include the global health status/QoL and the functional and 
symptom domain scores from the EORTC questionnaires, the utility score from EQ-5-D 


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questionnaire, and the pain severity and pain interference scores from the BPI-SF 
questionnaires.  
Analyses of the above PRO variables and the corresponding endpoints will be specified in 
the Statistical Analysis Plan (SAP) to answer the following primary questions:
●
Is there a statistically significant difference between treatment arms in the 
longitudinal changes in overall quality of life and specific symptoms from 
baseline to pre-specified time points (details will be specified in SAP);
●
Are the longitudinal changes meaningful?
Change from baseline to post-baseline assessment visit between two treatment arms will 
be compared using ANCOVA model with treatment and corresponding baseline value as 
covariates.  Additional statistical analyses may be performed if deemed necessary and 
helpful in understanding the drug effect, such as an analysis of repeated measure may be 
used to compare overall change from baseline between two treatment groups by including 
baseline value, treatment, and time of visit as covariates.  Clinical meaningful changes 
from baseline to assessment points will be based on minimum important difference (MID) 
derived from the data using published distribution and anchor based methods.40  Time to 
the first deterioration in overall QoL may also be assessed using survival analysis based 
on pre-specified MID for deterioration based on published information.
8.1.6.3
Performance Status
Analyses of changes from baseline will be performed for each scheduled post-baseline 
visit for ECOG performance status using an analysis of covariance (ANCOVA) model 
with treatment group as the factor and baseline value as a covariate.  Subjects that do not 
have a baseline measurement or do not have any post-baseline measurements will not be 
included.


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8.1.7
Additional Efficacy Analyses
The primary and secondary efficacy endpoints will also be analyzed using all randomized 
subjects' data, regardless whether or not the subject has suspected deleterious or 
deleterious mutation confirmed by the Sponsor core lab.
In addition to the stratified log-rank test for the primary and secondary efficacy endpoints, 
the unstratified log-rank test, Wilcoxon test, and the Cox proportional hazards model may 
be used for the comparison of PFS and overall survival between veliparib 120 mg BID + 
carboplatin + paclitaxel and placebo + carboplatin + paclitaxel.
PFS, ORR, CBR, and duration of overall response based on radiological and clinical 
assessment by the central imaging center will also be analyzed using the same statistical 
methodology as that for the corresponding primary and secondary efficacy endpoints.
For those subjects who take other anti-cancer therapies after discontinuation of the study 
treatment, the primary efficacy and secondary efficacy endpoints of PFS, and overall 
survival will be censored at the date of subject's initiation of other anti-cancer therapies.  
These modified primary and secondary efficacy endpoints will be analyzed using the 
same methodology as detailed in previous sections.
For PFS and OS, additional analyses may also be performed, such as 1) including only 
data and events occurring on treatment or within 30 days of the last dose of study 
treatment, 2) using a Cox proportional hazard model to explore the effect of baseline 
factors including (but not limited to) the following:  ER/PgR status, BRCA1/2 status, prior 
platinum therapy (yes versus no), ECOG performance status, stage of the disease, and 
others, 3) subgroup analysis by ER/PgR status, BRCA1/2 status, prior platinum therapy 
(yes versus no), CNS metastases (yes versus no), ECOG performance status, stage of the 
disease, and others, 4) stratified log-rank test by region (US versus non-US), and ECOG 
performance status (0 to 1 versus 2), and 5) using interval censoring methods to analyze 
PFS.


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Alternative statistical analyses may be performed if deemed necessary and helpful in 
understanding the drug effect.
8.1.8
Interim Analysis
An independent data monitoring committee (IDMC) reviewed the unblinded safety data 
for this veliparib Phase 3 study (including all subjects enrolled in the study) when 
approximately 60 subjects met at least one of the following criteria:
●
Received 6 cycles of treatment
●
Reached an event of disease progression
●
Discontinued the study due to toxicity/adverse events
BRCA status discordances between Sponsor core laboratory and local labs were assessed 
internally at the time of the interim analysis.  Subsequent IDMC reviews of unblinded 
safety data prior to the primary analysis were carried out based on IDMC 
recommendations. No additional reviews by the IDMC will occur since the Sponsor 
management team was unblinded after completing the primary analysis.
An alpha of 0.0001 (the Haybittle-Peto stopping boundary) will be allocated for PFS at 
the interim analysis, although there is no intention to stop the study early for efficacy.  
The final PFS analysis will be tested at one-sided alpha of 0.025.  With this stopping 
boundary, the overall Type 1 error rate is controlled at 0.025 or less.
8.1.9
Safety Assessments
The safety of veliparib + carboplatin + paclitaxel and placebo + carboplatin + paclitaxel 
will be assessed by evaluating study treatment 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 treatment (veliparib 
or placebo) will not be included in the analyses of safety.


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8.1.10
Statistical Analyses of Safety
8.1.10.1
Duration of Study Treatment
A summary of the number of days and/or cycles subjects were exposed to study treatment 
will be provided.
8.1.10.2
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 treatment.
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)37 adverse event coding dictionary.  The percentage of subjects experiencing 
an adverse event at a given severity, NCI CTCAE version 4.0 grade, and relationship to 
study treatment will be provided.  Comparisons of the percentages of subjects 
experiencing an adverse event between veliparib + carboplatin + paclitaxel and placebo + 
carboplatin + paclitaxel will be performed using Fisher's exact test.
8.1.10.3
Serious Adverse Events
Serious adverse events will be summarized using the same methods as adverse events 
described above in Section 8.1.10.2.
8.1.10.4
Deaths
The number of subject deaths will be summarized 1) for deaths occurring while the 
subject was still receiving study treatment in this study, 2) for deaths occurring off 
treatment within 30 days after the last dose of study treatment, and 3) for all deaths in this 
study regardless of the number of days after the last dose of study treatment.


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8.1.10.5
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 treatment 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 
veliparib + carboplatin + paclitaxel and placebo BID + carboplatin + paclitaxel will be 
made using ANOVA with treatment group as the factor.
8.1.10.6
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 treatment, and as the grade of the last post-
baseline measurement collected no more than 30 days after the last dose of study 
treatment.  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 to maximum 
postbaseline grades of 3 to 4, and from baseline grades of 0 to 2 to final postbaseline 
grades of 3 to 4 between veliparib + carboplatin + paclitaxel and placebo + carboplatin + 
paclitaxel will be performed using Fisher's exact tests.
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 treatment, will be included in 
these listings.


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8.1.10.7
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 
treatment, will be included in these listings.
8.1.10.8
Multiplicity Adjustments
If the veliparib treatment group demonstrates statistically significantly better PFS than the 
placebo group, then the secondary endpoints will be tested using the fixed sequence 
testing procedure with the following testing order:  OS, CBR, ORR, and PFS2.
A multiplicity issue is introduced through the multiple testing of the OS endpoint.  It is 
anticipated that, at the analysis time of the primary efficacy endpoint PFS, there will be 
too few death events to support an adequately powered OS analysis.  Therefore, two OS 
analyses are planned, the first one based on the "Primary PFS Analysis" database, and the 
second one based on the "OS Analysis" database with a total of 357 death events.  
Statistical significance for OS will be declared if a significant result is obtained for either 
analysis, consistent with group sequential testing methods.
The Lan DeMets alpha spending function with an O'Brien-Fleming boundary will be used 
to ensure that the one-sided false positive rate will be 0.025 or less for overall survival.  
The exact α level to be used at the first OS analysis will be dependent on the information 
fraction for OS at the time of the 'Primary PFS Analysis'.  This approach is being taken so 
that the majority of the α- level will be withheld until a total of 357 death events have 
occurred.
8.1.10.9
Censoring Dates for Subjects that had the Prematurely 
Blind Broken
For progression free survival analysis, if the subjects does not experience an event of 
disease progression or death (as defined above for PFS endpoint) on or before the date of 


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blind break, the subject's data will be censored at the date of the subject's last available 
disease progression assessment on or before the blind break.
For duration of overall response and clinical benefit rate through the end of Week 24 
(CBR) analyses, if the subject does not experience an event of disease progression on or 
before the date of blind break, the subject's data will be censored at the date of the 
subject's last available disease progression assessment on or before the blind break.
For objective response rate (ORR) analysis, disease progression assessment data after the 
blind break date will not be included.
A blind break performed by AbbVie pharmacovigilance will not be considered a 
premature blind break.
8.2
Determination of Sample Size
Assuming the true hazard ratio in favor of the veliparib + carboplatin + paclitaxel 
treatment group is 0.69 for PFS, a total of 344 PFS events will be needed for the study to 
have at least 90% power at 2-sided α level of 0.05 to detect a statistically significant 
treatment effect for the veliparib + carboplatin + paclitaxel treatment group using the 
log-rank test for PFS.  Assuming the median PFS of 12 months in the placebo arm, a 
hazard ratio of 0.69 would correspond approximately to an increase in median PFS of 
5.5 months under the exponential model assumption. 
In addition, assuming the true hazard ratio in favor of the veliparib 120 mg BID + 
carboplatin + paclitaxel treatment group is 0.714 for OS, a total of 357 death events will 
be needed for the study to have at least 85% power at 2-sided α level of 0.05 to detect a 
statistically significant treatment effect for the veliparib + carboplatin + paclitaxel 
treatment group using the log-rank test for OS.
A total of approximately 500 subjects with a BRCA mutation as documented by the 
Sponsor core laboratory will be enrolled into the study to accrue the anticipated 344 PFS 


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events and 357 death events.  The required number of PFS events has been increased to 
ensure 90% power if true HR is 0.69.  
8.3
Randomization Methods
IVRS/IWRS will be utilized to randomize subjects.  Before the study is initiated 
directions for the IVRS/IWRS will be provided to each site.  The investigational site will 
contact the IVRS/IWRS on or within 2 days prior to the subject's Study Day 1 (C1D-2).  
The randomization numbers will assign subjects in 2:1 ratio to either veliparib + 
carboplatin + paclitaxel, or placebo + carboplatin + paclitaxel.  Subject randomization will 
be stratified by ER and/or PgR positive versus ER/PgR negative, prior platinum therapy 
(yes versus no), and CNS metastases (yes versus no).
One set of 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 IVRS/IWRS vendor.
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, 


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maintain and archive study essential documents according to International Conferences on 
Harmonization (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 
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, 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.
In the event that the COVID-19 pandemic leads to difficulties in performing protocol-
specified procedures, AbbVie will engage with study site personnel in efforts to ensure 
the safety of subjects, maintain protocol compliance, and minimize risks to the integrity of 
the study while trying to best manage subject continuity of care.  This may include 
alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local lab instead of a central lab), and shipping 
investigational product and/or supplies direct to subjects to ensure continuity of treatment 
where allowed.  In all cases, these alternative measures must be allowed by local 
regulations and permitted by IRB/IEC.  Investigators should notify AbbVie if any urgent 
safety measures are taken to protect the subjects against any immediate hazard.
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 


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screening procedures being performed on the subject, the informed consent statement will 
be reviewed, 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.  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.
In the event a subject withdraws consent to participate from the study, stored biomarker 
and exploratory research samples will continue to be used for research and analysis.  In 
the event that a subject would like to withdraw consent for research using these samples, 
the subject may request that their samples be withdrawn.  Once AbbVie receives the 
request, remaining biomarker and exploratory research samples will be destroyed.  If the 
subject changes his/her consent, and the samples have already been tested, those results 
will still remain as part of the overall research data.
An informed consent, approved by an IRB/IEC, must be voluntarily signed and dated 
before samples are collected for optional exploratory research.  The nature of the testing 
should be explained and the subject given an opportunity to ask questions.  The informed 
consent must be signed before the samples are collected and any testing is performed.  If 
the subject does not consent to provide samples for the optional exploratory research, it 
will not impact their participation in the study.
Due to the COVID-19 pandemic, modifications to the protocol may be necessary.  
Subjects should be informed of the changes to the conduct of the study relevant to their 
participation (e.g., cancellation of visits, change in laboratory testing site, drug delivery 
method, etc.).  Documentation of this notification and verbal consent should be 
maintained at the site.  A signed and dated informed consent form should be obtained 
from the subject afterwards as soon as possible, if required by local regulations.


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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 QoL questionnaires (EORTC QLQ-C30/BR23, EQ-5D-5L) will be completed by the 
subject on worksheets and will be considered source data.
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 electronic data capture (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.


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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 
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 
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 trial 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
Prior to enrolling any subject in the study, a Site Initiation Visit will be held with AbbVie 
personnel (and/or their representatives), the Investigators, and the appropriate site 
personnel.  This meeting will include a detailed discussion and review of the protocol and 
essential documents, performance of study procedures, eCRF completion, and specimen 
collection methods.  The personnel at the study site will be trained on the study 
procedures, when applicable, by an AbbVie monitor or designee.
The AbbVie monitor or designee will monitor the study site throughout the study.  A 
source document review will be performed against entries on the eCRFs and a quality 
assurance check will be performed to ensure that the Investigator is complying with the 
protocol and regulations.  In addition, ongoing review of the data will be conducted by a 
physician or representative at AbbVie.


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Data entered into eCRFs will be electronically transferred to AbbVie and imported into 
the database using validated software throughout the study.  Computer logic checks will 
be run to identify such items as inconsistent study dates.  Any necessary corrections will 
be made to the eCRF.
If applicable, data hand-entered directly in the database from paper CRFs or reports will 
be verified by a double-key entry procedure at AbbVie.  Any discrepancies will be 
reviewed against the hard-copy CRF and corrected on-line.  After completion of the entry 
process, computer logic checks will be run to identify such items as inconsistent study 
dates.  Any necessary corrections will be made to the database in the same manner via the 
appropriate change form.
Routine hematology, serum chemistry and serology, and urinalysis will be conducted 
using a central laboratory.  The data from these analyses will be electronically transferred 
from the central laboratory to the study database.
A review of all laboratory results will be conducted by a physician and clinical review 
team at AbbVie, the AbbVie monitors (or their representatives), the Investigator, and 
other appropriate personnel from AbbVie.
12.0
Use of Information
Any research that may be done using optional exploratory research samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision-making or subject management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, 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.  Data from optional exploratory research may be 
provided to investigators and used in scientific publications or presented at medical 
conventions.  Optional exploratory research information will be published or presented 
only in a way that does not identify any individual subject.


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12.1
Publication
The Investigators have the right to publish the results of the study, but with due regard to 
the protection of confidential information.  Accordingly, AbbVie shall have the right to 
review and approve any paper for publication, including oral presentation and abstracts, 
which utilize data generated from this study.  At least 60 days before any such paper or 
abstract is presented or submitted for publication, a complete copy shall be given to 
AbbVie for review.  AbbVie shall review any such paper or abstract and give its 
comments to the author(s) promptly.  The Investigator shall comply with AbbVie's 
confidential information in any such paper and agrees to withhold publication of same for 
an additional 60 days in order to permit AbbVie to obtain patent or other proprietary 
rights protection, if AbbVie deems it necessary.
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.


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The end-of-study is defined as the date of the last subject's last visit.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for veliparib (ABT-888).
2.
I have received and reviewed the locally approved product label or applicable 
Summary of Product Characteristics for carboplatin, and paclitaxel.
3.
I have read this protocol and agree that the study is ethical.
4.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
5.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
Protocol Title:
A Phase 3 Randomized, Placebo-Controlled Trial of Carboplatin and 
Paclitaxel With or Without the PARP Inhibitor Veliparib (ABT-888) 
in HER2-Negative Metastatic or Locally Advanced Unresectable 
BRCA-Associated Breast Cancer
Protocol Date:
23 July 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
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Garcia M, Jemal A, Ward EM, et al.  Global Cancer Facts and Figures 2007.  
Atlanta, GA:  American Cancer Society; 2007.
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American Cancer Society.  Cancer Facts and Figures 2008.  Atlanta, GA:  
American Cancer Society; 2008.
3.
Ferlay U, Parkin DM, Steliarova-Foucher E.  Estimates of cancer incidence and 
mortality in Europe in 2008.  Eur J Canc.  2010;46:765-81.
4.
Peto J, Collins N, Barfoot R, et al.  Prevalence of BRCA1 and BRCA2 gene 
mutations in patients with early-onset breast cancer.  J Natl Cancer Inst.  
1999;91(11):943-9.
5.
National Cancer Institute (NCI).  Breast cancer treatment (PDR):  health 
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Farmer H, McCabe N, Lord CJ, et al.  Targeting the DNA repair defect in BRCA 
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Plummer ER, Calvert H.  Targeting poly(ADP-ribose) polymerase:  a two-armed 
strategy for cancer therapy.  Clin Cancer Res.  2007;13(21):6252-6.
8.
Honrado E, Benítez J, Palacios J.  Histopathology of BRCA1- and BRCA2 
associated breast cancer.  Critical Rev Oncol Hematol.  2006;59(1):27-39.  Epub 
2006 Mar 10.
9.
Cleator S, Heller W, Coombes RC.  Triple-negative breast cancer:  therapeutic 
options.  Lancet Oncology.  2007;8(3):235-44.
10.
Schneider BP, Winer EP, Foulkes WD, et al.  Triple-negative breast cancer:  risk 
factors to potential targets.  Clin Cancer Res.  2008;14(24):8010-8.


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11.
Lakhani SR, Van De Vijver MJ, Jacquemier J, et al.  The pathology of familial 
breast cancer:  predictive value of immunohistochemical markers estrogen receptor, 
progesterone receptor; HER-2, and p53 in patients with mutations in BRCA1 and 
BRCA2.  J Clin Oncol.  2002;20(9):2310-8.
12.
Romond EH, Perez EA, Bryant J, et al.  Trastuzumab plus adjuvant chemotherapy 
for operable HER2-positive breast cancer.  N Engl J Med.  2005;353(16):1673-84.
13.
Slamon DJ, Leyland-Jones B, Shak S, et al.  Use of chemotherapy plus a 
monoclonal antibody against HER2 for metastatic breast cancer that overexpresses 
HER2.  New Engl J Med.  2001;344(11):783-92.
14.
Decatris MP, Sundar S, O'Byrne KJ.  Platinum-based chemotherapy in metastatic 
breast cancer:  current status.  Cancer Treat Rev.  2005;4:53-81.
15.
Byrski T, Huzarski T, Dent R, et al.  Response to neoadjuvant therapy with 
cisplatin in BRCA1-positive breast cancer patients.  Breast Cancer Res Treat.  
2009;115:359-63.
16.
Gronwald J, Byrski T, Huzarski T, et al.  Neoadjuvant therapy with cisplatin in 
BRCA1-positive breast cancer patients [abstract].  J Clin Oncol.  
2009;27(18Suppl):502.
17.
Byrski T, Gronwald J, Huzarski T, et al.  Pathologic complete response rates in 
young women with BRCA1-positive breast cancers after neoadjuvant 
chemotherapy.  J Clin Oncol.  2010;28:375-9.
18.
Tutt A, Ellis P, Kilburn L, et al.  The TNT trial:  a randomized phase III trial of 
carboplatin (C) compared with docetaxel (D) for patients with metastatic or 
recurrent locally advanced triple negative or BRCA1/2 breast cancer 
(CRUK/07/012).  Oral Presentation at:  San Antonio Breast Cancer Symposium; 
December 9-13, 2014; San Antonio, TX.  Oral Presentation S3-01.
19.
Belani CP, Kearns CM, Zuhowski EG, et al.  Phase 1 trial, including 
pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and 
carboplatin in patients with metastatic non-small-cell lung cancer.  J Clin Oncol.  
1999,19(2):676-84.


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20.
Chiarugi A.  Poly(ADP-ribose) polymerase:  killer or conspirator?  The 'suicide 
hypothesis' revisited.  Trends Pharmacol Sci.  2002;23(3):122-9.
21.
Virág L, Szabó C.  The therapeutic potential of poly(ADP-Ribose) polymerase 
inhibitors.  Pharmacol Rev.  2002;54(3):375-429.
22.
Sharpless NE, DePinho RA.  Telomeres, stem cells, senescence, and cancer.  J Clin 
Invest.  2004;113(2):160-8.
23.
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.
24.
Bryant HE, Schultz N, Thomas HD, et al.  Specific killing of BRCA2-deficient 
tumours with inhibitors of poly(ADP-ribose) polymerase.  Nature.  
2005;434(7035):913-7.
25.
Puhalla SL, Appleman LJ, Beumer JH, et al.  Two phase I trials exploring different 
dosing schedules of carboplatin (C), paclitaxel (P), and the poly-ADP-ribose 
polymerase (PARP) inhibitor, veliparib (ABT-888) (V) with activity in triple 
negative breast cancer (TNBC).  Cancer Res.  2012;72(24 Suppl):PD09-06.
26.
Tutt A, Robson M, Garber JE, et al.  Oral poly(ADP ribose) polymerase inhibitor 
olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer:  
a proof-of concept trial.  Lancet.  2010;376(9737):235-44.
27.
Audeh MW, Carmichael J, Penson RT, et al.  Oral poly(ADP-ribose) polymerase 
inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent 
ovarian cancer:  a proof-of-concept trial.  Lancet.  2010;376(973):245-51.
28.
Langer CJ, Leighton JC, Comis RL, et al.  Paclitaxel and carboplatin in 
combination in the treatment of advanced non-small cell lung cancer:  a phase II 
toxicity, response, and survival analysis.  J Clin Oncol.  1995;13(8):1860-70.
29.
Appleman LJ, Beumer JH, Jiang Y, et al.  A phase 1 study of veliparib (ABT-888) 
in combination with carboplatin and paclitaxel in advanced solid malignancies.  J 
Clin Onc.  2012;30(suppl);abstr 3049.


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30.
Rodler ET, Specht JM, Gadi VK, et al.  Phase I study of PARP inhibitor ABT-888 
(Veliparib) in combination with cisplatin and vinorelbine for patients with 
advanced triple negative breast cancer and/or BRCA-mutation associated breast 
cancer.  Cancer Res.  2011;71(24s):SABCS Meeting Abstract P1-17-04.
31.
Basch E, Prestrud AA, Hesketh PJ, et al.  Antiemetics:  American Society of 
Clinical Oncology practice guideline update.  J Clin Oncol.  2011;29(31):4189-98.
32.
National Comprehensive Cancer Network.  NCCN clinical practice guidelines in 
oncology:  genetic/familial high-risk assessment:  breast and ovarian, version 2.  
2016.
33.
Eisenhauer EA, Therasse P, Bogaerts B, et al.  New response evaluation criteria in 
solid tumors:  Revised RECIST guideline version 1.1.  Eur J Cancer.  
2009;45(2):228-47.
34.
Sprangers MA, Groenvold M, Arraras JI, et al:  The EORTC breast cancer-specific 
quality-of-life questionnaire module:  First results from a three-country field study.  
J Clin Oncol.  1996;14(10):2756-2768.
35.
Rabin R, de Charro F.  EQ-5D:  a measure of health status from the EuroQol Group 
Ann Med.  2001;33(5):337-43.  Erasmus University Rotterdam, Centre for Health 
Policy and Law
36.
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
Published:  May 28, 2009 (v4.03:  June 14, 2010).  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
Accessed on:  2016 April 26.
37.
Coding Guidelines for MedDRA Term Selection, AbbVie Global Pharmaceutical 
Research and Development (GPRD), Global Pharmacovigilance and Clinical 
Project Team, current version on file at AbbVie.
38.
AbbVie.  Information for Clinical Investigators (Clinical Brochure) for ABT-888 
(A-861695), Edition 8.  13 June 2014.
39.
Cleeland C.  Brief Pain Inventory User Guide.  Houston:  University of Texas M. 
D. Anderson Cancer Center; 2009.


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40.
Revicki D, Hays RD, Cella D, Sloan J.  Recommended methods for determining 
responsiveness and minimally important differences for patient-reported outcomes.  
J Clin Epidemiol.  2008;61(2):102-109.
41.
American Society of Clinical Oncology; College of American Pathologists.  
ASCO-CAP HER2 Test Guideline Recommendations.  Summary of Guideline 
2007 and 2013 Recommendations.  2013.


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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
Statistics
Clinical
Clinical
Clinical
Pharmacokinetics


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Appendix C.
Study Activities for Blinded Study Treatment (Veliparib/Placebo + Paclitaxel + Carboplatin)
Activity
Screening
C1D-2
C1D1
C1D8a
C1D15a
Day 1 of 
Subsequent 
Cyclest
Days 8 and 15 
of Subsequent 
Cyclesa
Every 
12 Weeksl
Informed Consentb
X
Medical and Cancer History
X
Physical Exam (including weight)
Xc
Xd
X
X
12-lead ECG
X
Xe
Vital Signs
X
X
X
X
X
X
X
Pregnancy Test (women of 
childbearing potential)f
X
X
Hematology/Chemistryg,h
X
Xi
X
X
X
X
X
Urinalysisg
X
X
APTT/INRj
X
BRCA1 and 2 germline mutation 
testing
Xk
Tumor Assessmentl
Xm
X
Full Body Bone Scan
Xn
Performance Status (ECOG)
X
X
X
QLQ C30, BR23, EQ 5D 5L 
Questionnaires
Xo
Xp
BPI-SF Questionnaire
Xo
X
AE Assessment
X
X
X
X
X
X
Randomization
X
Dispense veliparib or placebo
Xq
X
Xq


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Activity
Screening
C1D-2
C1D1
C1D8a
C1D15a
Day 1 of 
Subsequent 
Cyclest
Days 8 and 15 
of Subsequent 
Cyclesa
Every 
12 Weeksl
Administer paclitaxel 
premedicationr
X
X
X
X
X
Administer carboplatin
Xs
Xs
Administer paclitaxel
Xs
X
X
Xs
X
a.
If a subject discontinues paclitaxel on Day 8 and/or Day 15, the study visit and assessments for that specific day can be omitted.
b.
Must be performed prior to the initiation of any screening or study-specific procedures.
c.
Height will be recorded at Screening Visit only.
d.
Physical exam not required, if performed within 7 days prior to C1D-2, unless clinically indicated.
e.
ECG must be obtained one hour after dosing with veliparib/placebo and prior to the paclitaxel or carboplatin infusions.
f.
Pregnancy tests must be completed and confirmed as not indicative of pregnancy prior to randomization (within 24 hours) and may be repeated during the study according 
country requirements.
g.
Refer to Table 4 for detailed list of tests to be performed and frequency.
h.
For Day 1 visits, study samples for central laboratory analysis may be performed within 72 hours prior to dosing. For Day 8 and Day 15 visits, study samples for central 
laboratory analysis may be performed within 24 hours of the scheduled day.  There is no visit window for C1D-2 as any sample prior to randomization is still considered to be 
screening.  A qualified (e.g., certification or accreditation) local laboratory may be used to perform laboratory analyses for treatment decisions but this cannot replace the 
central laboratory analysis on a protocol defined visit, unless AbbVie removes the requirements for sites to send clinical laboratory samples to the central laboratory or under 
special situations (i.e., pandemic) that are approved by the Sponsor and allowed as per local regulation.
i.
For Screening labs performed greater than 7 days prior to C1D-2, hematology/chemistry should be split (and sent to central lab) at C1D-2 and local labs reviewed prior to 
dosing.
j.
For subjects on prophylactic or therapeutic anticoagulation with warfarin, INR should be monitored before each treatment.  Treatment should be held for INR of > 1.5 × ULN 
on prophylactic warfarin or > therapeutic range if on full dose warfarin.
k.
BRCA1 and BRCA2 germline mutation testing will be collected on all subjects even if Sponsor core laboratory testing was performed prior to screening.


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l.
Tumor assessments to support evidence of PD for PFS endpoint were conducted every 9 weeks until PD, death or withdrawal of consent for follow-up until PD. Following 
the primary analysis and implementation of Protocol Amendment 4, the tumor assessment interval may be increased to every 12 weeks (tumor assessments may be conducted 
± 10 business days following the scheduled assessment from last scan). At the investigator's discretion, the interval between scans may be longer than every 12 weeks for 
subjects who have durable disease control but must not exceed 24 weeks.
m.
The baseline tumor assessment, including diagnostic CT scans of the chest, abdomen, and pelvis, and brain MRI or contrast CT will be obtained no more than 28 days prior to 
randomization.
n.
Full body bone scan will be obtained no more than 28 days prior to randomization with subsequent bone scans to be obtained as clinically indicated.
o.
Should be completed on C1D-2 prior to dosing.
p.
QLQ C30, BR23, EQ 5D 5L questionnaires will be administered every other cycle prior to dosing beginning with Cycle 2 (C2, C4, C6, etc.).
q.
Sufficient medication will be dispensed to cover the entire cycle.  The site is advised to contact the subject on the morning of Day –2 to reiterate the dosing instructions of 
veliparib/placebo.  It is recommended the site contact the subject on Day 5 to instruct about ceasing dosing.
r.
The US paclitaxel package insert recommends a premedication regimen, such as dexamethasone 20 mg PO administered approximately 12 and 6 hours before paclitaxel, 
diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel.
s.
Carboplatin and paclitaxel are to be given only after veliparib/placebo dosing on cycle Day –2 and Day –1 are confirmed.
t.
For subjects who have been receiving single-agent veliparib/placebo at a stable dose without adjustments for multiple cycles and who have no ongoing study drug related 
uncontrolled AEs, it is possible to alternate on-site visits and phone visits every other cycle.  Study procedures for phone visits are detailed in the Appendix F.
Note:
Study procedures (excluding labs and tumor assessments) may be performed four (4) business days prior to the scheduled study visit date.  C1D1 procedures may be 
performed within 24 hours surrounding the scheduled study visit.


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Appendix D.
Study Activities for Unblinded Veliparib Monotherapy (Crossover Treatment)
Note: The following schedule of assessments should be followed for subjects who crossed over (were previously randomized to 
placebo, discontinued study treatment because of disease progression and received Sponsor approval for crossover treatment).
Activity
C1D1
C1D15g
Day 1 of Each Cycle 
Starting with C2i
Every 9 Weeks 
from C1D1c
Physical Exam (including weight)
X
X
X
12-lead ECG
Xf
Vital Signs
X
X
X
Pregnancy Test (women of childbearing potential)h
Hematology/Chemistrya,b
X
X
X
Urinalysisa
X
Tumor Assessmentc
Xd
X
Performance Status (ECOG)
X
X
QLQ C30, BR23, EQ 5D 5L Questionnaires
X
Xe
BPI-SF Questionnaire
X
X
AE Assessment
X
X
X
Dispense veliparib
X
X
a.
Refer to Table 4 for detailed list of tests to be performed and frequency.
b.
Study samples for central laboratory analysis may be performed within 72 hours of the scheduled day.  A qualified (e.g., certification or accreditation) local laboratory may be 
used to perform laboratory analyses for treatment decisions but this cannot replace the central laboratory analysis on a protocol defined visit, unless AbbVie removes the 
requirements for sites to send clinical laboratory samples to the central laboratory or under special situations (i.e., pandemic) that are approved by the Sponsor and allowed as 
per local regulation.


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c.
Tumor assessments will be conducted every 9 weeks (± 5 business days from the scheduled C1D1 assessment. Following the primary analysis and implementation of 
Protocol Amendment 4, if a crossover subject has disease control after 6 scans while following the 9 week scan interval schedule, the tumor assessment frequency can be 
changed to every 12 weeks from last scan (± 10 business days). At the investigator's discretion, the interval between scans may be longer than every 12 weeks for subjects 
who have durable disease control but must not exceed 24 weeks.
d.
To be performed if a tumor assessment has not been performed within 4 weeks.
e.
QLQ C30, BR23, EQ 5D 5L questionnaires will be administered every other cycle prior to dosing beginning with Cycle 2 (C2, C4, C6 etc.).
f.
ECG must be obtained 1 hour after dosing with veliparib.
g.
If the subject tolerates 300 mg BID for 2 weeks veliparib may be increased to 400 mg BID at the investigator's discretion.
h.
Pregnancy tests may be repeated during the study according country requirements.
i.
For subjects who have been receiving veliparib monotherapy at a stable dose without adjustments for multiple cycles and who have no ongoing study drug related 
uncontrolled AEs, it is possible to alternate on-site visits and phone visits every other cycle. Study procedures for phone visits are detailed in the Appendix F.
Notes:
Study procedures (excluding labs and tumor assessments) may be performed four (4) business days prior to the scheduled study visit date. C1D1 procedures may be 
performed within 24 hours surrounding the scheduled study visit.


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Appendix E.
Study Activities for Post Treatment Phase
Discontinuation of Therapy
(all subjects)
Discontinuation of therapy
without disease progression 
(on study, off drug)a,b,d
Activity
Final Visita
30-Day 
Follow-Up 
Visitb
Post 
Treatment 
Follow-Up
Every 12 weeks from last 
scane
Physical Exam
(including weight)d
X
X
12-lead ECG
X
Vital Signsd
X
X
Hematology/Chemistryd
X
X
Urinalysisd
X
Tumor Assessment
Xe
Performance Status (ECOG)
X
X
QLQ C30, BR23, EQ 5D 5L, 
BPI-SF Questionnaires
X
X
AE Assessmentd
X
X
Survivalc
X
X
a.
When a subject discontinues the blinded or unblinded study treatment, a Final Visit will be conducted.
b.
All subjects will have one Follow-up Visit approximately 30 days after the last dose of study drug.  This Follow-up 
Visit does not need to be performed for subjects who have had a Final Visit conducted ≥30 days after the last dose 
of study drug or for subjects who are entering unblinded veliparib monotherapy treatment.  Follow-up visits should 
not precede a Final Visit.
c.
If a subject meets criteria for discontinuation of therapy, survival and post treatment therapy will be collected every 
two months (unless requested by sponsor more frequently to support data analysis) beginning on the date the 
subject discontinues therapy.  All randomized subjects should be followed for disease progression (PFS) and for 
the second progression (PFS2), until the endpoint of death (OS), until the subject has become lost to follow-up, or 
until study termination by AbbVie.
d.
Refer to Table 4 for detailed list of tests to be performed and frequency.  Laboratory assessments, physical 
examinations and vital signs will only be completed for AE follow-up or reported SAEs after the 30-day follow-up 
visit per Section 6.1.5.
e.
Tumor assessments to support evidence of PD for PFS endpoint were conducted every 9 weeks until PD, death or 
withdrawal of consent for follow-up until PD. Following the primary analysis and implementation of Protocol 
Amendment 4, the tumor assessment interval may be increased to every 12 weeks (tumor assessments may be
conducted ± 10 business days following the scheduled assessment from last scan). At the investigator's discretion, 
the interval between scans may be longer than every 12 weeks for subjects who have durable disease control, but 
must not exceed 24 weeks.
Note:
Study procedures (excluding labs and tumor assessments) may be performed four (4) business days prior to 
the scheduled study visit date.


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Appendix F.
Study Activities for Blinded or Unblinded Study Treatment Phone 
Visit
Activity
Day 1 Phone Visita
Performance Status (ECOG)
X
QLQ C30, BR23, EQ 5D 5L Questionnairesb
Xc
BPI-SF Questionnaireb
X
AE and Concomitant Medication Assessment
Xd
Treatment Compliance Assessment
Xd
Disease Progression Assessment
Xd
Dispense Veliparib or Placeboe
X
a.
For subjects who have been receiving single-agent veliparib/placebo at a stable dose without adjustments for 
multiple cycles and who have no ongoing study drug related uncontrolled AEs, it is possible to alternate on-site 
visits and phone visits by the investigator or designee every other cycle.  At a minimum, subjects should have an 
on-site visit every other cycle. If an on-site visit is not possible for 2 consecutive cycles, or if the subject is not on 
a stable dose or has ongoing study drug related uncontrolled AEs but wishes to alternate on-site and phone visits, 
the plan for the subject's visits should be discussed with the AbbVie TA MD (see Section 7.0 for contact 
information).
b.
During the on-site visits the Investigator or designee will provide the PRO Questionnaires (QLQ C30, BR23, EQ 
5D 5L and BPI-SF) for the next cycle to the subject, so these can be completed at home.
c.
QLQ C30, BR23, EQ 5D 5L questionnaires will be administered every other cycle prior to dosing beginning with 
Cycle 2 (C2, C4, C6, etc.).  If questionnaires were completed during an on-site visit, they may not be required at 
the subsequent phone visit.
d.
In addition to assessing AEs and Concomitant Therapies, the investigator or designee should assess treatment 
compliance and to the extent possible, assess for any clinical evidence of disease progression.  If there are concerns 
about new or worsening AEs or if there is suspicion of disease progression, an unscheduled on-site visit, local labs,
and/or tumor assessment should be scheduled.
e.
During the on-site visits, the Investigator or designee will dispense medication for 2 cycles via IRT and the double 
amount of Dosing Cards, so subjects can complete them for both cycles.
Note:
Phone visit may be performed four (4) business days prior or after the scheduled study visit date.


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Appendix G.
EORTC QLQ-C30


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Appendix H.
EORTC QLQ - BR23
Patients sometimes report that they have the following symptoms or problems.  Please 
indicate the extent to which you have experienced these symptoms or problems during the 
past week.
During the past week:
Not at All
A Little
Quite a Bit
Very Much
31.
Did you have a dry mouth?
1
2
3
4
32.
Did food and drink taste different than 
usual?
1
2
3
4
33.
Were your eyes painful, irritated or 
watery?
1
2
3
4
34.
Have you lost any hair?
1
2
3
4
35.
Answer this question only if you had 
any hair loss:  Were you upset by the 
loss of your hair?
1
2
3
4
36.
Did you feel ill or unwell?
1
2
3
4
37.
Did you have hot flushes?
1
2
3
4
38.
Did you have headaches?
1
2
3
4
39.
Have you felt physically less attractive 
as a result of your disease or 
treatment?
1
2
3
4
During the past four weeks:
Not at All
A Little
Quite a Bit
Very Much
40.
Have you been feeling less feminine 
as a result of your disease or 
treatment?
1
2
3
4
41.
Did you find it difficult to look at 
yourself naked?
1
2
3
4
42.
Have you been dissatisfied with your 
body?
1
2
3
4
43.
Were you worried about your health in 
the future?
1
2
3
4


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During the past four weeks:
Not at All
A Little
Quite a Bit
Very Much
44.
To what extent were you interested in 
sex?
1
2
3
4
45.
To what extent were you sexually 
active? (with or without intercourse)
1
2
3
4
46.
Answer this question only if you have 
been sexually active:  To what extent 
was sex enjoyable for you?
1
2
3
4
During the past week:
Not at All
A Little
Quite a Bit
Very Much
47.
Did you have any pain in your arm or 
shoulder?
1
2
3
4
48.
Did you have a swollen arm or hand?
1
2
3
4
49.
Was it difficult to raise your arm or 
to move it sideways?
1
2
3
4
50.
Have you had any pain in the area of 
your affected breast?
1
2
3
4
51.
Was the area of your affected breast 
swollen?
1
2
3
4
52.
Was the area of your affected breast 
oversensitive?
1
2
3
4
53.
Have you had skin problems on or in 
the area of your affected breast (e.g., 
itchy, dry, flaky)?
1
2
3
4
© Copyright 1994 EORTC Quality of Life Group.  All rights reserved.  Version 1.0


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Appendix I.
EQ-5D 5L Health Questionnaire
EQ-5D-5L
Health Questionnaire
(English version for the US)
© EuroQoL Group 2009


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Under each heading, please check the ONE box that best describes your health TODAY
Mobility
I have no problems walking
☐
I have slight problems walking
☐
I have moderate problems walking
☐
I have severe problems walking
☐
I am unable to walk
☐
Self-Care
I have no problems washing or dressing myself
☐
I have slight problems washing or dressing myself
☐
I have moderate problems washing or dressing myself
☐
I have severe problems washing or dressing myself
☐
I am unable to wash or dress myself
☐
Usual Activities (e.g., work, study, housework, family or leisure activities)
I have no problems doing my usual activities
☐
I have slight problems doing my usual activities
☐
I have moderate problems doing my usual activities
☐
I have severe problems doing my usual activities
☐
I am unable to do my usual activities
☐
Pain/Discomfort
I have no pain or discomfort
☐
I have slight pain or discomfort
☐
I have moderate pain or discomfort
☐
I have severe pain or discomfort
☐
I have extreme pain or discomfort
☐
Anxiety/Depression
I am not anxious or depressed
☐
I am slightly anxious or depressed
☐
I am moderately anxious or depressed
☐
I am severely anxious or depressed
☐
I am extremely anxious or depressed
☐


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!
We would like to know how good or bad your health is 
TODAY.
!
This scale is numbered from 0 to 100.
!
100 means the best health you can imagine.
0 means the worst health you can imagine.
!
Mark an X on the scale to indicate how your health is 
TODAY.
!
Now, please write the number you marked on the scale 
in the box below.
YOUR HEALTH TODAY = 


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Appendix J.
Brief Pain Inventory – Short Form


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Appendix K.
ASCO-CAP HER2 Test Guideline Recommendations
ASCO-CAP HER2 Test Guideline Recommendations41
Topic
2013 Recommendations
Optimal algorithm for 
HER2 testing
Must report a HER2 test result as negative if a single test (or both tests) 
performed show:
1.
IHC 1+ as defined by incomplete membrane staining that is 
faint/barely perceptible and within >10% of the invasive tumor cells 
2.
IHC 0 as defined by no staining observed or membrane staining that 
is incomplete and is faint/barely perceptible and within ≤ 10% of the 
invasive tumor cells
3.
ISH negative based on:
o
Single-probe average HER2 copy number < 4.0 signals/cell
o
Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 
copy number < 4.0 signals/cell
Source:
American Society of Clinical Oncology; College of American Pathologists.  ASCO-CAP HER2 Test 
Guideline Recommendations.  Summary of Guideline 2007 and 2013 Recommendations.  2013.


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Appendix L.
General Chemotherapy Guidelines
●
A patient will be permitted to have a new cycle of chemotherapy delayed up to 
7 days (without this being considered to be a protocol violation) for major life 
events (e.g., serious illness in a family member, major holiday, vacation which 
is unable to be re-scheduled).  Documentation to justify this decision should be 
provided. 
●
It will be acceptable for individual chemotherapy doses to be delivered within 
a 24-hour window before and after the protocol-defined date for Day 1 
treatment.  If the treatment due date is a Friday, and the patient cannot be 
treated on that Friday, then the window for treatment would include the 
Thursday (1 day earlier than due) through the Monday (Day 3 past due). 
●
For weekly regimens, it will be acceptable for individual chemotherapy doses 
to be delivered within a "24-hour window" for scheduling conflicts; for 
example:  "Day 8 chemotherapy" can be delivered on Day 7, Day 8, or Day 9 
and "Day 15 chemotherapy" can be given on Day 14, Day 15, or Day 16.
●
Chemotherapy doses can be "rounded" according to institutional standards 
without being considered a protocol violation (most institutions use a rule of 
approximately ± 5% of the calculated dose).
●
Chemotherapy doses are required to be recalculated if the patient has a weight 
change of greater than or equal to 10%.  Subjects are permitted to have 
chemotherapy doses recalculated for < 10% weight changes.




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Protocol Title:  A Phase 3 Randomized Placebo-Controlled Trial of Carboplatin and Paclitaxel With or 
Without the PARP Inhibitor Veliparib (ABT-888) in HER2-Negative Metastatic or Locally Advanced 
Unresectable BRCA-Associated Breast Cancer
Objectives:  The primary endpoint is to assess the progression-free survival (PFS) of veliparib in 
combination with carboplatin (C) and paclitaxel (P) compared to placebo with C/P in subjects with a 
BRCA1 and/or BRCA2 Mutation and HER2-Negative Metastatic or Locally Advanced Unresectable 
Breast Cancer.
The secondary objectives of the study are to assess overall survival (OS), clinical benefit rate (CBR), 
objective response rate (ORR), PFS2 and duration of overall response (DOR) in subjects treated with 
veliparib in combination with C/P versus subjects treated with placebo with C/P.  The tertiary objectives 
are to assess change in ECOG performance status, change in Quality of Life (QoL).
Study Sites:  Multicenter; Approximately 200
Study Population:  Men and women ≥ 18 years of age with HER2-negative metastatic or locally 
advanced unresectable breast cancer and clinically significant (suspected deleterious or deleterious) 
BRCA1 and/or BRCA2 germline mutation.  Patients with bone-only disease and/or hormone receptor 
positive (ER and/or PR) disease should be deemed appropriate candidates for combination chemotherapy.
Number of Subjects to be Enrolled:  Approximately 500
Methodology:
This is a Phase 3, randomized, double-blinded study to evaluate the efficacy and tolerability of veliparib 
in combination with C/P compared to placebo plus C/P in subjects with BRCA1 or BRCA2 germline 
mutation and with HER2-negative metastatic or locally advanced unresectable breast cancer who have 
received no more than 2 prior lines of cytotoxic therapy for metastatic disease.
Veliparib/placebo will be dosed in combination with carboplatin AUC 6 with weekly paclitaxel 
(80 mg/m2), on a 21-day cycle.  Subject randomization will be in a 2:1 ratio to veliparib/C/P or 
placebo/C/P and stratified by estrogen receptor (ER) and/or progesterone receptor (PgR) positive versus 
ER/PgR negative, prior platinum therapy (yes versus no), and CNS metastases (yes versus no).
Subjects with BRCA1/BRCA2 mutation per local lab testing and who meet the remaining eligibility 
criteria may be randomized.  Patients who meet NCCN guidelines for BRCA1/BRCA2 testing are eligible 
for testing during the screening period.  BRCA mutation status will be documented for all patients by the 
central laboratory (Myriad).
Subjects who discontinue carboplatin and paclitaxel and who have not progressed will continue 
veliparib/placebo as a single agent at the recommended Phase 2 single agent dose.  Subjects will continue 
dosing until they meet the defined treatment discontinuation criteria.  Subjects who discontinue 
carboplatin, paclitaxel, and veliparib/placebo for reasons other than progression should remain on study.  
At the time PD is documented according to RECIST 1.1, subjects randomized to placebo may be eligible 
to crossover to unblinded veliparib monotherapy.


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Methodology (Continued):
Tumor assessments (CT scan or MRI of the full chest, abdomen, pelvis and brain MRI or contrast CT) 
will be performed at screening and then every 9 weeks from C1D-2 until tumor progression to determine 
the extent of tumor burden per RECIST 1.1 (post-baseline brain MRI or contrast CT is only required in 
subjects with CNS lesions at baseline; in all other subjects, CNS imaging will be obtained as clinically 
indicated based upon symptoms indicative of CNS disease).  In addition to being reviewed by the 
investigator and/or site staff, radiographic scans will be sent to a central imaging center for review.  
Subjects who discontinue study treatment prior to disease progression should remain on study and 
continue to undergo a modified schedule of assessments until disease progression per RECIST 1.1.  For 
subjects who meet study discontinuation criteria and who have not progressed (such as patients who 
initiate another anti-cancer therapy), tumor assessment data per RECIST 1.1 will continue to be collected 
to document tumor status and the date of progression.  Post treatment information (including dates and 
response to subsequent therapies) and survival information will be collected every two months beginning 
on the date the subject is registered as off study until the endpoint of death, the subject is lost to follow-
up or until the study termination by AbbVie.
QoL assessment via the EORTC QLQ-C30/BR23 and EQ-5D-5L questionnaires will be collected on 
C1D-2 pre-dose, Day 1 of Cycle 2 and every other cycle thereafter beginning with Cycle 4 (C6, C8, etc.), 
Final Visit, and 30-Day Follow-Up Visit.  Subjects who crossover to the unblinded veliparib 
monotherapy arm will continue to have QoL assessments performed as per this schedule (Day 1 of the 
first and second cycle of unblinded monotherapy and every other cycle thereafter beginning with Cycle 4 
until 2nd disease progression or until they meet the defined study treatment discontinuation criteria and at 
the Final Visit and 30-Day Follow-Up Visit).  Pain assessment via the BPI-SF will be collected at every 
cycle.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Men and women ≥ 18 years of age.
2.
Histologically or cytologically confirmed breast cancer that is either locally advanced or metastatic. 
!
Locally advanced breast cancer must not be primarily amenable to surgical resection or radiation 
with curative intent.
!
Patients with bone-only disease and/or hormone receptor positive disease should be deemed by 
the investigator as appropriate candidates for combination chemotherapy.
3.
Suspected deleterious or deleterious BRCA1 and/or BRCA2 germline mutation.
The investigator should ensure that the testing is consistent with local guidelines, and clinical 
practice, and that the test uses either 1) direct DNA sequencing/multiplex ligation-dependent probe 
amplification (MLPA) or 2) a well-characterized methodology previously validated by sequencing, 
such as that used to assess founder mutations.  If testing has been performed prior to Study M12-914, 
subjects may be enrolled but must be re-tested by the Sponsor core laboratory for documentation of 
BRCA1 or BRCA2 germline mutations.
Subjects with BRCA variants of uncertain significance or polymorphisms in BRCA1 or BRCA2 will 
not be eligible for the study.
4.
Breast cancer must be HER2-negative, defined as IHC 0 – 1+ OR HER2-neu negative according to 
ASCO-CAP guideline recommendations.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
5.
Measurable or non-measurable (but radiologically evaluable) disease per RECIST version 1.1 on 
computed tomography (CT) scan (within 28 days of randomization) with at least one lesion outside 
previously irradiated areas.
6.
ECOG Performance status of 0 to 2.
7.
Subject is able to swallow and retain oral medication and does not have uncontrolled emesis.
8.
Adequate hematologic, renal, and hepatic function as follows (within 28 days of randomization):
•
Bone Marrow:  Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 × 109/L); Platelets 
≥100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.5 g/dL (5.89 mmol/L);
•
Renal Function:  Serum creatinine ≤ 1.5 × upper limit of normal (ULN) range OR creatinine 
clearance ≥ 50 mL/min/1.73 m2 (according to local assessment method) for subjects with 
creatinine levels above institutional normal;
•
Hepatic Function:  Aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal; alanine 
transaminase (ALT) ≤ 2.5 × upper limit of normal; bilirubin ≤ 1.5 × the ULN range.  For 
subjects with liver metastases, AST < 5 × ULN range; ALT < 5 × ULN range.  Subjects with 
Gilbert's Syndrome may have a bilirubin ≥ 1.5 × the ULN range if no evidence of biliary 
obstruction exists;
•
Activated Partial Thromboplastin Time (APTT) must be ≤ 1.5 × the ULN range and 
international normalized ratio (INR) < 1.5.  Subjects on anticoagulant therapy will have an 
appropriate APTT and INR as determined by the investigator.
9.
Women of childbearing potential and men must agree to use adequate contraception (one of the 
following listed below) prior to study entry, for the duration of study participation, and for 6 months 
following completion of therapy.  Women of childbearing potential must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test prior to randomization.  To be 
considered of non-childbearing potential, postmenopausal women must be amenorrheic for at least 
12 months or subjects must be surgically sterile.
!
Total abstinence from sexual intercourse (abstinence is only acceptable as a contraceptive 
method if it is established as the subject's preferred and usual lifestyle);
!
Vasectomized male subjects or vasectomized partner of female subjects;
!
Double-barrier method (condoms, contraceptive sponge, diaphragm, or vaginal ring with 
spermicidal jellies or cream); or
!
Intra-Uterine Device (IUD).
!
Additionally, male subjects (including those who are vasectomized) whose partners are pregnant 
or might be pregnant must agree to use condoms and refrain from sperm donation for the 
duration of the study and for 6 months following completion of therapy.
10. Capable of understanding and complying with parameters as outlined in the protocol and able to sign 
and date the informed consent, approved by an Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB), prior to initiation of any screening or study-specific procedures.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:
Subjects who meet any of the following exclusion criteria are not eligible:
1.
Received anticancer agent(s) or an investigational agent within 21 days prior to C1D-2 or 
radiotherapy within 28 days prior to C1D-2.
!
Prior treatment with palliative local breast or bone lesion radiation (other than pelvis) can occur, 
if administered at least 14 days prior to C1D-2.
!
Anticancer hormonal therapy must be stopped 7 days before starting C1D-2.
!
Anti-cancer therapy should not be initiated by the site during the screening period, as a 21-day 
interval would be needed from the last dose and would lead to additional delays in therapy and 
potential exclusion of the subject.
2.
Received more than 2 prior lines of cytotoxic chemotherapy (e.g., gemcitabine, doxorubicin, 
capecitabine) for metastatic disease.*
!
Regimens received in the adjuvant/neoadjuvant setting or for locally advanced breast cancer 
within the past 6 months will also be considered toward the maximum of 2 prior lines of 
therapy.  Adjuvant/neoadjuvant chemotherapy for one cancer event will count as one prior line 
of therapy, if received within the past 6 months.
!
Previous treatments with hormonal therapy (tamoxifen, aromatase inhibitors) and signal 
transduction agents (e.g., erlotinib, gefitinib, everolimus, bevacizumab) are allowed and are not 
counted towards the prior line of therapy.
3.
Progressed or recurred within 12 months of completing platinum therapy or received > 1 prior line of 
platinum therapy for breast cancer in any setting (adjuvant, neoadjuvant or metastatic).
4.
Subjects experiencing a significant adverse effect or toxicity (Grade 3 or Grade 4) causally attributed
to previous anticancer treatment that has not recovered to at least Grade 2.
5.
Prior therapy with PARP inhibitors.*
6.
Prior taxane therapy administered for the treatment of metastatic breast cancer with the below 
exceptions.*
!
Prior taxane therapy for metastatic breast cancer is allowed if the patient received ≤ 1 full cycle 
(i.e., therapy discontinued within 4 weeks for subjects receiving weekly paclitaxel or Abraxane; 
therapy discontinued within 3 weeks for subjects receiving paclitaxel or docetaxel every 
3 weeks) in the absence of progression or if taxane therapy for metastatic disease was 
> 12 months prior to C1D-2.
!
Use of taxanes as adjuvant therapy or to treat locally advanced disease is permitted, if given 
more than 6 months prior to C1D-2.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
7.
Subjects with active brain metastases or leptomeningeal disease.
!
Subjects should have a brain MRI within 28 days of randomization to confirm the absence of 
CNS metastases.  Contrast CT is acceptable for subjects who are unable to undergo a brain MRI.
!
Subjects with known brain metastases must have clinically controlled neurologic symptoms and 
have received previous adequate treatment, defined as surgical excision and/or radiation therapy 
with stable neurologic function and no evidence of Central Nervous System (CNS) disease 
progression as determined by comparing a computed tomography (CT) scan or magnetic 
resonance imaging (MRI) scan performed during screening to a prior scan performed at least 
4 weeks earlier and provided that the subject is asymptomatic, has no evidence of cavitation or 
hemorrhage, and does not require corticosteroids (must have discontinued steroids for 
management of neurological symptoms at least 3 months prior to study drug administration).
8.
A history of uncontrolled seizure disorder; including focal or generalized seizure within the past year.
9.
Pre-existing neuropathy in excess of Grade 1 (except focal neuropathy such as brachial plexopathy or 
carpal tunnel syndrome).
10. Major surgery within 3 weeks of randomization.
11. Known history of allergic reaction to cremophor-paclitaxel, carboplatin, Azo-Colourant Tartrazine 
(also known as FD&C Yellow 5 or E102), Azo-Colourant Orange Yellow-S (also known as FD&C 
Yellow 6 or E110) or known contraindications to any study supplied drug.
12. Clinically significant uncontrolled condition(s):
!
Active infection;
!
Symptomatic congestive heart failure;
!
Unstable angina pectoris or cardiac arrhythmia;
!
Myocardial infarction within last 6 months;
!
Known active hepatitis B or hepatitis C with abnormal liver function tests or organ dysfunction;
!
Uncontrolled hypertension (sustained systolic blood pressure > 150 mmHg or diastolic pressure 
> 100 mmHg despite optimal medical management);
!
Psychiatric illness/social situations that would limit compliance with study requirements; or
!
Any medical condition that, in the opinion of the investigator, places the subject at an 
unacceptably high risk for toxicities.
13. A previous or concurrent cancer that is distinct in primary site or histology from breast cancer, except 
cervical carcinoma in situ, non-melanoma carcinoma of the skin, or in situ carcinoma of the bladder 
or another in situ cancer that is considered cured by the Investigator.  Any cancer curatively treated 
greater than 3 years prior to entry is permitted.  For these subjects, metastases must be histologically 
or cytologically confirmed to be breast cancer.
14. Pregnant or breastfeeding.
* Note: For prior chemotherapy, treatment for 1 full cycle or less will not be considered as prior therapy 
unless the patient experienced progression of disease while on that therapy.


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Investigational Product:
Veliparib or Placebo
Dose:
120 mg BID Days –2 through 5 of 21-day cycle in combination with 
carboplatin and paclitaxel
Mode of Administration:
Oral
Reference Therapy:
Carboplatin
Dose:
AUC 6 Day 1 of 21-day cycle
Mode of Administration:
Intravenously (IV)
Reference Therapy:
Paclitaxel
Dose:
80 mg/m2 on Days 1, 8, 15 of 21-day cycle
Mode of Administration:
Intravenously (IV)
Investigational Product:
Veliparib or Placebo
Dose:
Starting dose of 300 mg BID Days 1 through 21 of 21-day cycle as 
single agent therapy, if tolerated, escalation to 400 mg BID will be 
allowed
Mode of Administration:
Oral
Interim Analyses:
To ensure subject safety, an IDMC will review unblinded safety data 
(which will include all subjects enrolled in the study) when 
approximately 60 subjects have met at least one of the following criteria:
!
Received 6 cycles of treatment
!
Reached an event of disease progression
!
Discontinued the study due to toxicity/adverse events
Subsequent reviews will be based on recommendations from the 
IDMC.
Criteria for Evaluation:
Progression-free Survival (PFS):  will be evaluated according to progression per RECIST (version 1.1) 
and survival information (death).  Radiologic tumor response and disease progression will be assessed by 
CT scan utilizing RECIST (version 1.1).  Assessments will be performed at Screening, at 9-week 
intervals (from C1D-2) thereafter until disease progression and at each blinded and unblinded study 
treatment Final Visit, if not performed within the last 4 weeks.
Clinical benefit rate (CBR), Objective Response Rate (ORR) and Duration of Overall Response 
(DOR):  will be evaluated according to progression per RECIST (version 1.1).  Radiologic tumor 
response and disease progression will be assessed by CT scan utilizing RECIST (version 1.1).  
Assessments will be performed at Screening, at 9-week intervals (from C1D-2) thereafter, and at each 
blinded and unblinded study treatment Final Visit, if not performed within the last 4 weeks (a 2-week 
window for obtaining the final visit scan is acceptable for maintaining at least a 6-week interval between 
scans as per local guidance and regulations).
Overall Survival (OS):  will be evaluated according to survival information and post treatment 
information (including therapy, dates of therapy and response) collected at two month intervals beginning 
on the date the subject is registered off study and until the endpoint of death, the subject is lost to 
follow-up or until the study termination by AbbVie.


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Criteria for Evaluation (Continued):
PFS2:  will be evaluated according to survival information and post treatment information (includes 
dates of therapy and response per RECIST 1.1) collected at two month intervals.
Statistical Methods:  Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a two-sided P value ≤ 0.05 when rounded.
Sample Size Determination:
Assuming the true hazard ratio for PFS in favor of the veliparib + C/P group is 0.69, a total of 344 PFS 
events will be needed for the study to have 90% power at 2-sided α level of 0.05 to detect a statistically 
significant treatment effect for the veliparib + C/P group using the log-rank test for progression free 
survival.  A total of approximately 500 subjects will be enrolled into the study.
Efficacy (Primary and Secondary Endpoints):
The analysis of the primary endpoint and secondary endpoints will include only the subjects who have 
been documented to have suspected deleterious or deleterious mutations by the Sponsor core lab.  The 
primary and secondary analyses will be based upon the investigator's assessment of response and disease 
progression per RECIST 1.1.  Sensitivity analyses of PFS, ORR, CBR, and duration of overall response 
based on radiological and clinical assessment by the Central Imaging Center will be conducted.
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 disease progression, or to the date of death (all causes of 
mortality) if disease progression is not reached.
Clinical Benefit Rate (CBR):  will be defined as the progression-free rate at 24 weeks from the 
Kaplan-Meier curve for time to progression (defined as from the date of randomization to the date of 
disease progression).
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.
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).  All subjects who have had at 
least one measurable lesion at baseline will be included in the ORR calculation.
PFS2:  will be defined as the number of days from the day the subject is randomized to the date that the 
subject has disease progression or death of any cause on the subsequent therapy, whichever occurs first.
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 PD is objectively documented.  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.
Safety:  Safety will be assessed by evaluating study drug exposure, adverse events, serious adverse 
events, all deaths, as well as changes in laboratory determinations and vital sign parameters.  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.


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Has been changed to read:
AbbVie
Protocol Number:  M12-914
Name of Study Drug:  Veliparib (ABT-888)
Phase of Development:  Phase 3
Name of Active Ingredient:  Not applicable 
Date of Protocol Synopsis:  23 July 2020
Protocol Title:  A Phase 3 Randomized Placebo-Controlled Trial of Carboplatin and Paclitaxel With or 
Without the PARP Inhibitor Veliparib (ABT-888) in HER2-Negative Metastatic or Locally Advanced 
Unresectable BRCA-Associated Breast Cancer
Objectives:  The primary endpoint is to assess the progression-free survival (PFS) of veliparib in 
combination with carboplatin (C) and paclitaxel (P) compared to placebo with C/P in subjects with a 
BRCA1 and/or BRCA2 Mutation and HER2-Negative Metastatic or Locally Advanced Unresectable 
Breast Cancer.
The secondary objectives of the study are to assess overall survival (OS), clinical benefit rate (CBR), 
objective response rate (ORR), and PFS2 in subjects treated with veliparib in combination with C/P 
versus subjects treated with placebo with C/P.  The tertiary objectives are to assess duration of overall 
response (DOR), change in ECOG performance status, and change in Quality of Life (QoL).
Study Sites:  Multicenter; Approximately 200
Study Population:  Men and women ≥ 18 years of age with HER2-negative metastatic or locally 
advanced unresectable breast cancer and clinically significant (suspected deleterious or deleterious) 
BRCA1 and/or BRCA2 germline mutation.  Patients with bone-only disease and/or hormone receptor 
positive (ER and/or PR) disease should be deemed appropriate candidates for combination chemotherapy.
Number of Subjects to be Enrolled:  Approximately 500
Methodology:
This is a Phase 3, randomized, double-blinded study to evaluate the efficacy and tolerability of veliparib 
in combination with C/P compared to placebo plus C/P in subjects with BRCA1 or BRCA2 germline 
mutation and with HER2-negative metastatic or locally advanced unresectable breast cancer who have 
received no more than 2 prior lines of cytotoxic therapy for metastatic disease.
Veliparib/placebo will be dosed in combination with carboplatin AUC 6 with weekly paclitaxel 
(80 mg/m2), on a 21-day cycle.  Subject randomization will be in a 2:1 ratio to veliparib/C/P or 
placebo/C/P and stratified by estrogen receptor (ER) and/or progesterone receptor (PgR) positive versus 
ER/PgR negative, prior platinum therapy (yes versus no), and CNS metastases (yes versus no).
Subjects with BRCA1/BRCA2 mutation per local lab testing and who meet the remaining eligibility 
criteria may be randomized.  Patients who meet NCCN guidelines for BRCA1/BRCA2 testing are eligible 
for testing during the screening period.  BRCA mutation status will be documented for all subjects by the 
central laboratory (Myriad).
Subjects who discontinue carboplatin and paclitaxel and who have not progressed will continue 
veliparib/placebo as a single agent at the recommended Phase 2 single agent dose.  Subjects will continue 
dosing until they meet the defined treatment discontinuation criteria.  Subjects who discontinue 
carboplatin, paclitaxel, and veliparib/placebo for reasons other than progression should remain on study.  
At the time PD is documented according to RECIST 1.1, subjects randomized to placebo may be eligible 
to crossover to unblinded veliparib monotherapy.


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Methodology (Continued):
Tumor assessments (CT scan or MRI of the full chest, abdomen, pelvis and brain MRI or contrast CT) 
were performed at screening and then every 9 weeks from C1D-2 until tumor progression to determine 
the extent of tumor burden per RECIST 1.1.  Following the primary analysis and implementation of 
Protocol Amendment 4, the tumor assessment interval may be increased to every 12 weeks from last scan 
until tumor progression. At the investigator's discretion, the interval between scans may be longer than 
every 12 weeks for subjects who have durable disease control but must not exceed 24 weeks.  Post-
baseline brain MRI or contrast CT is only required in subjects with CNS lesions at baseline; in all other 
subjects, CNS imaging will be obtained as clinically indicated based upon symptoms indicative of CNS 
disease. Refer to Section 5.3.1.1 and Appendix C, Appendix D, and Appendix E for additional tumor 
assessment schedule details, including details for subjects on open-label crossover veliparib.
In addition to being reviewed by the investigator and/or site staff, radiographic scans will be sent to a 
central imaging center for review.  Subjects who discontinue study treatment prior to disease progression 
should remain on study and continue to undergo a modified schedule of assessments until disease 
progression per RECIST 1.1.  For these subjects who meet study treatment discontinuation criteria and 
who have not progressed (such as subjects who initiate another anti-cancer therapy), tumor assessment 
data per RECIST 1.1 will continue to be collected to document tumor status and the date of progression.  
Post treatment information (including dates and response to subsequent therapies) and survival 
information will be collected every two months beginning on the date the subject has discontinued study 
therapy until the endpoint of death, the subject is lost to follow-up or until the study termination by 
AbbVie.
QoL assessment via the EORTC QLQ-C30/BR23 and EQ-5D-5L questionnaires will be collected on 
C1D-2 pre-dose, Day 1 of Cycle 2 and every other cycle thereafter beginning with Cycle 4 (C6, C8, etc.), 
Final Visit, and 30-Day Follow-Up Visit.  Subjects who crossover to the unblinded veliparib 
monotherapy arm will continue to have QoL assessments performed as per this schedule (Day 1 of the 
first and second cycle of unblinded monotherapy and every other cycle thereafter beginning with Cycle 4 
until 2nd disease progression or until they meet the defined study treatment discontinuation criteria and at 
the Final Visit and 30-Day Follow-Up Visit).  Pain assessment via the BPI-SF will be collected at every 
cycle.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Men and women ≥ 18 years of age.
2.
Histologically or cytologically confirmed breast cancer that is either locally advanced or metastatic. 
!
Locally advanced breast cancer must not be primarily amenable to surgical resection or radiation 
with curative intent.
!
Patients with bone-only disease and/or hormone receptor positive disease should be deemed by 
the investigator as appropriate candidates for combination chemotherapy.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
3.
Suspected deleterious or deleterious BRCA1 and/or BRCA2 germline mutation.
The investigator should ensure that the testing is consistent with local guidelines, and clinical 
practice, and that the test uses either 1) direct DNA sequencing/multiplex ligation-dependent probe 
amplification (MLPA) or 2) a well-characterized methodology previously validated by sequencing, 
such as that used to assess founder mutations.  If testing has been performed prior to Study M12-914, 
subjects may be enrolled but must be re-tested by the Sponsor core laboratory for documentation of 
BRCA1 or BRCA2 germline mutations.
Subjects with BRCA variants of uncertain significance or polymorphisms in BRCA1 or BRCA2 will 
not be eligible for the study.
4.
Breast cancer must be HER2-negative, defined as IHC 0 – 1+ OR HER2-neu negative according to 
ASCO-CAP guideline recommendations.
5.
Measurable or non-measurable (but radiologically evaluable) disease per RECIST version 1.1 on 
computed tomography (CT) scan (within 28 days of randomization) with at least one lesion outside 
previously irradiated areas.
6.
ECOG Performance status of 0 to 2.
7.
Subject is able to swallow and retain oral medication and does not have uncontrolled emesis.
8.
Adequate hematologic, renal, and hepatic function as follows (within 28 days of randomization):
!
Bone Marrow:  Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 × 109/L); Platelets 
≥100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.5 g/dL (5.89 mmol/L);
!
Renal Function:  Serum creatinine ≤ 1.5 × upper limit of normal (ULN) range OR creatinine 
clearance ≥ 50 mL/min/1.73 m2 (according to local assessment method) for subjects with 
creatinine levels above institutional normal;
!
Hepatic Function:  Aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal; alanine 
transaminase (ALT) ≤ 2.5 × upper limit of normal; bilirubin ≤ 1.5 × the ULN range.  For 
subjects with liver metastases, AST < 5 × ULN range; ALT < 5 × ULN range.  Subjects with 
Gilbert's Syndrome may have a bilirubin ≥ 1.5 × the ULN range if no evidence of biliary 
obstruction exists;
!
Activated Partial Thromboplastin Time (APTT) must be ≤ 1.5 × the ULN range and 
international normalized ratio (INR) < 1.5.  Subjects on anticoagulant therapy will have an 
appropriate APTT and INR as determined by the investigator.
9.
Women of childbearing potential and men must agree to use adequate contraception (one of the 
following listed below) prior to study entry, for the duration of study participation, and for 6 months 
following completion of therapy.  Women of childbearing potential must have a negative serum 
pregnancy test at screening and a negative urine pregnancy test prior to randomization.  To be 
considered of non-childbearing potential, postmenopausal women must be amenorrheic for at least 
12 months or subjects must be surgically sterile.
!
Total abstinence from sexual intercourse (abstinence is only acceptable as a contraceptive 
method if it is established as the subject's preferred and usual lifestyle);
!
Vasectomized male subjects or vasectomized partner of female subjects;


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Inclusion (Continued):
!
Double-barrier method (condoms, contraceptive sponge, diaphragm, or vaginal ring with 
spermicidal jellies or cream); or
!
Intra-Uterine Device (IUD).
!
Additionally, male subjects (including those who are vasectomized) whose partners are pregnant 
or might be pregnant must agree to use condoms and refrain from sperm donation for the 
duration of the study and for 6 months following completion of therapy.
10. Capable of understanding and complying with parameters as outlined in the protocol and able to sign 
and date the informed consent, approved by an Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB), prior to initiation of any screening or study-specific procedures.
Main Exclusion:
Subjects who meet any of the following exclusion criteria are not eligible:
1.
Received anticancer agent(s) or an investigational agent within 21 days prior to C1D-2 or 
radiotherapy within 28 days prior to C1D-2.
!
Prior treatment with palliative local breast or bone lesion radiation (other than pelvis) can occur, 
if administered at least 14 days prior to C1D-2.
!
Anticancer hormonal therapy must be stopped 7 days before starting C1D-2.
!
Anti-cancer therapy should not be initiated by the site during the screening period, as a 21-day 
interval would be needed from the last dose and would lead to additional delays in therapy and 
potential exclusion of the subject.
2.
Received more than 2 prior lines of cytotoxic chemotherapy (e.g., gemcitabine, doxorubicin, 
capecitabine) for metastatic disease.*
!
Regimens received in the adjuvant/neoadjuvant setting or for locally advanced breast cancer 
within the past 6 months will also be considered toward the maximum of 2 prior lines of 
therapy.  Adjuvant/neoadjuvant chemotherapy for one cancer event will count as one prior line 
of therapy, if received within the past 6 months.
!
Previous treatments with hormonal therapy (tamoxifen, aromatase inhibitors) and signal 
transduction agents (e.g., erlotinib, gefitinib, everolimus, bevacizumab) are allowed and are not 
counted towards the prior line of therapy.
3.
Progressed or recurred within 12 months of completing platinum therapy or received > 1 prior line of 
platinum therapy for breast cancer in any setting (adjuvant, neoadjuvant or metastatic).
4.
Subjects experiencing a significant adverse effect or toxicity (Grade 3 or Grade 4) causally attributed 
to previous anticancer treatment that has not recovered to at least Grade 2.
5.
Prior therapy with PARP inhibitors.*
6.
Prior taxane therapy administered for the treatment of metastatic breast cancer with the below 
exceptions.*
!
Prior taxane therapy for metastatic breast cancer is allowed if the patient received ≤ 1 full cycle 
(i.e., therapy discontinued within 4 weeks for subjects receiving weekly paclitaxel or Abraxane; 
therapy discontinued within 3 weeks for subjects receiving paclitaxel or docetaxel every 
3 weeks) in the absence of progression or if taxane therapy for metastatic disease was 
> 12 months prior to C1D-2.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
!
Use of taxanes as adjuvant therapy or to treat locally advanced disease is permitted, if given 
more than 6 months prior to C1D-2.
7.
Subjects with active brain metastases or leptomeningeal disease.
!
Subjects should have a brain MRI within 28 days of randomization to confirm the absence of 
CNS metastases.  Contrast CT is acceptable for subjects who are unable to undergo a brain MRI.
!
Subjects with known brain metastases must have clinically controlled neurologic symptoms and 
have received previous adequate treatment, defined as surgical excision and/or radiation therapy 
with stable neurologic function and no evidence of Central Nervous System (CNS) disease 
progression as determined by comparing a computed tomography (CT) scan or magnetic 
resonance imaging (MRI) scan performed during screening to a prior scan performed at least 
4 weeks earlier and provided that the subject is asymptomatic, has no evidence of cavitation or 
hemorrhage, and does not require corticosteroids (must have discontinued steroids for 
management of neurological symptoms at least 3 months prior to study drug administration).
8.
A history of uncontrolled seizure disorder; including focal or generalized seizure within the past year.
9.
Pre-existing neuropathy in excess of Grade 1 (except focal neuropathy such as brachial plexopathy or 
carpal tunnel syndrome).
10. Major surgery within 3 weeks of randomization.
11. Known history of allergic reaction to cremophor-paclitaxel, carboplatin, Azo-Colourant Tartrazine 
(also known as FD&C Yellow 5 or E102), Azo-Colourant Orange Yellow-S (also known as FD&C 
Yellow 6 or E110) or known contraindications to any study supplied drug.
12. Clinically significant uncontrolled condition(s):
!
Active infection;
!
Symptomatic congestive heart failure;
!
Unstable angina pectoris or cardiac arrhythmia;
!
Myocardial infarction within last 6 months;
!
Known active hepatitis B or hepatitis C with abnormal liver function tests or organ dysfunction;
!
Uncontrolled hypertension (sustained systolic blood pressure > 150 mmHg or diastolic pressure 
> 100 mmHg despite optimal medical management);
!
Psychiatric illness/social situations that would limit compliance with study requirements; or
!
Any medical condition that, in the opinion of the investigator, places the subject at an 
unacceptably high risk for toxicities.
13. A previous or concurrent cancer that is distinct in primary site or histology from breast cancer, except 
cervical carcinoma in situ, non-melanoma carcinoma of the skin, or in situ carcinoma of the bladder 
or another in situ cancer that is considered cured by the Investigator.  Any cancer curatively treated 
greater than 3 years prior to entry is permitted.  For these subjects, metastases must be histologically 
or cytologically confirmed to be breast cancer.
14. Pregnant or breastfeeding.
*Note:
For prior chemotherapy, treatment for 1 full cycle or less will not be considered as prior therapy 
unless the patient experienced progression of disease while on that therapy.


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Investigational Product:
Veliparib or Placebo
Dose:
120 mg BID Days –2 through 5 of 21-day cycle in combination with 
carboplatin and paclitaxel
Mode of Administration:
Oral
Reference Therapy:
Carboplatin
Dose:
AUC 6 Day 1 of 21-day cycle
Mode of Administration:
Intravenously (IV)
Reference Therapy:
Paclitaxel
Dose:
80 mg/m2 on Days 1, 8, 15 of 21-day cycle
Mode of Administration:
Intravenously (IV)
Investigational Product:
Veliparib or Placebo
Dose:
Starting dose of 300 mg BID Days 1 through 21 of 21-day cycle as 
single agent therapy, if tolerated, escalation to 400 mg BID will be 
allowed
Mode of Administration:
Oral
Interim Analyses:
To ensure subject safety, an IDMC reviewed unblinded safety data 
(which included all subjects enrolled in the study) when approximately 
60 subjects met at least one of the following criteria:
!
Received 6 cycles of treatment
!
Reached an event of disease progression
!
Discontinued the study due to toxicity/adverse events
Subsequent IDMC reviews of unblinded safety data prior to the primary 
analysis were carried out based on IDMC recommendations. No 
additional reviews by the IDMC will occur since the Sponsor 
management team was unblinded after completing the primary analysis.
Criteria for Evaluation:
Progression-free Survival (PFS):  will be evaluated according to progression per RECIST (version 1.1) 
and survival information (death).  Radiologic tumor response and disease progression will be assessed by 
CT scan utilizing RECIST (version 1.1).  Assessments were be performed at Screening, at 9-week 
intervals (from C1D-2) thereafter until disease progression. Following the primary analysis and 
implementation of Protocol Amendment 4 the tumor assessment interval may be increased to every 
12 weeks from last scan until tumor progression; at investigator discretion, the interval between scans 
may be longer than 12 weeks but must not exceed 24 weeks.
Clinical benefit rate (CBR), Objective Response Rate (ORR) and Duration of Overall Response 
(DOR):  will be evaluated according to progression per RECIST (version 1.1).  Radiologic tumor 
response and disease progression will be assessed by CT scan utilizing RECIST (version 1.1).  
Assessments were be performed at Screening, at 9-week intervals (from C1D-2) thereafter. Following 
the primary analysis and implementation of Protocol Amendment 4, the tumor assessment interval may 
be increased to every 12 weeks from last scan until tumor progression; at investigator discretion, the 
interval between scans may be longer than 12 weeks but must not exceed 24 weeks.


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Criteria for Evaluation (Continued):
Overall Survival (OS):  will be evaluated according to survival information and post treatment 
information (including therapy, dates of therapy and response) collected at two month intervals beginning 
on the date the subject is registered off study and until the endpoint of death, the subject is lost to 
follow-up or until the study termination by AbbVie.
PFS2:  will be evaluated according to survival information and post treatment information (includes 
dates of therapy and response per RECIST 1.1) collected at two-month intervals.
Statistical Methods:  Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a two-sided P value ≤ 0.05 when rounded.
Sample Size Determination:
Assuming the true hazard ratio for PFS in favor of the veliparib + C/P group is 0.69, a total of 344 PFS 
events will be needed for the study to have 90% power at 2-sided α level of 0.05 to detect a statistically 
significant treatment effect for the veliparib + C/P group using the log-rank test for progression free 
survival.  A total of approximately 500 subjects will be enrolled into the study.
Efficacy (Primary and Secondary Endpoints):
The analysis of the primary endpoint and secondary endpoints will include only the subjects who have 
been documented to have suspected deleterious or deleterious mutations by the Sponsor core lab.  The 
primary and secondary analyses will be based upon the investigator's assessment of response and disease 
progression per RECIST 1.1.  Sensitivity analyses of PFS, ORR, and CBR based on radiological and 
clinical assessment by the Central Imaging Center will be conducted.
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 disease progression, or to the date of death (all causes of 
mortality) if disease progression is not reached.
Clinical Benefit Rate (CBR):  will be defined as the progression-free rate at 24 weeks from the 
Kaplan-Meier curve for time to progression (defined as from the date of randomization to the date of 
disease progression).
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.
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).  All subjects who have had at 
least one measurable lesion at baseline will be included in the ORR calculation.
PFS2:  will be defined as the number of days from the day the subject is randomized to the date that the 
subject has disease progression or death of any cause on the subsequent therapy, whichever occurs first.
Safety:  Safety will be assessed by evaluating study drug exposure, adverse events, serious adverse 
events, all deaths, as well as changes in laboratory determinations and vital sign parameters.  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.


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Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
TA MD
Therapeutic Area Medical Director
Section 3.5  Benefits and Risks
Add:  new last paragraph
The benefits and risks of study participation have been evaluated in the context of the 
ongoing COVID-19 pandemic. No data are available to characterize the risk of 
participation in this trial specific to COVID-19. COVID-19-related risks are not expected 
to differ substantially between trial participants and the broader population of individuals 
receiving treatment for advanced breast cancer. In consideration of the life-threatening 
nature of the disease under study, the benefit/risk balance for participation in this trial is 
not changed.
Section 4.0  Study Objectives
Second and third paragraph previously read:
The secondary objectives of the study are to assess overall survival (OS), clinical benefit 
rate (CBR) through the end of Week 24, duration of overall response, objective response 
rate (ORR) and PFS2 in subjects treated with veliparib in combination with carboplatin 
and paclitaxel versus placebo in combination with carboplatin and paclitaxel.
The tertiary objectives are to assess ECOG performance status, QoL, and exploratory 
correlative endpoints.
Has been changed to read:
The secondary objectives of the study are to assess overall survival (OS), clinical benefit 
rate (CBR) through the end of Week 24, objective response rate (ORR) and PFS2 in 
subjects treated with veliparib in combination with carboplatin and paclitaxel versus 
placebo in combination with carboplatin and paclitaxel.


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The tertiary objectives are to assess ECOG performance status, QoL, duration of overall 
response, and exploratory correlative endpoints.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel)
Third paragraph, last sentence previously read:
Subjects will continue to follow the schedule of assessments as outlined in Appendix C.
Has been changed to read:
For subjects who have been receiving single-agent veliparib/placebo at a stable dose 
without adjustment for multiple cycles and who have no ongoing study drug related 
uncontrolled AEs (Adverse Events), it is possible to alternate on-site visits and phone 
visits every other cycle. At a minimum, these subjects should have an on-site visit every 
other cycle. If an on-site visit is not possible for 2 consecutive cycles, or if the subject is 
not on a stable dose or has ongoing study drug-related uncontrolled AEs but wishes to 
alternate on-site and phone visits every other cycle, the plan for the subject's visits should 
be discussed with the AbbVie TA MD (see Section 7.0 for contact information).  Subjects 
will continue to follow the schedule of assessments as outlined in Appendix C and 
Appendix F.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel)
Fourth paragraph previously read:
Subjects who have discontinued blinded study treatment due to unmanageable toxicity or 
for reasons other than progression will remain on study and follow a reduced schedule of 
study assessments (tumor assessment per RECIST 1.1, Performance Status, QLQ C30, 
BR23, EQ 5D 5L and BPI-SF Questionnaires) and standard of care assessments (physical 
exam and vital signs) until disease progression as outlined in Appendix E.


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Has been changed to read:
Subjects who have discontinued blinded study treatment due to unmanageable toxicity or 
for reasons other than progression will remain on study, off drug and follow a reduced 
schedule of study assessments which will include tumor assessments per RECIST 1.1 and 
survival status assessments, until disease progression as outlined in Appendix E.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel)
Last paragraph, first sentence previously read:
Once a subject discontinues the blinded portion of the study, a Final Visit will be 
conducted.
Has been changed to read:
Once a subject discontinues blinded study treatment (including subjects that discontinued 
treatment due to unmanageable toxicity or for reasons other than progression), a Final 
Visit will be conducted.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Optional Unblinded Veliparib Monotherapy Treatment (Crossover)
First paragraph, first bullet, last paragraph previously read:
Note:  Discussion with the Unblinded AbbVie TA MD (see Section 7.0 for contact 
information) may be needed prior to unblinding and crossover to verify that criteria for 
unequivocal PD are met.
Has been changed to read:
Note:  Discussion with the AbbVie TA MD (see Section 7.0 for contact information) may 
be needed prior to unblinding and crossover to verify that criteria for unequivocal PD are 
met.


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Section 5.1  Overall Study Design and Plan:  Description
Subsection Optional Unblinded Veliparib Monotherapy Treatment (Crossover)
Second paragraph, last sentence previously read:
Transitions that occur after 60 days should be discussed with the Unblinded AbbVie TA 
MD.
Has been changed to read:
Transitions that occur after 60 days should be discussed with the AbbVie TA MD.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Optional Unblinded Veliparib Monotherapy Treatment (Crossover)
Third paragraph, third sentence previously read:
Subjects will follow the schedule of assessments as outlined in Appendix D.
Has been changed to read:
For subjects who have been receiving veliparib monotherapy at a stable dose without 
adjustment for multiple cycles and who have no ongoing study drug related uncontrolled 
AEs, it is possible to alternate on-site visits and phone visits every other cycle. At a 
minimum, subjects should have an on-site visit every other cycle. If an on-site visit is not 
possible for 2 consecutive cycles, or if the subject is not on a stable dose or has ongoing 
study drug-related uncontrolled AEs but wishes to alternate on-site and phone visits every 
other cycle, the plan for the subject's visits should be discussed with the AbbVie TA MD 
(see Section 7.0 for contact information). Subjects will follow the schedule of 
assessments as outlined in Appendix D and Appendix F.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Optional Unblinded Veliparib Monotherapy Treatment (Crossover)
Fourth paragraph previously read:
Subjects who have discontinued unblinded study treatment due to unmanageable toxicity 
or for reasons other than progression will remain on study and follow a reduced schedule 
of study assessments (tumor assessment per RECIST 1.1, Performance Status, QLQ C30, 


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BR23, EQ 5D 5L and BPI-SF Questionnaires) and standard of care assessments (physical 
exam and vital signs) until disease progression as outlined in Appendix E.
Has been changed to read:
Subjects who have discontinued unblinded study treatment due to unmanageable toxicity 
or for reasons other than progression will remain on study, off drug and follow a reduced 
schedule of study assessments, which will include tumor assessments per RECIST 1.1 and 
survival status until disease progression as outlined in Appendix E.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Optional Unblinded Veliparib Monotherapy Treatment (Crossover)
Last paragraph, first sentence previously read:
Once a subject discontinues the unblinded portion of the study, a Final Visit will be 
conducted.
Has been changed to read:
Once a subject discontinues the unblinded study treatment (including subjects that 
discontinued treatment due to unmanageable toxicity or for reasons other than 
progression), a Final Visit will be conducted.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Survival and Post Blinded and Unblinded Study Treatment Information
First sentence previously read:
Once a subject meets study discontinuation criteria, subjects will be followed for survival 
and post study treatment information as outlined in Section 5.3.1.1 will be collected every 
two months (unless requested by sponsor more frequently to support data analysis) 
beginning on the date the subject is registered off study.
Has been changed to read:
Once a subject meets study treatment discontinuation criteria, subjects will be followed 
for survival and post study treatment information as outlined in Section 5.3.1.1 will be 


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collected every two months (unless requested by sponsor more frequently to support data 
analysis) beginning on the date the subject is discontinued from therapy.
Section 5.2.3  Prior and Concomitant Therapy
Last paragraph previously read:
The Blinded AbbVie TA MD identified in Section 6.1.6 should be contacted if there are 
any questions regarding prior or concomitant therapy.
Has been changed to read:
The AbbVie TA MD identified in Section 6.1.6 should be contacted if there are any 
questions regarding prior or concomitant therapy(ies).
Section 5.2.3.2  Concomitant Therapy
"Anticancer Agents:"
First paragraph, last sentence previously read:
This should be discussed with the Blinded AbbVie TA MD.
Has been changed to read:
This should be discussed with the AbbVie TA MD.
Section 5.2.3.2  Concomitant Therapy
"Radiation:"
Last paragraph, last sentence previously read:
If a subject becomes a candidate for local treatment with radiation therapy, this should be 
discussed with the appropriate Blinded or Unblinded AbbVie TA MD and should be 
consistent with standard or institutional guidelines (a subject with multiple metastases is 
unlikely to benefit from local therapy).


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Has been changed to read:
If a subject becomes a candidate for local treatment with radiation therapy, this should be 
discussed with the AbbVie TA MD and should be consistent with standard or institutional 
guidelines (a subject with multiple metastases is unlikely to benefit from local therapy).
Section 5.2.3.2  Concomitant Therapy
"Surgery:"
First paragraph, first sentence previously read:
If the subject requires surgery during the study, timing of the procedure, study drug 
interruption, and resuming the study drug needs to be discussed with the appropriate 
Blinded or Unblinded AbbVie TA MD.  
Has been changed to read:
If the subject requires surgery during the study, timing of the procedure, study drug 
interruption, and resuming the study drug needs to be discussed with AbbVie TA MD.  
Section 5.2.3.2  Concomitant Therapy
"Surgery:"
Second paragraph previously read:
As a precautionary measure, it is recommended, but not strictly required, that if patients 
require placement of a central venous access device (CVAD), that procedure should be 
done 7 days prior to first study treatment start.
Has been changed to read:
As a precautionary measure, it is recommended, but not strictly required, that if subjects 
require placement of a central venous access device (CVAD), that procedure should be 
done 7 days prior to first study treatment start.


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Section 5.2.3.2  Concomitant Therapy
"Surgery:"
Last paragraph, lasts sentence previously read:
If a subject becomes a candidate for surgical resection, this should be discussed with the 
appropriate Blinded or Unblinded AbbVie TA MD and should be consistent with standard 
or institutional guidelines (a subject with multiple metastases is unlikely to benefit from 
local therapy).
Has been changed to read:
If a subject becomes a candidate for surgical resection, this should be discussed with the 
AbbVie TA MD and should be consistent with standard or institutional guidelines (a 
subject with multiple metastases is unlikely to benefit from local therapy).
Section 5.3.1  Efficacy and Safety Measurements Assessed and Flow Chart
First sentence previously read:
A schedule of study activities is presented in Appendix C, Appendix D, and Appendix E.  
Has been changed to read:
A schedule of study activities is presented in Appendix C, Appendix D, Appendix E, and 
Appendix F.  
Table 2.  Schedule Biomarker and Exploratory Research Assessments (Blinded 
Study Treatment)
Procedure "PD Blood Sampling+ Plasma Markersa,b" previously read:
PD Blood Sampling+ Plasma Markersa,b
Has been changed to read:
PD Blood Sampling Plasma Markersa,b


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Section 5.3.1.1  Study Procedures
First paragraph, first sentence previously read:
The study procedures outlined in Appendix C, Appendix D, and Appendix E are 
discussed in detail in this section, with the exception of the monitoring of treatment 
compliance (Section 5.5.6) and the collection of concomitant medication (Section 5.2.3) 
and adverse event information (Section 6.1).
Has been changed to read:
The study procedures outlined in Appendix C, Appendix D, Appendix E, and Appendix F
are discussed in detail in this section, with the exception of the monitoring of treatment 
compliance (Section 5.5.6) and the collection of concomitant medication (Section 5.2.3) 
and adverse event information (Section 6.1).
Section 5.3.1.1  Study Procedures
Add:  new last paragraph
Study visits may be impacted by changes in local regulations due to the COVID-19 
pandemic.  Every effort should be made to ensure the safety of subjects and site staff, 
while maintaining the integrity of the study.  If visits cannot be conducted as outlined per 
the protocol due to travel restrictions or other pandemic-related reasons, the site should 
contact the Sponsor for further guidance.
Section 5.3.1.1  Study Procedures
Subsection Pregnancy Test (In Women of Childbearing Potential)
First paragraph, first sentence previously read:
For female subjects of childbearing potential, a serum pregnancy test will be done at 
screening and a negative urine pregnancy test will be done prior to randomization (within 
24 hours).


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Has been changed to read:
For female subjects of childbearing potential, a serum pregnancy test will be done at 
screening and a urine pregnancy test will be done prior to randomization (within 
24 hours).
Section 5.3.1.1  Study Procedures
Subsection Pregnancy Test (In Women of Childbearing Potential)
Second paragraph previously read:
If pregnancy results are equivocal (e.g., false positive due to B-hCG being a tumor 
marker) in subjects with evidence to support lack of pregnancy (e.g., surgically sterile), 
the results should be discussed with the Blinded AbbVie TA MD and the investigator's 
interpretation along with supporting information documented in the source documents.
Has been changed to read:
If pregnancy results are equivocal (e.g., false positive due to B-hCG being a tumor 
marker) in subjects with evidence to support lack of pregnancy (e.g., surgically sterile), 
the results should be discussed with the AbbVie TA MD and the investigator's 
interpretation along with supporting information documented in the source documents.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Third paragraph, second sentence previously read:
When necessary, local labs can be split and used determine subject eligibility upon 
discussion with the Blinded AbbVie TA MD.  
Has been changed to read:
When necessary, local labs can be split and used to determine subject eligibility upon 
discussion with the AbbVie TA MD.  


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Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Add:  new fourth, fifth, and sixth paragraph
Due to travel restrictions and other changes in local regulations in cases of state of 
emergency or pandemic or other special situations that prevent the site from collecting a 
Central Laboratory sample, if possible, sites should arrange for subjects to have laboratory 
work done at a local lab, hospital, or other facility.  Local lab results should be obtained 
along with reference ranges and kept within the subjects' source documentation.  Local lab 
results should be reviewed by the investigator as soon as possible.
If laboratory samples cannot be obtained per the protocol, the site should discuss with the 
AbbVie TA MD prior to continuing dosing.
AbbVie may discontinue the requirement for concurrent samples to be sent to the central 
laboratory, and require instead local laboratory results only at protocol-specified 
timepoints, at any time during the course of the study.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Fourth paragraph
Add:  new fourth sentence
For visits conducted by phone as outlined in Appendix F, lab tests do not need to be 
performed and are to be collected at a minimum at the on-site visits (every other cycle).
Section 5.3.1.1  Study Procedures
Subsection Tumor Assessments (Radiologic)
Second paragraph previously read:
Axial plane CT scans of the full chest, abdomen, pelvis (or MRI), and brain MRI or 
contrast CT to determine the extent of tumor burden will be performed for all tumor 
assessments at Screening (within 28 days of randomization), every 9 weeks from C1D-2 
(tumor assessments may be conducted 5 days prior or 5 days following the scheduled 
assessment) until progression, and at each blinded and unblinded study treatment Final 


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Visit (if not performed within the last 4 weeks) with a 2-week window to allow for local 
regulatory requirements.  Subjects who have discontinued study treatment due to 
unmanageable toxicity or reasons other than progression will continue to complete tumor 
assessments every 9 weeks until unequivocal progression per RECIST 1.1 is documented.  
Scheduled tumor assessments will not be affected by delays in therapy and/or drug 
holidays.  Subjects will continue to be monitored by the same diagnostic method 
throughout the study, unless evidence of tumor metastasis warrants otherwise.  
Has been changed to read:
Axial plane CT scans of the full chest, abdomen, pelvis (or MRI), and brain MRI or 
contrast CT to determine the extent of tumor burden were performed for all tumor 
assessments at Screening (within 28 days of randomization), and every 9 weeks from
C1D-2 (tumor assessments could be conducted 5 days prior or 5 days following the 
scheduled assessment) until progression. For subjects in the blinded treatment period, 
following the primary analysis and implementation of Protocol Amendment 4, the tumor 
assessment interval may be increased to every 12 weeks from last scan (tumor 
assessments may be conducted 10 business days prior or 10 business days following the 
scheduled assessment). At the investigator's discretion, the interval between scans may be 
longer than every 12 weeks for subjects who have durable disease control but must not 
exceed 24 weeks.
For subjects on open-label crossover veliparib, tumor assessments will be conducted 
every 9 weeks (± 5 business days) from C1D1.  Following the primary analysis and 
implementation of Protocol Amendment 4, if a crossover subject has disease control after 
6 scans while following the 9 week scan interval schedule, the tumor assessment 
frequency can be increased to every 12 weeks (± 10 business days) from the last scan. At 
the investigator's discretion, the interval between scans may be longer than every 
12 weeks for subjects who have durable disease control, but must not exceed 24 weeks.
Subjects who have discontinued study treatment due to unmanageable toxicity or reasons 
other than progression will remain on study but off drug and continue to complete 


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scheduled tumor assessments until unequivocal progression per RECIST 1.1 is 
documented as per Appendix E.
Scheduled tumor assessments will not be affected by delays in therapy and/or drug 
holidays.  Subjects will continue to be monitored by the same diagnostic method 
throughout the study, unless evidence of tumor metastasis warrants otherwise.
Section 5.3.1.1  Study Procedures
Subsection Tumor Assessments (Radiologic)
Last paragraph
Add:  new last sentence
AbbVie may discontinue the requirement for radiology scans to be sent to the central 
imaging center or the requirement for completing central reviews at any time during the 
course of the study.
Section 5.3.1.1  Study Procedures
Subsection ECOG Performance Status
First paragraph previously read:
ECOG performance status will be assessed as outlined in Appendix C, Appendix D, and 
Appendix E.
Has been changed to read:
ECOG performance status will be assessed as outlined in Appendix C, Appendix D, 
Appendix E, and Appendix F.
Section 5.3.1.1  Study Procedures
Subsection Patient Reported Outcomes (PRO) Questionnaires
First paragraph, sixth and seventh sentence previously read:
Subjects who have discontinued study treatment prior to disease progression will continue 
to complete the PRO questionnaires as outlined in the schedule of assessments in 
Appendix E.  These subjects may complete the questionnaires by telephone or during their 
scheduled clinic visit.


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Has been changed to read:
For subjects who are eligible to alternate on-site visits and phone visits, the PRO 
questionnaires should still be completed at the phone visits.  PRO questionnaires to be 
completed for the cycle during which the phone visit occurs should be provided to the 
subject by the investigator or designee during the preceding on-site visit, so these can be 
completed at home as outlined in the schedule of assessments in Appendix F.
Section 5.3.1.1  Study Procedures
Subsection Patient Reported Outcomes (PRO) Questionnaires
Second paragraph, third sentence previously read:
It comprises 23 items divided in four functioning scales (body image, sexual functioning, 
sexual satisfaction, and future perspective) and four symptom scales (side effects of 
systemic therapy, breast symptoms, arm symptoms, and upset by hair loss).  
Has been changed to read:
It comprises of 23 items divided in four functioning scales (body image, sexual 
functioning, sexual satisfaction, and future perspective) and four symptom scales (side 
effects of systemic therapy, breast symptoms, arm symptoms, and upset by hair loss).  
Section 5.3.1.1  Study Procedures
Subsection Patient Reported Outcomes (PRO) Questionnaires
Add:  new last paragraph
Due to the COVID-19 pandemic and any local restrictions, sites may administer PRO 
questionnaires over the phone as needed.  Sites may read the PRO questions and response 
options to the subject and record the subject's responses.  Sites may send the 
questionnaires (email or hard copy) to the subjects to allow them to read/understand the 
questions and responses when the subject is providing responses over the phone.  The date 
and time of PRO data collection should be recorded along with who collected the 
information.


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Section 5.3.1.1  Study Procedures
Subsection Dispensing Study Drug
Add:  new third and fourth paragraph
Depending on local regulations due to the COVID-19 pandemic, provision of study drug 
for direct-to-patient (DTP) and direct-frompatient (DFP) transfer will be available upon 
request.  AbbVie has contracted with third party vendors for sites to ship study drug DTP 
and DFP.  Sites will be able to use the third party vendor and/or another local courier for 
drug shipment, as needed.  If necessary, notify AbbVie if DTP and/or DFP shipping will 
be used. 
Sites will be responsible to:
●
Meet IRB/IEC reporting requirements and submit the booking form (which 
will be provided to site by the courier) to the local IRB/IEC, as applicable.
●
Submit the booking form at least 72 business hours before the drug needs to be 
picked up, or as per the requirements of the courier.
●
Discuss the DTP and DFP process with the subject including:
○
Obtain consent to provide delivery information to the courier and 
document this in the source.
○
Obtain results of required safety procedures before registering subject 
dispensation of study drug in IRT.
○
Confirm the subject will be available to accept delivery.
○
Confirm the subject will maintain the drug containers, as well as any 
unused drug for return to site.
●
Follow up with the subject after shipment is received.
●
Retain documentation of the shipment for IP accountability and monitoring.


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Section 5.3.1.1  Study Procedures
Subsection Dispensing Study Drug
Heading "Blinded Study Treatment"
Add:  new fourth and fifth paragraph
On Day 1, subjects on blinded single-agent veliparib/placebo will be given study drug for 
dosing through Day 21.
For subjects who are eligible to alternate on-site visits and phone visits every other cycle, 
during the on-site visits, the investigator or designee should dispense blinded study drug 
via IRT and subject dosing cards for 2 consecutive cycles, as outlined in the schedule of 
assessments in Appendix F.
Section 5.3.1.1  Study Procedures
Subsection Dispensing Study Drug
Heading "Unblinded Study Treatment"
Add:  new last paragraph
For subjects who are eligible to alternate on-site visits and phone visits every other cycle, 
during the on-site visits, the investigator or designee should dispense unblinded study 
drug via IRT and subject dosing cards for 2 consecutive cycles, as outlined in the schedule 
of assessments in Appendix F.
Section 5.3.1.1  Study Procedures
Subsection Post-Progression/Survival Follow-Up Information
First paragraph previously read:
Once a subject meets study discontinuation criteria, subjects will continue to be followed 
during the Post Treatment Follow-Up Phase for survival (i.e., the date and cause of death) 
and post-therapy information, including date of progression to the first post-study therapy.  
These data will be collected on the appropriate eCRF at 2 month intervals (or as requested 
by Sponsor to support data analysis), beginning on the date the subject is registered off 
study until the endpoint of death, the subject has become lost-to follow-up, or AbbVie 
terminates the study.


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Has been changed to read:
Once a subject meets study treatment discontinuation criteria, subjects will continue to be 
followed during the Post Treatment Follow-Up Phase for survival (i.e., the date and cause 
of death) and post-therapy information, including date of progression to the first post-
study therapy.  These data will be collected on the appropriate eCRF at 2 month intervals 
(or as requested by Sponsor to support data analysis), beginning on the date the subject 
discontinued from study therapy until the endpoint of death, the subject has become lost-
to follow-up, or AbbVie terminates the study.
Section 5.3.1.1  Study Procedures
Subsection Post-Progression/Survival Follow-Up Information
Add:  new fourth paragraph
Subjects who have discontinued study treatment due to unmanageable toxicity or reasons 
other than progression will remain on study, off drug and continue to be followed for 
survival and post-treatment therapy information at 2 months intervals (or as requested by 
Sponsor to support data analysis) as outlined in the schedule of assessments in 
Appendix E.
Section 5.3.3  Efficacy Variables
Second and third sentence previously read:
The secondary efficacy endpoints will be OS, CBR, ORR, PFS2 and DOR.  The tertiary 
endpoints will include change in ECOG performance status, change in QoL indices.
Has been changed to read:
The secondary efficacy endpoints will be OS, CBR, ORR, and PFS2. The tertiary 
endpoints will include DOR, change in ECOG performance status, and change in QoL 
indices.
Section 5.3.5  Safety Variables
Third paragraph previously read:
During the conduct of the study, an IDMC will review unblinded safety data.


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Has been changed to read:
An IDMC reviewed unblinded safety data intermittently prior to the primary analysis.  No 
additional reviews by the IDMC will occur since the Sponsor management team was 
unblinded after completing the primary analysis.
Section 5.4.1  Discontinuation of Individual Subjects
First paragraph, first sentence previously read:
Subjects will receive therapy until disease progression according to Section 5.3.4, 
RECIST 1.1, unmanageable toxicity (per discussion with appropriate Blinded or 
Unblinded AbbVie TA MD), or they meet the study treatment discontinuation criteria as 
outlined below.  
Has been changed to read:
Subjects will receive therapy until disease progression according to Section 5.3.4, 
RECIST 1.1, unmanageable toxicity (per discussion with the AbbVie TA MD), or they 
meet the study treatment discontinuation criteria as outlined below.  
Section 5.4.1  Discontinuation of Individual Subjects
Add:  new fourth paragraph
In cases of state of emergency or pandemic situations, if subjects withdraw consent from 
study treatment, they should be considered as on study, off drug and follow the schedule 
of assessments per Appendix E, if the subject consents to continued follow up.
Section 5.4.1  Discontinuation of Individual Subjects
Fourth paragraph, first and second sentence previously read:
When a subject discontinues either the blinded or unblinded portion of the study, a Final 
Visit will be conducted.  During a Final Visit, the reasons for the discontinuation from the 
study treatment will be recorded and a physical examination, vital signs measurement, 
laboratory analyses, performance status, ECG (if not performed within the last 4 weeks), 


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QoL assessment, tumor assessment (if not performed within the last 4 weeks), collection 
of unused study drug, and an assessment of adverse events will be performed.
Has been changed to read:
When a subject discontinues either the blinded or unblinded study treatment, a Final Visit 
will be conducted. During a Final Visit, the reasons for the discontinuation from the 
study treatment will be recorded and a physical examination, vital signs measurement, 
laboratory analyses, performance status, ECG (if not performed within the last 4 weeks), 
QoL assessment, collection of unused study drug, and an assessment of adverse events 
will be performed.
Section 5.4.1  Discontinuation of Individual Subjects
Sixth paragraph previously read:
When a subject discontinuation is planned without the subject reaching a protocol-defined 
endpoint, the investigator will notify the appropriate Blinded or Unblinded AbbVie TA 
MD or the clinical team representative (Section 6.1.6) via telephone, as soon as possible 
(provided, in each case, subject care and safety are not compromised).  If not notified 
prior to discontinuation, the Blinded or Unblinded AbbVie TA MD may contact the site to 
discuss the reason for withdrawal from the study.
Has been changed to read:
When a subject discontinuation is planned without the subject reaching a protocol-defined 
endpoint, the investigator will notify the AbbVie TA MD or the clinical team 
representative (Section 6.1.6) via telephone, as soon as possible (provided, in each case, 
subject care and safety are not compromised).  If not notified prior to discontinuation, the 
AbbVie TA MD may contact the site to discuss the reason for withdrawal from the study.


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Section 5.4.1.1  Discontinuation of Blinded Study Treatment (Veliparib/Placebo + 
Carboplatin + Paclitaxel)
First paragraph, fourth sentence previously read:
Discontinuation of carboplatin and paclitaxel in the absence of toxicity requiring dose 
modification should be discussed with the Blinded AbbVie TA MD.
Has been changed to read:
Discontinuation of carboplatin and paclitaxel in the absence of toxicity requiring dose 
modification should be discussed with the AbbVie TA MD.
Section 5.4.2  Discontinuation of Entire Study
First paragraph
Add:  new last sentence
If AbbVie terminates the study for safety reasons, AbbVie will immediately notify the 
investigator by telephone and subsequently provide written instructions for study 
termination.
Section 5.5.1  Treatments Administered
Subsection Paclitaxel
Add:  new last paragraph
If needed per dose modifications guidelines, it is recommended that growth factors (i.e., 
filgrastim, peg-filgrastim) dosed according to institutional standard will be administered 
daily subcutaneously starting 24 – 72 hours after the last dose of carboplatin/paclitaxel or 
after last dose of weekly paclitaxel.  Pegfilgrastim should not be used for subjects 
receiving Day 15 paclitaxel as they do not have a 2-week chemotherapy-free interval.
Section 5.5.1  Treatments Administered
Subsection Carboplatin
Add:  new last paragraph
If needed per dose modifications guidelines, it is recommended that growth factors (i.e., 
filgrastim, peg-filgrastim) dosed according to institutional standard will be administered 


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daily subcutaneously starting 24 – 72 hours after the last dose of carboplatin/paclitaxel or 
after last dose of weekly paclitaxel.
Section 5.5.5  Blinding
Last sentence previously read:
Following progression of disease, a separate unblinded study team will be responsible for 
study conduct and data monitoring for subjects who crossover to veliparib monotherapy.
Has been changed to read:
Following progression of disease, a separate unblinded study team was responsible for 
study conduct and data monitoring for subjects who crossed over to veliparib 
monotherapy. 
After completion of the primary analysis the sponsor was unblinded to treatment 
assignment. A separate unblinded study team is no longer responsible for study conduct 
and data monitoring for subjects who crossover to veliparib monotherapy.  Primary site 
monitors, investigators and subjects continue to be blinded to treatment assignment until 
disease progression, after which unblinding to determine eligibility for crossover can be 
requested.
Section 5.5.5.1  Blinding of Investigational Product
Second sentence previously read:
The Blinded AbbVie TA MD (listed in Section 6.1.6) must be notified before the blind is 
broken 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).
Has been changed to read:
The AbbVie TA MD (listed in Section 6.1.6) must be notified before the blind is broken 
unless identification of the study drug is required for medical emergency, i.e., situation in 


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which the knowledge of the specific blinded treatment will affect the immediate 
management of the subject's conditions (e.g., antidote is available).
Section 5.5.6  Treatment Compliance
Fifth paragraph, first sentence previously read:
The study coordinator will document compliance on the appropriate eCRF.
Has been changed to read:
The study coordinator will document subject study drug administration details on the 
appropriate eCRF.
Section 5.7  Dose Reductions or Delays
Third paragraph previously read:
The Blinded AbbVie TA MD is to be contacted for subjects who require cycle delays of 
> 28 days due to toxicity.
Has been changed to read:
The AbbVie TA MD is to be contacted for subjects who require cycle delays of > 28 days 
due to toxicity.
Section 5.7  Dose Reductions or Delays
Last paragraph previously read:
In the case of delays, interruptions or study treatment discontinuation, tumor assessments 
should continue at intervals of 9 weeks from C1D-2.
Has been changed to read:
In the case of delays, interruptions or study treatment discontinuation, tumor assessments 
should have continued at intervals of 9 weeks from C1D-2.  Following the primary 
analysis and implementation of Protocol Amendment 4, the tumor assessment interval 
may be increased to every 12 weeks (or not to exceed 24 weeks for subjects with durable 
disease control, at investigator discretion) from last scan.


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Due to the COVID-19 pandemic, temporary study drug interruption may occur.  The
AbbVie TA MD is to be contacted for subjects who require cycle interruptions of 
> 28 days.
Section 5.7.1.1  Carboplatin + Paclitaxel Dose Reduction and Delays
Second paragraph previously read:
On Day 1 of each cycle, ANC must be ≥ 1,500/mm3 and platelet count must be 
≥100,000/mm3. If the counts are lower than the limit, treatment should be delayed until 
recovery to the required ANC and platelet count.  
Has been changed to read: 
It is recommended that treatment on Day 1 of each cycle proceeds only if ANC is 
≥1500 cells/mm3 and the platelet count is ≥ 100,000/mm3. Recommended dose 
modifications/delays based on hematologic toxicities on Day 1 are outlined in Table 8. 
For subjects with an ANC of 1000 – 1499/mm3 or platelet count 75,000 – 99,999/mm3 on 
Day 1, dosing may continue without modification or delay until recovery, at investigator 
discretion, if drug-related toxicity has been ruled out.  If ANC is below 1000/mm3 or the 
platelet count is below 75,000/mm3, treatment should be delayed until recovery.
Table 9.  Blinded Study Treatment (Veliparib/Placebo + Carboplatin + Paclitaxel) 
Dose Reduction and Delays for Hematologic Toxicities on Day 8 or 15
Table note "Note:," last sentence previously read:
Pegfilgrastim should not be used for patients receiving Day 15 paclitaxel as they do not 
have a 2-week chemotherapy-free interval.
Has been changed to read:
Pegfilgrastim should not be used for subjects receiving Day 15 paclitaxel as they do not 
have a 2-week chemotherapy-free interval.


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Section 5.7.1.2  Veliparib or Placebo Dose Reductions and Delays in Combination 
with Carboplatin + Paclitaxel
Item 3, last sentence previously read:
The treatment plan for subjects who experience a robust and durable response (such as a 
confirmed CR following 10 or more cycles of therapy) and for whom the investigator 
considers the potential risks of continued cytotoxic chemotherapy outweigh the benefits 
should be discussed with the Blinded AbbVie TA MD prior to initiating single-agent 
blinded veliparib/placebo.
Has been changed to read:
The treatment plan for subjects who experience a robust and durable response (such as a 
confirmed CR following 10 or more cycles of therapy) and for whom the investigator 
considers the potential risks of continued cytotoxic chemotherapy outweigh the benefits 
should be discussed with the AbbVie TA MD prior to initiating single-agent blinded 
veliparib/placebo.
Section 5.7.1.2  Veliparib or Placebo Dose Reductions and Delays in Combination 
with Carboplatin + Paclitaxel
Item 5 previously read:
For any ≥ Grade 2 event of seizure attributed to veliparib/placebo, veliparib/placebo is to 
be interrupted, brain CT or MRI obtained, and the event should be discussed with the
Blinded AbbVie TA MD.
Has been changed to read:
For any ≥ Grade 2 event of seizure attributed to veliparib/placebo, veliparib/placebo is to 
be interrupted, brain CT or MRI obtained, and the event should be discussed with the
AbbVie TA MD.


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Section 5.7.1.3  Blinded Veliparib/Placebo and Unblinded Veliparib Monotherapy 
Dose Reductions and Delays
Frist paragraph, last sentence previously read:
If veliparib/placebo monotherapy is initiated, the starting dose should be 300 mg for 
2 weeks followed by an increase to 400 mg, if well tolerated.
Has been changed to read:
If veliparib/placebo monotherapy is initiated, the starting dose should be 300 mg BID for 
2 weeks followed by an increase to 400 mg BID, if well tolerated.
Section 5.7.1.3  Blinded Veliparib/Placebo and Unblinded Veliparib Monotherapy 
Dose Reductions and Delays
Third paragraph previously read:
Subjects should have an Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 and a platelet 
count ≥ 100,000/mm3 prior to initiating the subsequent cycle.  For any subject who 
experiences Grade 3 or 4 toxicity despite optimal supportive care and the toxicity is not 
attributable to underlying disease, the veliparib/placebo dose will be held until the toxicity 
resolves to Grade 1 or lower or to baseline if Grade 2 is present at the time of study entry.
Has been changed to read:
It is recommended that treatment on Day 1 of each cycle proceeds only if ANC is 
≥1500 cells/mm3 and the platelet count is ≥ 100,000/mm3.  Dosing may continue in 
subjects with ANC and/or platelet counts ranges of ANC of 1000 – 1499/mm3 or platelet 
count 75,000 – 99,999/mm3 without modification at investigator discretion if drug-related 
toxicity has been ruled out.
For any subject who experiences Grade 3 or 4 toxicity despite optimal supportive care and 
the toxicity is not attributable to underlying disease, the veliparib/placebo dose will be 
held until the toxicity resolves to Grade 1 or lower or to baseline if Grade 2 is present at 
the time of study entry.


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Section 5.7.1.3  Blinded Veliparib/Placebo and Unblinded Veliparib Monotherapy 
Dose Reductions and Delays
Sixth paragraph, first bullet, last sub-bullet previously read:
For any > Grade 2 event of seizure attributed to veliparib/placebo, veliparib/placebo is to 
be interrupted, brain CT or MRI obtained, and the event should be discussed with the 
appropriate blinded or unblinded AbbVie TA MD.
Has been changed to read:
For any > Grade 2 event of seizure attributed to veliparib/placebo, veliparib/placebo is to 
be interrupted, brain CT or MRI obtained, and the event should be discussed with the 
AbbVie TA MD.
Section 5.7.1.3  Blinded Veliparib/Placebo and Unblinded Veliparib Monotherapy 
Dose Reductions and Delays
Last paragraph, last sentence previously read:
This should be discussed with the appropriate blinded or unblinded AbbVie TA MD.
Has been changed to read:
This should be discussed with the appropriate AbbVie TA MD.
Section 5.7.1.4  Allergic Reaction/Hypersensitivity
Subsection Carboplatin:
Last sentence previously read:
This should be discussed with the Blinded AbbVie TA MD.
Has been changed to read:
This should be discussed with the AbbVie TA MD.


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Figure 2.  Adverse Event Collection
Previously read:
*
Only if considered by the Investigator to be causally related to study-required procedures.
Has been changed to read:
*
Only if considered by the Investigator to be causally related to study-required procedures.
**
Adverse events of myelodysplastic syndrome, acute myeloid leukemia or any second primary malignancy should 
be reported throughout the entire duration of follow-up phase even if the onset is > 30 days following 
discontinuation of study treatment.
Section 6.1.6  Adverse Event Reporting
First paragraph, last sentence previously read:
Serious adverse events that occur prior to the site having access to the Rave (EDC) system 
should be faxed to AbbVie Clinical Pharmacovigilance within 24 hours of being made 
aware of the serious adverse event.


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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 faxed to AbbVie Clinical Pharmacovigilance within 
24 hours of being made aware of the serious adverse event.
Section 6.1.6  Adverse Event Reporting
Second, third, fourth, and fifth paragraph previously read:
For safety reporting related questions or concerns for the blinded study treatment arm, 
contact the Oncology Safety Team at:
Oncology Group Safety Desk
AbbVie
Dept. R48S, Bldg. AP30
1 North Waukegan Road
North Chicago, IL  60064
Office:
+ 1 847 935-2609
Fax:
+ 1 847 785-8224
Email:
SafetyManagement_Oncology@abbvie.com
For safety reporting related questions or concerns for the unblinded veliparib 
monotherapy (crossover) treatment arm, contact the Oncology Safety Team at:
Email:  M12-914_Unblinded_Team@abbvie.com






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Section 6.1.6  Adverse Event Reporting
Add:  new eighth and ninth paragraph
Due to the COVID-19 pandemic and evolving local regulations, urgent safety measures 
may need to be employed in order to protect participating subjects from any immediate 
hazard.  Such events and measures should be reported to the sponsor emergency medical 
contact listed above immediately.
COVID-19 infections should be captured as adverse events.  If the event meets the criteria 
for a serious adverse event (SAE), then follow the SAE reporting directions per the 
protocol and above.  If a subject has a confirmed or suspected COVID-19 infection, the 
investigator should contact the AbbVie TA MD before reintroducing study drug.






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Has been changed to read:
Secondary efficacy analyses comparing the effects of veliparib 120 mg BID + carboplatin 
+ paclitaxel and placebo + carboplatin + paclitaxel on the following set of endpoints will 
be performed:  overall survival (OS), clinical benefit rate (CBR) through the end of 
Week 24, objective response rate (ORR) and progression-free survival on subsequent 
therapy (PFS2).
Section 8.1.2.2  Secondary Efficacy Endpoints
Delete:  fifth paragraph
Duration of response will be defined as the number of days from the day that the criteria 
are met for CR or PR, whichever is recorded first, to the date that progressive disease is 
documented.  If a subject's response is ongoing at the analysis cutoff date then the subjects 
data will be censored at the date of the last disease progression assessment performed 
prior to the cutoff.  Subjects who never experience a confirmed PR or CR will not be 
included in the analysis.
Section 8.1.2.3  Tertiary Efficacy Endpoints
First paragraph previously read:
In addition to the primary and secondary efficacy analyses, tertiary efficacy analyses will 
be performed comparing the effects of veliparib 120 mg BID + carboplatin + paclitaxel 
versus placebo + carboplatin + paclitaxel on duration of overall response, quality of life, 
and performance status.
Has been changed to read:
In addition to the primary and secondary efficacy analyses, tertiary efficacy analyses will 
be performed comparing the effects of veliparib 120 mg BID + carboplatin + paclitaxel 
versus placebo + carboplatin + paclitaxel on duration of response (DOR), quality of life, 
and performance status.
Duration of response will be defined as the number of days from the day that the criteria 
are met for CR or PR, whichever is recorded first, to the date that progressive disease is 


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documented.  If a subject's response is ongoing at the analysis cutoff date then the subjects 
data will be censored at the date of the last disease progression assessment performed 
prior to the cutoff.  Subjects who never experience a confirmed PR or CR will not be 
included in the analysis.
Section 8.1.3  Timing of Efficacy Analyses and Safety Evaluations
Third paragraph
Add:  new fourth and fifth sentence
Additional OS analyses may be performed before the 'Final OS analysis,' if requested by 
regulatory agencies or otherwise warranted.  For each additional interim analysis of OS, a 
small amount of alpha (0.00001) will be spent.
Section 8.1.5  Secondary Analyses of Efficacy
Last sentence previously read:
P values for secondary efficacy analyses will be subject to multiple comparison 
adjustments using the fixed sequence testing method, with analyses performed in the 
following order:  OS, CBR, ORR, PFS2 and DOR.
Has been changed to read:
P values for secondary efficacy analyses will be subject to multiple comparison 
adjustments using the fixed sequence testing method, with analyses performed in the 
following order:  OS, CBR, ORR, and PFS2.
Section 8.1.5.4  PFS2
Previously read:
The distribution of PFS2 will be estimated for each treatment group using Kaplan-Meier 
methodology and compared between veliparib 120 mg BD + carboplatin + paclitaxel and 
placebo + carboplatin + paclitaxel treatment groups using the log-rank test, stratified by 
ER and/or PgR positive versus ER/PgR negative and prior platinum therapy (yes versus 
no).


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Has been changed to read:
The distribution of PFS2 will be estimated for each treatment group using Kaplan-Meier 
methodology and compared between veliparib 120 mg BID + carboplatin + paclitaxel and 
placebo + carboplatin + paclitaxel treatment groups using the log-rank test, stratified by 
ER and/or PgR positive versus ER/PgR negative and prior platinum therapy (yes versus 
no).
Section 8.1.6  Tertiary Analyses of Efficacy
Add:  new section title
8.1.6
Tertiary Analyses of Efficacy
Section 8.1.6  Tertiary Analyses of Efficacy
Delete:  section title
8.1.6
Tertiary Analyses of Efficacy
Section 8.1.8  Interim Analysis
First and second paragraph previously read:
An independent data monitoring committee (IDMC) will review the unblinded safety data 
for this veliparib Phase 3 study (which will include all subjects enrolled in the study) 
when approximately 60 subjects have met at least one of the following criteria:
●
Received 6 cycles of treatment
●
Reached an event of disease progression
●
Discontinued the study due to toxicity/adverse events
BRCA status discordances between Sponsor core laboratory and local labs will also be 
assessed internally at the time of the interim analysis.  Subsequent reviews will be based 
on recommendations from the IDMC.


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Has been changed to read:
An independent data monitoring committee (IDMC) reviewed the unblinded safety data 
for this veliparib Phase 3 study (including all subjects enrolled in the study) when 
approximately 60 subjects met at least one of the following criteria:
●
Received 6 cycles of treatment
●
Reached an event of disease progression
●
Discontinued the study due to toxicity/adverse events
BRCA status discordances between Sponsor core laboratory and local labs were assessed 
internally at the time of the interim analysis.  Subsequent IDMC reviews of unblinded 
safety data prior to the primary analysis were carried out based on IDMC 
recommendations. No additional reviews by the IDMC will occur since the Sponsor 
management team was unblinded after completing the primary analysis.
Section 8.1.10.8  Multiplicity Adjustments
First paragraph previously read:
If the veliparib treatment group demonstrates statistically significantly better PFS than the 
placebo group, then the secondary endpoints will be tested using the fixed sequence 
testing procedure with the following testing order:  OS, CBR, ORR, DOR, and PFS2.
Has been changed to read:
If the veliparib treatment group demonstrates statistically significantly better PFS than the 
placebo group, then the secondary endpoints will be tested using the fixed sequence 
testing procedure with the following testing order:  OS, CBR, ORR, and PFS2.
Section 9.2  Ethical Conduct of the Study
Add:  new last paragraph
In the event that the COVID-19 pandemic leads to difficulties in performing protocol-
specified procedures, AbbVie will engage with study site personnel in efforts to ensure 
the safety of subjects, maintain protocol compliance, and minimize risks to the integrity of 


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the study while trying to best manage subject continuity of care.  This may include 
alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local lab instead of a central lab), and shipping 
investigational product and/or supplies direct to subjects to ensure continuity of treatment 
where allowed.  In all cases, these alternative measures must be allowed by local 
regulations and permitted by IRB/IEC.  Investigators should notify AbbVie if any urgent 
safety measures are taken to protect the subjects against any immediate hazard.
Section 9.3  Subject Information and Consent
Add:  new last paragraph
Due to the COVID-19 pandemic, modifications to the protocol may be necessary.  
Subjects should be informed of the changes to the conduct of the study relevant to their 
participation (e.g., cancellation of visits, change in laboratory testing site, drug delivery 
method, etc.).  Documentation of this notification and verbal consent should be 
maintained at the site.  A signed and dated informed consent form should be obtained 
from the subject afterwards as soon as possible, if required by local regulations.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical
Global Drug Supply
Statistics
Clinical
Clinical
Bioanalysis
Statistics
Pharmacokinetics


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Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Statistics
Clinical
Clinical
Clinical
Pharmacokinetics
Appendix C.  Study Activities for Blinded Study Treatment (Veliparib/Placebo + 
Paclitaxel + Carboplatin)
Header row, column "Day 1 of Subsequent Cycles" previously read:
Day 1 of Subsequent Cycles
Has been changed to read:
Day 1 of Subsequent Cyclest
Appendix C.  Study Activities for Blinded Study Treatment (Veliparib/Placebo + 
Paclitaxel + Carboplatin)
Header row, column "Every 9 Weeks from C1D 2" previously read:
Every 9 Weeks from C1D 2
Has been changed to read:
Every 12 Weeksl


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Appendix C.  Study Activities for Blinded Study Treatment (Veliparib/Placebo + Paclitaxel + Carboplatin)
Activity "AE Assessment" previously read:
Activity
Screening
C1D-2
C1D1
C1D8a
C1D15a
Day 1 of 
Subsequent 
Cycles
Days 8 and 15 
of Subsequent 
Cyclesa
Every 9 
Weeks from 
C1D 2
AE Assessment
X
X
X
X
X
X
X
Has been changed to read:
Activity
Screening
C1D-2
C1D1
C1D8a
C1D15a
Day 1 of 
Subsequent 
Cyclest
Days 8 and 15 
of Subsequent 
Cyclesa
Every 
12 Weeks
AE Assessment
X
X
X
X
X
X
Appendix C.  Study Activities for Blinded Study Treatment (Veliparib/Placebo + Paclitaxel + Carboplatin)
Delete:  Activity "Survival"
Activity
Screening
C1D-2
C1D1
C1D8a
C1D15a
Day 1 of 
Subsequent 
Cycles
Days 8 and 15 
of Subsequent 
Cyclesa
Every 9 
Weeks from 
C1D 2
Survival


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Appendix C.  Study Activities for Blinded Study Treatment (Veliparib/Placebo + 
Paclitaxel + Carboplatin)
Table note "h.," "j.," "l.," and "Note:" previously read:
h.
For Day 1 visits, study samples for central laboratory analysis may be performed within 72 hours prior to dosing.  
For Day 8 and Day 15 visits, study samples for central laboratory analysis may be performed within 24 hours of the 
scheduled day.  There is no visit window for C1D-2 as any sample prior to randomization is still considered to be 
screening.  A qualified (e.g., certification or accreditation) local laboratory may be used to perform laboratory 
analyses for treatment decisions but this cannot replace the central laboratory analysis on a protocol defined visit.
j.
For patients on prophylactic or therapeutic anticoagulation with warfarin, INR should be monitored before each 
treatment.  Treatment should be held for INR of > 1.5 × ULN on prophylactic warfarin or > therapeutic range if on 
full dose warfarin.
l.
Tumor assessments to support evidence of PD for PFS and/or PFS2 endpoints will be conducted every 9 weeks 
until PD, death or withdrawal of consent for follow-up until PD. (tumor assessments may be conducted 5 days 
prior or 5 days following the scheduled assessment from C1D-2).
Note:
Study procedures (excluding labs and tumor assessments) may be performed four (4) days prior to the 
scheduled study visit date.  C1D1 procedures may be performed within 24 hours surrounding the scheduled 
study visit.
Has been changed to read:
h.
For Day 1 visits, study samples for central laboratory analysis may be performed within 72 hours prior to dosing.  
For Day 8 and Day 15 visits, study samples for central laboratory analysis may be performed within 24 hours of the 
scheduled day.  There is no visit window for C1D-2 as any sample prior to randomization is still considered to be 
screening.  A qualified (e.g., certification or accreditation) local laboratory may be used to perform laboratory 
analyses for treatment decisions but this cannot replace the central laboratory analysis on a protocol defined visit, 
unless AbbVie removes the requirements for sites to send clinical laboratory samples to the central laboratory or 
under special situations (i.e., pandemic) that are approved by the Sponsor and allowed as per local regulation.
j.
For subjects on prophylactic or therapeutic anticoagulation with warfarin, INR should be monitored before each 
treatment.  Treatment should be held for INR of > 1.5 × ULN on prophylactic warfarin or > therapeutic range if on 
full dose warfarin.
l.
Tumor assessments to support evidence of PD for PFS endpoint were conducted every 9 weeks until PD, death or 
withdrawal of consent for follow-up until PD. Following the primary analysis and implementation of Protocol 
Amendment 4, the tumor assessment interval may be increased to every 12 weeks (tumor assessments may be 
conducted ± 10 business days following the scheduled assessment from last scan). At the investigator's discretion, 
the interval between scans may be longer than every 12 weeks for subjects who have durable disease control but 
must not exceed 24 weeks.
Note:
Study procedures (excluding labs and tumor assessments) may be performed four (4) business days prior to 
the scheduled study visit date.  C1D1 procedures may be performed within 24 hours surrounding the 
scheduled study visit.


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Appendix C.  Study Activities for Blinded Study Treatment (Veliparib/Placebo + 
Paclitaxel + Carboplatin)
Add:  new table note "t."
For subjects who have been receiving single-agent veliparib/placebo at a stable dose
without adjustments for multiple cycles and who have no ongoing study drug related 
uncontrolled AEs, it is possible to alternate on-site visits and phone visits every other 
cycle.  Study procedures for phone visits are detailed in the Appendix F.


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Appendix D.  Study Activities for Unblinded Veliparib Monotherapy (Crossover Treatment)
Previously read:
Activity
C1D1
C1D15g
Day 1 of Each Cycle 
Starting with C2
Every 9 Weeks 
from C1D1
Physical Exam (including weight)
X
X
X
12-lead ECG
Xf
Vital Signs
X
X
X
Pregnancy Test (women of childbearing potential)h
Hematology/Chemistrya,b
X
X
X
Urinalysis
X
Tumor Assessmentc
Xd
X
Performance Status (ECOG)
X
X
QLQ C30, BR23, EQ 5D 5L Questionnaires
X
Xe
BPI-SF Questionnaire
X
X
AE Assessment
X
X
X
X
Dispense veliparib
X
X
a.
Refer to Table 4 for detailed list of tests to be performed and frequency.
b.
Study samples for central laboratory analysis may be performed within 72 hours of the scheduled day.  A qualified (e.g., certification or accreditation) local laboratory may be 
used to perform laboratory analyses for treatment decisions but this cannot replace the central laboratory analysis on a protocol defined visit.
c.
Tumor assessments will be conducted every 9 weeks (tumor assessments may be conducted 5 days prior or 5 days following the scheduled assessment from C1D1).
d.
To be performed if a tumor assessment has not been performed within 4 weeks.
e.
QLQ C30, BR23, EQ 5D 5L questionnaires will be administered every other cycle prior to dosing beginning with Cycle 2 (C2, C4, C6 etc.).
f.
ECG must be obtained 1 hour after dosing with veliparib.
g.
If the subject tolerates 300 mg BID for 2 weeks veliparib may be increased to 400 mg BID at the investigator's discretion.


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h.
Pregnancy tests may be repeated during the study according country requirements.
Notes:
The unblinded verliparib monotherapy schedule of assessments should be followed for subjects who were previously randomized to placebo and who discontinue study 
treatment because of disease progression.
Study procedures (excluding labs and tumor assessments) may be performed four (4) days prior to the scheduled study visit date. C1D1 procedures may be performed 
within 24 hours surrounding the scheduled study visit.


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Has been changed to read:
Note: The following schedule of assessments should be followed for subjects who crossed over (were previously randomized to 
placebo, discontinued study treatment because of disease progression and received Sponsor approval for crossover treatment).
Activity
C1D1
C1D15g
Day 1 of Each Cycle 
Starting with C2i
Every 9 Weeks 
from C1D1c
Physical Exam (including weight)
X
X
X
12-lead ECG
Xf
Vital Signs
X
X
X
Pregnancy Test (women of childbearing potential)h
Hematology/Chemistrya,b
X
X
X
Urinalysisa
X
Tumor Assessmentc
Xd
X
Performance Status (ECOG)
X
X
QLQ C30, BR23, EQ 5D 5L Questionnaires
X
Xe
BPI-SF Questionnaire
X
X
AE Assessment
X
X
X
Dispense veliparib
X
X
a.
Refer to Table 4 for detailed list of tests to be performed and frequency.
b.
Study samples for central laboratory analysis may be performed within 72 hours of the scheduled day.  A qualified (e.g., certification or accreditation) local laboratory may be 
used to perform laboratory analyses for treatment decisions but this cannot replace the central laboratory analysis on a protocol defined visit, unless AbbVie removes the 
requirements for sites to send clinical laboratory samples to the central laboratory or under special situations (i.e., pandemic) that are approved by the Sponsor and allowed as 
per local regulation.


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c.
Tumor assessments will be conducted every 9 weeks (± 5 business days from the scheduled C1D1 assessment. Following the primary analysis and implementation of 
Protocol Amendment 4, if a crossover subject has disease control after 6 scans while following the 9 week scan interval schedule, the tumor assessment frequency can be 
changed to every 12 weeks from last scan (± 10 business days). At the investigator's discretion, the interval between scans may be longer than every 12 weeks for subjects 
who have durable disease control but must not exceed 24 weeks.
d.
To be performed if a tumor assessment has not been performed within 4 weeks.
e.
QLQ C30, BR23, EQ 5D 5L questionnaires will be administered every other cycle prior to dosing beginning with Cycle 2 (C2, C4, C6 etc.).
f.
ECG must be obtained 1 hour after dosing with veliparib.
g.
If the subject tolerates 300 mg BID for 2 weeks veliparib may be increased to 400 mg BID at the investigator's discretion.
h.
Pregnancy tests may be repeated during the study according country requirements.
i.
For subjects who have been receiving veliparib monotherapy at a stable dose without adjustments for multiple cycles and who have no ongoing study drug related 
uncontrolled AEs, it is possible to alternate on-site visits and phone visits every other cycle. Study procedures for phone visits are detailed in the Appendix F.
Notes:
Study procedures (excluding labs and tumor assessments) may be performed four (4) business days prior to the scheduled study visit date. C1D1 procedures may be 
performed within 24 hours surrounding the scheduled study visit.


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Appendix E.  Study Procedures for Post Treatment Phase
Appendix title and text previously read:
Appendix E.
Study Procedures for Post Treatment Phase
Discontinuation of Therapy
Without Disease Progression
Discontinuation of Therapy due to Disease Progression
Procedure
3 Weeks Post Study 
Treatment Discontinuation
Every 9 Weeks from C1D-2 
Until Disease Progression
Final Visita
30-Day Follow-Up Visitb
Post Treatment Follow-Up
Physical Exam
(including weight)
X
X
X
X
12-lead ECG
X
Vital Signs
X
X
X
X
Hematology/Chemistryd
Xd
Xd
X
X
Urinalysisd
X
Tumor Assessmente
X
Xf
Full Body Bone Scang
Performance Status 
(ECOG)
X
X
X
X
QLQ C30, BR23, EQ 5D 
5L Questionnairesh
X
X
X
X
BPI-SF Questionnairei
X
X
X
X
AE Assessmentj
X
X
X
X
Survivalc
X
a.
When a subject discontinues the blinded or unblinded portion of the study, a Final Visit will be conducted. 


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b.
All subjects will have one Follow-up Visit approximately 30 days after they have met study discontinuation criteria.  This Follow-up Visit does not need to be performed for 
subjects who have had a Final Visit conducted ≥ 30 days after the last dose of study drug or for subjects who are entering unblinded veliparib monotherapy treatment.  
Follow-up visits should not precede a Final Visit.
c.
If a subject meets criteria for study discontinuation, survival and post treatment therapy will be collected every two months (unless requested by sponsor more frequently to 
support data analysis) beginning on the date the subject is registered off study.  All randomized subjects should be followed for disease progression (PFS) and for the 
second progression (PFS2), until the endpoint of death (OS), until the subject has become lost to follow-up, or until study termination by AbbVie.
d.
Refer to Table 4 for detailed list of tests to be performed and frequency.  Laboratory assessments will only be completed for AE follow-up or reported SAEs.
e.
Tumor assessments to support evidence of PD for PFS and/or PFS2 endpoints will be conducted every 9 weeks until PD, death or withdrawal of consent for follow-up until 
PD (tumor assessments may be conducted 5 days prior or 5 days following the scheduled assessment from C1D-2).
f.
To be performed at the Final Visit, only if not performed within the last 4 weeks.  A 2-week window for obtaining the final visit scan is acceptable for maintaining at least a 
6-week interval between scans as per local guidance and regulations.
g.
Full body bone scans to be obtained as clinically indicated.
h.
QLQ C30, BR23, EQ 5D 5L questionnaires will be administered every 6 weeks in clinic or by telephone.
i.
BPI-SF questionnaires will be administered every 3 weeks in clinic or by telephone.
j.
AE assessments will be performed until 30 days following study treatment discontinuation and for SAEs per Section 6.1.5.
Note:
Study procedures (excluding labs and tumor assessments) may be performed four (4) days prior to the scheduled study visit date.


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Has been changed to read:
Appendix E.
Study Activities for Post Treatment Phase
Discontinuation of Therapy
Without Disease Progression
Discontinuation of therapy 
without disease progression 
(on study, off drug)a,b,d
Activity
Final Visita
30-Day 
Follow-Up 
Visitb
Post 
Treatment 
Follow-Up
Every 12 weeks from last 
scane
Physical Exam
(including weight)d
X
X
12-lead ECG
X
Vital Signsd
X
X
Hematology/Chemistryd
X
X
Urinalysisd
X
Tumor Assessment
Xe
Performance Status (ECOG)
X
X
QLQ C30, BR23, EQ 5D 5L 
Questionnaires
X
X
AE Assessmentd
X
X
Survivalc
X
X
a.
When a subject discontinues the blinded or unblinded study treatment, a Final Visit will be conducted.
b.
All subjects will have one Follow-up Visit approximately 30 days after the last dose of study drug.  This Follow-up 
Visit does not need to be performed for subjects who have had a Final Visit conducted ≥ 30 days after the last dose 
of study drug or for subjects who are entering unblinded veliparib monotherapy treatment.  Follow-up visits should 
not precede a Final Visit.
c.
If a subject meets criteria for discontinuation of therapy, survival and post treatment therapy will be collected every 
two months (unless requested by sponsor more frequently to support data analysis) beginning on the date the 
subject discontinues therapy.  All randomized subjects should be followed for disease progression (PFS) and for 
the second progression (PFS2), until the endpoint of death (OS), until the subject has become lost to follow-up, or 
until study termination by AbbVie.
d.
Refer to Table 4 for detailed list of tests to be performed and frequency.  Laboratory assessments, physical 
examinations and vital signs will only be completed for AE follow-up or reported SAEs after the 30-day follow-up 
visit per Section 6.1.5.
e.
Tumor assessments to support evidence of PD for PFS endpoint were conducted every 9 weeks until PD, death or 
withdrawal of consent for follow-up until PD. Following the primary analysis and implementation of Protocol 
Amendment 4, the tumor assessment interval may be increased to every 12 weeks (tumor assessments may be 
conducted ± 10 business days following the scheduled assessment from last scan). At the investigator's discretion, 
the interval between scans may be longer than every 12 weeks for subjects who have durable disease control, but 
must not exceed 24 weeks.


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Note:
Study procedures (excluding labs and tumor assessments) may be performed four (4) business days prior to 
the scheduled study visit date.
Appendix F.  Study Activities for Blinded or Unblinded Study Treatment Phone 
Visit
Add:  new appendix title and text
Appendix F.
Study Activities for Blinded or Unblinded Study Treatment Phone 
Visit
Activity
Day 1 Phone Visita
Performance Status (ECOG)
X
QLQ C30, BR23, EQ 5D 5L Questionnairesb
Xc
BPI-SF Questionnaireb
X
AE and Concomitant Medication Assessment
Xd
Treatment Compliance Assessment
Xd
Disease Progression Assessment
Xd
Dispense Veliparib or Placeboe
X
a.
For subjects who have been receiving single-agent veliparib/placebo at a stable dose without adjustments for 
multiple cycles and who have no ongoing study drug related uncontrolled AEs, it is possible to alternate on-site 
visits and phone visits by the investigator or designee every other cycle.  At a minimum, subjects should have an 
on-site visit every other cycle. If an on-site visit is not possible for 2 consecutive cycles, or if the subject is not on 
a stable dose or has ongoing study drug related uncontrolled AEs but wishes to alternate on-site and phone visits, 
the plan for the subject's visits should be discussed with the AbbVie TA MD (see Section 7.0 for contact 
information).
b.
During the on-site visits the Investigator or designee will provide the PRO Questionnaires (QLQ C30, BR23, EQ 
5D 5L and BPI-SF) for the next cycle to the subject, so these can be completed at home.
c.
QLQ C30, BR23, EQ 5D 5L questionnaires will be administered every other cycle prior to dosing beginning with 
Cycle 2 (C2, C4, C6, etc.).  If questionnaires were completed during an on-site visit, they may not be required at 
the subsequent phone visit.
d.
In addition to assessing AEs and Concomitant Therapies, the investigator or designee should assess treatment 
compliance and to the extent possible, assess for any clinical evidence of disease progression.  If there are concerns 
about new or worsening AEs or if there is suspicion of disease progression, an unscheduled on-site visit, local labs,
and/or tumor assessment should be scheduled.
e.
During the on-site visits, the Investigator or designee will dispense medication for 2 cycles via IRT and the double 
amount of Dosing Cards, so subjects can complete them for both cycles.
Note:
Phone visit may be performed four (4) business days prior or after the scheduled study visit date.


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Appendix K.  General Chemotherapy Guidelines
Last bullet, last sentence previously read:
Patients are permitted to have chemotherapy doses recalculated for < 10% weight 
changes.
Has been changed to read:
Subjects are permitted to have chemotherapy doses recalculated for < 10% weight 
changes.

SAP_001.pdf: 
ABT-888
M12-914 – Statistical Analysis Plan
Version 3.0 – 30 May 2019
1
1.0
Title Page
Statistical Analysis Plan
Study M12-914
A Phase 3 Randomized, Placebo-Controlled Trial of 
Carboplatin and Paclitaxel With or Without the PARP 
Inhibitor Veliparib (ABT-888) in HER2-Negative 
Metastatic or Locally Advanced Unresectable BRCA 
Associated Breast Cancer
Date:  30 May 2019
Version 3.0
NCT02163694


ABT-888
M12-914 – Statistical Analysis Plan
Version 3.0 – 30 May 2019
2
1.1
SAP Update: Summary of Changes
The purpose of this update is to:
●
Specify that RECIST overall responses are modified following local therapy 
on target lesions.  The progression free survival and objective response 
endpoints are impacted.
●
Indicate that the primary analysis cutoff date was chosen by the project team to 
be April 05th, 2019.
●
Change the description of the PFS2 endpoint to reflect accurately the way that 
the endpoint will be analyzed.
●
Add a set of efficacy summaries for subjects treated with crossover veliparib.
●
Expand the descriptions of the use of Cox modeling in PFS and OS, for the 
ITT population and in subgroups. 
●
Describe two additional progression free survival analyses with additional 
censoring mechanisms.
●
Remove a proposed additional PFS summary stratified by ECOG and region, 
as the number of subjects with one of the ECOG categories was found to be 
low.
●
The list of adverse events of special interest has been expanded to include 
secondary malignancies and teratogenicity.
●
A summary of time to adverse events resulting in study drug interruption or 
dose reduction has been added.
●
Update the details for the presentation of veliparib plasma concentration data.


ABT-888
M12-914 – Statistical Analysis Plan
Version 3.0 – 30 May 2019
3
2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
SAP Update: Summary of Changes...........................................................2
2.0
Table of Contents.....................................................................3
3.0
Introduction .............................................................................5
4.0
Study Objectives, Design and Procedures.............................5
4.1
Objectives ..................................................................................................5
4.2
Design ........................................................................................................5
4.3
Sample Size................................................................................................7
4.4
Interim Analysis.........................................................................................8
5.0
Analysis Populations ...............................................................9
5.1
Definition for Analysis Populations...........................................................9
5.2
Variables Used for Stratification of Randomization..................................9
6.0
Analysis Conventions ..............................................................9
7.0
Demographics, Baseline Characteristics, Medical 
History, Previous and Concomitant Medications...............16
7.1
Demographic and Baseline Characteristics .............................................16
7.2
Medical History .......................................................................................17
7.3
Previous Treatment and Concomitant Medications.................................17
8.0
Subject Disposition................................................................18
9.0
Study Drug Exposure............................................................18
10.0
Efficacy Analysis....................................................................20
10.1
General Considerations............................................................................20
10.2
Primary Efficacy Analysis .......................................................................20
10.3
Secondary Efficacy Analyses...................................................................21
10.3.1
Overall Survival.......................................................................................21
10.3.2
Clinical Benefit Rate................................................................................22
10.3.3
Objective Response Rate .........................................................................22
10.3.4
Progression-Free Survival on Subsequent Therapy (PFS2).....................23
10.4
Tertiary Efficacy Analyses.......................................................................23
10.4.1
Quality of Life..........................................................................................23
10.4.2
Performance Status ..................................................................................28


ABT-888
M12-914 – Statistical Analysis Plan
Version 3.0 – 30 May 2019
4
10.4.3
Duration of Overall Response..................................................................28
10.4.4
10.4.4 Crossover Period Efficacy ............................................................28
10.5
Additional Efficacy Analyses ..................................................................29
10.6
Handling of Multiplicity ..........................................................................30
11.0
Safety Analysis.......................................................................30
11.1
General Considerations............................................................................30
11.2
Analysis of Adverse Events.....................................................................31
11.2.1
Treatment-Emergent Adverse Events ......................................................31
11.2.2
Adverse Events of Special Interest ..........................................................33
11.3
Deaths ......................................................................................................35
11.4
Analysis of Laboratory and Vital Signs Data ..........................................35
11.4.1
General Considerations............................................................................35
11.4.2
Analyses of Laboratory Test Data Using NCI CTCAE Criteria..............36
11.5
Analyses of Vital Signs Using Criteria for Potential Clinical 
Significance..............................................................................................36
12.0
Pharmacokinetic Analyses....................................................37
12.1
Tabulations and Summary Statistics........................................................37
List of Tables
Table 1.
Veliparib/Placebo and Carboplatin Dose Schema .....................................6
Table 2.
Paclitaxel Dose Schema.............................................................................6
Table 3.
Time Windows for Longitudinal Analysis of ECOG and QoL ...............11
Table 4.
EORTC QLQ-C30 Scales........................................................................24
Table 5.
EORTC QLQ-BR23 Scales .....................................................................26
Table 6.
Adverse Events of Special Interest ..........................................................34
Table 7.
Criteria for Potential Clinical Significance in Vital Signs 
Variables ..................................................................................................37


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
the AbbVie Global Statistics Department for veliparib (ABT-888) study 
Protocol M12-914 dated 17 Jun 2016.  It provides details to further elaborate statistical 
methods as outlined in the protocol and describes analysis conventions to guide the 
statistical programming work.
This is the third version of the SAP for Protocol M12-914.
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
The primary objective of this study is to assess the progression-free survival (PFS) of 
veliparib in combination with carboplatin and paclitaxel compared to placebo plus 
carboplatin and paclitaxel in subjects with BRCA-associated metastatic or locally 
advanced unresectable breast cancer.
The secondary objectives of the study are to assess overall survival (OS), clinical benefit 
rate (CBR) through the end of Week 24, objective response rate (ORR), and progression-
free survival on subsequent therapy (PFS2). 
The tertiary objectives are to assess Eastern Cooperative Oncology Group (ECOG) 
performance status, quality of life (QoL), and duration of overall response.
4.2
Design
This is a Phase 3 randomized, double-blind, multinational, multicenter study to evaluate 
the efficacy and tolerability of veliparib in combination with carboplatin and paclitaxel 
compared to placebo plus carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 
mutation as documented by the Sponsor core laboratory with HER2-negative metastatic or 


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locally advanced unresectable breast cancer who have received no more than two prior 
lines of DNA-damaging cytotoxic therapy for metastatic disease. 
Subjects will be randomized in a 2:1 ratio to veliparib in combination with carboplatin 
and paclitaxel (veliparib/C/P) or placebo for veliparib in combination with carboplatin and 
paclitaxel (placebo/C/P).  Subject randomization will be stratified by receptor status 
(estrogen receptor [ER]-positive and/or progesterone receptor [PgR]-positive versus 
ER-negative and PgR-negative status), prior platinum therapy (yes versus no), and the 
presence or absence of central nervous system metastases.
In the main study period, subjects will receive veliparib/placebo in combination with 
carboplatin/paclitaxel until unacceptable toxicity or radiographic progression occurs or 
until subjects experience a robust and durable response for which the investigator 
considers the potential risks of continued cytotoxic chemotherapy to outweigh the 
benefits.  The dose schedules for the combination therapy are detailed below.
Table 1.
Veliparib/Placebo and Carboplatin Dose Schema
Days
–2
–1
1
2
3
4
5
6 – 19
Veliparib 
or Placebo
Twice a 
day
Twice a 
day
Twice a 
day*
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
No drug 
dosing
Carboplatin
IV
No drug 
dosing
*
Veliparib or placebo morning dose should be administered orally in the clinic prior to paclitaxel/carboplatin 
infusion.
Table 2.
Paclitaxel Dose Schema
Days
–2
–1
1
2 – 7
8
9 – 14
15
16 – 19
Weekly Paclitaxel
IV
IV
IV
Dosing of study drug will begin 2 days prior to the start of the carboplatin/paclitaxel 
infusion (on Cycle Day –2) and will continue twice a day for 7 consecutive days.  
Subjects will receive carboplatin and paclitaxel via intravenous infusion on Cycle Day 1.  
Subjects will also receive paclitaxel on Cycle Days 8 and 15.  


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Carboplatin and paclitaxel are to be given only after study drug dosing on Cycle Days –2 
and –1 have been confirmed.  If study drug has not been taken for 2 days then a new 
supply of study drug is to be dispensed and Cycle Days –2 and –1 are to be repeated for 
the cycle.
The subject's Cycle Day 1 ANC and platelet counts must meet protocol-specified 
minimum values or else treatment should be delayed.  In such cases veliparib will be 
re-administered after the delay for 2 days prior to infusion with paclitaxel and carboplatin.  
For subjects receiving paclitaxel on the second and third weeks of a cycle, ANC and 
platelet counts must meet protocol-specified minimums or else treatment should be 
withheld.  When an investigator has determined that a subject should discontinue the 
blinded portion of the study, a Final Visit will be conducted.  All subjects will have 
one Follow-Up Visit approximately 30 days after the last dose of veliparib or placebo.  
This Follow-Up Visit does not need to be conducted if the Final Visit is ≥ 30 days after 
the last dose of veliparib or placebo.
Post-treatment therapy and survival information will be collected every 2 months (or as 
requested by Sponsor to support data analysis) beginning on the date the subject is 
registered off study until the endpoint of death, the subject has become lost-to follow-up, 
or until study termination by the AbbVie.
Subjects who discontinue the blinded study because of disease progression may be 
eligible to receive veliparib monotherapy starting at 300 mg BID in the crossover study 
period upon unblinding and confirmation that they were receiving placebo.  If the subject 
tolerates veliparib at 300 mg BID for 2 weeks, veliparib may be increased to 400 mg BID 
at the investigator's discretion.  Treatment with veliparib monotherapy should continue 
until a second disease progression event or unacceptable toxicity occurs.
4.3
Sample Size
Assuming the true hazard ratio in favor of the veliparib + carboplatin + paclitaxel 
treatment group is 0.69 for PFS, a total of 344 PFS events will be needed for the study to 


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have at least 90% power at two-sided α level of 0.05 to detect a statistically significant 
treatment effect for the veliparib + carboplatin + paclitaxel treatment group using the 
log-rank test for PFS.
In addition, assuming the true hazard ratio in favor of veliparib + carboplatin + paclitaxel 
treatment group is 0.714 for OS, a total of 357 death events will be needed for the study to 
have at least 85% power at two-sided α level of 0.05 to detect a statistically significant 
treatment effect for the veliparib + carboplatin + paclitaxel treatment group using the 
log-rank test for OS.
A total of approximately 500 subjects will be enrolled into the study to observe 344 PFS 
and 357 death events.
4.4
Interim Analysis
To ensure subject safety, an independent data monitoring committee (IDMC) will review 
unblinded safety data (which will include all subjects enrolled in the study) when 
approximately 60 subjects have met at least one of the following criteria:
●
Received 6 cycles of treatment 
●
Reached an event of disease progression
●
Discontinued the study due to toxicity/adverse events
Subsequent reviews will be based on recommendations from the IDMC.
An alpha of 0.0001 will be allocated for PFS at the interim analysis although there is no 
intention to stop the study early for efficacy.
A total of five interim analyses on safety information have been conducted during the 
trial.  The final PFS analysis will be tested at one sided alpha of 0.025.


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5.0
Analysis Populations
5.1
Definition for Analysis Populations
ITT population:  Includes randomized subjects who have been documented to have 
suspected deleterious or deleterious mutations by the sponsor core lab.  In this population 
subjects will be grouped according to the treatment assigned at randomization.
As-Treated (AST) population:  Includes subjects who receive at least one dose of study 
drug (veliparib or placebo).  In this population subjects will be grouped by the actual
treatment received on the first dosing day. 
Crossover population:  Includes subjects who receive at least one dose of veliparib in the 
crossover study period. 
5.2
Variables Used for Stratification of Randomization
Subjects will be randomized in a 2:1 ratio to veliparib/C/P or placebo/C/P and stratified 
by receptor status (ER and/or PgR-positive versus ER/PgR negative), prior platinum 
therapy (yes versus no), and presence of CNS metastases (yes versus no).
6.0
Analysis Conventions
General Considerations
Except where otherwise noted, statistical significance will be determined by a one-sided 
significance level of 0.025 for all efficacy analyses and by two-sided significance level of 
0.05 for all safety statistical analyses.
The following conventions are applicable to analyses of blinded study period data.  
Definition of Study Drug
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Usage of Multiple Values Reported on the Same Day
In cases where multiple values are collected on the same day (including baseline visit and 
post-baseline visits), the worst (e.g., maximum grade) value will be selected as the value 
for that day for the shift analysis of laboratory parameters; the arithmetic average will be 
calculated and used as the value for that day for mean changes in quality of life and 
performance status parameters.
Definition of Baseline
Unless otherwise specified, the baseline for the main study period is defined as the last 
non-missing observation collected on or prior to the first dose of study drug, or to the date 
of randomization for non-treated subjects.  
Definition of Final Observation
For QoL, laboratory, and vital signs variables, the final observation is defined as the last 
non missing observation collected within 30 days following the last dose of study drug. 
Definition of Study Rx Days (Days Relative to the First Dose of Study Drug)
Study Rx Days are calculated for each time point relative to the first dose date of study 
drug (veliparib/placebo). 
When the date of a study event is on, or later than, the date of first dosing with study drug, 
then the study day for the event is defined to be the event date – the first dosing date + 1.  
When the date of an event is prior to the date of first dosing with study drug then study 
day is defined to be the event date – the first dosing date.
Definition of Within – Cycle Rx Days 
Cycle Rx Days for each cycle are calculated for each time point relative to first dose of 
veliparib/placebo/carboplatin/paclitaxel in each cycle.


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Definition of Analysis Windows
During the treatment period, all time points and corresponding time windows are based on 
Cycle Rx Days, the first dose date of study drug in each cycle.
For longitudinal analyses such as the analysis of mean changes in QoL and ECOG, 
values, the time windows specified in Table 3 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 Rx Day for each scheduled visit.
●
Determine the window around a specific nominal Cycle Rx Day according to 
Table 3.
●
If more than one observation is included in a time window, the observation 
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.
Table 3.
Time Windows for Longitudinal Analysis of ECOG and QoL
Scheduled Visit
Nominal Cycle Rx Day
Time Window (Cycle Rx Day Range)
Cycle 1 Day 1 
BASELINE
As baseline definition
Cycle 2 Day 1
1
(–7, 7)
Cycle X Day 1
1
(–7, 7)
*
For quality of life measures X is every other cycle starting with C4.
For longitudinal analyses, the data will be analyzed as long as there are observations for at 
least 5 subjects in each treatment group.
Total Daily Doses
Study drug administration may be documented with multiple records for overlapping 
treatment periods.  In such cases the overall total daily dose for a day will be calculated as 
the sum of the reported total daily doses for the day rounded to the nearest 10 milligrams.


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Determination of Times-to-Event
The event time for a subject meeting one of the criteria for clinical benefit rate, 
progression-free survival, overall survival, or PFS2 will be calculated as the difference 
between the date that the event occurs and the randomization date plus 1 day.  Response 
durations will be calculated as the difference between the date at which the response was 
first observed and the date at which disease progression is reported plus 1 day.
Censoring conventions for additional PFS analyses
In the primary analysis of progression-free survival, all evaluable data obtained in the 
blinded study period through the primary analysis cutoff date will be analyzed.  In 
additional analyses of PFS, other censoring rules will be applied, as described next.
Impact of Local Therapy:  procedures during study treatment such as surgery or radiative 
therapy may result in the RECIST overall response becoming unevaluable.  When the 
local therapy is on one or more target lesions then the overall response will be considered 
to be Non-CR/Non-PD in such instances until criteria for progressive disease are met, 
except when anti-cancer therapy initiation is grounds for censoring.
Anti-cancer Therapies:  Local therapies reported in the radiographic assessment data and 
post-treatment therapies initiated prior to a PFS event will be considered together as anti-
cancer therapies.  The earliest local therapy date or post-treatment therapy start date will 
be the overall anti-cancer therapy start date. 
Missed radiographic assessments:  In instances where two missed radiographic 
assessments have occurred a subject's data will be censored at the last assessment before 
the gap.  Assessments are scheduled to occur at nine-week intervals with a window of 
five days around the target date: gaps of more than 18 weeks and five days (131 days) 
will be considered as two missed assessments.
Interval censoring:  Analysis with interval censoring will be performed using the 
EM-ICM (Expectation Maximization-Iterative Convex Minorent) method for finding the 


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maximum likelihood estimate of the probability function for the event (PD) to occur at a 
point within an interval (between tumor assessment visits and also in the case of longer 
intervals due to missed tumor assessment visits).  SAS code that will be used for the 
analysis is described in the reference Analyzing Interval-Censored Survival Data with 
SAS® Software, Ying So and Gordon Johnston, SAS Institute Inc., Cary, NC, Se Hee Kim, 
University of North Carolina, Chapel Hill, NC.  SAS Global Forum 2010.  A Kaplan-
Meier curve will be produced from non-parametric maximum likelihood estimates 
(NPMLE) obtained from macro EMICM, specifying the EM-ICM algorithm.  Generalized 
log-rank tests from Zhao & Sun and Sun, Zhao & Sun will be obtained from SAS macro 
ICSTEST.
Determination of Censoring Dates for Overall Survival
The overall survival censoring date for a subject will be the latest assessment date from 
the following list of data record types:  
●
Vital signs
●
Physical exam
●
Lab variables, including SAE lab reports
●
ECOG performance status
●
Quality of life measures
●
Study drug administration
●
Tumor assessments
●
Transfusions
●
Electrocardiogram
●
Adverse event (event start date)
●
Survival follow-up (last-known-alive date)
Records that indicate that the assessment was not done will not be used in determining the 
censoring date.


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Censoring conventions for Objective Responses
Impact of Local Therapy:  procedures during study treatment such as surgery or radiative 
therapy may result in the RECIST overall response becoming unevaluable.  When the 
local therapy is on one or more target lesions then the overall response will be considered 
to be Non-CR/Non-PD in such instances until criteria for progressive disease are met.  
The response duration will be censored at the date of the latest assessment through the 
date of local therapy.
PFS2 Events
The following study outcomes will be counted as a PFS2 event;
●
Radiographic progression on a post-treatment anti-cancer therapy
●
Radiographic progression reported during crossover treatment with veliparib
●
Subject deaths.
Progressions on post-treatment anti-cancer therapy and deaths may have been reported 
either in the blinded study period or in post-treatment follow-up. 
Determination of Censoring Dates for PFS2
If a subject has not had a PFS2 event and has not yet entered survival follow-up then the 
subject's data will be censored at the date of the last available radiographic assessment.  If 
a subject does not have a post-baseline radiographic assessment then the randomization 
date will be used for censoring.  Once in survival follow-up, the last known alive date 
from follow-up will be the censoring date. 
Definition of Treatment-Emergent Adverse Events
Adverse Events will be considered "treatment-emergent" when their onset is on or after 
the day of the first dose of study drug and also are at most 30 days after the last dose of 


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study drug.  Events must also occur prior to the initiation of crossover treatment with 
veliparib.
If the onset date for an adverse event is reported with a month and year but without the 
day of the month, and the reported month matches that of the start of treatment with study 
drug, then the adverse event will be treatment-emergent.  Similarly, if the reported month 
matches the month in which the post-treatment follow-up period ends then the adverse 
event will be treatment-emergent.
Laboratory Test Data
Central lab serum chemistry test results for this study are available from the Roche and 
Abbott Architect analysis platforms.  When a sample was analyzed initially using the 
Roche platform, a projected Architect value for each test has been supplied by the lab 
vendor along with the Roche platform test value.  Projected Roche values are similarly 
available along with Architect test results when the sample was analyzed initially with the 
Abbott system.  The Architect values, actual or projected, will be used in analyses of lab 
test data.
NCI Grades for Laboratory Variables
Laboratory test values will be graded using CTCAE version 4.03 criteria prior to analysis.  
Criteria are specified for the assignment of grades with values between 1 and 4.  The 
criteria are unidirectional:  any one set of criteria constitute a screening either for low or 
high values of potential clinical significance.  
For laboratory tests for which a normal range limit is one end of the grade 1 range then 
values that are either within the normal range or outside it in the direction opposite the test 
will be classified as grade 0 values.  For other tests, values outside the grade 1 range in the 
direction opposite that of the test will be classified as grade 0. 
There can be instances in which the criteria for more than one grade apply to a lab test 
value.  In those instances the highest applicable grade will be assigned to the value.


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7.0
Demographics, Baseline Characteristics, Medical 
History, Previous and Concomitant Medications
These summaries will be prepared by treatment group for the ITT population.  A separate 
demographics summary will be produced for the crossover population.
7.1
Demographic and Baseline Characteristics
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
mean, standard deviation, minimum, maximum, and range.  Frequencies and percentages 
will be computed for the following categorical parameters:  
●
sex
●
race and ethnicity
●
geographic region
●
core lab and historical BRCA1 and BRCA2 status
●
ER/PgR status (ER/PgR+, triple-negative)
●
sites of metastases (per investigator), including
●
bone disease only
●
any bone disease
●
liver, metastases
●
lung metastases
●
central nervous system metastases
●
all sites other than bone, liver, lung and CNS 
●
prior platinum therapy use
●
prior cytotoxic therapy 
●
for metastatic breast cancer
●
in the neoadjuvant and adjuvant settings
●
history of central nervous system metastases
●
presence of measurable disease (per investigator)
●
number of target and non-target lesions (per investigator)


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●
ECOG performance status.
Prior platinum therapy use and estrogen and progesterone status will be summarized both 
as recorded in the process of randomization and in the subject's oncology history.  Prior 
cytotoxic therapies will be identified by the project team from the oncology history data 
and then summarized.
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the CRF.  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.  
7.3
Previous Treatment and Concomitant Medications
The frequency 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 the WHO dictionary.  
This analysis will be performed for prior and concomitant medications separately.  Any 
medication initiated before the first day of treatment with study drug is a prior treatment.  
Medications initiated during the study from the first day of treatment with study drug, or 
else initiated before treatment with study drug and continued into the study treatment 
period, are concomitant medications.
The frequency and percentage of subjects who have had prior oncology therapies will be 
summarized by regimen names.  In addition, the best response to any therapies prior to 
study drug (or randomization for non-treated subjects) will be summarized.


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8.0
Subject Disposition
The number of randomized subjects and the number of treated subjects will be 
summarized by treatment group and by investigator site/country.
The numbers and percentages of discontinuations of study drug, carboplatin, paclitaxel 
and the study will be summarized by treatment group and reason for discontinuation.
9.0
Study Drug Exposure
Analyses of study drug exposure listed below will be performed on the AST population.  
Exposure to study drug, carboplatin, and paclitaxel in the main study period will be 
summarized using the following measures:  
●
Total days of exposure
●
Cycles of exposure
●
Dose reductions
●
Dose delays
When subjects discontinue carboplatin and paclitaxel but continue to receive study drug 
as a single-agent, the study drug regimen changes from seven days per cycle at 120 mg 
BID to daily dosing, initially at 300 mg BID.  Days of exposure to study drug in the main 
study period will be summarized over the following sub-periods:  
●
Combination therapy
●
Single-agent therapy
●
Total study drug exposure.
Days of exposure to veliparib in the crossover period will be summarized separately.
Total days of exposure to study drug will be calculated using the start and end dates in the 
study drug administration records.  Exposure to study drug is presumed for each day from 


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the start date through the end date in a study drug administration record.  Days of 
exposure to carboplatin and paclitaxel will be determined from the number of records 
reported for each subject, as each record covers one day of treatment with those therapies.
The number of cycles received is to be determined from the visit schedule information 
associated with the study drug administration records.
For total days of exposure and cycles of exposure, descriptive statistics (mean, standard 
deviation, median, and range) will be presented by treatment group for study drug, 
carboplatin, and paclitaxel.  
Cycles of exposure to study drug, paclitaxel, and carboplatin, will be summarized further 
with subject frequency counts and percentages by treatment group.  In these summaries, 
cycles of exposure will be grouped in multiples of six (1 to 6 cycles, 7 to 12 cycles, and so 
on) prior to tabulation until the total number of subjects remaining is at most 25.  The 
number and percentage of subjects treated with three days of paclitaxel in each of the 
first 12 cycles will be tabulated.
If the difference between starting dose dates of two consecutive cycles of paclitaxel or 
carboplatin exceeds 35 days then a subject will be considered as having had a delay in 
dosing with those agents.  The percentages of subjects with treatment delays will be 
summarized for each treatment group.
A permanent decrease in the total daily dose of veliparib will be counted as a dose 
reduction.  Carboplatin dose reductions will be identified based on the reported AUC dose 
levels.  The body surface area based dose level (mg/m2) will be used to identify dose 
reductions of paclitaxel.  Dose level changes in study drug following discontinuations of 
paclitaxel and carboplatin will be summarized separately.  The percentages of subjects 
with dose reductions will be summarized for each treatment.  The number and percentage 
of subjects treated at the initial dose level or with one or two dose reductions at the end of 
each of the first 12 cycles will be tabulated.  The counts and percentages of dose 
reductions at the final dosing level will also be tabulated.


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10.0
Efficacy Analysis
10.1
General Considerations
The analysis set for efficacy endpoints will be the ITT population.  Except where noted, 
comparisons of efficacy endpoints will be performed between the two treatments as 
assigned by the IVRS/IWR (veliparib + carboplatin + paclitaxel versus placebo + 
carboplatin + paclitaxel).
The primary and secondary efficacy endpoints that include radiographic assessments will 
be based on investigators' assessments, per RECIST 1.1. 
The primary analysis cutoff date is April 05th, 2019, by which time at least the requisite 
number of PFS needed for performing the primary analysis at 90% power is expected to 
have occurred. The corresponding database will be termed the Primary PFS database.
Overall Survival will be analyzed with data from the Primary PFS database, with a 
second OS analysis planned at a later date at which 357 deaths have occurred in the event 
that the first analysis is not statistically positive.  The Lan DeMets alpha-spending 
function with an O'Brien-Fleming boundary will be used to ensure that the one-sided false 
positive rate will be 0.025 or less for overall survival. 
10.2
Primary Efficacy Analysis
The primary efficacy analysis will be a comparison of progression-free survival between 
the veliparib + carboplatin + paclitaxel and the placebo + carboplatin + paclitaxel 
treatment groups. 
For a given subject, time to PFS will be defined as the number of days from the date the 
subject was randomized to the date the subject experiences radiographic disease 
progression (as determined by the investigators), or to the date of death (all causes of 
mortality) if disease progression is not reached.  All events of disease progression 
occurring on or before the Primary Analysis Cutoff date will be included, regardless of 
whether the event occurred while the subject was still taking study drug or had previously 


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discontinued study drug.  Events of death will be included for subjects who had not 
experienced disease progression, provided the death occurred on or prior to the primary 
analysis data and within 9 weeks (63 days) of the last available disease progression 
assessment.  If the subject does not have an event of disease progression and the subject 
has not died on or before the Primary Analysis Cutoff date the subject's data will be 
censored at the date of the subject's last available disease progression assessment.  If the 
randomized subject did not have any post-baseline disease progression assessments, 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 and compared between treatment groups using the log-rank test, stratified by 
prior platinum therapy (Yes versus No) and receptor status (ER and/or PgR positive 
versus ER/PgR negative). 
A Cox proportional hazard model, stratified by prior platinum therapy and ER/PgR 
receptor status, will be used to estimate the hazard ratio and 95% confidence interval 
comparing the two treatment arms.
10.3
Secondary Efficacy Analyses
Secondary efficacy analyses comparing the effects between veliparib + carboplatin + 
paclitaxel and placebo + carboplatin + paclitaxel on the following set of endpoints will be 
performed:  overall survival (OS), clinical benefit rate through the end of Week 24 (CBR), 
objective response rate (ORR), and progression-free survival on subsequent therapy 
(PFS2). 
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 the subject was randomized to the date of the subject's death.  All events of 
death which occur up to the analysis cutoff date will be included, regardless of whether 
the event occurred while the subject was still taking study drug or after the subject 


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discontinued study drug.  If a subject has not died, the data for the subject will be 
censored at the date last known to be alive or at the analysis cutoff date if that is earlier.
The distribution of overall survival will be estimated for each treatment group using 
Kaplan-Meier methodology and compared between two treatment groups using the log 
rank test, stratified by prior platinum therapy (Yes versus No) and receptor status (ER 
and/or PgR positive versus ER/PgR negative).
10.3.2
Clinical Benefit Rate
The clinical benefit rate for each treatment group will be obtained from a time-to-event 
analysis of radiographic disease progression per the investigator.  The endpoint will be 
defined to be the progression-free rate at 24 weeks (168 days). 
Progression-free rates at 24 weeks will be estimated for each treatment arm using Kaplan-
Meier methodology.  95%-confidence intervals for the rates will be obtained using a log-
log transformation.  Standard errors for the rates will also be obtained from the time-to-
progression model.  A chi-square test statistic constructed as the ratio of the squared 
difference of the Kaplan-Meier estimates of the progression-free rates and the estimate of 
the associated variance of the difference will be used to test the null hypothesis that the 
clinical benefit rate at Week 24 for the two treatment groups are the same.
All events of disease progression in the primary PFS analysis database will be included, 
regardless of whether the event occurred while the subject was still taking, or had 
previously discontinued, study drug.  If the subject has not yet progressed then the 
subject's data will be censored at the date of the last evaluable disease progression 
assessment.  Subjects without post-baseline assessments will be censored at the date of 
randomization.
10.3.3
Objective Response Rate
The objective response rate (ORR) will be calculated as the proportion of subjects who 
have a confirmed PR or CR based on assessment by the investigators per RECIST 


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(version 1.1).  Subjects in the ITT population with at least one measurable lesion at 
baseline will be included in the analysis, as will be the case for the analysis of any 
response data.
ORR will be estimated for each treatment group and compared between two treatment 
groups using a CMH test stratified by prior platinum therapy (Yes versus No) and 
estrogen/progesterone receptor status (ER and/or PgR positive versus ER/PgR negative).  
In addition, 95% confidence interval will be constructed for ORR.
10.3.4
Progression-Free Survival on Subsequent Therapy (PFS2)
PFS2 will be defined as the number of days from the date of randomization to the time of 
disease progression on subsequent therapy or death from any cause. 
The distribution of PFS2 will be estimated for each treatment group using Kaplan-Meier 
methodology and compared between two treatment groups using the log-rank test, 
stratified by prior platinum therapy (Yes versus No) and receptor status (ER and/or PgR 
positive versus ER/PgR negative).
10.4
Tertiary Efficacy Analyses
In addition to the primary and secondary efficacy analyses, tertiary efficacy analyses will 
be performed to compare the effects of veliparib + carboplatin + paclitaxel and placebo + 
carboplatin + paclitaxel on quality of life, performance status, and duration of 
radiographic response.
Subjects must have both a baseline and post-baseline assessment to be included in these 
analyses.
10.4.1
Quality of Life
Quality of life assessments will be performed through the use of the EORTC QLQ-C30, 
EORTC BR23, and EQ-5D-5L questionnaires.  Pain assessments will be analyzed via the 


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Brief Pain Inventory Short Form (BPI-SF).  Performance status over time will be analyzed 
using the ECOG scale.
EORTC QLQ-C30
The overall and domain specific scores will be calculated from the 30 items in the 
EORTC QLQ-C30 for each subject based on the QLQ-C30 scoring instruction.  The items 
and scales of the QLQ-C30 are as follows:
Table 4.
EORTC QLQ-C30 Scales
Scale
Number of Items
Item Range
Item Numbers
Global Health Status/Quality of Life
Global Health Status/Quality of Life
QL2
2
6
29, 30
Functional Scales
Physical Functioning*
PF2
5
3
1 – 5
Role Function*
RF2
2
3
6 – 7
Emotional Functioning*
EF
4
3
21 – 24
Cognitive Functioning*
CF
2
3
20, 25
Social Functioning*
SF
2
3
26 – 27
Symptom Scales
Fatigue
FA
3
3
10, 12, 18
Nausea and Vomiting
NV
2
3
14 – 15
Pain
PA
2
3
9, 19
Dyspnoea
DY
1
3
8
Insomnia
SL
1
3
11
Appetite Loss
AP
1
3
13
Constipation
CO
1
3
16
Diarrhoea
DI
1
3
17
Financial Difficulties
FI
1
3
28
*
Function scales.
Note:
Item range is the difference between the possible maximum and the minimum response to individual items.
Scoring algorithms for scales are as follows:


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For all Scales, the Raw Score (RS) is the Mean of the Component Items:
If items I1, I2,…, In are included in a scale, the procedures are as follows:
Raw Score (RS) = (I1 + I2 +… + In)/(number of non-missing items),
Then the Functional Scales:
Score = (1 - (RS-1)/range)*100, where range is provided by the table above.
For example:  
Emotional Functioning:  RS = (Q21 + Q22 + Q23 + Q24)/4
EF Score = (1 - (RS-1)/3)*100
For the Symptoms Scales/Items and Global Health Status/QOL:
Score = ((RS – 1)/range)*100
For example:  
Fatigue:  RS = (Q10 + Q12 + Q18)/3
FA Score = ((RS-1)/3)*100
Descriptive statistics will be presented for baseline, each scheduled post-baseline visit, 
and the final visit, of domain specific scores by each treatment group.  Mean change 
(95% CI) from baseline to each scheduled post-baseline visit within each treatment group 
and the mean difference of change (95% CI) from baseline to each scheduled post-
baseline visit and the final visit between the two treatment groups will be obtained from 
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EORTC QLQ-BR23
The EORTC QLQ-BR23 is a 23-item breast cancer-specific questionnaire about the 
common side effects of therapy, body image, sexuality, and outlook for the future.  
Domain specific scores will be calculated from the 23 items for each subject based on the 
QLQ-BR23 scoring instructions.  The items and scales of the QLQ-BR23 are as follows.
Table 5.
EORTC QLQ-BR23 Scales
Functional Scales
Scale Name
Number of Items
Item Range
Item Numbers
Body Image
BRBI
4
3
9 – 12
Sexual Functioning
BRSEF
2
3
14, 15
Sexual Enjoyment
BRSEE
1
3
16
Future Perspective
BRFU
1
3
13
Symptom Scales/Items
Systemic Therapy Side Effects
BRST
7
3
1 – 4, 6, 7, 8
Breast Symptoms
BRBS
4
3
20 – 23
Arm Symptoms
BRAS
3
3
17 – 19
Upset by Hair Loss
BRHL
1
3
5
Descriptive statistics will be presented for baseline, each scheduled post-baseline visit, 
and the Final Visit of domain specific scores by each treatment group.  Mean change 
(95% CI) from baseline to each scheduled post-baseline visit and the Final Visit within 
each treatment group and the mean difference of change (95% CI) from baseline to each 
scheduled post-baseline visit and the Final Visit between treatment groups will be 
obtained from the ANCOVA model with treatment group as the factor and baseline value 
as a covariate.
EQ-5D-5L
EQ-5D-5L consists of 5 items:  mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression and a self-rated health visual analogue scale (EQ VAS).  An 
EQ-5D-5L utility score will be calculated based on US preference-weighted index score 
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in utility score (and 95% CI) from baseline to each scheduled post-baseline visit within 
each treatment group and the mean difference of change (95% CI) from baseline to each 
scheduled post-baseline visit and the final visit between the two treatment groups will be 
obtained from the ANCOVA model with treatment group as the factor and baseline value 
as a covariate. 
Item 6 of EQ-5D-5L, a visual analog scale (VAS) will be analyzed using the same 
methodology as detailed for the utility score.
Brief Pain Inventory
The Short Form of the Brief Pain Inventory includes four questions pertaining to pain 
severity reported by the subject on a scale of 0 (no pain) – 10 (pain as bad as is 
imaginable).  Summary statistics for each question on severity will be reported by 
treatment group.  Summary statistics on pain severity overall will be reported by treatment 
group.  Pain severity overall is scored as the average of the 4 pain severity items 
(i.e., average, worst, least, current) and will be provided if at least 2 items are completed.
There are seven questions in the inventory used to gauge the degree of interference in 
subject activity due to pain, scored from 0 – 10.  Pain interference is scored as the mean of 
the seven pain interference items, if at least four of the seven total items are completed.  
Positive change scores denote improved QoL except for the symptom scale which is 
reversed.  The subject's responses will be included in an evaluation of the average degree 
of interference in subject activity at each assessment.
Mean change (95% CI) from baseline to each scheduled post-baseline visit and the Final 
Visit within each treatment group and the mean difference of change (95% CI) from 
baseline to each scheduled post-baseline visit and the Final Visit between treatment 
groups will be obtained from the ANCOVA model with treatment group as the factor and 
the baseline value as a covariate.  Analyses will be done for each item as well as 
sub-domain scales.


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10.4.2
Performance Status
Descriptive statistics on the ECOG score will be presented for baseline, each scheduled 
post-baseline visit, and the Final Visit for each treatment group.  Mean change (95% CI) 
from baseline to each scheduled post-baseline visit and the Final Visit within each 
treatment group and the mean difference of change (95% CI) from baseline to each 
scheduled post-baseline visit and the Final Visit between treatment groups will be 
obtained from an ANCOVA model with treatment group as the factor and baseline ECOG 
score as a covariate.
10.4.3
Duration of Overall Response
The distribution of the duration of overall response will be estimated for each treatment 
group using Kaplan-Meier methodology. 
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 
PD is documented.  If a subject's response is ongoing at the analysis cutoff date then the 
subject's data will be censored at date of the last disease progression assessment 
performed on or prior to the cutoff.
Subjects in the ITT population with at least one measurable lesion at baseline will be 
eligible for inclusion in the analysis.  Subjects who never experience a confirmed PR or 
CR will not be included in the analysis.
10.4.4
Crossover Period Efficacy
For subjects receiving crossover veliparib therapy, progression-free survival, objective 
response, best response, clinical benefit rate at 6 months, and duration of response will be 
summarized.  The start date for the time-to-event analyses will be the first day of 
treatment with crossover veliparib.  The analyses will otherwise be carried out as 
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10.5
Additional Efficacy Analyses
The primary endpoint may also be analyzed for all randomized subjects, regardless of 
whether or not the subject has a deleterious mutation confirmed by the Sponsor core lab, 
or for the AST population restricted to subjects with confirmed or suspected mutations.
In addition to the stratified log-rank test for the primary endpoint, the unstratified log-rank 
test. Stratified and unstratified Cox proportional hazards models may be used for the 
comparison of PFS between two treatment groups. 
PFS and ORR based on data from the central reader will be analyzed using the same 
methodology as detailed in previous sections.
Cox proportional hazard modeling will be performed to compare PFS and OS by 
treatment group in subgroups.  Subgroup analyses within the ER/PgR status levels will be 
performed with treatment alone in the Cox model.  Cox modeling with ER/PgR status as 
stratification factor along with the treatment in the model will be used to examine PFS and 
OS in subgroups including but not limited to the following:  BRCA1/2 status (BRCA1 
positive or suspected mutation versus negative; BRCA2 positive or suspected mutation 
versus negative), prior platinum therapy use, ECOG performance status 
(0 versus 1 versus 2), geographic region (US versus non-US), race (white or any other 
race), age group (< 45 versus ≥ 45), and history of CNS (Yes versus No).  A hazard ratio, 
95% confidence interval, and p-value will be obtained for each subgroup and tabulated.  
The hazard ratios and confidence intervals will also be displayed visually in forest plots.
Progression free survival and OS will be compared by treatment group in the above 
subgroups by performing log-rank tests.  The log-rank tests within ER/PgR strata will be 
unstratified.  The logrank test performed on all other subgroups will be stratified by 
ER/PgR status.
In two additional PFS analyses data will be censored prior to the date of the final 
radiographic assessment if some or all of the following study events occur before then:  1) 
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local therapy on at least one of the target or non-target lesions, 3) at the date of the last 
radiographic assessment prior to a gap when two or more assessments are missed, and 4) 
at the date of a site blind break.  In one analysis data will be censored if an anti-cancer 
therapy is initiated or local therapy is received.  In the second analysis data will be 
censored if any of the above-identified events have occurred.  This modified data will be 
analyzed using the same methodology as detailed for the primary PFS analysis.
Additional analyses may also be performed for PFS, such as 1) including only data and 
events occurring on treatment or within 30 days of the last dose of study drug; and 2) 
analysis using interval censoring methods.
10.6
Handling of Multiplicity
If the veliparib treatment group demonstrates statistically significantly better PFS than the 
control group, then the secondary endpoints will be tested using the fixed sequence testing 
procedure in the following order:  OS, CBR, ORR, and PFS2.
An additional multiplicity issue is introduced through the multiple testing of the OS 
endpoint.  It is anticipated that, at the analysis time of the primary efficacy endpoint PFS, 
there will be too few deaths to support an adequately powered OS analysis.  Therefore, 
two OS analyses are planned, the first one based on the "Primary PFS Analysis" database, 
and the second one based on the "OS Analysis" database (with a total of 357 deaths).  
Statistical significance for OS will be declared if a significant result is obtained for either 
analysis, consistent with group-sequential testing methods specified in Section 10.1.
11.0
Safety Analysis
11.1
General Considerations
Safety analyses will be performed on the as-treated (AST) and crossover populations. 


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11.2
Analysis of Adverse Events
11.2.1
Treatment-Emergent 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.  Analyses will not include 
those events 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 percentages of subjects experiencing an 
adverse event at a given NCI CTCAE version 4.03 terminology grade and relationship to 
study drug will be provided. 
Comparisons of the percentages of subjects in the AST population experiencing an 
adverse event between veliparib + carboplatin + paclitaxel and placebo + carboplatin + 
paclitaxel will be performed using Fisher's exact test.  P values > 0.100 when rounded to 
three decimal places will not be presented.
The numbers and percentages of subjects experiencing treatment-emergent adverse events 
will be summarized for the following adverse event categories:
●
All adverse events
●
Events with a reasonable possibility of being related to study drug according to 
the investigator.
●
Events with a reasonable possibility of being related to carboplatin according 
to the investigator
●
Events with a reasonable possibility of being related to paclitaxel according to 
the investigator
●
NCI grade 3 or higher adverse events
●
NCI grade 3 or higher Events with a reasonable possibility of being related to 
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●
NCI grade 3 or higher Events with a reasonable possibility of being related to 
carboplatin according to the investigator
●
NCI grade 3 or higher Events with a reasonable possibility of being related to 
paclitaxel according to the investigator
●
All adverse events broken down by maximum NCI terminology grade
●
Serious adverse events
●
Serious adverse events with a reasonable possibility of being related to study 
drug
●
Serious adverse events with a reasonable possibility of being related to 
carboplatin
●
Serious adverse events with a reasonable possibility of being related to 
paclitaxel
●
Events leading to discontinuation of study participation 
●
Events leading to discontinuation of study drug
●
Events leading to discontinuation of carboplatin
●
Events leading to discontinuation of paclitaxel
●
Events leading to discontinuation of study participation with a reasonable 
possibility of being related to study drug 
●
Events leading to discontinuation of study drug with a reasonable possibility of 
being related to study drug 
●
Events leading to discontinuation of carboplatin with a reasonable possibility 
of being related to carboplatin
●
Events leading to discontinuation of paclitaxel with a reasonable possibility of 
being related to paclitaxel 
●
Events leading to discontinuation of study participation due to disease 
progression 
●
Events leading to discontinuation of study drug due to disease progression 
●
Events leading to discontinuation of carboplatin due to disease progression 
●
Events leading to discontinuation of paclitaxel due to disease progression 
●
Events leading to discontinuation of study not due to disease progression 
●
Events leading to discontinuation of study drug not due to disease progression 


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●
Events leading to discontinuation of carboplatin not due to disease progression 
●
Events leading to discontinuation of paclitaxel not due to disease progression
●
Events leading to study drug interruption
●
Events leading to study drug dose reduction
●
Events leading to carboplatin interruption
●
Events leading to carboplatin dose reduction
●
Events leading to paclitaxel dose interruption
●
Events leading to paclitaxel dose reduction
●
Any treatment emergent adverse event leading to death
●
Any treatment-emergent adverse event leading to death with a reasonable 
possibility of being related to study drug
The above-listed summaries that apply to treatment with single-agent veliparib therapy 
will be prepared for the crossover population and for adverse events with onset during 
blinded single-agent therapy.
A summary of times to first adverse events leading to study drug interruption or dose 
reduction will be produced. The number of subjects having such an event, the median and 
range of the times will be tabulated by treatment group.
11.2.2
Adverse Events of Special Interest
Treatment-emergent adverse events and serious adverse events of special interest based on 
Standard or Custom MedDRA Queries (SMQ-s or CMQ-s) will also be summarized.  The 
adverse event types and MedDRA queries used are described in the following table:


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Table 6.
Adverse Events of Special Interest
Adverse Event of 
Special Interest
Search Criteria
Event Definition/Medical Concept
Nausea and vomiting
Nausea and vomiting MedDRA 
preferred terms (PT code 
10028813, 10047700)
Treatment-emergent adverse events coded to 
MedDRA preferred terms 
Seizures
Convulsions SMQ 20000079 
(query for convulsions)
Treatment-emergent adverse events coded to 
MedDRA terms on the broad search list.
Anemia
Haematopoietic erythropenia 
SMQ 20000029
Treatment-emergent adverse events coded to 
MedDRA terms on the broad search list.
Thrombocytopenia
Haematopoietic 
thrombocytopenia SMQ 
20000031
Treatment-emergent adverse events coded to 
MedDRA terms on the broad search list.
Neutropenia
Hematological Toxicity-
Neutropenia CMQ 80000154
Treatment-emergent adverse events coded to 
MedDRA terms on the broad search list.
Infection events 
within 14 days after 
neutropenia events
Infections CMQ 80000018 and 
hematological toxicity-
neutropenia CMQ 80000154 
Treatment-emergent adverse events from the 
MedDRA terms on the broad search list.
Haemorrhages events 
within 14 days after 
thrombocytopenia
Haemorrhage terms (excl 
laboratory terms) SMQ 
20000039 and hematopoietic 
thrombocytopenia SMQ 
20000031 
Treatment-emergent adverse events from the 
MedDRA terms on the broad search list.
Second/Secondary 
Malignancies
Malignant Tumors SMQ 
20000194 and Tumors of 
Unspecified Malignancy SMQ 
20000195
Treatment-emergent adverse events from the 
MedDRA terms on the narrow search list for 
malignancies are used as a starting point for 
medical review to search for secondary 
malignancies.
Myelodysplastic 
Syndromes (MDS)
Myelodysplastic syndrome 
SMQ (Narrow) 20000217
Treatment-emergent adverse events from the 
MedDRA terms on the search list.
Acute Myeloid 
Leukemia (AML)
Acute myeloid leukaemia PT 
(10000880)
Treatment-emergent adverse events from the 
MedDRA preferred terms on the search list.
Changes in 
reproductive organ 
function
SMQ 20000210 (fertility 
disorders)
Treatment-emergent adverse events from the 
MedDRA terms on the search list.
Teratogenicity
Pregnancies and outcomes will be analyzed 
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For the infection after neutropenia AESI, subjects who have an infection at most 14 days 
after a report of neutropenia will be identified.  Subjects with a hemorrhage (bleeding) 
adverse event within 14 days following a report of thrombocytopenia will be counted in 
the hemorrhages/thrombocytopenia AESI.  In each case the 14 day comparisons will be 
based on the start dates of the adverse events.
With the exception of secondary malignancies and teratogenicity, adverse events 
identified through the searches will be tabulated.  An overview summary of adverse event 
types for each AESI will be produced.  Tabulations of all treatment-emergent events, 
events with grade > three, and serious adverse events will be provided for each AESI by 
system organ class and primary MedDRA preferred term.
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.  There will be no 
statistical comparison for above analyses.
11.4
Analysis of Laboratory and Vital Signs Data
11.4.1
General Considerations
Laboratory test variables for which NCI 4.03 common terminology criteria exist will be 
classified per those criteria and then analyzed in shift summaries.  The AST population 
will be subject to analysis.
The vital signs variables to be analyzed are systolic and diastolic blood pressure, heart rate 
and body temperature.


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11.4.2
Analyses of Laboratory Test Data Using NCI CTCAE Criteria
For hematology and chemistry variables for which NCI CTCAE 4.03 criteria exist, 
baseline and post-baseline hematology and chemistry variable observations will be 
categorized as grade 0 to grade 4.  For each graded variable, cross tabulations will be 
made of the number of subjects with each baseline grade versus post-baseline 
observations at both the maximum and final observation grade.  Additionally, for each 
variable, the number and percentage of subjects that have a baseline observation 
categorized as grade 0 to grade 2 and also have a grade 3 or 4 post-baseline observation at 
maximum grade or final observation will be presented.  Subjects for whom the baseline 
grade is 3 or higher for a laboratory test will not be included in the shift summary for that 
variable.  Shift rates for the two treatment groups in the AST population will be compared 
using Fisher's exact tests.
A listing of all observations collected during the study will be generated for subjects that 
had at least one post-baseline observation classified as a grade 3 or 4 value per NCI 
CTCAE 4.03 criteria.  A corresponding listing will be produced for lab test results 
reported for subjects receiving veliparib in the crossover period.
11.5
Analyses of Vital Signs Using Criteria for Potential Clinical 
Significance
Vital signs values will be assessed for potential clinical significance through the 
application of criteria developed at AbbVie as detailed in the following table:  


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Table 7.
Criteria for Potential Clinical Significance in Vital Signs Variables
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 frequency and percentage of subjects with post-baseline values meeting Criteria for 
Potentially Clinically Significant Vital Signs values will be summarized.  Subjects must 
have at least one post-baseline measurement to be included in the summary.  If a subject 
does not have a vital signs measurement at baseline but has post-baseline measurement 
which meets the above absolute criteria for blood pressure and pulse rate, this subject will 
be considered as meeting the potentially clinically significant vital signs values for the 
measurement.  A listing will be provided that presents all reports of a vital signs variable 
for subjects with a value meeting the criteria for potential clinical significance.  
Comparisons of the rates of subjects in the AST population meeting the above criteria 
between veliparib 120 mg BID + carboplatin + paclitaxel and placebo for veliparib 
120 mg BID + carboplatin + paclitaxel will be performed using Fisher's exact test.
12.0
Pharmacokinetic Analyses
12.1
Tabulations and Summary Statistics
Plasma concentrations of veliparib and possible metabolites(s) will be listed for each 
subject by scheduled visit.  Summary statistics will also be computed for each subject 
randomized to the veliparib treatment by scheduled visit and nominal time.