Conditions: Metastatic Breast Cancer
Keywords: PARP TMZ Temodal Carboplatin veliparib BRCA2 mutation carrier Breast cancer Metastatic breast cancer temozolomide BRCA1 mutation carrier ABT-888 Paclitaxel Recurrent breast cancer Temodar Locally recurrent
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 294
Healthy volunteers: no

Brief summary:
The primary objective of the study is to assess the progression-free survival (PFS) of oral veliparib in combination with TMZ or in combination with carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 mutation and locally recurrent or metastatic breast cancer.

Detailed description:

Arms:
arm 1: Veliparib 40 mg twice daily (BID) Days 1 through 7 plus TMZ 150 to 200 mg/m\^2 QD Days 1 through 5 in each 28-day cycle. arm 2: Placebo BID Days 1 through 7 plus carboplatin target area under the curve (mg•min/mL) (AUC) 6 administered on Day 3 of each 21-day cycle and paclitaxel 175 mg/m\^2 administered on Day 3 of each 21-day cycle. arm 3: Veliparib 80 mg BID Days 1 through 7 plus carboplatin target AUC 6 administered on Day 3 of each 21-day cycle and paclitaxel 175 mg/m\^2 administered on Day 3 of each 21-day cycle.

Interventions: intervention 1: Placebo intervention 2: Veliparib intervention 3: Carboplatin intervention 4: Temozolomide intervention 5: Paclitaxel
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol document:
Prot_000.pdf: 
Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
1
1.0
Title Page
Clinical Study Protocol M12-895
A Randomized, Phase 2 Study of the Efficacy and 
Tolerability of Veliparib in Combination with 
Temozolomide or Veliparib in Combination with 
Carboplatin and Paclitaxel Versus Placebo Plus 
Carboplatin and Paclitaxel in Subjects with BRCA1 
or BRCA2 Mutation and Metastatic Breast Cancer
Incorporating Amendment 1, Administrative 
Change 1, Amendments 2, Amendment 2.01 for 
Sweden, Amendment 3 and Amendment 4
AbbVie Investigational
  Product:
Veliparib (ABT-888)
Date:
07 June 2019
Development Phase:
2
EudraCT:
2011-002913-12
Study Design:
A Randomized Phase 2 Study of the Efficacy and 
Tolerability of Veliparib in Combination with 
Temozolomide or Veliparib in Combination with 
Carboplatin and Paclitaxel versus Placebo plus Carboplatin 
and Paclitaxel in Subjects with BRCA1 or BRCA2 Mutation 
and Metastatic Breast Cancer.
Investigators:
Multicenter Trial:  Investigator information is on file at 
AbbVie.
Sponsor:
AbbVie Inc.*
NCT01506609


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
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Sponsor/Emergency 
  Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Fax:
*The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are provided 
within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application with the 
Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
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1.1
Protocol Amendment:  Summary of Changes
The purpose of this Amendment is to:
●
Modify Study Activities schedule (Section 5.3, Efficacy, Pharmacokinetic, 
Pharmacodynamic, Pharmacogenetic and Safety Assessments/Variables and 
Table 5).
Rationale:  Primary analysis of progression-free survival for this study 
occurred in 2016.  One subject remains on study treatment; this subject was 
randomized to veliparib/placebo plus carboplatin/paclitaxel and has been on 
study for over 5 years.  There are no other subjects currently on study.  
Because the one subject on study has been tolerating study treatment for over 
5 years, the protocol-specified study activities are being modified to a schedule 
reflecting standard of care safety monitoring and tumor assessments and to 
remove study activities not pertinent to safety monitoring.
●
Update language on Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting (Section 6.5, Adverse Event Reporting)
Rationale:  To reflect current procedures.
●
Update AbbVie contacts
Rationale:  To reflect changes in Sponsor personnel.
An itemized list of all changes made to the protocol under this Amendment can be found 
in Appendix F.


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
4
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M12-895
Name of Study Drug:  Veliparib (ABT-888)
Phase of Development:  Phase 2
Name of Active Ingredient:  Not applicable
Date of Protocol Synopsis:  07 June 2019
Protocol Title:
A Randomized, Phase 2 Study of the Efficacy and Tolerability of Veliparib in Combination with 
Temozolomide or Veliparib in Combination with Carboplatin and Paclitaxel Versus Placebo Plus 
Carboplatin and Paclitaxel in Subjects with BRCA1 or BRCA2 Mutation and Metastatic Breast Cancer
Objectives:  The primary objective of the study is to assess the progression-free survival (PFS) of oral 
veliparib in combination with temozolomide (TMZ) or in combination with carboplatin and paclitaxel 
compared to placebo plus carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 mutation and 
locally recurrent or metastatic breast cancer.
The secondary objectives of the study are to assess overall survival (OS), clinical benefit rate (CBR), 
objective response rate (ORR) in those subjects treated with veliparib in combination with TMZ or 
treated with veliparib plus carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel.  
Chemotherapy-Induced Peripheral Neuropathy (CIPN) (as assessed by the EORTC QLQ-CIPN20 
questionnaire and NCI-CTCAE 4.0 grading for peripheral neuropathy) will be assessed in those subjects 
treated with veliparib plus carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel.
The tertiary objectives are to assess Eastern Cooperative Oncology Group (ECOG) performance status 
and quality of life (QoL) and to assess exploratory correlative endpoints.
Investigators:  Multicenter
Study Sites:  Approximately 120
Study Population:  Men and women ≥ 18 years of age with locally recurrent breast cancer, not 
amenable to therapy with curative intent, or metastatic breast cancer and a documented BRCA1 or 
BRCA2 deleterious germline mutation.  If human epidermal growth factor receptor 2 (HER2) positive, 
the subject must have received and progressed on at least one prior standard HER2-directed therapy or 
the subject must be ineligible to receive anti-HER2 therapy.
Number of Subjects to be Enrolled:  Approximately 290 (including approximately 4 subjects enrolled 
under the original protocol)
Methodology:  This is a Phase 2, randomized, partially blinded, multinational, multicenter study to 
evaluate the efficacy and tolerability of veliparib in combination with TMZ or veliparib in combination 
with carboplatin and paclitaxel compared to placebo plus carboplatin and paclitaxel in subjects with 
BRCA1 or BRCA2 deleterious mutation and locally recurrent or metastatic breast cancer who have 
received no more than two prior lines of deoxyribonucleic acid (DNA) damaging cytotoxic therapy for 
metastatic disease.  Subject randomization will be stratified by estrogen receptor (ER) and/or 
progesterone receptor (PgR) positive versus ER and PgR negative, prior cytotoxic therapy versus no 
prior cytotoxic therapy and ECOG 0-1 versus 2.  Subjects will be randomized in a 1:1:1 ratio to one of 
the three treatment arms.


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
5
Methodology (Continued):
For subjects randomized to the veliparib + TMZ treatment arm, study visits will be conducted at Day 1, 
Day 15, and Day 22 for the first two cycles and then Day 1 of every cycle thereafter.  For subjects 
randomized to the veliparib/placebo + carboplatin + paclitaxel treatment arms, study visits will be 
conducted at Day 1, Day 3, and Day 17 of Cycle 1 and Day 1 and Day 3 of every cycle thereafter.  For 
subjects on study treatment more than 5 years, Day 1 visit is not required. BRCA mutation status, as 
defined by the Sponsor core laboratory, will be documented for all patients.  For those patients in which 
a BRCA1 or BRCA2 mutation was defined by an alternative laboratory, the test will be conducted by the 
Sponsor core laboratory.  For patients who provide informed consent, archival tissue and optional paired 
tissue biopsies (C1D1 and Final Visit) will be obtained for correlative studies.
Subjects will continue dosing until they meet the defined discontinuation criteria.  When a subject meets 
the criteria for study discontinuation, a Final Visit will be conducted.  All subjects will have 
one Follow-up Visit approximately 30 days after the last dose of veliparib + TMZ or veliparib/placebo + 
carboplatin + paclitaxel.
Survival information (i.e., the date and cause of death, and post treatment information) will be collected 
at monthly intervals (or as requested by Sponsor to support data analysis), beginning on the date the 
subject is registered off study and for up to three (3) years until the endpoint of death, until the subject 
has become lost to follow-up or until study termination by AbbVie.  For subjects on study treatment 
more than 5 years, there will be no post-treatment follow-up.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
Patients must meet the following criteria to be eligible:
1.
≥ 18 years of age.
2.
Histologically or cytologically confirmed breast cancer that is either locally recurrent or metastatic.  
Locally recurrent disease must not be amenable to surgical resection or radiation with curative 
intent.
3.
Must have a documented 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 well-characterized methodology previously validated by sequencing, such as that 
used to assess founder mutations.  If testing has been performed by a laboratory other than Sponsor 
core laboratory, subjects may be enrolled but must be re-tested by Sponsor core laboratory for 
confirmation of BRCA1 or BRCA2 germline mutations.
4.
If HER2 positive (HER2 3+ by immunohistochemistry or amplification by fluorescence in situ 
hybridization [FISH > 2]), subjects must have received and progressed on at least one prior 
standard HER2-directed therapy or the subject must be ineligible to receive anti-HER2 therapy.


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
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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 C1D1) with at least one lesion outside 
previously irradiated areas.
6.
ECOG Performance status of 0 to 2.
7.
Adequate hematologic, renal, and hepatic function as follows:
•
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); Leukocytes 
> 3,000/mm3;
•
Renal Function:  Serum creatinine ≤ 1.5 × upper limit of normal (ULN) range OR creatinine 
clearance ≥ 50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal;
•
Hepatic Function:  Aspartate aminotransferase (AST) and/or alanine transaminase (ALT) 
≤2.5 × institutional upper limit of normal.  For subjects with liver metastases, AST and/or ALT 
< 5 × ULN range; bilirubin ≤ 1.5 × the 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.
8.
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 90 days 
following completion of therapy.  Women of childbearing potential must have a negative serum 
pregnancy test within 7 days prior to initiation.  To be considered of non-child bearing potential, 
postmenopausal women must be amenorrheic for at least 12 months or subjects must be surgically 
sterile.
•
Total abstinence from sexual intercourse (for a minimum of one complete menstrual cycle prior 
to study drug administration);
•
Vasectomized male subjects or vasectomized partner of female subjects;
•
Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with 
spermicidal jellies or cream);
•
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 for the duration of the study and for 
90 days following completion of therapy.
9.
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.


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
7
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Exclusion:
Subjects must meet none of the following exclusion criteria to be eligible:
1.
Received anticancer agent(s) or an investigational agent within 21 days prior to C1D1 or 
radiotherapy within 28 days prior to C1D1.  Prior treatment with palliative local breast or bone 
lesion radiation (other than pelvis) can occur, if administered at least 14 days prior to C1D1.  
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 are excluded.  
Anticancer hormonal therapy must be stopped 7 days before starting C1D1.  Subjects receiving 
bisphosphonates or denosumab are eligible.
2.
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 recurrent breast cancer 
within the past 6 months will also be considered toward the maximum of 2 prior lines of 
therapy.
•
A regimen will be considered a line of therapy if it includes a cytotoxic agent administered for 
more than 1 full cycle.  Therapy administered for 1 full cycle or less will not be counted 
towards the number of lines of therapy unless the patient experienced progression of disease 
while on that therapy.
•
Previous treatments with hormonal therapy (tamoxifen, aromatase inhibitors) and signal 
transduction agents (e.g., trastuzumab lapatinib, erlotinib, gefitinib, bevacizumab) are allowed 
and are not counted towards the prior line of therapy.
3.
Prior treatment of breast cancer with temozolomide, a platinum agent, or a 
Poly-(ADP-ribose)-Polymerase (PARP)-inhibitor.
•
Therapy with temozolomide, a platinum agent, or a PARP inhibitor administered for 1 full 
cycle or less will not be considered as prior therapy unless the patient experienced progression 
of disease while on that therapy.
4.
Prior taxane therapy administered for the treatment of metastatic breast cancer disease with the 
below exceptions.
•
Prior taxane therapy for metastatic breast cancer is allowed if the patient received ≤ 1 full cycle 
(i.e., within 4 weeks for subjects receiving weekly paclitaxel or Abraxane; 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 C1D1.
•
Use of taxanes as adjuvant therapy or to treat locally recurrent disease is permitted, if given 
more than 6 months prior to C1D1.
In all cases, the subject must be an appropriate candidate for paclitaxel therapy as per standard practice 
and per the investigator's discretion.
5.
A history of or evidence of brain metastases or leptomeningeal disease.  Subjects with symptoms to 
suggest central nervous system (CNS) metastases should have a brain MRI within 28 days of 
enrollment to confirm the absence of CNS metastases.  Contrast CT is acceptable for subjects who 
are unable to undergo a brain MRI.
6.
A history of uncontrolled seizure disorder.
7.
Pre-existing neuropathy from any cause in excess of Grade 1.


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
8
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion (Continued):
8.
Known history of allergic reactions to cremophor-paclitaxel.
9.
Clinically significant uncontrolled condition(s).
•
Active infection;
•
Symptomatic congestive heart failure;
•
Unstable angina pectoris or cardiac arrhythmia;
•
Myocardial infarction within last 6 months;
•
Psychiatric illness/social situations that would limit compliance with study requirements; 
or
•
Any medical condition which in the opinion of the investigator places the subject at an 
unacceptably high risk for toxicities.
10. 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.  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.
11. Pregnant or breastfeeding. 
Investigational Product:
Veliparib (ABT-888) 
Dose:
40 mg twice a day (BID) Days 1 through 7 of 28-day cycle (in 
combination with temozolomide)
Mode of Administration:
Oral
Reference Therapy:
Temozolomide
Dose:
150 mg/m2 to 200 mg/m2 once daily (QD) Days 1 through 5 of 28-day 
cycle (in combination with veliparib)
Mode of Administration:
Oral
Investigational Product:
Veliparib or Placebo
Dose:
80 mg BID or 120 mg BID Days 1 through 7 of 21-day cycle (in 
combination with carboplatin + paclitaxel)
Mode of Administration:
Oral
Reference Therapy:
Carboplatin
Dose:
AUC 6 Day 3 of 21-day cycle 
Mode of Administration:
Intravenously (IV)


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
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Reference Therapy:
Paclitaxel
Dose:
175 mg/m2 Day 3 of 21-day cycle 
Mode of Administration:
Intravenously (IV)
Duration of Treatment:  Subjects with controlled disease (complete response [CR], partial response 
[PR], or stable disease [SD] per RECIST version 1.1 and with tolerable side effects may continue to 
receive treatment with veliparib + TMZ until reaching a protocol-defined event of disease progression, 
or experiencing unmanageable toxicity, or reaching a maximum of 24 cycles of veliparib + TMZ.  If 
TMZ has been discontinued, veliparib will also be discontinued.  If the subject has not progressed and 
the investigator feels there is benefit from continued treatment for longer than 24 cycles, a discussion 
between the investigator and the AbbVie Medical Monitor is required.  If both the investigator and the 
AbbVie Medical Monitor confirm that the subject would benefit from continued treatment, then the 
subject may continue to receive veliparib + TMZ until the subject has disease progression or experiences 
a toxicity that requires discontinuation of further treatment.  Subjects randomized to veliparib/placebo + 
carboplatin + paclitaxel with controlled disease and with tolerable side effects may continue to receive 
treatment until reaching a protocol-defined event of disease progression or experiencing unmanageable 
toxicity.  If both carboplatin and paclitaxel have been discontinued due to toxicity, veliparib will also be 
discontinued.
Interim Analyses:  To ensure subject safety, an IDMC will review unblinded safety data (which will 
include all subjects enrolled in the study) when approximately 36 subjects enrolled under Amendment 1 
have met at least one of the following criteria: 
•
Received two 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.
In addition, an interim futility analysis will be conducted and reviewed after the Week 27 tumor 
assessment of the first 30 subjects who have been documented to have deleterious mutations by the 
Sponsor core laboratory with at least one measurable lesion at baseline and randomized to the 
veliparib + TMZ treatment group (across both Group 1 and Group 2).  If futility is declared at the time 
of the futility analysis for the veliparib + TMZ treatment arm, any subjects receiving veliparib + TMZ 
will be allowed the option of either receiving veliparib + carboplatin + paclitaxel or discontinuing 
therapy and remain on study and continue to follow the scheduled for study visits and procedures.


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
10
Criteria for Evaluation:
Efficacy:  Progression-free survival (PFS) using modified RECIST version 1.1 assessment at 9-week 
intervals.  In addition to being reviewed by the investigator and/or site staff, radiographic scans will be 
sent to a central imaging center for review.  Events of disease progression will be determined by the 
central imaging center.  Only subjects with deleterious mutations documented by the Sponsor core lab 
will be used in the primary efficacy analyses of PFS.  Post treatment information and survival 
information will be collected at monthly intervals (or as requested by Sponsor to support data analysis) 
beginning on the date the subject is registered off study and for up to three (3) years until the endpoint of 
death, the subject is lost to follow-up or until the study termination by AbbVie.
The Clinical Benefit Rate (CBR) and Objective Response Rate (ORR) using RECIST (version 1.1) will 
be assessed.
QoL assessment criteria via the EORTC QLQ-C15/BR23 Scale will be collected pre-dose on C1D1, 
Day 1 of Cycle 2 and every other cycle thereafter beginning with Cycle 4 (C6, C8, etc.), Final Visit, and 
at the Follow-up Visit.  In addition to the EORTC QLQ-C15/BR23 Scale, subjects randomized to the 
veliparib/placebo + carboplatin + paclitaxel treatment arms will complete the EORTC QLQ-CIPN20 
Scale.
Safety:  The safety of each treatment group will be assessed by evaluating study drug exposure, adverse 
events, serious adverse events, all deaths, changes in laboratory determinations, and vital sign 
parameters.  Subjects who did not receive study drug (veliparib or placebo) will not be included in the 
analyses of safety.
Statistical Methods:  Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a two-sided P value ≤0.05 when rounded.
Efficacy (Primary and Secondary Endpoints):  The analysis of the primary and secondary efficacy 
endpoints will include only the subjects who have been documented to have deleterious mutations by the 
Sponsor core lab.  Sensitivity analyses will be conducted to evaluate the impact of any discrepancies 
between results from the local laboratory and from the Sponsor core laboratory.
Progression-Free Survival:  PFS will be defined as the number of days from the date the subject is 
randomized to the date the subject experiences a confirmed event of disease progression (as confirmed 
by the Central Imaging Center), or to the date of death (all causes of mortality) if disease progression is 
not reached.  Events of death will be included for subjects who had not experienced a confirmed event of 
disease progression provided the death occurred within 9 weeks of the last available disease progression 
assessment.  If the subject does not have a confirmed 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 available 
disease progression assessment.
Overall Survival:  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.
Clinical Benefit Rate:  Clinical benefit rate (CR, PR, SD or Non-CR/Non-PD) at Week 18 will be 
defined as the progression-free rate at 18 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 
central imaging center).  All intent to treat (ITT) subjects will be included in the analysis.


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
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Statistical Methods (Continued):
Objective Response Rate:  ORR is defined as the proportion of subjects with confirmed complete or 
partial response per RECIST (version 1.1) as determined by central imaging center.  All subjects who 
have had at least one measurable lesion at baseline will be included in the ORR calculation.
Chemotherapy-Induced Peripheral Neuropathy:  CIPN (as assessed by the EORTC QLQ CIPN20 
questionnaire and NCI-CTCAE 4.0 grading for peripheral neuropathy).
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.


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
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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
BCNU
Trade name for Carmustine
BID
Twice a Day
BSA
Body Surface Area
BRCA
Breast Cancer Gene
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CBR
Clinical Benefit Rate
CFR
Code of Federal Regulations
CIPN
Chemotherapy-Induced Peripheral Neuropathy
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
CYP
Cytochrome P450


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M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
13
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
ESMO
European Society for Medical Oncology
EORTC
European Organization for Research and Treatment of Cancer
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
IUD
Intra-Uterine Device


Veliparib
M12-895 Protocol Amendment 4
EudraCT 2011-002913-12
14
IV
Intravenously
IVRS/IWRS
Interactive Voice Response System/Interactive Web Response System
LD
Longest Diameter
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
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
QA
Quality Assurance
QC
Quality Control
QD
Once Daily
QoL
Quality of Life
q PCR
Quantitative Polymerase Chain Reaction
QTc
QT interval corrected for heart rate


Veliparib
M12-895 Protocol Amendment 4
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15
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
TMZ
Temozolomide
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 .....................................................................................................4
1.3
List of Abbreviations and Definition of Terms........................................12
2.0
Table of Contents...................................................................16
3.0
Introduction ...........................................................................22
3.1
Breast Cancer...........................................................................................22
3.2
Carboplatin and Paclitaxel .......................................................................24
3.3
Temozolomide .........................................................................................26
3.4
Veliparib ..................................................................................................27
3.4.1
Preclinical Experience..............................................................................27
3.4.1.1
Pharmacokinetics/Pharmacodynamics.....................................................33
3.4.1.2
Toxicology ...............................................................................................34
3.4.2
Clinical Experience..................................................................................35
3.5
Benefits and Risks....................................................................................41
3.6
Differences Statement..............................................................................42
4.0
Study Objectives....................................................................42
5.0
Investigational Plan...............................................................43
5.1
Overall Study Design and Plan:  Description ..........................................43
5.2
Selection of Study Population..................................................................48
5.2.1
Inclusion Criteria .....................................................................................48
5.2.2
Exclusion Criteria ....................................................................................50
5.2.3
Prior and Concomitant Therapy...............................................................53
5.2.3.1
Prior Therapy ...........................................................................................53
5.2.3.2
Concomitant Therapy...............................................................................54
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Pharmacogenetic 
and Safety Assessments/Variables...........................................................57
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................57
5.3.1.1
Study Procedures .....................................................................................68
5.3.1.2
Blood Samples for Pharmacogenetic Analysis ........................................83
5.3.1.3
Blood Samples for Pharmacodynamic Analysis......................................84


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5.3.1.4
Collection and Handling of Pharmacodynamic Samples.........................90
5.3.2
Drug Concentration Measurements .........................................................90
5.3.2.1
Collection of  Samples for Analysis ........................................................90
5.3.2.2
Handling/Processing of  Samples ............................................................91
5.3.2.3
Disposition of Samples ............................................................................93
5.3.2.4
Measurement Methods.............................................................................93
5.3.3
Efficacy Variables....................................................................................93
5.3.4
RECIST (Version 1.1) for Tumor Response............................................94
5.3.4.1
Definition of Disease Progression..........................................................100
5.3.5
Safety Variables.....................................................................................101
5.3.6
Pharmacokinetic Variables ....................................................................101
5.3.7
Pharmacogenetic Variables....................................................................102
5.3.8
Pharmacodynamic Variables..................................................................102
5.4
Removal of Subjects from Therapy or Assessment...............................105
5.4.1
Discontinuation of Individual Subjects..................................................105
5.4.1.1
Discontinuation of Veliparib and TMZ .................................................107
5.4.1.2
Discontinuation of Veliparib or Placebo and Carboplatin + 
Paclitaxel................................................................................................108
5.4.2
Discontinuation of Entire Study.............................................................108
5.5
Treatments..............................................................................................109
5.5.1
Treatments Administered.......................................................................109
5.5.1.1
Veliparib + TMZ Treatment ..................................................................109
5.5.1.2
Veliparib + Carboplatin/Paclitaxel and Placebo + Carboplatin + 
Paclitaxel Treatment ..............................................................................110
5.5.2
Identity of Investigational Products.......................................................112
5.5.2.1
Packaging and Labeling.........................................................................113
5.5.2.2
Storage and Disposition of Study Drugs................................................113
5.5.3
Method of Assigning Subjects to Treatment Groups.............................114
5.5.4
Selection and Timing of Dose for Each Subject....................................115
5.5.5
Blinding..................................................................................................116
5.5.5.1
Blinding of Investigational Product.......................................................116
5.5.6
Treatment Compliance...........................................................................117
5.5.7
Drug Accountability...............................................................................117


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5.6
Discussion and Justification of Study Design........................................118
5.6.1
Discussion of Study Design and Choice of Control Groups..................118
5.6.2
Appropriateness of Measurements.........................................................119
5.6.3
Suitability of Subject Population ...........................................................119
5.6.4
Selection of Doses in the Study .............................................................120
5.7
Dose Reductions or Delays....................................................................121
5.7.1
Veliparib + TMZ Dose Reduction and Delays ......................................122
5.7.1.1
Veliparib Dose Reduction and Delays...................................................122
5.7.1.2
TMZ Dose Reduction and Delays..........................................................122
5.7.2
Veliparib + Carboplatin + Paclitaxel and Placebo + Carboplatin + 
Paclitaxel Dose Reduction and Delays ..................................................124
5.7.2.1
Veliparib or Placebo Dose Reductions and Delays ...............................124
5.7.2.2
Carboplatin + Paclitaxel Dose Reduction and Delays ...........................125
6.0
Adverse Events.....................................................................130
6.1
Definitions..............................................................................................130
6.1.1
Adverse Event........................................................................................130
6.1.2
Serious Adverse Events .........................................................................131
6.2
Adverse Event Severity..........................................................................132
6.3
Relationship to Study Drug....................................................................133
6.4
Adverse Event Collection Period...........................................................134
6.5
Adverse Event Reporting.......................................................................134
6.6
Pregnancy...............................................................................................136
6.7
Toxicity Management ............................................................................137
7.0
Protocol Deviations..............................................................138
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................138
8.1
Statistical and Analytical Plans..............................................................139
8.1.1
Baseline Characteristics.........................................................................139
8.1.1.1
Demographics ........................................................................................139
8.1.1.2
Medical Histories...................................................................................140
8.1.2
Efficacy Endpoints.................................................................................140
8.1.2.1
Primary Efficacy Endpoint ....................................................................140
8.1.2.2
Secondary Efficacy Endpoints...............................................................141


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8.1.2.3
Tertiary Efficacy Endpoints...................................................................142
8.1.3
Timing of Efficacy Analyses and Safety Evaluations ...........................142
8.1.4
Primary Analysis of Efficacy.................................................................143
8.1.5
Secondary Analyses of Efficacy ............................................................143
8.1.5.1
Overall Survival.....................................................................................143
8.1.5.2
Clinical Benefit Rate..............................................................................143
8.1.5.3
Objective Response Rate .......................................................................144
8.1.5.4
Chemotherapy-Induced Peripheral Neuropathy (CIPN)........................144
8.1.6
Tertiary Analyses of Efficacy ................................................................145
8.1.6.1
Quality of Life........................................................................................145
8.1.6.2
Performance Status ................................................................................145
8.1.7
Additional Efficacy Analyses ................................................................145
8.1.8
Interim Analysis.....................................................................................146
8.1.9
Safety Assessments................................................................................147
8.1.10
Statistical Analyses of Safety.................................................................147
8.1.10.1
Duration of Study Drug .........................................................................147
8.1.10.2
Adverse Events ......................................................................................148
8.1.10.3
Serious Adverse Events .........................................................................148
8.1.10.4
Deaths ....................................................................................................148
8.1.10.5
Longitudinal Analyses of Laboratory and Vital Signs Data..................148
8.1.10.6
Analyses of Laboratory Data Using NCI CTCAE.................................149
8.1.10.7
Analyses of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values.................................................................150
8.1.10.8
Multiplicity Adjustments .......................................................................150
8.1.10.9
Censoring Dates for Subjects that had the Blind Broken.......................151
8.2
Determination of Sample Size ...............................................................151
8.3
Randomization Methods ........................................................................152
9.0
Ethics.....................................................................................152
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................152
9.2
Ethical Conduct of the Study.................................................................153
9.3
Subject Information and Consent...........................................................153


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10.0
Source Documents and Case Report Form 
Completion ...........................................................................154
10.1
Source Documents .................................................................................154
10.2
Case Report Forms.................................................................................154
11.0
Data Quality Assurance ......................................................156
12.0
Use of Information...............................................................157
12.1
Use of Information.................................................................................157
12.2
Publication .............................................................................................157
13.0
Completion of the Study .....................................................158
14.0
Investigator's Agreement....................................................159
15.0
Reference List ......................................................................160
List of Tables
Table 1.
Treatment Schema for Subjects Randomized to Veliparib + TMZ 
Treatment Arm.........................................................................................45
Table 2.
TMZ Dosing Modification Following Cycle 1 ........................................45
Table 3.
Treatment Schema for Subjects Randomized to Veliparib + 
Carboplatin + Paclitaxel or Placebo + Carboplatin + Paclitaxel 
Treatment Arms .......................................................................................47
Table 4.
Study Activities (Subjects Randomized to Veliparib + TMZ 
Treatment Arm) .......................................................................................58
Table 5.
Study Activities (Subjects Randomized to Veliparib/Placebo + 
Carboplatin + Paclitaxel Treatment Arms)..............................................61
Table 6.
Schedule Pharmacodynamic and Pharmacogenetic Assessments ...........65
Table 7.
Schedule of Pharmacokinetic Assessment (Subjects Randomized 
to Veliparib + TMZ Treatment Arm).......................................................66
Table 8.
Schedule of Pharmacokinetic Assessments (Subjects Randomized 
to Veliparib or Placebo + Carboplatin + Paclitaxel Treatment 
Arms) .......................................................................................................67
Table 9.
Clinical Laboratory Tests.........................................................................73
Table 10.
Identity of Investigational Products.......................................................112
Table 11.
Study Drug Storage Conditions .............................................................114


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Table 12.
Veliparib and TMZ Dose Reduction or Delay Starting in Cycle 2 
and All Subsequent Cycles ....................................................................123
Table 13.
Veliparib/Placebo + Carboplatin + Paclitaxel Dose Reduction and 
Delays ....................................................................................................127
List of Figures
Figure 1.
Combination Therapy of Veliparib + TMZ .............................................29
Figure 2.
Veliparib in Combination with Carboplatin in the MX-1 Breast 
Carcinoma Xenograft Model in SCID Mice............................................30
Figure 3.
Analogues of Veliparib Attenuated Allodynia (Vincristine Model 
of Chemotherapy-Induced Pain)..............................................................32
Figure 4.
Analogues of Veliparib Attenuated Allodynia (Cisplatin and 
Oxaliplatin Model of Chemotherapy-Induced Pain)................................33
Figure 5.
Adverse Event Collection ......................................................................134
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................166
Appendix B.
List of Protocol Signatories....................................................................168
Appendix C.
EORTC QLQ-C15-PAL (Version 1).....................................................169
Appendix D.
EORTC QLQ-BR23...............................................................................171
Appendix E.
EORTC QLQ-CIPN20...........................................................................173
Appendix F.
Protocol Amendment:  List of Changes.................................................175


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3.0
Introduction
3.1
Breast Cancer
Breast cancer 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  Despite 
recent advances in breast cancer treatment, with very few exceptions, metastatic breast 
cancer remains incurable, and the aim of treatment is to palliate symptoms and prolong 
the time to progression.  Although the number of agents approved for the treatment of 
metastatic 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 BRCA2.4  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


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Hierarchical clustering of genomic expression data from breast cancer specimens has 
demonstrated several distinct tumor subgroups with unique expression profiles, including 
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.  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, 


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trastuzumab therapy results in improved survival when used in combination with 
paclitaxel chemotherapy compared to paclitaxel alone.13  Second-line therapy with the 
small molecule anti-HER2 agent lapatinib in combination with capecitabine showed an 
improved progression-free survival compared to capecitabine alone.14  Despite these 
important advances, most subjects eventually progress and metastatic breast cancer is still 
considered incurable.
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.15  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 
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 


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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%).16  The data were recently updated to 
include 25 patients in the expanded cohort, and it was found that the pathological 
complete response had fallen to 72%.17  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 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%).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.19  Notably, data suggest 
that the administration of carboplatin in combination with paclitaxel results in less 
thrombocytopenia than is expected from the use of carboplatin alone.15  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.


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3.3
Temozolomide
One of the most studied alkylating agents in combination with PARP inhibition is 
temozolomide (TMZ).  TMZ is a newer-generation DNA-methylating agent that crosses 
the blood-brain barrier.  TMZ is a prodrug of the active alkylating agent 5 
(3 methyltrizen-1-yl) imidazole4-carbozimide (MTIC).  Adverse events associated with 
TMZ observed in previously conducted studies in glioblastoma, include myelosuppression 
with Grade 3 or 4 neutropenia (reported as adverse event or laboratory abnormality) in 8% 
of subjects and Grade 3 or 4 thrombocytopenia (reported as adverse event or laboratory 
abnormality) in 14% of subjects.  For additional information regarding TMZ, please refer 
to the Temodar® package insert or the Temodal Summary of Product Characteristics 
(SmPC).20,21  While TMZ is thought to have little activity in unselected breast cancer, 
recent data suggest that the combination of a PARP inhibitor with TMZ may have utility 
for metastatic breast cancer in patients who are carriers of BRCA1/2 mutation.22
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.23,24  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.26  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.27  In 


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particular, tumor cells with BRCA1 or BRCA2 deficiencies are exquisitely sensitive to 
PARP inhibition, even in the absence of any other insults.6,28
PARP-enabled DNA repair may also compensate for the loss of other repair pathways.  
Higher expression of PARP in cancer cells compared to normal cells has been linked to 
drug resistance and the overall ability of cancer cells to sustain genotoxic stress.29-32
Consistent with the observation that PARP activity may act as a resistance factor in some 
tumors, PARP inhibitors have been shown in preclinical models to sensitize tumors to 
ionizing radiation therapy and a variety of DNA-damaging agents, including alkylators, 
such as TMZ, and cross-linking agents, such as carboplatin.
3.4
Veliparib
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the Investigator's Brochure.33
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.
In cellular assays, veliparib increases sensitivity of tumor cells to DNA-damaging agents 
including TMZ, irinotecan, cyclophosphamide, BCNU, cisplatin, and radiation.  In 
preclinical models one of the most efficacious alkylating agents in combination with 
PARP inhibition is TMZ.  Preclinical studies delivering veliparib by osmotic minipump 
indicate that maximal efficacy in combination with TMZ is achieved with steady state 
plasma concentrations of veliparib at 70 ng/mL.  No significant increase in body weight 
loss was observed with these combinations relative to TMZ monotherapy.  Human 


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pharmacokinetics indicate that an oral dose of 40 mg BID, the maximum tolerated dose 
(MTD) in combination with TMZ, produces an average steady-state AUC0-24 of 
4.41 μg•hr/mL, exposures greater than those achieved with the preclinical maximally 
efficacious dose (AUC0-24 of 3.0 μg•hr/mL).
The combination of veliparib + TMZ has demonstrated significant efficacy in a variety of 
preclinical tumor models, including settings where TMZ alone is ineffective and in both 
BRCA1- or BRCA2-competent and BRCA1- or BRCA2-mutated backgrounds.  In the 
BRCA-deficient MX-1 breast cancer model, TMZ given alone at the standard dose of 
50 mg/kg/day for 5 days exhibits minimal inhibition of tumor growth (35% TGI, 
Figure 1a) with no evidence of complete pathological tumor regression.  In contrast, 
addition of veliparib at 25 mg/kg/day to the therapy regimen results in profound antitumor 
activity (97% TGI), including 50% complete tumor regressions.  In Capan-1, a human 
BRCA2-deficient pancreatic cancer cell line (6174delT in Exon 11 resulting in a truncated 
BRCA2), the combination of veliparib with TMZ resulted in significantly more tumor 
regressions than either agent alone (Figure 1b).




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Figure 2.
Veliparib in Combination with Carboplatin in the MX-1 Breast 
Carcinoma Xenograft Model in SCID Mice
Veliparib and Neuropathy
Analogues of veliparib attenuated development of mechanical allodynia in vincristine, 
cisplatin and oxaliplatin preclinical models of chemotherapy-induced pain.  Neuropathy 
was induced in rats by the administration of vincristine.  To investigate the ability of 
PARP inhibitors to attenuate vincristine-induced pain, rats were administered a PARP 
inhibitor, A-861696 or A-902274, at doses of 25 mg/kg/day or 50 mg/kg/day (IP), for 
2 days prior to the initiation of vincristine administration.  After 2 days of pre-dosing with 
the PARP inhibitor, two minipumps were implanted in rats for vincristine and compound 
administration.  Vincristine was administered via a subcutaneous mini-osmotic pump that 
delivered 30 μg/kg/day (IV) for 12 days.  PARP inhibitor, A-861696 or A-902274, or 
vehicle was administered via a subcutaneous mini osmotic pump that delivered 
25 mg/kg/day, 50 mg/kg/day, or vehicle (IP) for 12 days.  A positive control group of rats 
receiving vincristine were dosed acutely with morphine (6 mg/kg, IP) on testing days.  


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Another control group of rats received saline IV instead of vincristine.  Mechanical 
threshold was determined using von Frey monofilaments.  Mechanical allodynia was 
observed in rats treated with vincristine compared to the saline group.  In vincristine 
treated rats, morphine fully reversed mechanical allodynia on all testing days.  PARP 
inhibitors had no effect in naive rats.  The PARP inhibitors, A-861696 and A-902274, 
attenuated development of mechanical allodynia in the vincristine model of 
chemotherapy-induced pain (Figure 3).
In mice, neuropathy was induced by administration of cisplatin or oxaliplatin.  Mice were 
administered a PARP Inhibitor, A-861696, at doses of 25 mg/kg/day or 50 mg/kg/day (IP) 
for 2 days prior to the initiation of cisplatin.  The 50 mg/kg dose of A-861696 was 
administered (IP) for 2 days prior to oxaliplatin administration.  After 2 days of 
pre-dosing with the PARP Inhibitor, mice were co-administered A-861696 with cisplatin 
or oxaliplatin for 5 days (daily injections, IP), followed by 5 days off, and then followed 
by 5 daily injections (IP).  Cumulative dose of cisplatin was 23 mg/kg.  Cumulative dose 
of oxaliplatin was 30 mg/kg.  Behavioral assays were performed on all groups of mice 
using von Frey monofilaments before dosing, and then at Weeks 3, 6, and 8.  Behavioral 
assays included determining mechanical threshold with von Frey monofilaments, latency 
to paw withdrawal from a radiant heat source, and number of paw lifts from a cold plate.  
A-861696 attenuated development of mechanical allodynia in the cisplatin model at 
Weeks 3, 6, and 8, and in the oxaliplatin model at Week 3 and Week 6 (Figure 4).  In 
addition, A-861696 attenuated development of heat hyperalgesia in the cisplatin model at 
Week 3 and Week 6.  A-861696 attenuated development of cold hyperalgesia in the 
oxaliplatin model at Week 6.  Together, these data establish PARP as a novel mechanism 
of painful neuropathy.  Furthermore, these data suggest therapeutic potential of PARP 
inhibitors for the prevention of chemotherapy-induced peripheral neuropathy (CIPN).




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Figure 4.
Analogues of Veliparib Attenuated Allodynia (Cisplatin and 
Oxaliplatin Model of Chemotherapy-Induced Pain)
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 150 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 


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human cytochrome P450s (CYPs), suggesting a minimal potential for DDIs at the 
anticipated therapeutic concentrations.  Preliminary results indicate the absence of a DDI 
between veliparib and TMZ.
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).  Veliparib also 


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absorbs ultraviolet light and is distributed to both the skin and the eyes following systemic 
exposure, which poses a potential phototoxicity risk.
3.4.2
Clinical Experience
A Phase 0 dose-ranging pharmacokinetic and pharmacodynamic study has been 
completed (NCI IND).  Thirteen subjects with various types of advanced cancer received 
a single dose of single-agent veliparib (10 mg, n = 3; 25 mg, n = 3; 50 mg, n = 7).  The 
pharmacokinetic results from this study demonstrated that veliparib is orally bioavailable 
and primarily cleared through renal excretion, with a half-life of 4 to 5 hours.  
Additionally, this study provided proof of mechanism, as tumor PARP inhibition (> 90%) 
was demonstrated in 5 out of 6 human tumor biopsies that were obtained 3 to 6 hours after 
dosing with either 25 mg or 50 mg veliparib.  No serious adverse events, dose-limiting 
toxicities (DLTs), or deaths were reported for this study.34
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 
carboplatin or temozolomide.  By a similar mechanism, PARP inhibitors may potentiate 
the toxicities of the 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.  
Study M06-862 is a dose-escalating Phase 1 study of veliparib BID on Days 1 through 7 
in combination with TMZ QD on Days 1 through 5 (28-day cycle) in subjects with 
nonhematologic malignancies.  No DLTs were reported for the first 3 dose cohorts 
(veliparib 10, 20, and 40 mg BID).  In cohorts receiving 60 mg and 80 mg, events of 
Grade 4 thrombocytopenia and neutropenia were reported.  The MTD combination dose 
was defined as veliparib 40 mg BID and TMZ 200 mg/m2 QD.  Although no DLTs were 
reported in subjects in the 40 mg veliparib BID/200 mg/m2 TMZ QD dose-escalation 
cohort, 8 of all 12 subjects receiving 40 mg veliparib BID/200 mg/m2 in an expanded 


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safety cohort experienced Grade 3 or 4 neutropenia and/or thrombocytopenia.  In general, 
subjects with these events recovered after dose reduction and remained on study.  In order 
to minimize these hematologic toxicities, the protocol was modified to treat new subjects 
with 40 mg veliparib BID in combination with 150 mg/m2 TMZ QD in the first cycle.  If a 
subject did not experience Grade 3 or 4 hematologic toxicities or other clinically 
significant NCI Common Terminology Criteria for Adverse Events (CTCAE) toxicities 
greater than Grade 3, the TMZ dose was escalated to 200 mg/m2 QD.  The study also 
included 20 mg and 30 mg BID expanded safety cohorts who were dosed following the 
amended protocol.  Overall, as the dosage of veliparib increased from 20 to 40 mg BID, 
there appeared to be a trend of increase in frequency of Grade 3 and 4 hematological 
toxicities.
Study M10-440 is a Phase 2 randomized, double-blind, placebo-controlled study of 
veliparib (20 or 40 mg BID) in combination with TMZ (150 mg/m2/day with possible 
escalation to 200 mg/m2).  This study is fully enrolled and ongoing (n = 346).  The most 
common adverse events (reported in ≥ 30% of subjects receiving veliparib + TMZ) were 
nausea, fatigue, constipation, thrombocytopenia, and vomiting.
In a Phase 2, investigator-initiated study,22 to date, 41 subjects with metastatic breast 
cancer have received veliparib 40 mg BID Days 1 through 7 plus TMZ 150 to 200 mg/m2
Days 1 through 5 of a 28-day cycle.  In the subjects without known deleterious BRCA1 or 
BRCA2 mutation, there were no responses.  In contrast, the 8 subjects with a known 
deleterious BRCA1/2 mutation, to date, have demonstrated 1 confirmed CR, 4 PR 
(3 confirmed), and 3 subjects with progressive disease (ORR) = 50% and CBR = 62.5%).  
Of the subjects with deleterious mutations of BRCA1/2, there were 3 BRCA1 carriers 
(1 PR, 2 PD) and 5 BRCA2 carriers (1 CR, 3 PR, and 1 PD).  Progression has occurred as 
the best response in 34 of the 41 subjects, many within 1 to 2 cycles.  Adverse events in 
this study include Grade 3/4 toxicities of thrombocytopenia and neutropenia.  There have 
been no bleeding complications or febrile neutropenia.  Hypophosphatemia occurred 
twice in the same patient and was reported as not related to study drug and was 
pre-existing.  Due to the number of subjects with hematological toxicities, the protocol 


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was amended in December 2009 to change the dose of veliparib from 40 mg BID to 
30 mg BID (in combination with 200 mg/m2 of TMZ).  All of the subjects who responded 
to veliparib with TMZ received 40 mg BID veliparib initially, then 30 mg BID following 
the dose-reduction amendment.
This study was amended to include an expanded cohort of 20 BRCA1/2 mutation carriers 
with metastatic breast cancer to further evaluate safety, tolerability, and efficacy of the 
veliparib plus TMZ combination in this specific population.  Subjects in this cohort have 
received veliparib 30 mg BID with TMZ 150 to 200 mg/m2 Days 1 through 5.  To date, 
hematological toxicities have been similar to those observed in the initial cohort; however, 
the response rate has diminished.  In addition to the reduced dose of veliparib, the 
expansion cohort differed from the initial subjects in that approximately half of the 
patients had received prior platinum therapy.  This is notable, as previous studies suggest 
that similar mechanisms of resistance can lead to decreased activity of both platinums and 
PARP inhibitors, such as reversion of BRCA1/2 mutation to a wild-type phenotype.35,36  
Based upon the experience to date across the veliparib program in which hematological 
toxicities have been manageable with veliparib 40 mg BID and the potential decrease in 
efficacy at the 30 mg dose, veliparib will be used at 40 mg BID in combination with TMZ 
(150 to 200 mg/m2) in this 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 
study is a Phase 1 dose escalation study evaluating the addition of veliparib to carboplatin 
+ paclitaxel in subjects with advanced or metastatic solid tumors.  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.  At this dose, two out 
of six subjects developed protocol defined dose limiting toxicities (DLTs).  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 febrile grade 3 


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neutropenia in a subject who previously received multiple cycles of dacarbazine (an 
alkylating agent which may cause cumulative bone marrow damage).  The event of febrile 
neutropenia resolved after G-CSF therapy and anti-bacterial therapy, and the subject 
continued veliparib + carboplatin + paclitaxel therapy.  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 patients with metastatic breast cancer had confirmed 
responses (3 CR, 5 PR).37  In a subsequent analysis of preliminary data in refractory triple 
negative breast cancer receiving veliparib in combination with carboplatin and paclitaxel 
on either a q 3 week regimen (CTEP 7967) or a weekly regimen (carboplatin AUC 2, 
paclitaxel 80 mg/m2; 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 3 week regimen (2 CR, 4 PR).38
GOG 9923 is an ongoing Phase 1 dose escalation study that is also evaluating veliparib in 
combination with carboplatin, paclitaxel, and bevacizumab (initiated in cycle 2) in 
subjects with advanced or metastatic ovarian cancer (chemotherapy-naïve).  The 
intermittent regimen with veliparib in combination with q-3 weekly carboplatin and 
paclitaxel has escalated to dose greater than 200 mg BID, further supporting the use of 
veliparib 120 mg BID in combination with carboplatin and paclitaxel.
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 
TMZ resulted in responses in patients with deleterious germline mutations in BRCA1/2, 
with a 50% ORR.  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.39  A similar trial in BRCA1/2 mutation 


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carriers with metastatic ovarian cancer showed a response rate of 33%.40  Notably, both 
single-agent studies demonstrated increased response rates with higher doses of PARP 
inhibitor (olaparib 100 mg BID and 400 mg BID), where both doses are considered 
biologically active.  Together, these results validate the proof of concept that PARP 
inhibition is an attractive therapeutic target in breast and other cancers.
A therapeutic potential for veliparib has also been suggested in BRCA1/2-mutated breast 
cancer, and specifically for the utility of the veliparib + TMZ combination.  The 
combination of veliparib and TMZ resulted in dramatic tumor growth delay or regression 
in many preclinical models, including BRCA-deficient tumor models, where TMZ by 
itself is not efficacious (Section 3.4.1).  Preclinical studies indicate that veliparib may 
have activity in tumor types in which TMZ is typically not thought to have activity 
(Section 3.4.1), with possible mechanisms including synergism between DNA-damaging 
agents and inhibitors of DNA repair41 and prevention of resistance to TMZ, which is 
thought to be responsible for the low efficacy of TMZ in many tumor types.42,43  In the 
ongoing Phase 2 trial in metastatic breast cancer, a 50% CBR (14/28; 1 CR, 6 PR, 7 SD) 
has occurred to date in patients with deleterious BRCA mutations (including both the 
original and the expansion cohort).  This is in contrast to historical clinical data that 
suggest that TMZ monotherapy has low activity in breast cancer.  Most notably, 
two Phase 2 studies with a dose-dense TMZ regimen demonstrated no responses (0/18) in 
patients with metastatic breast cancer and 2 responses (2/51) in patients with brain 
metastases from histologically confirmed breast cancer.43,44  While the Phase 2a study 
indicates that veliparib in combination with TMZ is an active regimen, this study was 
initially designed as a single-arm study in an unselected patient population; thus, further 
evaluation is needed to determine the activity of this regimen relative to efficacious 
regimens in metastatic breast cancer.
Therapeutic potential in breast cancer has also been observed with veliparib in 
combination with carboplatin + paclitaxel.  AbbVie is conducting a Phase 1, 
dose-escalation trial of veliparib with carboplatin + paclitaxel (CTEP 7967) in 
collaboration with Cancer Therapy Evaluation Program (CTEP).  In this study, the 


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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.45  In the preliminary efficacy 
analysis, 1 out of 4 chemotherapy-naïve metastatic NSCLC patients had a confirmed 
response to veliparib with carboplatin + paclitaxel chemotherapy (22% ORR in ECOG 
trial), and 4 out of 11 patients with metastatic breast cancer had confirmed responses 
(2 CR, 2 PR), with an additional 2 patients with unconfirmed responses (1 PR, 1 CR).  In 
the CTEP 7967 study, the maximum tolerated dose for veliparib was 120 mg BID with 
2 out of 6 patients experiencing DLTs (febrile neutropenia, vomiting).  The study also 
includes a separate, ongoing, dose escalation in patients with BRCA-mutated tumors with 
veliparib in combination with carboplatin (AUC 6) and paclitaxel (175 mg/m2).  
In addition to CTEP 7967, veliparib in combination with carboplatin and paclitaxel has 
been evaluated in GOG 9923.  As of 15 Dec 2011, three patients have been treated with 
veliparib 150 mg BID on Days 1 to 21 with carboplatin AUC 6 and paclitaxel 175 mg/m2
on Day 1 of a 21-day cycle.  No grade 3/4 toxicity or DLTs occurred at the 150 mg BID 
dose level during DLT evaluation period; thus, in the GOG 9923 study, the veliparib 
200 mg BID dose level is currently being evaluated.  
Given that the patient population in GOG 9923 is the most similar to Study M12-895 
(ovarian cancer patients, many of whom will have BRCA1/2 mutation or have tumors 
with a BRCAness phenotype) and the similarity in paclitaxel dosing between the 
two studies, in addition to the data indicating increased response rates with higher doses 
of the PARP inhibitor, the veliparib 120 mg BID dose was selected for use in combination 
with carboplatin and paclitaxel in this study.  In patients with metastatic breast cancer, 
previous studies have indicated that a longer duration of first-line chemotherapy is 
associated with potential benefit in PFS and OS; thus, therapy in this study will be 
continued until PD or toxicity results in treatment discontinuation.46


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3.5
Benefits and Risks
This study proposes to establish improved clinical outcomes for patients with metastatic 
or locally recurrent breast cancer with a deleterious germline mutation of BRCA1 or 
BRCA2 through the addition of veliparib to therapy with carboplatin and paclitaxel or to 
temozolomide.  Preclinical data demonstrate that veliparib potentiates the anti-tumor 
activity of platinums and temozolomide, and data from early-phase clinical studies 
(completed or preliminary) are consistent with these observations.
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 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.
Veliparib in combination with TMZ has been evaluated in 7 AbbVie-sponsored clinical 
studies in subjects with various solid tumors.  Based on preliminary data from the 
seven studies with veliparib and temozolomide (N = 527), the most common serious 
adverse event was thrombocytopenia (17 subjects, 3.2%).  The most common 
treatment-emergent adverse events, reported in > 30% of all subjects, were nausea 
(384 subjects, 72.9%), fatigue (348 subjects, 66.0%), constipation (248 subjects, 47.1%), 
thrombocytopenia (233 subjects, 44.2%), and vomiting (201 subjects, 38.1%).  The 
preliminary safety results from a randomized Phase 2 placebo-controlled study comparing 
temozolomide plus veliparib (20 or 40 mg twice daily on Days 1 – 7) every 4 weeks 
versus temozolomide plus placebo in patients with advanced melanoma indicate that the 


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toxicity profile of veliparib with temozolomide is similar to that of temozolomide alone, 
with some increase in the frequency of hematological toxicities (Grade 3 or 4 
thrombocytopenia 23.8% versus 15.0%, respectively, and neutropenia 16.0% versus 
5.3%).  These toxicities are commonly associated with cancer therapy, and standard 
clinical practices to manage these toxicities are well-established. 
Other potential risks of veliparib administration, identified in preclinical studies or based 
on pharmacological mechanism, but not confirmed in clinical studies must also be 
considered.  These risks include seizures, changes in testes/ovaries, toxicity to the 
developing fetus and secondary malignancies.
In summary, veliparib is an orally available PARP inhibitor that has been shown to 
significantly potentiate the effects of carboplatin/paclitaxel and temozolomide 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 further evaluation of 
veliparib in combination with carboplatin and paclitaxel or with temozolomide in the 
Phase 2 study.
3.6
Differences Statement
This is the first randomized, Phase 2 study of veliparib in locally recurrent or metastatic 
breast cancer in patients with deleterious germline mutation of BRCA1 or BRCA2.
4.0
Study Objectives
The primary objective of the study is to assess the PFS of oral veliparib in combination 
with TMZ or in combination with carboplatin and paclitaxel compared to placebo plus 
carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 mutation and locally 
recurrent or metastatic breast cancer.


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The secondary objectives of the study are to assess OS, CBR through the end of Week 18, 
and ORR, in those subjects treated with veliparib in combination with TMZ or treated 
with veliparib in combination with carboplatin and paclitaxel versus placebo in 
combination with carboplatin and paclitaxel.  In addition, CIPN (as assessed by the 
EORTC QLQ CIPN20 questionnaire and NCI-CTCAE 4.0 grading for peripheral 
neuropathy) will be assessed in those 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.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 2 randomized, partially blinded, multinational, multicenter study to 
evaluate the efficacy and tolerability of veliparib in combination with TMZ or veliparib in 
combination with carboplatin and paclitaxel compared to placebo plus carboplatin and 
paclitaxel in approximately 290 subjects with BRCA1 or BRCA2 mutation as 
documented by the Sponsor core laboratory and locally recurrent breast cancer (not 
amenable to therapy with curative intent) or metastatic breast cancer who have received 
no more than two prior lines of cytotoxic therapy for metastatic disease.  Approximately 
120 research sites will participate.
Subjects will be randomized in a 1:1:1 ratio to one of the three treatment arms described 
below.  Subject randomization will be stratified by ER-positive and/or PgR-positive 
versus ER-negative and PgR-negative status, prior cytotoxic therapy versus no prior 
cytotoxic therapy, and ECOG 0-1 versus 2.
Under the original protocol, approximately 4 subjects were randomized in a 1:1:1 ratio 
(Group 1) to one of the three treatment arms (1 subject in veliparib 40 mg BID + TMZ 
arm and a total of 3 subjects in either the veliparib 80 mg BID + carboplatin + paclitaxel 
or the placebo BID + carboplatin + paclitaxel arms) at approximately 3 research sites.  


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Subjects randomized under the original protocol will be considered Group 1 and will not 
be considered towards the primary efficacy analyses.
Following approval of Amendment 1, the veliparib dose in combination with carboplatin 
and paclitaxel was increased to 120 mg BID.  Approximately 290 subjects will be 
randomized in a 1:1:1 ratio (Group 2) to one of the three treatment arms (veliparib 40 mg 
BID + TMZ, veliparib 120 mg BID + carboplatin + paclitaxel, placebo BID + carboplatin 
+ paclitaxel) at approximately 120 research sites.  Subjects randomized following 
approval of Amendment 1 will be considered Group 2 and will be considered towards the 
primary efficacy analyses.
Veliparib + Temozolomide Dosing Arm
Subjects randomized to receive veliparib 40 mg BID + TMZ will self-administer the 
morning dose of veliparib and TMZ at the same time and the evening dose of veliparib 
approximately 12 hours after the morning dose in the same calendar day on Days 1 to 7 of 
each 28-day cycle as per Table 1.
For Cycle 1, the TMZ dose will start at 150 mg/m2 QD on Days 1 to 5 of each 28-day 
cycle as per Table 1.  The TMZ dose will be determined by body surface area (BSA) 
calculated from the height obtained at the baseline evaluation and the weight obtained 
prior to each cycle.  The daily dose will be rounded to the nearest 5 mg.  However, for 
subject convenience, the dose may be rounded down to 5% from calculated dose in order 
to minimize the number of capsules per dose.  The exact dose administered will be 
recorded in the electronic case report form (eCRF).
If during the first cycle, platelets (nadir) are > 100,000/μL and the ANC (nadir) is 
> 1,500/μL and no Grade 3 or 4 CTCAE nonhematologic toxicities attributable to TMZ 
are observed, then the TMZ dose will be escalated to 200 mg/m2 QD (per BSA) for 
Cycle 2 (Table 2).  If the dose was not escalated at Cycle 2, then the dose should not be 
escalated in future cycles.  For all cycles, dose delays and reductions will be managed 
according to Section 5.7.


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Table 1.
Treatment Schema for Subjects Randomized to Veliparib + TMZ 
Treatment Arm
Days
1
2
3
4
5
6
7
8-28
Veliparib
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
No 
drug 
dosing
TMZ 
Once a 
day with 
a m. 
Veliparib
Once a 
day with 
a.m. 
Veliparib
Once a 
day with 
a.m. 
Veliparib
Once a 
day with 
a.m. 
Veliparib
Once a 
day with 
a.m. 
Veliparib
No 
drug 
dosing
Table 2.
TMZ Dosing Modification Following Cycle 1
150 mg/m2/d × 5d (Starting Dose)
Based on lowest counts at either Day 22 or Day 29
ANC < 1000/μL 
or 
platelets < 50,000/μL
ANC 1000/μL to 1500/μL
or 
platelets 50,000/μL to 100,000/μL
ANC > 1500/μL 
and 
platelets > 100,000/μL, and 
no CTCAE Grade 3 or 4 
clinically significant 
toxicities attributable to 
TMZ
Postpone therapy until 
ANC > 1500/μL and 
platelets > 100,000/μL; 
reduce dose by 50 mg/m2/d for 
subsequent cycle
Postpone therapy until 
ANC > 1500/μL and 
platelets > 100,000/μL; 
maintain initial dose of 
150 mg/m2/d for subsequent cycle
Increase dose to 
200 mg/m2/d × 5d for 
subsequent cycle
Veliparib or Placebo + Carboplatin and Paclitaxel Dosing Arms
Upon approval of protocol Amendment 1 and the availability of the 40 mg clinical 
supplies to support a dose of 120 mg BID of veliparib, all subjects randomized to the 


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veliparib/placebo + carboplatin + paclitaxel treatment arms will receive 120 mg BID of 
veliparib/placebo.  Subjects randomized to the 80 mg BID veliparib/placebo starting dose 
will continue to receive veliparib/placebo as specified per the original protocol for the 
duration of their study treatment.   
Subjects randomized to receive veliparib/placebo + carboplatin + paclitaxel will 
self-administer veliparib or placebo on Days 1 to 7 of each 21-day cycle as per Table 3.  
The evening dose of veliparib/placebo should be administered approximately 12 hours 
after the morning dose.  Carboplatin and paclitaxel will be administered on Day 3 of each 
21-day cycle.  Paclitaxel will be infused before carboplatin.  The dose of carboplatin and 
paclitaxel will be based upon the baseline weight (C1D1) for all cycles; however, the dose 
should be recalculated on the basis of new weight, if there is a weight change of > 10% 
from baseline; adjustments for weight change < 10% are allowed per institutional 
guidelines.  The morning dosing of veliparib/placebo on Day 3 of every cycle should be 
taken before the carboplatin + paclitaxel infusion per Table 3 below.
Paclitaxel
Subjects should be pretreated with corticosteroids, diphenhydramine, and H2 antagonists 
according to local institutional standard guidelines, the locally approved product label, 
local practice, or the applicable summary of product characteristics (SmPC).47  The 
medications used for the pretreatment of paclitaxel will be recorded in the eCRF.
Paclitaxel will be administered intravenously over approximately 3 hours at a dose of 
175 mg/m2.
Carboplatin
Carboplatin48 will be administered intravenously over approximately 15 to 30 minutes at 
AUC 6, immediately following paclitaxel infusion.  The duration of carboplatin infusion 
may be lengthened according to institutional guidelines.  When glomerular filtration rate 
(GFR) is estimated by serum creatinine using the Isotope Dilution Mass Spectroscopy 
(IDMS) method, the maximum dose of carboplatin should be limited to 900 mg.  


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Similarly, when the GFR is estimated using Isotopic/edetic acid (EDTA) clearance, 
maximum carboplatin dosing should be based upon standard guidelines and institutional 
practices.
Table 3.
Treatment Schema for Subjects Randomized to Veliparib + 
Carboplatin + Paclitaxel or Placebo + Carboplatin + Paclitaxel 
Treatment Arms
Days
1
2
3
4
5
6
7
8 – 21
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
Paclitaxel
IV
No drug 
dosing
*
Veliparib or placebo morning dose should be administered orally in the clinic prior to paclitaxel/carboplatin 
infusion.
If the Screening Visit is performed more than 7 days prior to Study Day 1, the physical 
exam must be repeated on C1D1.  For Screening labs performed greater than 7 days prior 
to C1D1, hematology/chemistry should be split at C1D1 and local labs reviewed prior to 
dosing.  Vital signs, laboratory tests, and performance status assessment will be 
performed on C1D1 for all subjects prior to dosing.
Study procedures will be performed as outlined in Section 5.3.1.1.  Subjects will continue 
dosing until they meet the defined discontinuation criteria discussed in Section 5.4.1.  
When an investigator has determined that a subject should discontinue 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 + TMZ or veliparib/placebo + carboplatin + paclitaxel.  This Follow-up Visit 
does not need to be conducted if the Final Visit is ≥ 30 days after the last dose of veliparib 
+ TMZ or veliparib + carboplatin + paclitaxel or placebo + carboplatin + paclitaxel.


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Post treatment and survival information (i.e., the date and cause of death) will be collected 
via Interactive Voice or Web Response System (IVRS/IWRS) at monthly intervals (or as 
requested by Sponsor to support data analysis) beginning on the date the subject is 
registered off study and continuing for a minimum of three (3) years for all subjects until 
the endpoint of death, the subject has become lost-to follow-up, or AbbVie terminates the 
study.
5.2
Selection of Study Population
5.2.1
Inclusion Criteria
Subjects will be adult men and women with metastatic breast cancer and a documented 
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 
recurrent or metastatic.  Locally recurrent disease must not be amenable to surgical 
resection or radiation with curative intent.
3.
Must have a documented 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/MLPA or 
2) a well-characterized methodology previously validated by sequencing, such as 
that used to assess founder mutations.  If testing has been performed by a 
laboratory other than the Sponsor core laboratory, subjects may be enrolled but 
must be re-tested by Sponsor core laboratory for confirmation of BRCA1 or 
BRCA2 germline mutations.
4.
If HER2-positive (HER2 3+ by immunohistochemistry or amplification by FISH 
> 2), subjects must have received and progressed on at least one prior standard 
HER2-directed therapy or be ineligible to receive anti-HER2 therapy.


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5.
Measurable or non-measurable (but radiologically evaluable) disease per 
RECIST version 1.1 on CT scan (within 28 days of C1D1) with at least one lesion 
outside previously irradiated areas.
6.
ECOG performance status of 0 to 2.
7.
Adequate hematologic, renal, and hepatic function as follows (within 28 days of 
C1D1):
●
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); Leukocytes > 3,000/mm3;
●
Renal Function:  Serum creatinine ≤ 1.5 × upper limit of normal (ULN) range  
OR creatinine clearance ≥ 50 mL/min/1.73 m2 for subjects with creatinine 
levels above institutional normal;
●
Hepatic Function:  AST and/or ALT ≤ 2.5 × institutional upper limit of 
normal.  For subjects with liver metastases, AST and/or ALT < 5 × ULN 
range; bilirubin ≤ 1.5 × the 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.
8.
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 90 days following completion of therapy.  Women of 
childbearing potential must have a negative serum pregnancy test within 7 days 
prior to initiation of treatment.  To be considered of non-child bearing potential, 
postmenopausal women must be amenorrheic for at least 12 months or subjects 
must be surgically sterile.
●
Total abstinence from sexual intercourse (for minimum of one complete 
menstrual cycle prior to study drug administration);
●
Vasectomized male subjects or vasectomized partner of female subjects;


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●
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 for the 
duration of the study and for 90 days following completion of therapy.
9.
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 – 6)  To select the appropriate subject population with sufficient disease severity for 
evaluation.
(7)  For the safety of the subjects.
(8)  The impact of veliparib + TMZ, carboplatin, and paclitaxel on the unborn fetus is 
unknown; therefore, these criteria ensure that adequate precautions are taken to avoid 
pregnancy.
(9)  In accordance with harmonized Good Clinical Practice (GCP).
5.2.2
Exclusion Criteria
Subjects must meet none of the following exclusion criteria to be eligible.


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1.
Received anticancer agent(s) or an investigational agent within 21 days prior to 
C1D1 or radiotherapy within 28 days prior to C1D1.  Prior treatment with 
palliative local breast or bone lesion radiation (other than pelvis) can occur, if 
administered at least 14 days prior to C1D1.  Subjects experiencing a significant 
adverse effect or toxicity (Grade 3 or 4), causally attributed to previous anticancer 
treatment that has not recovered to at least Grade 2 are excluded.  Anticancer 
hormonal therapy must be stopped 7 days before starting C1D1.  Subjects receiving 
bisphosphonates or denosumab are eligible.
2.
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 recurrent 
breast cancer within the past 6 months will also be considered towards the 
maximum of 2 prior lines of therapy.
●
A regimen will be considered a line of therapy if it includes a cytotoxic agent 
administered for the treatment of breast cancer more than 1 full cycle.  
Therapy administered for 1 full cycle or less will not be counted towards the 
number of lines of therapy unless the patient experienced progression of 
disease while on that therapy.
●
Previous treatments with hormonal therapy (tamoxifen, aromatase inhibitors) 
and signal transduction agents, (e.g., trastuzumab, lapatinib, erlotinib, 
gefitinib, bevacizumab) are allowed and are not counted toward the prior line 
of therapy.
3.
Prior treatment of breast cancer with temozolomide, a platinum agent, or a PARP 
inhibitor.
●
Therapy with temozolomide, a platinum agent, or a PARP inhibitor 
administered for 1 full cycle or less will not be considered as prior therapy 
unless the patient experienced progression of disease while on that therapy.
4.
Prior taxane therapy administered for the treatment of metastatic breast cancer with 
the below exceptions.


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●
Prior taxane therapy for metastatic breast cancer is allowed if the patient 
received ≤ 1 full cycle (i.e., within 4 weeks for subjects receiving weekly 
paclitaxel or Abraxane; 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 C1D1.
●
Use of taxanes as adjuvant therapy or to treat locally recurrent disease is 
permitted, if given more than 6 months prior to C1D1.
In all cases, the subject must be an appropriate candidate for paclitaxel therapy as 
per standard practice and per the investigator's discretion.
5.
A history of or evidence of brain metastases or leptomeningeal disease.  Subjects 
with symptoms suggestive of CNS metastases should have a brain MRI within 
28 days of enrollment to confirm the absence of CNS metastases.  Contrast CT is 
acceptable for subjects who are unable to undergo a brain MRI.
6.
A history of uncontrolled seizure disorder.
7.
Pre-existing neuropathy from any cause in excess of Grade 1.
8.
Known history of allergic reaction to cremophor/paclitaxel.
9.
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;
●
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.


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10.
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.  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.
11.
Pregnant or breastfeeding.
Rationale for Exclusion Criteria
(1 – 9)  For the safety of the subjects.
(10)  To select the appropriate subject population with sufficient disease severity for 
evaluation.
(11)  The impact of veliparib + TMZ 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 drug 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.
The AbbVie Medical Monitor identified in Section 6.5 should be contacted if there are 
any questions regarding prior or concomitant therapy.
5.2.3.1
Prior Therapy
For the purposes of this protocol, antitumor treatment may be defined as, but is not 
limited to, anticancer agents (cytotoxic chemotherapy, hormonal therapy, immunotherapy, 


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biologic therapy), radiotherapy, and investigational agents.  An investigational agent is 
any drug or therapy not currently approved for use in humans.
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 recurrent disease within the past 6 months will also be 
considered towards the maximum of two prior lines 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., trastuzumab, lapatinib, 
erlotinib, gefitinib, bevacizumab), are allowed and will not 
count toward prior lines of therapy.
Anticancer hormonal therapy is not permitted within 7 days 
prior to C1D1.
Radiation:
Prior treatment with radiation is allowed as long as the last 
treatment was at least 28 days prior to C1D1.  Prior treatment 
with palliative local breast or bone lesion radiation (other than 
pelvis) is allowed if last treatment was at least 14 days prior to 
C1D1.
5.2.3.2
Concomitant Therapy
The locally approved product label, institutional guidelines, local practice, or applicable 
SmPC for TMZ, carboplatin, and paclitaxel should be referenced for any concomitant 
therapy guidelines.


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Premedication:
The prophylactic use of a 5-HT3-antagonist is strongly 
recommended before TMZ administration.  Additional 
National Comprehensive Cancer Network (NCCN), European 
Society for Medical Oncology (ESMO), or institution standard 
of care/approved prophylactic antiemetics may be given, as 
appropriate.
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).
Anticancer Agents:
Anticancer agents are not permitted during the treatment 
portion of the study.  All subjects will receive carboplatin + 
paclitaxel with veliparib/placebo or temozolomide with 
veliparib during the treatment portion of the study.  The locally 
approved carboplatin, paclitaxel, and temozolomide 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.).


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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, 
bisphosphonates or denosumab) according to institutional 
guidelines or American Society of Clinical Oncology (ASCO) 
guidelines.  
ASCO guidelines recommend a two drug combination of 
palonosetron and dexamethasone for moderately emetic 
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.49
Prophylactic antimicrobials should be considered in subjects 
receiving concurrent immunosuppressive (i.e., corticosteroids) 
therapy and those with lymphopenia (absolute lymphocyte 
count < 800) and continued until lymphopenia resolves.
Growth Factors:
Biologic response modifiers administered for erythropoiesis 
(e.g., erythropoietin, darbepoetin alpha) and colony-stimulating 
factors (e.g., neulasta, G-CSF, GM CSF, etc.) may be 
administered to maintain dose intensity or to avoid dose delays 
according to standard institutional practice or clinical practice 
guidelines (e.g., ASCO, ESMO).
Radiation:
Radiation therapy is not allowed during the study.  If radiation 
therapy is needed to treat the symptoms due to underlying 
breast cancer, the subject will be discontinued from the study 
(as defined in Section 5.3.4.1).
Surgery:
If the subject requires surgery during the study, then this needs 
to be discussed with the AbbVie Medical Monitor.


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Alternate Therapy
No anticancer Chinese medicine/herbal remedies may be taken 
concurrently with veliparib (a 14-day washout period must be 
documented).
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, 
Pharmacogenetic and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
A schedule of study activities is presented in Table 4 and Table 5.  Pharmacodynamic 
(PD) and pharmacogenetic (PG) assessments will be performed as summarized in Table 6.  
Pharmacokinetic (PK) assessment will be performed as summarized in Table 7 and 
Table 8.


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Table 4.
Study Activities (Subjects Randomized to Veliparib + TMZ Treatment Arm)
Activity
Screening
Cycle 1
(Day) 
Cycle 2
(Day) 
Day 1 of 
Each 
Cycle 
(Starting 
with C3)
Day 1 of 
Every 
Other 
Cycle 
(Starting 
with C4
Every 
9 Weeks 
from 
C1D1j
Final 
Visitm
30-Day 
Follow-up 
Visito
Post 
Treatment 
Follow-upp
1
15
22
1
15
22
Informed Consenta
X
Medical and Cancer 
History
X
Physical Exam 
(including weight)
Xb
Xc
X
X
X
X
X
X
X
X
12-lead ECG
X
Xd
Xk
Vital Signs
X
X
X
X
X
X
X
X
X
X
Pregnancy Test 
(women of 
childbearing 
potential)
X
X
Hematologye
X
Xf
X
X
X
X
X
Xg
X
X
Chemistrye
X
Xf
X
X
X
Xg
X
X
Urinalysise
X
Xf
X
Xg
X
APTT/PT/INR
X
BRCA1/2 germline 
mutation testingh
X


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Table 4.
Study Activities (Subjects Randomized to Veliparib + TMZ Treatment Arm) (Continued)
Activity
Screening
Cycle 1
(Day) 
Cycle 2
(Day) 
Day 1 of 
Each 
Cycle 
(Starting 
with C3)
Day 1 of 
Every 
Other 
Cycle 
(Starting 
with C4)
Every 
9 Weeks 
from 
C1D1j
Final 
Visitn
30-Day 
Follow-up 
Visito
Post 
Treatment 
Follow-upp
1
15
22
1
15
22
Tumor Assessment
Xi
Xj
Xk
Full Body Bone Scan
Xl
Performance Status 
(ECOG)
X
X
X
X
X
X
X
X
X
X
EORTC 
QLQ-C15/BR23
Xm
X
X
X
X
AE Assessment
X
X
X
X
X
X
X
X
X
Randomization
X
Dispense veliparib, 
TMZ
X
X
X
Survival
X
Note:
Study procedures (excluding labs) may be performed within four (4) days surrounding the scheduled study visit date.


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Table 4.
Study Activities (Subjects Randomized to Veliparib + Temozolomide Treatment Arm) (Continued)
a.
Must be performed prior to the initiation of any screening or study-specific procedures.
b.
Height will be recorded at Screening Visit only.
c.
Physical exam not required, if performed within 7 days prior to C1D1, unless clinically indicated.
d.
An ECG will be completed on C1D1 (at approximately 2 hours after the first dose of veliparib + TMZ).
e.
Refer to Table 9 for detailed list of tests to be performed and frequency.
f.
For Screening labs performed greater than 7 days prior to C1D1, hematology/chemistry should be split at C1D1 and local labs reviewed prior to dosing.
g.
For Day 1 of each cycle after Cycle 2, clinical laboratory test may be collected within 48 hours of dosing veliparib/TMZ.  A certified local laboratory may be used 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.
h.
If BRCA germline mutation status is known from Sponsor core laboratory, the subject will not be retested.
i.
The baseline tumor assessment, including diagnostic CT scans of the chest, abdomen, and pelvis, will be obtained no more than 28-days prior to C1D1.
j.
Tumor assessments will be conducted every 9 weeks (tumor assessments may be conducted 8 days prior or 2 days following the scheduled assessment from C1D1).
k.
To be performed at the Final Visit, only if not performed within the last 4 weeks.
l.
Full body bone scan will be obtained no more than 28-days prior to C1D1.
m.
Should be completed on C1D1 prior to dosing.
n.
When an investigator has determined that a subject should discontinue the study, a Final Visit will be conducted.
o.
All subjects will have one Follow-up Visit approximately 30 days after the last dose of study drug unless the subject had a Final Visit conducted ≥ 30 days after the last dose 
of study drug.
p.
Information pertaining to survival and post treatment therapy will be collected monthly (unless requested by Sponsor more frequently to support data analysis) beginning on 
the date the subject is registered off study for a minimum of three (3) years until the endpoint of death, until the subject has become lost to follow-up, or until study 
termination by AbbVie.


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Table 5.
Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin + Paclitaxel Treatment Arms)
Activity
Screening
C1D1
C1D3
C1D17
Day 1 of Each 
Cycle 
(Starting with 
Cycle 2)r
Day 3 of 
Each 
Cycler
Day 1 of 
Every Other 
Cycle 
(Starting 
with C4)
Every 
9 Weeks 
from 
C1D1j
Final 
Visitn
30-Day 
Follow-up 
Visito
Post 
Treatment 
Follow-upp
Informed Consenta
X
Medical and Cancer 
History
X
Physical Exam 
(including weight)
Xb
Xc
X
X
X
X
12-lead ECG
X
Xd
Xk
Vital Signs
X
X
X
X
X
X
X
X
Pregnancy Test 
(women of 
childbearing 
potential)
X
X
Hematologye
X
Xf
X
Xg
X
X
Chemistrye
X
Xf
X
Xg
X
X
Urinalysise
X
Xf
Xg
X
APTT/PT/INR
X
BRCA1 and 2 
germline mutation 
testingh
X


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Table 5.
Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin + Paclitaxel Treatment Arms) 
(Continued)
Activity
Screening
C1D1
C1D3
C1D17
Day 1 of Each 
Cycle 
(Starting with 
Cycle 2)r
Day 3 of 
Each 
Cycler
Day 1 of 
Every Other  
Cycle 
(Starting 
with C4)
Every
9 Weeks 
from 
C1D1j
Final 
Visitn
30-Day 
Follow-up 
Visito
Post 
Treatment 
Follow-upp
Tumor Assessment
Xi
X
Xk
Full Body Bone Scan
Xl
Performance Status 
(ECOG)
X
X
X
X
X
X
CIPN Assessment 
(QLQ-CIPN20)
Xm
X
X
X
X
EORTC 
QLQ-C15/BR23
Xm
X
X
X
X
AE Assessment
X
X
X
X
X
Randomization
X
Dispense veliparib or 
placebo
X
X
Administer paclitaxel 
premedicationq
X
X
Administer carboplatin 
+ paclitaxel
X
X
Survival
X
Note:
Study procedures (excluding labs) may be performed within four (4) days surrounding the scheduled study visit date.


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Table 5.
Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin + Paclitaxel Treatment Arms) 
(Continued)
a.
Must be performed prior to the initiation of any screening or study-specific procedures.
b.
Height will be recorded at Screening Visit only.
c.
Physical exam not required, if performed within 7 days prior to C1D1, unless clinically indicated.
d.
An ECG will be completed on C1D3 (at approximately 2 hours after the morning dose of veliparib/placebo).
e.
Refer to Table 9 for detailed list of tests to be performed and frequency.
f.
For Screening labs performed greater than 7 days prior to C1D1, hematology/chemistry should be split at C1D1 and local labs reviewed prior to dosing.
g.
For Day 1 of each cycle after Cycle 1, clinical laboratory test may be collected up to 48 hours prior to dosing veliparib/placebo.  A certified local laboratory may be used 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.  If, 
based on these results, the subject is not anticipated to be able to receive carboplatin + paclitaxel on Day 3 of the cycle, then veliparib/placebo on Day 1 should be held until 
dosing of the entire regimen can resume.  For subjects on study treatment for more than 5 years, central laboratory testing is no longer required.
h.
If BRCA germline mutation status is known from Sponsor core laboratory, the subject will not be retested.
i.
The baseline tumor assessment, including diagnostic CT scans of the chest, abdomen, and pelvis, will be obtained no more than 28 days prior to C1D1.
j.
Tumor assessments will be conducted every 9 weeks (tumor assessments may be conducted 8 days prior or 2 days following the scheduled assessment from C1D1).  For 
subjects on study treatment more than 5 years, tumor assessments will be conducted every 6 months.
k.
To be performed at the Final Visit, only if not performed within the last 4 weeks.
l.
Full body bone scan will be obtained no more than 28 days prior to C1D1.
m.
Should be completed on C1D1 prior to dosing.
n.
When an investigator has determined that a subject should discontinue the study, a Final Visit will be conducted.  For subjects on study treatment more than 5 years, 12-lead 
ECG, urinalysis, CIPN Assessment (QLQ-CIPN20), EORTC QLQ-C15/BR23, and tumor assessments do not need to be performed at Final Visit.
o.
All subjects will have one Follow-up Visit approximately 30 days after the last dose of study drug unless the subject had a Final Visit conducted ≥ 30 days after the last dose 
of study drug.  For subjects on study treatment more than 5 years, CIPN Assessment (QLQ-CIPN20) and EORTC QLQ-C15/BR23 do not need to be performed at the Follow-
up Visit.
p.
Information pertaining to survival and post treatment therapy will be collected monthly (unless requested by Sponsor more frequently to support data analysis) beginning on 
the date the subject is registered off study for a minimum of three (3) years until the endpoint of death, until the subject has become lost to follow-up, or until study 
termination by AbbVie.  For subjects on study treatment more than 5 years, there will be no post-treatment follow-up.


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Table 5.
Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin + Paclitaxel Treatment Arms) 
(Continued)
q.
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.
r.
For subjects remaining on study for more than 1 year, select Day 1 procedures can be performed on Day 3 after discussion with the AbbVie Medical Monitor.  For subjects on 
study treatment more than 5 years, Day 1 visit is not required. Physical Exam, Hematology, Chemistry, Performance Status (ECOG), AE assessment, and Dispense 
Veliparib/Placebo can be performed on Day 3 instead. Urinalysis, CIPN Assessment (QLQ-CIPN20), and EORTC QLQ-C15/BR23 no longer need to be performed on either 
Day 1 or Day 3 for these subjects.


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Table 6.
Schedule Pharmacodynamic and Pharmacogenetic Assessments
Procedure
Visit Schedulef
Before Drug 
Administration
Sampling Plan
Specimen Matrix
PD Blood Sampling+
Plasma Markersa,b
C1D1, C2D1, and Day 1 of every 10th cycle (C10, C20, etc.)
Pre-dose
Blood → Plasma
Frozen –70°C or colder
Final Visit
At the time of the clinic visit
Serum Markers
C1D1, C2D1, and Day 1 of every 10th cycle (C10, C20, etc.)
Pre-dose
Blood → Serum
Frozen –70°C or colder
Final Visit
At the time of the clinic visit
BRCA Sequencing:  Bridging 
Sample
C1D1
Blood
Frozen –20°C or colder
Circulating tumor cells (CTC)c
US Sites Only
C1D1 and C2D1
Pre-dose
Blood Shipped Fresh
on the day of collection (must be kept 
ambient until shipped)
C1D15d/C1D17e
and Final Visit
At the time of the clinic visit
Optional with Consent
Serial Biopsies*
C1D1
Pre-dose
Flash Frozen –70°C and
FFPE 4°C
Final Visit
At the time of clinic visit
Optional with Consent
Tissue Sample Collection*
IHC/FISH
FFPE tissue blocks
Diagnostic, formalin fixed, paraffin 
embedded (FFPE) tissue blocks 4°C
Optional with Consent 
PG Blood Sampling*
Genetic (DNA)
C1D1
Blood
Frozen –20°C or colder
a.
An additional sample may be collected at the time of discontinuation due to an adverse event.
b.
Based on a discussion between AbbVie and the investigator, samples for an individual subject may be collected at an alternate time point.
c.
CTC/DNA repair collection should not be the first tube drawn.  For US sites only.
d.
For subjects randomized to the veliparib + TMZ treatment arm.
e.
For subjects randomized to the veliparib/placebo + carboplatin + paclitaxel treatment arms.
f.
For subjects on study treatment more than 5 years, any sampling scheduled for Day 1 of every 10th cycle or Final Visit will no longer be required.
*
Optional with consent.
+
If a drug interruption is needed, the subject will continue to have study visits as planned; however, PD samples will not be drawn during this period.


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Table 7.
Schedule of Pharmacokinetic Assessment (Subjects Randomized to Veliparib + TMZ Treatment Arm)
Procedure
Visit 
Schedule
Before Drug 
Administration
After Veliparib AM 
Dose
Sampling Plan
Specimen Matrix
Veliparib PK Samplinga
C1D1
--
0.5, 1, 2, 3 h
Blood → Plasma
Frozen –20°C or colder
a.
All samples should be drawn in conjunction with clinical lab blood draws.
Note:
The date and time of sample collection and the date and time of the morning dose of veliparib will be captured on the eCRF.


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Table 8.
Schedule of Pharmacokinetic Assessments (Subjects Randomized to Veliparib or Placebo + Carboplatin + 
Paclitaxel Treatment Arms)
Procedure
Visit 
Schedule
Before Drug 
Administration
After Veliparib 
AM Dose
Sampling Plan
Specimen Matrix
Veliparib PK Samplinga,
C1D3
0 ha
0.5, 1, 2, 3 h
Blood → Plasma
Frozen –20°C or colder
Veliparib PK Samplinga,
C2D3
0 ha
-
Blood → Plasma
Frozen –20°C or colder
Paclitaxel PK Sampling+
C1D3
--
2 h 55 min after start of 
Paclitaxel infusionb
Blood → Plasma
Frozen –20°C or colder
Free Platinum 
(for Carboplatin)*+
Pharmacokinetic Sampling
C1D3
--
25 min after start of the 
carboplatin infusionc
Blood → Plasma
Frozen –80°C or colder
a.
Before the administration of the morning dose of veliparib.  The morning dose of veliparib/placebo should be dosed in the clinic prior to carboplatin + paclitaxel on C1D3 and 
C2D3.
b.
Approximately 3 hours after the morning veliparib dose.
c.
Approximately 3.5 hours after the morning veliparib dose.
*
Sites without an -80 freezer, must ship samples the same day.
+
If a drug interruption is needed, the subject will continue to have study visits as planned; however, PK samples will not be drawn during this period.
Note:
The date and time of the sample collection and the date and time of the last two doses of veliparib will be captured on the eCRF.


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5.3.1.1
Study Procedures
The study procedures outlined in Table 4 and Table 5 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 6.0).  All study data will be recorded within the EDC system.
Screening procedures will occur within 28 days prior to C1D1 (excluding BRCA testing 
which may occur greater than 28 days prior to C1D1).  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.  For Day 1 of 
each cycle after Cycle 2, lab samples may be collected up to 48 hours prior to dosing 
veliparib/TMZ.  For Day 1 of each cycle after Cycle 1, lab samples may be collected up to 
48 hours prior to dosing veliparib/placebo. For subjects on study treatment more than 
5 years, laboratory samples may be collected up to 4 days prior to dosing 
carboplatin/paclitaxel on Day 3.
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.  A separate informed consent will be required for 
the optional pharmacogenetic testing, needle/excisional/punch biopsy, and archival tissue
collection.  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 


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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.
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:
○
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 C1D1 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 C1D1, PE is not required on C1D1, unless clinically indicated.  Clinically 


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significant changes from baseline will be documented in the source documentation and 
eCRF as adverse events.
12-lead Electrocardiogram (ECG)
For subjects randomized to the veliparib + TMZ treatment arm, a resting 12-lead ECG 
will be performed at the Screening Visit within 28 days of C1D1 (prior to the first dose of 
veliparib/TMZ to document the baseline status of the subject).  C1D1 (at approximately 
2 hours after the morning dose of study drug), and Final Visit (if not performed within the 
last 4 weeks).  For subjects randomized to the veliparib/placebo + carboplatin + paclitaxel 
treatment arms, a resting 12-lead ECG will be performed at the Screening Visit within 
28 days of C1D1 (prior to the first dose of veliparib/placebo to document the baseline 
status of the subject), C1D3 (at approximately 2 hours after the morning dose of 
veliparib/placebo), and at the Final Visit (if not performed within the last 4 weeks).  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.  Final Visit ECG will not be required for subjects on study treatment more than 
5 years.
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
For female subjects of childbearing potential, a serum pregnancy test will be performed 
within 7 days of C1D1 and a urine pregnancy test will be done at the C1D1 visit prior to 
the first dose of study drug.  A serum pregnancy test can be performed at C1D1 and 
analyzed locally prior to randomization.  If a serum pregnancy test is performed on C1D1, 


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a urine pregnancy test does not need to be completed.  Subjects considered not of
childbearing potential must be documented as being surgically sterile or postmenopausal 
(for at least 1 year).
The C1D1 urine pregnancy test results must be reviewed and determined to be negative 
prior to dosing.  If the urine pregnancy test is positive at C1D1, it should be confirmed by 
a serum pregnancy test and dosing should be delayed.  The test may be repeated at the 
discretion of the investigator at any time during the study.
Clinical Laboratory Tests
All subjects will undergo the laboratory assessments outlined in Table 9.
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.  The appropriate certifications will be collected from both the central and local 
laboratories, as needed.
For subjects remaining on study treatment for more than 5 years, use of the certified 
central laboratory will be discontinued. A certified local reference laboratory will 
perform CBC and chemistry test prior to dosing carboplatin/paclitaxel. Local laboratory 
results should be documented in the source and the electronic data capture (EDC) system 
as appropriate. Samples will no longer be sent to the central laboratory for analysis.
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 C1D1, hematology/chemistry should be split at C1D1 and local labs reviewed 


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prior to dosing.  For subjects randomized to veliparib + TMZ, for Day 1 of each cycle 
after Cycle 2, lab samples may be collected up to 48 hours prior to dosing veliparib/TMZ.  
For subjects randomized to veliparib/placebo + carboplatin + paclitaxel, for Day 1 of each 
cycle after Cycle 1, lab samples may be collected up to 48 hours prior to dosing 
veliparib/placebo.  For subjects on study treatment more than 5 years, lab samples may be 
collected up to 4 days prior to dosing carboplatin/paclitaxel.
●
Urinalysis samples will be collected at Screening and on Day 1 of each 
subsequent cycle.  Urinalysis will no longer be required for subjects on study 
treatment more than 5 years.
●
APTT/INR will be collected at Screening.
●
BRCA1 and BRCA2 germline mutation will be collected at Screening (unless 
BRCA germline mutation status is known per previous Sponsor core 
laboratory testing).
●
For subjects randomized to the veliparib + TMZ treatment arm, chemistry 
samples will not be collected on C1D22 and C2D22.
In addition:
●
For subjects randomized to the veliparib + TMZ treatment arm, only 
hematology samples will be collected Day 22 of Cycle 1 and Cycle 2.
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.


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Table 9.
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)
Estimated glomerular filtration 
rate (eGFR)
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.
**
Collected prior to C1D1 (unless BRCA germline mutation status is known per previous Sponsor core laboratory 
testing).
*** For subjects on study treatment for more than 5 years, hematology and chemistry laboratory tests should be per 
local standard of care/institutional guidelines, and should include neutrophils, platelets, SGOT/AST, SGPT/ALT, 
total bilirubin, and alkaline phosphatase.


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BRCA1/BRCA2 Testing
BRCA1 and BRCA2 Germline Mutation Testing
The diagnosis of a 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 unknown significance 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 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 C1D1. 
Note:  These subjects may be eligible for randomization prior to receiving 
results from the Sponsor core laboratory. 
●
Subjects who are considered high risk for carrying a BRCA1/BRCA2 mutation 
are eligible for Sponsor core BRCA testing if they meet one of the following 
criteria (per the most current NCCN guidelines):50
○
Breast cancer diagnosed at age ≤ 45 years;
○
Breast cancer diagnosed at age ≤ 50 years with ≥ 1 first-, second-, or 
third-degree blood relative with breast cancer diagnosis ≤ 50 years and/or 
≥1 first-, second-, or third-degree blood relative with epithelial 
ovarian/fallopian peritoneal cancer at any age;


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○
Diagnosed at age ≤ 60 years with a triple negative breast cancer;
○
Diagnosed at age ≤ 50 years with a limited family history;
○
Two breast primaries (i.e., bilateral disease or two or more clearly separate 
ipsilateral primary tumors) when first breast cancer diagnosis occurred 
≤age 50 years;
○
Personal history of epithelial ovarian/fallopian tube/primary peritoneal 
cancer;
○
Diagnosed at any age, with ≥ 2 first-, second-, or third-degree relatives 
with breast and/or epithelial ovarian/fallopian tube/primary peritoneal 
cancer at any age;
○
Breast cancer diagnosed at any age with ≥ 2 first-, second-, or third-degree 
relatives with pancreatic cancer at any age;
○
Individual from a family with a known deleterious BRCA1/BRCA2 
mutation;
○
Ashkenazi Jewish descent;
○
Personal history of male breast cancer; or
○
First-, second-, or third-degree male relative with breast cancer.
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 deleterious germline 
BRCA1/BRCA2 mutation by the Sponsor core laboratory.  Germline mutation testing 
obtained greater than 28 days prior to Cycle 1 Day 1 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 to be tested at a future date.


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Tumor Assessments (Radiologic)
Appropriate diagnostic CT assessments using modified RECIST version 1.151 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, and pelvis (or MRI) to determine the 
extent of tumor burden will be performed for all tumor assessments at Screening (within 
28 days of C1D1), every 9 weeks from C1D1 (tumor assessments may be conducted 
8 days prior or 2 days following the scheduled assessment), and at the Final Visit (if not 
performed within the last 4 weeks).  For subjects on study treatment more than 5 years, 
tumor assessments will be conducted every 6 months (± 6 weeks) from C1D1 instead of 
every 9 weeks from C1D1, and will not be required at Final Visit. 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.
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.  Subjects 


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who discontinue treatment for reasons other than radiographic disease progression will 
continue to be followed every 9 weeks from C1D1 to determine the extent of tumor 
burden, until disease progression occurs.  For subjects on study treatment more than 
5 years, tumor assessments will be discontinued if subject discontinues treatment for any 
reason.
In addition to being reviewed by the investigator and/or site staff, radiology scans will be 
sent to a central imaging center (Perceptive) within 2 days of collection for review.  
Subject treatment management will be based on review by the local investigator and/or 
site staff.  The central imaging center will provide instructions regarding the preparation 
and shipment of the images.  Radiology scans will be assessed by the central imaging 
center according to RECIST (version 1.1) as outlined in Section 5.3.4.  Interpretations 
from the central imaging center will not be sent to the site.  For subjects on study 
treatment more than 5 years, radiology scans will not be sent to the central imaging 
vendor.
All events of disease progression must be confirmed by the central imaging center (except 
for subjects on study treatment more than 5 years).  The investigator should treat 
according to clinical judgment.  However, it is recommended that the subjects interrupt 
dosing, but remain on study, until the investigator and/or site staff receives notification 
from AbbVie or the central imaging vendor that the subject's event of disease progression 
was confirmed.  If progression is not confirmed, the subject should remain on study and 
continue to undergo the scheduled assessment until objective evidence of progression is 
obtained.


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ECOG Performance Status
ECOG performance status will be assessed at all visits, unless indicated otherwise.
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.
Interim Futility Analysis:  Procedures if Futility Is Declared 
An interim futility analysis will be conducted after the Week 27 tumor assessment of the 
first 30 subjects randomized to the veliparib + TMZ treatment arm.  If futility is declared 
at the time of the futility analysis for the veliparib + TMZ treatment arm, any subjects 
receiving veliparib + TMZ will be allowed the option of either 1) receiving 120 mg BID 
veliparib + carboplatin + paclitaxel or 2) discontinuing therapy.
Subjects who choose to receive treatment with veliparib + carboplatin + paclitaxel must 
be allowed at least 28 days to washout from veliparib + TMZ and will be allowed up to 
60 days between the last treatment with veliparib + TMZ and the initial dose of 
veliparib + carboplatin + paclitaxel.  The investigator will contact the AbbVie Medical 
Monitor for direction regarding subjects who require a treatment gap of more than 
60 days.
For subjects who choose to receive veliparib + carboplatin + paclitaxel, the investigator 
must attest that the subjects continue to meet eligibility criteria and have adequate 
hematologic, renal, and hepatic function as follows:


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●
Bone Marrow:  ANC ≥ 1500/mm3 (1.5 × 109/L); Platelets ≥ 100,000/mm3 
(100 × 109/L); Hemoglobin ≥ 9.5 g/dL (5.89 mmol/L); Leukocytes 
> 3,000/mm3;
●
Renal Function:  Serum creatinine ≤ 1.5 × ULN range OR creatinine clearance 
≥ 50 mL/min/1.73 m2 for subjects with creatinine levels above institutional 
normal;
●
Hepatic Function:  AST and/or ALT ≤ 2.5 × institutional upper limit of 
normal.  For subjects with liver metastases, AST and/or ALT < 5 × ULN 
range; bilirubin ≤1.5 × the ULN range.  Subjects with Gilbert's syndrome may 
have a bilirubin ≥1.5 × the ULN range, if no evidence of biliary obstruction 
exists;
●
APTT must be ≤ 1.5 × the ULN range and INR < 1.5.  Subjects on 
anticoagulant therapy will have an appropriate PTT and INR, as determined by 
the investigator.
The investigator must also attest that the subject does not have any clinically significant 
uncontrolled conditions including, but not limited to:
●
Active infection;
●
Symptomatic congestive heart failure;
●
Unstable angina pectoris or cardiac arrhythmia;
●
Myocardial infarction within last 6 months;
●
Psychiatric illness/social situations that would limit compliance with study 
requirements; or
●
Any medical condition which in the opinion of the investigator places the 
subject at an unacceptably high risk for toxicities.
CIPN Assessment
CIPN (as assessed by the EORTC QLQ CIPN20 questionnaire and NCI-CTCAE 4.0 
grading for peripheral neuropathy) will be assessed on C1D1, C2D1 and every other cycle 
thereafter beginning with Cycle 4 (C6, C8, etc.) Final Visit, and at the Follow-up Visit in 
subjects randomized to the veliparib/placebo + carboplatin + paclitaxel treatment arms.  


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CIPN assessment will no longer be required at any visit for subjects on study treatment 
for more than 5 years.
Quality of Life
To assess the subject's QoL, the EORTC QLQ-C15/BR23 (including questions on 
cognition) questionnaires (Appendix C and Appendix D), respectively) will be 
administered at C1D1 pre-dose, C2D1, and every other cycle thereafter beginning with 
Cycle 4 (C6, C8, etc.), Final Visit, and at the Follow-up Visit.  The subject will complete 
quality of life questionnaire worksheets.  Site personnel will check the worksheets 
returned by the subject for completeness before the subject leaves the clinic.  If the subject 
is unable to complete the form, qualified site personnel may administer the questionnaires 
via interview and complete the worksheets for the subject.  EORTC QLQ-C15/BR23 
questionnaires will no longer be administered at any visit for subjects on study treatment 
for more than 5 years.
The EORTC QLQ-C15/BR23 is a 38-item questionnaire that was developed to assess 
health-related quality of life among subjects with breast cancer.  Scores can be calculated 
from the EORTC QLQ-C15/BR23, including physical and emotional well-being, and 
breast symptom-specific questions.52  Note:  The QlQ-BR23 is a module of the QLQ-C30.  
The QLQ-C30 (30-item questionnaire) is not being used for this study; therefore, the 
QLQ-BR23 questionnaire administered to the study subjects will begin with question 
number 31.
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.


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Subjects who complete all Screening procedures and meet the eligibility criteria in 
Section 5.2.1 and none of the exclusion criteria in Section 5.2.2 will proceed to 
randomization.  The site will access the system on or prior to the subject's C1D1 visit and 
a unique randomization number will be provided.
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.
Dispensation of Study Drug
Subjects randomized to the veliparib + TMZ treatment arm will receive sufficient 
quantities of veliparib for 7 days of administration in each 28-day cycle and sufficient 
quantities of TMZ for 5 days of administration in each 28-day cycle.  Veliparib + TMZ 
will be dispensed prior to dosing at each cycle (Day 1 of each cycle).
For subjects randomized to the veliparib/placebo + carboplatin + paclitaxel treatment 
arms, subjects will receive sufficient quantities of veliparib or placebo for 7 days of 
administration in each 21-day cycle and sufficient quantities of carboplatin at a dose of 
AUC 6 and paclitaxel at a dose of 175 mg/m2.  Trained site personnel will administer the 
carboplatin + paclitaxel intravenously on Day 3 of each 21-day cycle.  Subjects will be 
supervised at the time of the infusion.  For subjects on study treatment more than 5 years, 
veliparib/placebo may be dispensed at the Day 3 visit instead of the Day 1 visit. 
Sufficient medication will be dispensed to cover an entire cycle. The site is advised to 
contact the subject on the morning of Day 1 to reiterate the dosing instructions of 
veliparib/placebo. It is recommended the site contact the subject on Day 7 to instruct 
about ceasing dosing.
The IVRS/IWRS will assign bottles of veliparib or placebo and bottles/cartons of TMZ 
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.  Site personnel must contact 


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the IVRS/IWRS for the bottle number assignments no more than 5 days before Day 1 of 
each cycle (or Day 3 for subjects on study treatment more than 5 years who are having 
veliparib/placebo dispensed at Day 3).  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.
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).
Subjects will be provided with self-administration instructions and subject dosing cards.  
Subjects will be instructed to store veliparib or placebo and TMZ according to specific 
directions included in Section 5.5.2.2.  Subjects should return bottles of veliparib or 
placebo and TMZ (empty, partially filled, or full) to the study site prior to each cycle and 
at the Final Visit.
Post treatment Information
Post treatment information will be collected via IVRS/IWRS at monthly intervals (or as 
requested by Sponsor to support data analysis) beginning on the date the subject is 
registered off study and for up to three (3) years until the endpoint of death, the subject 
has become lost-to follow-up, or AbbVie terminates the study.
All subjects will be followed for survival information (i.e., the date and cause of death) 
unless the subject requests to be withdrawn specifically from study survival follow-up; 
this request must be documented in the subject's medical record and signed by the 
investigator.
If the subject withdraws from the study follow-up, the study staff may use public 
information source (such as county records) to obtain information about survival status 
only per local regulations, as appropriate.


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No post-treatment information will be collected for subjects on study treatment for over 
5 years.
If known, post treatment anticancer therapies, dates of initiation, and end dates will be 
reported.
5.3.1.2
Blood Samples for Pharmacogenetic Analysis
If PG testing is performed, results from individual subjects will be kept coded and 
confidential and will not be given to anyone not directly involved with this research study.  
AbbVie will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.  Samples will be coded so that subject identities will not be 
available to the scientists conducting the genotyping analyses.  Individual subject results 
will not be provided to the investigator, so that neither the subject nor the investigator will 
have knowledge of specific subject genotypes.  AbbVie will keep the DNA samples until 
they are destroyed by AbbVie when this research is completed.  These samples will not be 
stored longer than 20 years.
Collection of Pharmacogenetic Sample (Optional)
One 4-mL whole blood sample for DNA isolation will be collected at C1D1 from each 
subject who consents to provide samples for PG analysis.  The procedure for obtaining 
and documenting informed consent is discussed in Section 9.3.
Whole blood will be collected by standard phlebotomy techniques, as described below:
●
Collect approximately 4 mL of blood into an appropriately labeled EDTA 
tube.
●
Immediately invert the collection tube 8 to 10 times to reduce the likelihood of 
clot formation.
●
The sample collection tubes will be labeled as "PG Sample," with the protocol 
number, subject number, and study day and/or collection date.
●
Store samples at –20°C or colder within 30 minutes of the blood draw until 
shipped/transported.


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Shipment of Pharmacogenetic Samples
Samples and inventory sheet should be batch-shipped frozen on dry ice sufficient for 
3 days to a designated lab for DNA extraction and long-term storage.  Samples should not 
be allowed to thaw prior to arrival at the designated laboratory.  Shipment information 
will be provided in the laboratory manual.
5.3.1.3
Blood Samples for Pharmacodynamic Analysis
PD correlative studies are exploratory in nature.  Serum and plasma specimens may be 
utilized to evaluate known and novel markers (nucleic acids, peptides/proteins, and 
metabolites) of disease status.  Additional studies may include assessment of methylation 
and mutational status of circulating DNA for biomarkers that correspond with patient 
response to treatment.  Tissue biopsies and/or circulating tumor cells may be examined for 
the tumor-specific alterations of cellular proteins/peptides and/or nucleic acids.  
Furthermore, tumor tissues may be examined for resistance factors, including, but not 
limited to acquiring secondary mutations known to restore BRCA function.  AbbVie may 
examine the underlying causes of these alterations through determination of the 
amplification/mutation or methylation status of various genes, for example genes involved 
in DNA repair and tumor suppression.  PD variables will be further discussed in 
Section 5.3.8.
Blood Collection for Plasma Markers
Whole blood samples (approximately 12 mL at C1D1 and 6 mL at all other time points) 
will be collected by any standard phlebotomy technique from a peripheral venous access 
point to obtain plasma sample aliquots at the following time points:  pre-dose on C1D1, 
C2D1, Day 1 of every 10th cycle (C10, C20, etc.) and the time of the clinic visit for the 
Final Visit.  For subjects on study treatment more than 5 years, sampling scheduled for 
Day 1 of every 10th cycle or Final Visit will no longer be required.


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Handling and Processing of Plasma Markers
The complete process of centrifugation, transfer to cryovial, and freezing should be 
accomplished in less than 1 hour from blood draw.  Samples should be processed as 
follows:
1.
Collect the blood sample into appropriately labeled 6-mL EDTA (purple top) tubes 
(use 2 tubes for C1D1).
2.
Immediately invert the tubes 8 to 10 times to reduce the likelihood of clot 
formation.
3.
Centrifuge the blood samples at 1100 to 1300 × g for 15 minutes using a 
refrigerated centrifuge at 2°C to 8°C.
4.
Within 15 minutes, transfer the plasma sample into labeled 2-mL cryovials (divide 
the plasma between a total of four 2-mL cryovials for C1D1 and between a total of
two 2-mL cryovials for all subsequent samples).  The cryovials should be labeled 
with the study drug number, sample matrix (plasma), protocol number, subject 
number, time point, and date.
5.
Store the samples immobile and upright at –70°C or colder until shipped frozen to 
designated laboratory.  For sites that do not have access to a –70°C freezer, more 
frequent shipments (e.g., monthly versus quarterly) to the central laboratory may be 
required.
Blood Collection for Serum Markers
Approximately 5 mL of blood will be collected by venipuncture into a 5-mL SST (gold 
top) tube at the following time points:  pre-dose on C1D1, C2D1, Day 1 of every 
10th cycle (C10, C20, etc.) and at the time of clinic visit for the Final Visit.  For subjects 
on study treatment more than 5 years, any sampling scheduled for Day 1 of every 
10th cycle or Final Visit will no longer be required. The collection should be performed as 
described below.  The complete process of clot formation, centrifugation, transfer to 


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cryovials, and freezing should be accomplished in less than 90 minutes from the time of 
blood draw.
●
Collect the blood sample into a 5-mL SST (gold top) tube.
●
Immediately invert the collection tube 5 times.
●
Allow blood to clot for a minimum of 30 minutes in a vertical position, until a 
dense clot is observed.
●
Centrifuge sample at 1100 to 1300 × g for 15 minutes at room temperature to 
ensure adequate separation of the serum.
●
Within 15 minutes, transfer the serum into two separate 2-mL labeled 
cryovials and freeze at –70°C or colder.
●
Store samples at –70°C or colder until they are shipped to the central 
laboratory on dry ice sufficient for 3 days.
Shipment of Plasma and Serum Marker Samples
Samples and inventory sheet should be batch-shipped frozen on dry ice sufficient for 
3 days to the designated laboratory.  Samples should not be allowed to thaw prior to 
arrival at the designated laboratory.  Shipment information will be provided in the lab 
manual.
Blood Collection for BRCA Bridging Sample
Two 4-mL whole blood samples for DNA isolation will be collected at C1D1 from each 
subject for BRCA testing at the Sponsor core laboratory and at an FDA-approved study 
laboratory.
Whole blood will be collected by standard phlebotomy techniques, as described below:
●
Collect approximately 4 mL of blood into 2 appropriately labeled EDTA tubes.
●
Immediately invert the collection tube 8 to 10 times to reduce the likelihood of 
clot formation.
●
Store samples at –20°C or colder within 30 minutes of the blood draw, until 
shipped/transported on dry ice sufficient to last during shipment/transport to a 


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designated lab.  Samples should not be allowed to thaw prior to arrival at the 
designated laboratory.
Shipment of Plasma BRCA Bridging Samples
Samples and inventory sheet should be batch-shipped frozen on dry ice sufficient for 
3 days to a designated lab.  Samples should not be allowed to thaw prior to arrival at the 
designated laboratory.  Shipment information will be provided in the laboratory manual.
Blood Collection and Shipment for Circulating Tumor Cells (CTC) (US Sites Only)
Approximately 10 mL of blood will be collected by any standard phlebotomy technique 
from a peripheral venous access point into appropriately labeled 10-mL Cellsave tube at 
the following time points C1D1 and C1D15 for subjects randomized to the veliparib + 
TMZ treatment arm, C1D1 and C1D17 for subjects randomized to the veliparib/placebo + 
carboplatin + paclitaxel treatment arms, C2D1 and Final Visit (for subjects in all 
treatment arms in the US only).
●
Remove the tube from the adapter and gently invert it 8 times to mix and 
prevent clotting (inadequate or delayed mixing may result in inaccurate test 
results).
●
The sample requires shipment to AbbVie on the day of collection and, 
therefore, if sample is collected on Friday, it should be shipped for Monday 
delivery.
●
The specimen will be labeled with the study drug number, sample matrix 
(blood), assay type (CTC), protocol number, subject number, and collection 
date.
●
The specimen will be packed and shipped in a styrofoam container overnight 
to AbbVie.
●
Notify AbbVie of shipment via e-mail to
and/or
 and fax the completed form to 
+1


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Shipping address:
AbbVie
1150 S. Northpoint Blvd.
Waukegan, IL  60085
Phone:
Tissue Collection for IHC and FISH DNA Mutational/Methylation Analysis
Archived Tissue Samples
If available, fixed samples from most recent pathological analysis will be collected from 
subjects (with consent).
Immunohistochemistry (IHC), tumor DNA methylation and mutational analysis, FISH, 
and/or quantitative polymerase chain reaction (qPCR) may be performed on tissue slides 
from archived, diagnostic, formalin-fixed, paraffin-embedded (FFPE) tissue blocks from 
all subjects who consent in the study.
The site may either submit an archived tissue block or cut tissue section on slides.  From 
each representative FFPE tumor tissue, the local pathology laboratory should apply 
10 slices of tissue with a thickness of approximately 4 to 6 microns and 5 slices of tissue 
with a thickness of approximately 10 microns to positively charged slides to be used for 
IHC, mutational, and FISH analysis.  Therefore, a minimum of 15 slices of tissue sections 
should be collected from each subject block.  In cases where there is not enough 
appropriate tissue available to provide these sections, the investigator will communicate 
with the pathology laboratory to determine the maximum number of slides that can be 
provided and relay that information to AbbVie prior to slide preparation.
To ensure optimal sampling, two quality control slides must also be prepared by the 
pathology laboratory and included in the shipment of slides to the designated lab.  These 


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quality control slides will be representative of the beginning and of the end of the tissue 
section.  These slides are to be stained using hematoxylin and eosin (H&E) and reviewed 
by the local pathologist to ensure the diagnostic quality of viable tumor and normal cells 
(i.e., large regions of necrosis or areas composed primarily of fibrous connective tissue or 
adipose tissue are not the predominant feature).  The remaining tissue prepared for the 
unstained slides will be procured from the sections closest to the section that is of 
adequate diagnostic quality.
Included with each shipment should be a copy of the pathology report with all specific 
subject identification information removed or blacked out and a completed shipment 
inventory form.  The FFPE tissue block or slide boxes should be labeled with study drug 
number, sample matrix (tissue), protocol number, subject number, and collection date.  
Slide boxes should be packaged using suitable shipping materials and sent to the 
designated lab at ambient temperature.  If the blocks are to be returned, please provide 
clear instructions and the return address.
Serial Biopsies When Deemed Feasible by the Investigator
Biopsies (needle, punch, or excisional) will be obtained at the C1D1 visit prior to therapy 
and at the Final Visit, when feasible, for all subjects who consent and who have readily
accessible tumor tissue.  Because of the concern regarding increased risk associated with 
lung, mediastinal lymph nodes, and liver biopsies, no lung, liver, or mediastinal lymph 
node biopsies will be performed as part of this study.
It is preferred that at least 2 core biopsies be obtained.  These biopsies should be at least 
18 gauge in diameter and at least 1 cm in length.  Alternatively, biopsies for superficial 
lesions (cutaneous and subcutaneous), may be obtained via punch or excisional biopsy.  
For excisional and punch biopsies, a single specimen is adequate provided it can be 
bisected into 2 adequate samples.  It is estimated that there will be between 2 to 5 million 
cells from each biopsy.  All biopsies should be labeled with study drug number, sample 
matrix (tissue biopsy), protocol number, subject number, and collection date.


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One core or one portion of the punch or excisional biopsy should be fixed in formalin for 
between 8 to 24 hours, then embedded in paraffin.  These samples will be stored at 4°C to 
maintain the sample integrity until shipment to the designated laboratory.  These samples 
will be shipped at ambient temperature.  Upon notification from AbbVie, the samples will 
be shipped to the designated laboratory.  These samples can be batched and shipped either 
monthly or quarterly depending on the number of samples.
The second core or second portion of the punch or excisional biopsy specimen should be 
placed into a properly labeled cryovial.  The label on the cryovial should be wrapped with 
scotch tape so that the ends of the tape overlap and the label is completely covered.  This 
tumor sample, whether obtained via needle, excisional, or punch biopsy will be 
flash-frozen in liquid nitrogen immediately after collection (alternatively, a dry ice bath 
with ethanol or methanol may be used).  This specimen will be stored frozen at –70°C.
5.3.1.4
Collection and Handling of Pharmacodynamic Samples
The blood and tissue samples for PG and PD analyses will be shipped from the study site 
to a designated laboratory according to instructions in the laboratory manual from 
AbbVie.  Samples will be labeled with the drug number name, type of sample 
(e.g., blood), assay type (e.g., DNA), the protocol number, the subject number, and the 
study day and/or collection date.  An inventory of the samples included must accompany 
the package.
5.3.2
Drug Concentration Measurements
Pharmacokinetic variables are discussed in Section 5.3.6.
5.3.2.1
Collection of  Samples for Analysis 
Plasma Samples for Subjects Randomized to Veliparib + TMZ Arm
Blood samples for determination of plasma concentration of veliparib will be collected 
only from those subjects randomized to receive veliparib + TMZ on C1D1.  The date and 
time of sample collection and the date and time of the morning dose of veliparib will be 


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captured on the eCRF.  Approximately 4 mL of blood will be collected by venipuncture 
into one 4-mL potassium EDTA (purple cap) tube in conjunction with clinical lab blood 
draws (if possible) per Table 7.  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.
Sufficient blood will be collected to produce approximately 1.5 mL of plasma for each 
sample.  The date and time of collection for each sample will be recorded.
Plasma Samples for Subjects Randomized to Veliparib/Placebo + Carboplatin + 
Paclitaxel Arms
Blood samples for determination of plasma concentration of veliparib, paclitaxel, and free 
platinum (for carboplatin) will be collected from subjects randomized to receive 
veliparib/placebo + carboplatin + paclitaxel on C1D3 and determination of plasma 
concentration of veliparib on C2D3.  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 
4 mL of blood will be collected by venipuncture into one 4-mL potassium EDTA (purple 
cap) tube in conjunction with clinical lab blood draws (if possible) per Table 8.  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.
Sufficient blood will be collected to produce approximately 1.5 mL of plasma for each 
sample.  The date and time of collection for each sample will be recorded.
Samples should not be collected when subjects are on a dose interruption.
5.3.2.2
Handling/Processing of  Samples
Blood Samples for Veliparib and Paclitaxel Pharmacokinetic Analysis
The complete process of centrifugation, transfer to polypropylene tubes, and freezing 
should be accomplished within 60 minutes from blood draw.  The processing of 
pharmacokinetic samples should be performed, as described below:


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●
Collect the blood sample in a 4-mL EDTA (purple top) tube.
●
Immediately invert the collection tubes 8 to 10 times.
●
Centrifuge sample at 1100 to 1300 × g for 10 minutes at 2° to 8°C.  If a 
refrigerated centrifuge is not available, the samples must be thoroughly chilled 
in an ice water bath prior to centrifugation and then must be removed from the 
centrifuge as soon as the rotor comes to a complete stop and either placed back 
in the ice water bath or immediately processed and frozen.
●
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.
Blood Samples for Free Platinum Pharmacokinetic Analysis
The complete process of centrifugation, transfer to polypropylene tubes and freezing 
should be accomplished within 60 minutes from blood draw.  The processing of PK 
samples should be performed, as described below:
●
Collect the blood sample in a 4-mL EDTA (purple top) tube.
●
Immediately invert the collection tubes 8 to 10 times.
●
Centrifuge sample at 1100 to 1300 × g for 10 minutes at 2° to 8°C.  If a 
refrigerated centrifuge is not available, the samples must be thoroughly chilled 
in an ice water bath prior to centrifugation and then must be removed from the 
centrifuge as soon as the rotor comes to a complete stop and either placed back 
in the ice water bath or immediately processed and frozen.
●
Transfer plasma into an appropriately labeled (drug name, type of sample, 
protocol number, subject number, treatment cycle and day, the planned time of 
sample collection relative to dosing and the sample collection date) 
screw-capped polypropylene tube and pack on dry ice for shipping.


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●
Samples for free platinum analysis should be shipped on dry ice to the central 
lab on the same day of draw.  Note:  Samples will freeze when placed upright 
in the dry ice.
●
If plasma samples cannot be shipped same day of draw, then samples must be 
frozen upright at –80°C or colder within 1 hour after collection and must be 
shipped frozen to the central laboratory within 5 days.  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, paclitaxel, and free platinum (plasma ultrafiltrate) will 
be determined under the supervision of the Drug Analysis Department at AbbVie.
5.3.3
Efficacy Variables
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 C1D1) thereafter, and at the Final Visit, if not performed within the last 4 weeks.  
Assessments will be modified for subjects on study treatment more than 5 years as 
indicated in Section 5.3.1.1.
The primary efficacy endpoint will be PFS.  The secondary endpoints will be OS, CBR, 
and ORR in those subjects treated with veliparib plus TMZ or treated with veliparib plus 
carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel and to assess 
CIPN (as assessed by the EORTC QLQ-CIPN20 questionnaire and NCI-CTCAE 4.0 
grading for peripheral neuropathy) in those subjects treated with veliparib plus carboplatin 
and paclitaxel versus placebo plus carboplatin and paclitaxel.  The tertiary endpoints will 
include ECOG performance status, QoL, and exploratory correlative studies.


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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 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.
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.


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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 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.
All measurements should be taken using calipers and recorded in metric notation, if 
clinically assessed.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and not more than 28 days prior to the beginning of treatment.
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 


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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 axial contiguous 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.
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.


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Baseline Documentation of "Target" and "Non-Target" Lesions
All measurable lesions, up to a maximum of 2 lesions per organ and 5 lesions in total 
representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  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, 
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 assessments of response (CR or 
PR) must be confirmed by scans not less than 4 weeks apart.
All other lesions (or sites of disease), including pathological lymph nodes 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.


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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).
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.


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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 timepoints 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 and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits.
Progressive Disease (PD)
Unequivocal progression of existing non-target lesions.
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 


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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.  An example of this is the patient who has visceral 
disease at baseline and while on study has a CT or MRI brain, which reveals metastases.  
The subject's brain metastases are considered evidence of progressive disease even if he 
or she did not have brain imaging at baseline.
If a new lesion is equivocal (e.g., too small to measure), continued therapy and follow-up 
evaluation will clarify 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.
5.3.4.1
Definition of Disease Progression
Disease progression will be defined as progression of disease by RECIST version 1.1.  
Clinical data that support progression will be collected and submitted for central review 
(i.e., report of skin lesions measurements, cytology, bone scan).
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 


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discontinuation of treatment.  Clinical progression may be characterized, but not limited 
to, an increase of at least 2 points in ECOG performance status attributable to cancer 
progression, requirement for palliative radiation, chemotherapy, or surgery, or death from 
disease progression.
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.
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.
During the conduct of the study, an IDMC will review unblinded safety data.  Please refer 
to Section 8.1.9 for further details pertaining to the IDMC review.
5.3.6
Pharmacokinetic Variables
Collection and shipment of PK samples is discussed in Section 5.3.2.
Values for the PK parameters of veliparib, including maximum observed plasma 
concentration (Cmax), the time of Cmax (peak time, Tmax), and the area under the plasma 
concentration-time curve (AUC) will be determined using noncompartmental methods, if 
the data warrant.
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.


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5.3.7
Pharmacogenetic Variables
DNA samples may be analyzed for genetic factors contributing to the subject's response to 
veliparib, or other study treatment, in terms of pharmacodynamics, efficacy, tolerability, 
and safety.  Such genetic factors may include genes for drug-metabolizing enzymes, drug 
transport proteins, genes within the target pathway, or other genes believed to be related 
to drug response.  Some genes currently insufficiently characterized or unknown may be 
understood to be important at the time of analysis.  The samples may be analyzed as part 
of a multistudy assessment of genetic factors involved in the response to veliparib or 
drugs of this class.  The samples may also be used for the development of diagnostic tests 
related to veliparib (or drugs of this class).  The results of pharmacogenetic analyses may 
not be reported with the study summary.
5.3.8
Pharmacodynamic Variables
Several putative biomarkers of efficacy and response may be evaluated with the goal of 
defining the relationship between drug concentration, PARP inhibition, and disease status.  
The biomarker analysis may include the examination of plasma and serum components 
such as, nucleic acids, proteins/peptides, and metabolites.  If warranted, additional studies 
may include the analysis of the methylation and mutational status of circulating DNA or 
RNA and quantification and characterization of circulating tumor cells isolated from an 
individual.  Characteristics of tumor tissue and tumor nucleic acids may be explored and 
examined in archived or fresh tissue biopsies, circulating tumor cells, and cell-free nucleic 
acids isolated from blood components.  These characterizations may be included, but are 
not limited, quantification of protein, nucleic acid, or metabolites, and characterization of 
gene methylation/mutational status or post-translational modification of proteins, 
particularly those involved in DNA repair pathways.  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 


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will be retained while research on veliparib (or drugs of this class) continues for up to but 
no longer than 20 years.
Plasma and Serum Markers
Examination of the plasma and serum components subjects on the veliparib clinical trial 
may reveal patterns of nucleic acid, protein/peptide, and metabolite concentrations that 
may be further evaluated in future clinical studies to determine any prognostic value and 
any correlation with clinical response.  Samples may be analyzed for markers 
(e.g., CA15-3 and HER2/NEU) that could be either prognostic or predictive of 
drug-response.
Stratification Markers
Genetic amplification, chromosomal loss, and/or mutational status of various genes, 
including, but not limited to those, in the DNA repair pathway represent genetic lesions 
potentially associated with subject outcome.  Gene and protein expression, FISH, and/or 
mutational methylation analysis may be conducted on tissue from archived serial biopsy 
tumor samples, CTC, and/or nucleic acids extracted from plasma from subjects 
participating in this study to assess modifications, which may prove to be informative.  
The potential relationship between amplification/loss/mutation of these entities and the 
clinical outcome in these subjects may be examined as a patient stratification tool.
DNA methylation regulates gene expression (inactivates certain genes) and aberrant 
methylation of specific genes is associated with cancer development and poor clinical 
outcome.  Tumor-derived DNA may be examined for variable methylation status of genes 
that are known to have prognostic implications associated with subjects enrolled in this 
trial.  The list of potential genes includes, but is not restricted to: RASSF1A, CDH1, 
Cyclin D2, and TWIST.
Protein RNA and DNA Analysis on Tissue and Plasma
Tissue slides from diagnostic biopsies, serial biopsies, and CTC may be used to assess 
molecular characteristics and/or expression of protein, nucleic acids, and metabolites.  


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Additionally, these samples may be examined for mutations and/or methylation of nucleic 
acids.  Protein analysis of relevant proteins, including but not limited to, DNA repair 
proteins, such as ERCC1 and XPF, may be performed on sources of tumor tissue obtained 
from each consented subject when feasible.  Mutational analysis of tumor-derived DNA 
may include, but is not limited to, acquired secondary mutations in the BRCA genes that 
have been reported to restore the activity of the molecule.  These analyses might reveal 
putative stratification and/or resistance markers for correlation with efficacy.
If warranted, circulating tumor-derived nucleic acids may be extracted from plasma and 
quantitated and/or assessed for methylation and mutational status of genes relevant to 
veliparib mechanism of action, including the DNA repair genes.  Genes relevant to the 
mechanism of action of the combination therapy agents TMZ, carboplatin and/or 
paclitaxel may also be investigated.  If tumor tissue, CTCs, and plasma are available from 
the same patient, the results of studies will be compared to assess correlation of the 
methodologies.
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.
Circulating Breast Cancer Cells
Cancer cells derived from the primary breast cancer tumor may be found circulating in the 
blood.  These tumor cells can be enriched and enumerated using cell selection and breast 
cancer cell labeling techniques.  The quantification and characterization at the protein and 
molecular levels (nucleic acids and metabolites) of these tumor cells may contain 
information correlated with drug-responsiveness, resistance factors, and clinical 
outcomes.


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5.4
Removal of Subjects from Therapy or Assessment
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 be withdrawn from the study, if any 
of the following occur:
●
The subject experiences disease progression as defined by RECIST 
version 1.1;
●
If the subject discontinues for symptomatic deterioration, every effort will be 
made to document objective progression even after discontinuation of 
treatment;
●
The investigator believes it is in the best interest of the subject;
●
Clinically significant deterioration of the subject's medical status, as 
determined by the investigator;
●
The subject requires alternative anticancer agents, or radiation therapy 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.
5.4.1
Discontinuation of Individual Subjects
When a subject discontinuation is planned without the subject reaching a protocol-defined 
endpoint, the investigator will notify the AbbVie Medical Monitor (Section 6.5) or the 
clinical team representative (Section 7.0) 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 Medical Monitor may contact the site to discuss the reason 
for withdrawal from the study.


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The investigator must report the withdrawal to the IVRS/IWRS system within 3 days of 
the subject's discontinuation visit.
When a subject discontinues the study, a Final Visit will be conducted (preferably prior to 
the initiation of another anticancer therapy).  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of the study drug, the subject will be treated in accordance with the investigator's best 
clinical judgment.
At the Final Visit, the reasons for the discontinuation from the study 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, tumor assessment (if not 
performed within the last 4 weeks), collection of unused study drug, and an assessment of 
adverse events will be performed, as soon as possible after discontinuation from the study.  
For subjects on study treatment more than 5 years, 12-lead ECG, urinalysis, CIPN 
Assessment (QLQ-CIPN20), and EORTC QLQ-C15/BR23, and tumor assesement do not 
need to be performed at Final Visit.
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. For subjects on 
study treatment more than 5 years, CIPN Assessment (QLQ-CIPN20) and EORTC 
QLQ-C15/BR23 do not need to be performed at the Follow-up Visit.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
clinically significant laboratory result, the site will attempt to provide follow-up until a 
satisfactory clinical resolution of the laboratory results or adverse event is achieved.
Subjects who discontinue treatment with veliparib + TMZ or veliparib/placebo + 
carboplatin + paclitaxel prior to reaching an event of disease progression should remain 
on study and continue to follow the schedule for study visits and procedures until disease 


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progression is experienced, if possible.  For subjects on study treatment more than 
5 years, the subject will be discontinued from study if discontinuing treatment for any 
reason.
Overall survival and post treatment information will be collected via IVRS/IWRS at 
monthly intervals (or as requested by Sponsor to support data analysis) beginning on the 
date the subject is registered off study and continuing for a minimum of 3 years on all 
subjects until the endpoint of death, the subject has become lost to follow-up, or AbbVie 
terminates the study.  For subjects on study treatment for more than 5 years, overall 
survival and post treatment information are not required.
In the event that a positive result is obtained on a pregnancy test for a subject during the 
study, the administration of study drug to that subject must be discontinued immediately.  
The site must report the positive pregnancy test result 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 Veliparib and TMZ
Subjects will receive veliparib + TMZ for up to 24 cycles or until reaching a 
protocol-defined event of disease progression or experiencing unmanageable toxicity.  If 
the subject has not progressed and the investigator feels there is benefit to continue 
treatment beyond 24 cycles, a discussion between the site and the AbbVie Medical 
Monitor (Listed in Section 6.5) to discuss continued treatment is required.  If both the 
investigator and the AbbVie Medical Monitor confirm that the subject would benefit to 
continue treatment, the subject may continue to receive veliparib + TMZ until the subject
has disease progression or experiences a toxicity that requires discontinuation of further 
treatment.  If toxicities have resulted in discontinuation of either veliparib or TMZ, both 
are to be discontinued.


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Subjects who discontinue treatment with veliparib + TMZ prior to reaching an event of 
disease progression should remain on study and continue to follow the schedule for study 
visits and procedures until disease progression is experienced.
5.4.1.2
Discontinuation of Veliparib or Placebo and 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.  If toxicities have resulted in discontinuation of both 
carboplatin and paclitaxel, veliparib will also be discontinued.  At the investigator's 
discretion, carboplatin and paclitaxel administration may continue after veliparib has been 
discontinued.
Subjects who discontinue treatment with veliparib/placebo + carboplatin + paclitaxel prior 
to reaching an event of disease progression should remain on study and continue to follow 
the schedule for study visits and procedures until disease progression is experienced.
5.4.2
Discontinuation of Entire Study
Survival (i.e., the date and cause of death) and post treatment information including 
therapies received will be collected via IVRS/IWRS at monthly (or as requested by 
Sponsor to support data analysis) beginning on the date the subject is registered off study 
and continuing for a minimum of 3 years on all subjects until the endpoint of death, the 
subject has become lost to follow-up, or AbbVie terminates the study.  For subjects on 
study treatment for more than 5 years, survival follow-up is not required.
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 


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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.
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 1:1:1 ratio to receive one of the following treatments
●
Veliparib 40 mg BID Days 1 through 7 + TMZ 150 to 200 mg/m2 QD Days 1 
through 5 in each 28-day cycle;
●
Veliparib 80 mg (for subjects randomized under the original protocol) or 
Veliparib 120 mg (for subjects randomized after approval of protocol 
Amendment 1) BID Days 1 through 7 + Carboplatin AUC 6 administered on 
Day 3 and Paclitaxel 175 mg/m2 administered on Day 3 of each 21-day cycle;
●
Placebo BID Days 1 through 7 + Carboplatin AUC 6 administered on Day 3 
and Paclitaxel 175 mg/m2 administered on Day 3 of each 21-day cycle.
5.5.1.1
Veliparib + TMZ Treatment
Subjects will self-administer the morning dose of veliparib and TMZ at the same time 
under fasting conditions (to reduce the chance of nausea and vomiting per the TMZ label 
recommendation) and the evening doses of veliparib approximately 12 hours after the 


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morning dose with or without food in the same calendar day.  For Cycle 1, the TMZ dose 
will start at a dose of 150 mg/m2 QD per body surface area (BSA) on Days 1 through 5 of 
each 28-day cycle.  If during the first cycle, platelets (nadir) are > 100,000/μL and the 
ANC (nadir) is >1,500/μL and no Grade 3 or 4 CTCAE nonhematologic toxicities 
attributable to TMZ are observed, then the TMZ dose will be escalated to 200 mg/m2 QD 
for Cycle 2.  The TMZ dose will be determined using the BSA calculated from the height 
obtained at the baseline evaluation and the weight obtained prior to each cycle.  The daily 
dose will be rounded to the nearest 5 mg.  However, for subject convenience, the dose 
may be rounded down to 5% from calculated dose, in order to minimize the number of 
capsules per dose.  The exact dose administered will be recorded in the eCRF.
It is recommended that if a subject misses a scheduled dose of veliparib and/or TMZ 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.
If the subject vomits within 15 minutes of taking the TMZ, another dose should not be 
administered.  If the subject vomits within 15 minutes of taking veliparib, and the 
veliparib capsules are intact, another full dose should be administered.  The dose may 
only be repeated once.  If more than 15 minutes have passed from the time of oral dosing, 
then no additional doses should be taken.
5.5.1.2
Veliparib + Carboplatin/Paclitaxel and Placebo + Carboplatin 
+ Paclitaxel Treatment
Subjects will self-administer the morning dose of veliparib/placebo and the evening dose 
of veliparib/placebo approximately 12 hours after the morning dose with or without food 
in the same calendar day for Days 1 through 7 of the 21-day cycle.  If the subject vomits 
within 15 minutes of taking veliparib and all veliparib capsules remain intact, another full 
dose should be administered.  Carboplatin and paclitaxel will be administered on Day 3 of 


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every cycle.  Paclitaxel will be infused prior to carboplatin.  Dosing of veliparib/placebo 
on Day 3 of every cycle should be done before carboplatin + paclitaxel infusion.
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 3 hours at a dose of 
175 mg/m2.
Carboplatin
Carboplatin will be administered intravenously over approximately 15 to 30 minutes at 
(AUC 6 mg/mL/min) immediately following paclitaxel infusion.
The 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 results for the calculation of carboplatin dosing is strongly 
encouraged.
Similarly, when the GFR is estimated using isotopic/EDTA clearance, maximum 
carboplatin dosing should be based upon standard guidelines and institutional practices.


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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.
5.5.2
Identity of Investigational Products
Information about veliparib, placebo, TMZ, carboplatin, and paclitaxel formulations to be 
used in this study is presented in Table 10.
Table 10.
Identity of Investigational Products
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
Veliparib 
(ABT-888)
Capsule
10 mg active
20 mg active
40 mg active
20 mg placebo
40 mg placebo
Oral
AbbVie
Temozolomide 
(commercially 
available)
Capsule
5 mg 
20 mg 
100 mg
Oral
Schering® Corporation 
a subsidiary of 
MERCK & CO., INC. 
or Merck Sharp & 
Dohme Limited or 
generic manufacturer
Carboplatin 
(commercially 
available)
Solution in a vial
150 mg/15 mL 
aqueous
solution
450 mg/45 mL 
aqueous 
solution
Intravenously
Generic manufacturer
Paclitaxel 
(commercially 
available)
Solution in a vial
100 mg/16.7 mL 
non-aqueous 
solution
Intravenously
Generic manufacturer
AbbVie will supply veliparib capsules, a matching placebo for veliparib, and 
temozolomide capsules.  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 


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supply carboplatin and paclitaxel to sites depending on local regulations and availability 
of supplies.
5.5.2.1
Packaging and Labeling
For the veliparib 40 mg BID + TMZ treatment arm, veliparib will be packaged in bottles 
containing 16 capsules per bottle (this includes 2 additional capsules in each bottle).  For 
the veliparib/placebo 120 mg + carboplatin and paclitaxel treatment arms, veliparib and 
placebo will be packaged in bottles containing 64 capsules of 20 mg active or placebo per 
bottle and/or 48 capsules of 40 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.
TMZ will be packaged in bottles/cartons containing 5 capsules per bottle/cartons and will 
be supplied by AbbVie.  The site staff must complete all blank spaces on the label prior to 
dispensing drug to the subject.  TMZ may be dispensed to subjects in pharmacy bottles 
according to institutional guidelines.
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 Drugs
All clinical supplies provided by AbbVie must be stored in a secure place at the proper 
storage conditions as presented in Table 11, until they are dispensed for subject use or are 
returned to AbbVie.


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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.
Table 11.
Study Drug Storage Conditions
Study Drug
Country**
Storage Conditions
Veliparib or placebo
US
Store at 15° to 25°C (59° to 77°F).
EU
Store at 15° to 25°C (59° to 77°F).
Australia
Store below 25°C.
Temozolomide
US
Store at 15° to 25°C (59° to 77°F).
EU
Store at 15° to 30°C (59° to 86°F).
Australia
Store below 25°C.
Carboplatin
US
Store at 15° to 25°C (59° to 77°F).
EU
Store at 15° to 25°C (59° to 77°F).
Australia
Store below 25°C.
Paclitaxel
US
Store at 15° to 25°C (59° to 77°F).
EU
Store at 15° to 25°C (59° to 77°F).
Australia
Store below 25°C.
US = United States; EU = European Union
** For countries not listed, 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 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.


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Subjects who complete all Screening procedures and meet the inclusion criteria in 
Section 5.2.1, and none of the exclusion criteria in Section 5.2.2 will proceed to 
randomization.  The site will access the system on or prior to the subject's C1D1 and a 
unique randomization number will be provided.  
For Group 1 of the study, the IVRS/IWRS will randomize subjects in a 1:1:1 ratio, with a 
third of the subjects being randomized to the veliparib 40 mg BID + TMZ treatment arm, 
a third to the veliparib 80 mg BID + carboplatin + paclitaxel arm, and a third to the 
placebo BID + carboplatin + paclitaxel arm.  Subject randomization will be stratified by 
ER and/or PgR positive versus ER and PgR negative, prior cytotoxic therapy versus no 
prior cytotoxic therapy, and ECOG 0-1 versus 2.
For Group 2 of the study, the IVRS/IWRS will randomize subjects in a 1:1:1 ratio, with a 
third of the subjects being randomized to the veliparib 40 mg BID + TMZ treatment arm, 
a third to the veliparib 120 mg BID + carboplatin + paclitaxel arm, and a third to the 
placebo BID + carboplatin + paclitaxel arm.  Subject randomization will be stratified by 
ER and/or PgR positive versus ER and PgR negative, prior cytotoxic therapy versus no 
prior cytotoxic therapy, and ECOG 0-1 versus 2.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects will be randomized into 1 of 3 treatment arms.
Subjects randomized to the veliparib + TMZ treatment arm will self-administer the 
morning dose of veliparib and TMZ at the same time under fasting conditions (to reduce 
the chance of nausea and vomiting per the TMZ label recommendation) and the evening 
dose of veliparib approximately 12 hours after the morning dose with or without food in 
the same calendar day.  For Cycle 1, the TMZ dose will start at a dose of 150 mg/m2/day 
on Days 1 through 5 of each 28-day cycle.  The TMZ dose will be determined using the 
BSA calculated from the height obtained at the baseline evaluation and the weight 
obtained prior to each cycle.


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Subjects randomized to the veliparib/placebo + carboplatin + paclitaxel or placebo 
treatment arms will self-administer the morning dose of veliparib/placebo and the evening 
dose of veliparib approximately 12 hours after the morning dose with or without food in 
the same calendar day.  Subjects randomized to these 2 treatment arms will return to the 
site on Day 3 of each cycle to have their carboplatin and paclitaxel administered 
intravenously.
5.5.5
Blinding
This is a partially blinded study.  AbbVie, the investigator, the study site personnel, and 
the subject will remain blinded to each subject's treatment with veliparib or placebo in the 
carboplatin + paclitaxel arms throughout the course of the study.  The IVRS/IWRS will 
provide access to blinded subject treatment information for subjects randomized to the 
veliparib/placebo + carboplatin + paclitaxel treatment arms during the study in the case of 
a medical emergency.
All subjects randomized to the veliparib + TMZ treatment arm will be treated in an 
open-label fashion.
5.5.5.1
Blinding of Investigational Product
The IVRS/IWRS will provide access to blinded subject treatment information for an 
individual subject in the case of a medical emergency.  In the event of a medical 
emergency in which the investigator believes that knowledge of study drug treatment is 
required, every effort must be made to contact the AbbVie Medical Monitor (listed in 
Section 6.5) prior to contacting the IVRS/IWRS for treatment unblinding (as long as 
subject safety is not compromised).  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.


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5.5.6
Treatment Compliance
The investigator or his or her designated and qualified representatives will administer and 
dispense veliparib, placebo, TMZ, carboplatin, and paclitaxel only to subjects enrolled in 
the study in accordance with the protocol.  Veliparib, placebo, TMZ, carboplatin, and 
paclitaxel must not be used for reasons other than those described in the protocol.
Veliparib or placebo and TMZ 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 or placebo bottles and TMZ 
bottles/cartons (empty, partially filled, or full) to the study site personnel prior to each 
cycle and at the Final Visit.  The study site personnel will document the bottles/cartons of 
veliparib, placebo or TMZ 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 of veliparib, placebo, TMZ, carboplatin (when supplied by AbbVie), and 
paclitaxel (when supplied by AbbVie).
The study coordinator will document compliance 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 or TMZ 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, TMZ, 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 


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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, TMZ, 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, TMZ, 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, TMZ, carboplatin, and paclitaxel were dispensed for each 
subject.
Upon completion or termination of the study, all original bottles/cartons containing 
unused veliparib, placebo, TMZ, carboplatin, paclitaxel (empty containers will be defaced 
and discarded on site) will be returned to AbbVie according to AbbVie's instructions, or if 
pre-arranged between the Sponsor and site, destruction of used and unused veliparib, 
placebo, TMZ, 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, TMZ, carboplatin, or paclitaxel to any persons not enrolled in the study or not 
named as a subinvestigator 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 TMZ or 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 2, randomized, partially blinded study to evaluate the efficacy and 
tolerability of veliparib in combination with TMZ and in combination with carboplatin + 


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paclitaxel compared to an active, placebo-controlled arm of carboplatin + paclitaxel.  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.  
Additionally, the design allows for the comparison of veliparib + TMZ, a regimen for 
which non-randomized, Phase 2 data indicate activity,23 to an active comparator regimen, 
as TMZ alone would not be a viable comparator.  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 design does not allow crossover, as both PFS and OS will 
be assessed.
The randomization will be 1:1:1 so each arm will contain approximately the same number 
of subjects.  Randomization will be stratified on the basis of ER and/or PgR positive 
versus ER negative and PgR negative, prior cytotoxic therapy versus no prior cytotoxic 
therapy, and ECOG 0-1 versus 2.
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 locally recurrent (not amenable to therapy with curative intent) or metastatic 
breast cancer will be enrolled into the study.  If the subject is HER2 positive, the subject 
must have received and progressed on at least one prior standard anti-HER2 therapy or the 
subject must be ineligible to receive anti-HER2 therapy.  Subjects must have had no more 
than two prior 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.


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5.6.4
Selection of Doses in the Study
Veliparib 40 mg BID + TMZ 200 mg/m2 QD was defined as MTD combination dose in 
the Phase 1 study, M06-862.  Additionally, the veliparib PK results following the 20 and 
40 mg BID doses achieved the exposures (AUC) that were effective in murine efficacy 
models and PARP inhibition in humans (CTEP Phase 0).  In a Phase 2 
investigator-initiated study to date, 41 subjects with MBC have received veliparib 40 mg 
BID Days 1 through 7 plus TMZ 150 to 200 mg/m2 QD Days 1 through 5 of a 28-day 
cycle.  Because of the number of subjects with hematological toxicities, the protocol was 
amended in December 2009 to change the dose of veliparib from 40 mg BID to 30 mg 
BID.  All of the subjects who responded to veliparib + TMZ received 40 mg BID 
veliparib initially, then 30 mg BID following the dose reduction amendment.  The study 
was also amended to include an expansion cohort to further evaluate the safety and 
tolerability of veliparib 30 mg BID + TMZ.  To date, hematological toxicities have been 
similar to that observed in the initial cohort; however, the response rate has diminished.  
On the basis of experience to date across the veliparib program (including Phase 2 studies 
in metastatic melanoma, hormone-refractory prostate cancer, and high grade serous 
ovarian cancer) in which hematological toxicities have been manageable with veliparib 
40 mg BID and the potential decrease in efficacy at the 30 mg dose, veliparib will be used 
at 40 mg BID in combination with TMZ.
The initial starting dose of 80 mg BID veliparib in this trial was derived from the results 
obtained in the CTEP 7967 study.  Selection of the initial dose for this study is discussed 
in Section 3.4.2.
The 120 mg BID dose of veliparib was determined to be the recommended phase 
two dose (RPTD), based on the current data available from the GOG 9923 (Phase 1 dose 
escalation study in subjects with advanced or metastatic ovarian cancer) study.  As of 
15 December 2011, three patients have been treated with veliparib 150 mg BID on 
Days 1 to 21 with carboplatin AUC 6 and paclitaxel 175 mg/m2 on Day 1 of a 21-day 
cycle.  No grade 3/4 toxicity or DLTs occurred at the 150 mg BID dose level during DLT 


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evaluation period; thus, in the GOG 9923 study, the veliparib 200 mg BID dose level is 
currently being evaluated.
The maximum dose of veliparib for any subject under this protocol is 120 mg BID.
5.7
Dose Reductions or Delays
If a subject experiences an adverse event that results in a delay in starting a cycle or 
requires that study regimen is delayed or interrupted during a cycle, the subject will 
complete the planned activities per Section 5.3.1 until resuming treatment.  The intention 
is for veliparib to be administered concurrently with TMZ or 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, neuropathy, 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 chemotherapy.
If chemotherapy must be withheld because of hematological toxicity, CBC and platelet 
counts should be obtained weekly until the counts reach the lower limits for treatment as 
outlined.  The treatment schedule will then proceed in the usual sequence.
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.  In the case of delays, CT scans should continue to be assessed at 
intervals of 9 weeks from C1D1.
Since fatigue can be a symptom of cancer progression, dose reduction for fatigue will only 
be done if the fatigue is deemed to be drug-related in the investigator's opinion.
Investigators should evaluate subjects for carboplatin and paclitaxel or temozolomide 
treatment per the locally approved product label, local practice, or applicable SmPC.


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5.7.1
Veliparib + TMZ Dose Reduction and Delays
The following are guidelines for dose reduction, delay, and discontinuation of veliparib 
(and TMZ for subjects randomized to the veliparib + TMZ treatment arm of the study 
(Table 12).
5.7.1.1
Veliparib Dose Reduction and Delays
●
Veliparib should be discontinued at the same time as discontinuation of TMZ.
●
For any subject who experiences Grade 3 or 4 toxicity that is not attributable to 
TMZ or the underlying disease, the veliparib dose will be held until the 
toxicity resolves to Grade 1 or lower or to baseline if Grade 2 is present at the 
time of study entry.  Two dose reductions are allowed.  The dose of veliparib 
will be reduced to 30 mg BID (dose level –1) and may be reduced again to 
20 mg BID (dose level –2) for reasons of toxicity.  Any dose reduction beyond 
20 mg BID will result in veliparib discontinuation and removal of the subject 
from protocol-directed therapy.  When veliparib is discontinued, TMZ must 
also be discontinued.
●
Any ≥ Grade 2 event of seizure attributed to veliparib requires interruption of 
veliparib and discussion with the AbbVie Medical Monitor regarding the 
decision to resume treatment.
The AbbVie Medical Monitor should be contacted (see Section 6.5) for subjects who 
require more than a 2-week delay in the re-initiation of the next cycle.
5.7.1.2
TMZ Dose Reduction and Delays
Clinically significant hematological toxicities should result in TMZ dose reduction or 
delay.  During treatment, CBCs should be monitored and the next cycle of therapy should 
not be started until the ANC is > 1,500/μL and platelet count is > 100,000/μL.  For any 
Grade 3 or 4 toxicities attributable to TMZ, dose reduction and/or delay guidelines should 
be followed per Table 12.  Dose reductions in the next cycle should be based on lowest 
blood counts and worst nonhematologic toxicity observed in the previous cycle.  The 
75 mg/m2/day is the lowest dose of TMZ allowed in this study.  Subjects must stop TMZ 


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and veliparib if they are at the 75 mg/m2/day dose level of TMZ and require an additional 
dose reduction (Table 12) because of toxicities.  Subjects will be removed from 
protocol-directed therapy if this occurs.  When TMZ is discontinued, veliparib must also 
be discontinued.
Table 12.
Veliparib and TMZ Dose Reduction or Delay Starting in Cycle 2 
and All Subsequent Cycles
Adverse Event
Dose Reduction
Hematologic 
Toxicity 
Attributable to 
TMZ
ANC < 1000/μL* and/or
Platelets < 50,000/μL*
1.
Hold TMZ and veliparib.  Check CBC weekly until 
recovery to:  ANC > 1500/μL and platelets 
> 100,000/μL
and
2.
Reduce TMZ dose by one dose level at the next 
cycle**
ANC 1000/μL* to 1500/μL* 
Platelets 50,000/μL* to 
100,000/μL*
1.
Hold TMZ and veliparib.  Check CBC weekly until 
recovery to ANC  > 1500 μL and platelets 
> 100,000/μL 
and
2.
Maintain Current TMZ Dose at the next cycle
Adverse Event
Dose Reduction
Nonhematologic 
Toxicity 
Attributable to 
TMZ
Nausea/Vomiting CTC ≥Grade 3 
despite optimal antiemetic 
therapy
1.
Hold TMZ + veliparib.  Delay cycle until Grade 1 (or 
Grade 2 if present at baseline)
and
2.
Reduce TMZ dose by one dose level for the next 
cycle**
Fatigue, constipation, anorexia 
and headaches CTC ≥ Grade 3
Any other CTC ≥ Grade 3 deemed 
to be clinically significant by PI
Adverse Event
Dose Reduction
Attributable to 
Veliparib
Any Grade 3 or 4 toxicity which 
is not attributable to TMZ or 
underlying disease
1.
Hold TMZ + veliparib.  Delay cycle until Grade 1 (or 
Grade 2 if present at baseline)
and
2.
Reduce veliparib dose by one dose level for the next 
cycle***
*
Regardless of attribution.
**
TMZ dose cannot be reduced below 75 mg/m2/day.  TMZ will be discontinued, if further dose reduction is required 
below the 75 mg/m2/day.  The subject will be removed from protocol directed therapy if this occurs.  If TMZ is 
discontinued, veliparib must also be discontinued.
*** Two dose reductions of veliparib will be allowed.  Subjects must discontinue veliparib, if they require an additional 
dose reduction because of toxicities.  The subject will be removed from protocol-directed therapy if this occurs.  If 
veliparib is discontinued, TMZ must also be discontinued.


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TMZ Dose Level Definition Summary
Dose Level
Temozolomide Dose
1
200 mg/m2/day
2
150 mg/m2/day
3
100 mg/m2/day
4
75 mg/m2/day
Note:
Refer to Table 2 for TMZ Dosing Modifications following Cycle 1.
Veliparib Dose Level Definition Summary
Dose Level
Veliparib Dose BID
Strength
Capsules per Dosing
Starting Dose Level
40 mg
40 mg
1 BID
Dose Level –1
30 mg
20 mg
10 mg
1 BID
1 BID
Dose Level –2
20 mg
20 mg
1 BID
5.7.2
Veliparib + Carboplatin + Paclitaxel and Placebo + 
Carboplatin + Paclitaxel Dose Reduction and Delays
The following are guidelines for dose reduction, delay, and discontinuation of 
veliparib/placebo + carboplatin + paclitaxel (Table 13) for subjects randomized to these 
treatment arms.
5.7.2.1
Veliparib or Placebo Dose Reductions and Delays
The following are guidelines for dose reduction, delay, and discontinuation of veliparib.
For any subject who experiences Grade 3 or 4 toxicity, which is attributable to veliparib 
or placebo but not carboplatin, paclitaxel, or the underlying disease, veliparib or placebo 
will be stopped until the toxicity resolves to ≤ Grade 1 or to baseline if Grade 2 is present 
at the time of study entry.  After recovery to ≤ Grade 1 toxicity, the subject is allowed to 
resume veliparib or placebo dosing at 1 dose level lower than the current level.  If a dose 
reduction of veliparib or placebo is needed, the dose will be decreased by one dose level 
for each dose reduction.  Any dose reduction beyond dose level –2 will result in veliparib 


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discontinuation.  At the investigator's discretion, carboplatin and paclitaxel administration 
may continue after veliparib has been discontinued.
Veliparib or Placebo Dose Level Definition Summary
Dose Level
Veliparib or Placebo 
(subjects with starting 
dose 80 mg BID)
Strength
Capsules per Dosing
Starting Dose Level
80 mg
20 mg
4 BID
Dose Level –1
60 mg
20 mg
3 BID
Dose Level –2
40 mg
20 mg
2 BID
Dose Level
Veliparib or Placebo 
(subjects with starting 
dose 120 mg BID)
Strength
Capsules per Dosing
Starting Dose Level
120 mg
40 mg
3 BID
Dose Level –1
80 mg
40 mg
2 BID
Dose Level –2
40 mg
40 mg
1 BID
5.7.2.2
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.  If the investigator considers an event 
attributable to carboplatin and/or paclitaxel and not veliparib/placebo, the investigator 
may consider reducing carboplatin and/or paclitaxel, but not veliparib or placebo.  
Guidelines for dose reduction, delay, and discontinuation are included in Table 13.
Treatment should be delayed until the toxicity resolves to ≤ Grade 1 or to baseline if 
Grade 2 toxicity is present at the time of study entry.  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.  Any patient whose treatment is delayed must be evaluated on a weekly basis until 
adequate hematologic and nonhematologic parameters have been met.  Treatment could 
be postponed for up to 28 days because of toxicity, and longer toxicity-related delay will 


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lead to paclitaxel or carboplatin discontinuation.  No dose escalation is planned for this 
study.
If a dose reduction of paclitaxel is needed, the dose will be decreased to 135 mg/m2 for 
the first dose reduction and to 110 mg/m2 for the second.  If a dose reduction of 
carboplatin is required, the dose reduction will be decreased by 1 AUC for each reduction, 
with a minimum AUC of 4.  Subjects may have 2 dose reductions of each agent and then 
that agent will be discontinued.  If the subject remains on chemotherapy (carboplatin 
and/or paclitaxel) following dose modifications, veliparib or placebo may be continued.  
However, if both carboplatin and paclitaxel have been discontinued, then veliparib or 
placebo must also be discontinued.
For any Grade 3 or 4 toxicities not mentioned in the table, 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 per the guidelines at the beginning of Section 5.7.


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Table 13.
Veliparib/Placebo + Carboplatin + Paclitaxel Dose Reduction and Delays
Adverse Event
Dose Reduction/Delay
Paclitaxel
Carboplatin
Veliparib or Placebo
Hematological toxicity 
attributable to any or all 
treatment
ANC 1000 – 1499/mm3
or Platelets  75000 – 99999/mm3
within 24 hours prior to scheduled 
therapy
Hold until recovery to ANC 
≥1500/mm3 and Platelets 
≥100,000/mm3. Resume at the 
same level after recovery.
Hold until recovery to ANC 
≥1500/mm3 and Platelets 
≥100,000/mm3.  Resume at the 
same level after recovery.
No change in dose.  Delay so 
dosing corresponds to 
carboplatin + paclitaxel 
administration.
ANC < 1000/mm3 or Platelets 
25000 – 74999/ mm3 within 24 hours 
prior to scheduled therapya
Hold until recovery to ANC 
≥1500/mm3 and Platelets 
≥100,000/mm3.  Resume at the 
same level after recovery.
Hold until recovery to ANC 
≥1500/mm3 and Platelets 
≥100,000/mm3.  Reduce by 
1 dose level.
No change in dose.  Delay so 
dosing corresponds to 
carboplatin + paclitaxel 
administration.
Platelets < 25000/ mm3 within 
24 hours prior to scheduled therapy or 
Platelets 25000-50000/mm3
complicated by bleeding, easy 
bruising, petechiae, or requiring 
platelet transfusion
Hold until recovery to Platelets 
≥100,000/mm3.  Resume at 
one dose level below current 
dose level.
Hold until recovery to Platelets 
≥100,000/mm3.  Resume at 
one dose level below current 
dose level.
No change in dose.  Delay so 
dosing corresponds to 
carboplatin + paclitaxel 
administration.
Prolonged neutropenia (ANC 
< 500/mm3 for ≥ 7 days)
Hold until recovery to ANC 
≥1500/mm3.  Resume at 
one dose level below current 
dose level.
Hold until recovery to ANC 
≥1500/mm3.  Resume at 
one dose level below current 
dose level.
No change in dose.  Delay so 
dosing corresponds to 
carboplatin + paclitaxel 
administration.
Febrile neutropenia (ANC ≤ 1000/mm3
with temperature of > 38.5°Ca)
Hold until recovery to ANC 
≥1500/mm3.  Resume at 
one dose level below current 
dose level.
Hold until recovery to ANC 
≥1500/mm3.  Resume at the 
same level after recovery.
No change in dose.  Delay so 
dosing corresponds to 
carboplatin + paclitaxel 
administration.
Anemiab
No reduction or delay.
No reduction or delay.
No reduction or delay.


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Table 13.
Veliparib/Placebo + Carboplatin + Paclitaxel Dose Reduction and Delays (Continued)
Adverse Event
Dose Reduction/Delay
Paclitaxel
Carboplatin
Veliparib or Placebo
Hepatic Toxicityc
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.
Nonhematologic Grade 3 or 4 
toxicity attributable to any or all 
treatment
Grade 3 or 4 nausea/vomiting 
despite optimal antiemetic 
treatmentd
Hold until nausea/vomiting have 
resolved to ≤ Grade1.  Resume 
at one dose level below current 
dose level.
Hold until nausea/vomiting have 
resolved to ≤ Grade 1.  Resume 
at one 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.  Resume 
at one dose level below current 
dose level.
Hold until stomatitis has 
resolved to ≤ Grade 1.  Resume 
at one dose level below current 
dose level.
Hold until stomatitis has 
resolved to ≤ Grade 1.  Resume 
at previous dose.
≥ Grade 2 neuropathye
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.
Hold until recovery to Grade 1 
or less.  Resume at the same 
level after recovery.
Hold until recovery to Grade 1 
or less.  Resume at the same 
level after recovery.


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Table 13.
Veliparib/Placebo + Carboplatin + Paclitaxel Dose Reduction and Delays (Continued)
Adverse Event
Dose Reduction/Delay
Paclitaxel
Carboplatin
Veliparib or Placebo
Toxicity attributable to veliparib 
and not carboplatin or 
paclitaxel, nor underlying 
disease
Any Grade 3 or 4 toxicity
Hold until recovery to ≤ Grade 1 
or to baseline.  Resume at the 
same level after recovery.
Hold until recovery to ≤ Grade 1 
or to baseline.  Resume at the 
same level after recovery.
Hold until recovery to ≤ Grade 1 
or to baseline.  After recovery, 
resume at one dose level below 
the current dose level.
a.
Consider granulocyte colony-stimulating factor according to the locally approved product label, institutional guidelines, local practice, or applicable SmPC.
b.
For clinically significant anemia consider treatment with erythrocyte growth factor and RBC transfusion according to local institutional guidelines.
c.
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 patient's study treatment will be discontinued.
d.
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.
e.
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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6.0
Adverse Events
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course, (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events not 
considered "probably related" to study drug, 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
Definitions
6.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Laboratory abnormalities and changes in vital signs are considered to be adverse events 
only if they result in discontinuation from the study, necessitate therapeutic medical 
intervention, [meets protocol specific criteria (see Section 6.7) regarding toxicity 
management)] and/or if the Investigator considers them to be adverse events.


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An elective surgery/procedure scheduled to occur during the study 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 condition.  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 
performed will be considered an adverse event.
6.1.2
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.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes 
with the activities of daily living of a study subject.  Disability 
is not intended to include experiences of relatively minor 
medical significance, such as headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained 
ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but based 
on medical judgment may jeopardize the subject and may 
require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, 
hospitalization, prolongation of hospitalization, congenital 
anomaly, or persistent or significant disability/incapacity).  
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.
Spontaneous Abortion
Miscarriage experienced by study subject.
Elective Abortion
Elective abortion performed on study subject.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.2
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).53
For adverse events not captured by the NCI CTCAE Version 4.0, the Investigator will use 
the following definitions to rate the severity of each adverse event:
Mild (Grade 1)
The adverse event is transient and easily tolerated by the 
subject.
Moderate (Grade 2)
The adverse event causes the subject discomfort and interrupts 
the subject's usual activities.
Severe (Grade 3 or 4)
The adverse event causes considerable interference with the 
subject's usual activities and may be incapacitating or 
life-threatening.
Death (Grade 5)
The adverse event resulted in death of the subject (severe).


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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.
6.3
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:  For the purpose of this section, study drug is considered 
veliparib or placebo, TMZ, carboplatin and or paclitaxel.
Probably Related
An adverse event has a strong temporal relationship to study drug 
or recurs on re-challenge and an Other cause of event is unlikely or 
significantly less likely.
Possibly Related
An adverse event has a strong temporal relationship to the study 
drug and an Other cause of event is equally or less likely compared 
to the potential relationship to study drug.
Probably Not 
Related
An adverse event has little or no temporal relationship to the study 
drug and/or a more likely Other cause of event exists.
Not Related
An adverse event is due to an underlying or concurrent illness or 
effect of another drug and is not related to the study drug (e.g., has 
no temporal relationship to study drug or has a much more likely 
Other cause of event).
For causality assessments, events meeting the categories of probably or possibly related 
will be considered "associated."  Events that are probably not or not related will be 
considered "not associated."  In addition, when the Investigator has not reported a 
causality or deemed it not assessable, AbbVie will consider the event associated.
If an Investigator's opinion of possibly, probably not, or not related to study drug is given, 
an Other cause of event must be provided by the Investigator for the serious adverse 
event.


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6.4
Adverse Event Collection Period
All protocol related serious adverse events and nonserious adverse events must be
collected from the signing of the study-specific informed consent until study drug 
administration.
In addition, all adverse events reported from the time of study drug administration until 
30 days following discontinuation of study drug administration have elapsed will be 
collected, whether solicited or spontaneously reported by the subject.
Serious and nonserious adverse events, occurring after the study-specific informed 
consent is signed but prior to the initial dose of veliparib/placebo, TMZ, 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 5.
Figure 5.
Adverse Event Collection
6.5
Adverse Event Reporting
In the event of a serious adverse event, whether related to AbbVie study medication or 
not, the Investigator will notify Clinical Pharmacovigilance within 24 hours of the site 
being made aware of the serious adverse event by entering the serious adverse event data 


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into the Electronic Data Capture (EDC) system.  Serious adverse events that occur prior to 
the site having access to the Rave® (EDC) system or if Rave is not operable should be 
sent to 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 related concerns, contact the Oncology Safety Management Team at:
Oncology Group Safety Management
AbbVie
Dept. R478S, 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 any emergent safety concerns, please contact the physician listed below:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Office:
Mobile:
Fax:
Email:


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In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Phone:  +1 (973) 784-6402
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local guidelines. Appendix A of the Investigator Brochure will serve as the 
Reference Safety Information (RSI) for veliparib and Summary of Product Characteristics 
(SmPC) will be the RSI for carbloplatin, paclitaxel, and temozolomide.  The RSI in effect 
at the start of a DSUR reporting period serves as the RSI during the reporting period.  For 
follow-up reports, the RSI in place at the time of occurrence of the 'suspected' Serious 
Adverse Reaction will be used to assess expectedness.
6.6
Pregnancy
In the event of a positive pregnancy test, subjects must immediately discontinue study 
drug and must be discontinued from the study (Section 5.4).  The investigator must report 
the positive pregnancy test to the appropriate contact listed in protocol Section 6.5 within 
1 working day of the site becoming aware of the pregnancy.
All subjects should be informed that contraceptive measures should be taken throughout 
the study and for 90 days after discontinuing study drug.  Information regarding a 
pregnancy occurrence in a study subject and the outcome of the pregnancy will be 
collected.  The investigator must follow the pregnancy to completion and provide an 
update to AbbVie after delivery.
Male subjects should be informed that contraceptive measures should be taken by their 
female partners.  If the subject's partner should become pregnant during the study, this 
should also be reported and data may be collected.  In the event of pregnancy occurring in 


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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.
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.
6.7
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 (available on the CTEP home 
page http://ctep.info.nih.gov) is to 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 to be either possibly related or 
probably related to the study drug (Section 6.1.1).
A toxicity is deemed "clinically significant" on the basis of the investigator's medical 
judgment.
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.


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7.0
Protocol Deviations
The Investigator should not implement any deviation from the protocol without prior 
review and agreement by the Sponsor and in accordance with the IEC/IRB, and local 
regulations, except when necessary to eliminate an immediate hazard to study subjects.  
When a deviation from the protocol is deemed necessary for an individual subject, the 
Investigator must contact his or her assigned clinical monitor or the following AbbVie 
representatives:
Clinical Team Lead:
AbbVie Corporation
8401 Trans-Canada Highway
Saint-Laurent, Québec
H4S 1Z1
Canada
Office:
Fax:
Email:
Scientific Director:
AbbVie
North Chicago, IL  60064
Office:
Fax:
Email:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.  Any significant 
protocol deviations affecting subject eligibility and/or safety must be reviewed and/or 
approved by the IEC/IRB and regulatory authorities, as applicable, prior to 
implementation.
8.0
Statistical Methods and Determination of Sample 
Size
Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a 2-sided P value ≤ 0.05.  The date of randomization (enrollment) is 
defined as the date that the IVRS/IWRS issued a randomization number.


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The analysis of all efficacy endpoints will include only subjects in Group 2 of the study 
and who have been documented to have deleterious mutations by the Sponsor core lab.  
Sensitivity analyses will be conducted using all randomized subjects' data to evaluate 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 drug (veliparib or placebo) will be 
included in the safety analysis.
Comparisons will be performed between veliparib 40 mg BID + TMZ and placebo BID + 
carboplatin + paclitaxel as well as between veliparib 120 mg BID + carboplatin + 
paclitaxel and 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 drug (or randomization for non-treated subjects).  Unless otherwise 
stated, baseline for a given variable will be defined as the last value for that variable 
obtained prior to the first dose of study drug.
Baseline characteristic data will be summarized with all randomized subjects for Group 1 
(veliparib 40 mg BID + TMZ, veliparib 80 mg BID + carboplatin + paclitaxel, placebo 
BID + carboplatin + paclitaxel) and Group 2 (veliparib 40 mg BID + TMZ, veliparib 
120 mg BID + carboplatin + paclitaxel, placebo BID + carboplatin + paclitaxel) of the 
study separately.
8.1.1.1
Demographics
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
means, standard deviation, minimum, maximum, and range.  Frequencies and percentages 
will be computed for the following parameters:  gender, race, BRCA1, BRCA2, ER/PgR 


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status, HER2 status, triple negative breast cancer, number and sites of metastases, prior 
cytotoxic therapy use, and ECOG performance status.
8.1.1.2
Medical Histories
Frequencies and percentages will be computed for each medical history parameter.
8.1.2
Efficacy Endpoints
8.1.2.1
Primary Efficacy Endpoint
The primary efficacy analysis will be a comparison of progression-free survival (PFS) 
between veliparib + TMZ and placebo + carboplatin + paclitaxel as well as between 
veliparib + carboplatin + paclitaxel and placebo + carboplatin + paclitaxel among subjects 
who have been documented to have deleterious mutations by the Sponsor core lab.  
Comparisons between treatment groups will be performed using a Hochberg testing 
procedure for multiplicity adjustment (see Section 8.1.10.8 for details).
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 a confirmed event of disease 
progression (as determined by the central imaging center), or to the date of death (all 
causes of mortality), if disease progression is not reached.  All confirmed events of 
disease progression will be included, regardless of whether the event occurred while the 
subject was still taking study drug or had previously discontinued study drug.  Events of 
death will be included for subjects who had not experienced a confirmed event of disease 
progression, provided the death occurred within 9 weeks of the last available disease 
progression assessment (by central imaging center).  If the subject does not have a 
confirmed 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 available disease progression 
assessment (by central imaging center).


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8.1.2.2
Secondary Efficacy Endpoints
Secondary efficacy analyses comparing the effects of veliparib + TMZ and placebo + 
carboplatin + paclitaxel as well as between veliparib + 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 18, objective 
response rate (ORR), and CIPN.  Only subjects with deleterious mutations documented by 
the Sponsor core lab will be included in the analyses of the secondary efficacy analyses.
Time to death (overall survival) for a given subject will be defined as the number of days 
from the date the subject was randomized to the date of the subject's death.  All events of 
death will be included, regardless of whether the event occurred while the subject was still 
taking study drug or after the subject discontinued study drug.  If a subject has not died, 
the data will be censored at the date last known to be alive.
Clinical benefit rate (CR, PR, SD or Non-CR/Non-PD) at Week 18 will be defined as the 
progression-free rate at 18 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 central imaging center).  Time to progression will be defined as the number 
of days from the date the subject was randomized to the date the subject experiences a 
confirmed event of disease progression (as determined by the central imaging center).  If a 
subject does not have a confirmed event of disease progression, the subject's data will be 
censored at the date of the subject's last available disease progression assessment (by 
central imaging center).  All ITT subjects who had deleterious mutations documented by 
the Sponsor core lab will be included in the analysis.
Objective response rate is calculated as the proportion of subjects who have confirmed PR 
or CR based on assessment by the central imaging center.  All ITT subjects who have at 
least one measurable lesion at baseline and had deleterious mutations documented by the 
Sponsor core lab will be included in the analysis.


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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 + TMZ and placebo + carboplatin + 
paclitaxel as well as veliparib + carboplatin + paclitaxel and placebo + carboplatin + 
paclitaxel on quality of life and performance status.  All ITT subjects will be included in 
the analysis.
8.1.3
Timing of Efficacy Analyses and Safety Evaluations
Timing of efficacy analyses and safety evaluations will be based on data from Group 2 of 
the study only.
When both the 159th PFS event across all three treatment arms (if the veliparib + TMZ 
treatment arm is not terminated due to futility) and the 112th PFS event in the double-blind 
portion of the study occur, 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.  For all efficacy analyses, the data cutoff date will 
be the date of the159th PFS event across all three treatment arms (if the veliparib + TMZ 
treatment arm is not terminated due to futility) or the 112th PFS event in the double-blind 
portion of the study, whichever is later.  The exact data cutoff date will be specified in the 
SAP.
The clinical study report (CSR) will summarize the results from the above analyses.
Overall survival will be collected on all subjects for a minimum of 3 years after they 
discontinue from the study.  After a total of 194 death events across all three treatment 
arms (if the veliparib + TMZ treatment arm is not terminated due to futility) or a total of 
136 death events for the double-blind portion of the study, whichever is later.  The clinical 
database data will be extracted once again for documentation and a "Final OS Analysis" 
will be performed on this dataset.  The exact data cutoff date will be specified in the SAP.


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8.1.4
Primary Analysis of Efficacy
The distribution of PFS (PFS as determined by the central imaging center, as detailed in 
Section 5.3.3) will be estimated for each treatment group using Kaplan-Meier 
methodology and compared between veliparib + TMZ and placebo + carboplatin + 
paclitaxel as well as between veliparib + carboplatin + paclitaxel and placebo + 
carboplatin + paclitaxel treatment groups using the log-rank test, stratified by ER/PgR 
(ER and/or PgR positive versus ER and PgR negative) and prior cytotoxic therapy use 
(yes versus no).
8.1.5
Secondary Analyses of Efficacy
If only one veliparib treatment group is statistically significantly better than the placebo 
group for the primary endpoint of PFS, then 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, ORR, 
CBR through the end of Week 18, and CIPN.  For each secondary endpoint, Hochberg 
testing procedure will be used to preserve the family-wise error rate for multiple 
comparisons.
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 + TMZ and placebo + 
carboplatin + paclitaxel as well as between veliparib + carboplatin + paclitaxel and 
placebo + carboplatin + paclitaxel using the log-rank test, stratified by ER/PgR (ER 
and/or PgR positive versus ER and PgR negative) and prior cytotoxic therapy use (yes 
versus no).
8.1.5.2
Clinical Benefit Rate
Clinical benefit rate (CR, PR, SD or Non-CR/Non-PD) at Week 18 will be defined as the 
progression-free rate at 18 weeks from the Kaplan-Meier curve for time to progression 


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(defined as from the date of randomization to the date of disease progression as 
determined by central imaging center).  A test statistic based on Kaplan-Meier estimates 
of the progression-free probability at 18 weeks (Rx Day 126) and the estimated variance 
will be constructed to test the null hypothesis that the clinical benefit rate at Week 18 for 
the two treatment groups (between veliparib + TMZ and placebo + carboplatin + 
paclitaxel as well as between veliparib + carboplatin + paclitaxel and placebo + 
carboplatin + paclitaxel) are the same.  Clinical benefit rate (CR, PR, SD, or 
Non-CR/Non-PD) will be computed for all ITT subjects.
8.1.5.3
Objective Response Rate
The objective response rate (CR and PR) will be computed for all ITT subjects with at 
least one measurable lesion at baseline.  The proportion of subjects with a confirmed 
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 the 
treatment groups (veliparib + TMZ and placebo + carboplatin + paclitaxel as well as 
veliparib + carboplatin + paclitaxel and placebo + carboplatin + paclitaxel) using CMH 
test stratified by ER/PgR (ER and/or PgR positive versus ER and PgR negative) and prior 
cytotoxic therapy use (yes versus no).  In addition, 95% confidence interval will be 
constructed for ORR. 
8.1.5.4
Chemotherapy-Induced Peripheral Neuropathy (CIPN)
Chemotherapy-Induced Peripheral Neuropathy (CIPN) assessed by EORTC 
QLQ-CIPN20 questionnaire and NCI CTCAE 4.0 grading for peripheral neuropathy will 
be analyzed appropriately as identified in published literature.  All subjects with at least 
one dose of study drug and with deleterious mutations documented by the Sponsor core 
lab will be included.


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8.1.6
Tertiary Analyses of Efficacy
8.1.6.1
Quality of Life
The quality of life instrument EORTC QLQ-C15/BR23 will be summarized appropriately, 
as identified in published literature.  
8.1.6.2
Performance Status
Analyses of changes from baseline will be performed for each scheduled postbaseline 
visit and for the Final Visit for ECOG performance status using an analysis of covariance 
(ANCOVA) model with treatment group as the factor and baseline value as a covariate.  
Postbaseline measurements more than seven days after the last dose of study drug will not 
be included.  Subjects that do not have a baseline measurement or do not have any 
postbaseline measurements will not be included.
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 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 + TMZ and 
placebo + carboplatin + paclitaxel as well as between veliparib + carboplatin + paclitaxel 
and placebo + carboplatin + paclitaxel.
PFS, ORR, CBR, and duration of overall response based on radiological and clinical 
assessment by Investigator 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 anticancer therapies after discontinuation of the study, 
the primary efficacy and secondary efficacy endpoints of PFS, and overall survival will be 


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censored at the date of subject's initiation of other anticancer 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 drug, 
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 
cytotoxic therapy use, ECOG performance status, stage of the disease, and others, 
3) subgroup analysis by ER/PgR status, BRCA1/2 status, prior cytotoxic therapy use, 
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.
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) will review the safety data for this 
veliparib Phase 2 study after approximately 36 subjects in Group 2 of the study have met 
at least one of the criteria:
●
Received two 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.
In addition, an interim futility analysis will be conducted after the Week 27 tumor 
assessment of the first 30 subjects who have been documented to have deleterious 
mutations by the Sponsor core laboratory with at least one measurable lesion at baseline 
and randomized to the veliparib + TMZ treatment group (across both Group 1 and 


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Group 2).  This interim futility analysis will be reviewed by IDMC.  If there are less than 
5 responders (CR+PR) in the 30 subjects, then futility will be declared for the veliparib + 
TMZ treatment group.  This futility criterion corresponds to Bayesian posterior 
probability of at least 90% that the true objective response is ≤ 25%.
If futility is declared at the time of the futility analysis, any remaining subjects on 
veliparib + TMZ will be given the option either to receive veliparib 120 mg BID + 
carboplatin + paclitaxel or discontinue therapy.
8.1.9
Safety Assessments
The safety of veliparib + TMZ, veliparib + carboplatin + paclitaxel, and placebo + 
carboplatin + paclitaxel will be assessed by evaluating study drug exposure, adverse 
events, serious adverse events, and all deaths, as well as changes in laboratory 
determinations and vital sign parameters.  Subjects who were randomized but did not 
receive study drug (veliparib or placebo) will not be included in the analyses of safety.
Safety summaries will be presented by treatment group (veliparib 40 mg BID + TMZ, 
veliparib BID + carboplatin + paclitaxel or placebo BID + carboplatin + paclitaxel) for 
Group 1 and Group 2 of the study, separately.  In addition, the safety data from the 
veliparib 40 mg BID + TMZ group in both Group 1 and Group 2 of the study may be 
combined. 
Statistical comparisons will only be made for Group 2 of the study.
8.1.10
Statistical Analyses of Safety
8.1.10.1
Duration of Study Drug
A summary of the number of days and/or cycles subjects were exposed to study drug will 
be provided.


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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 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)54 adverse event coding dictionary.  The percentage of subjects experiencing 
an adverse event at a given severity, NCI CTCAE version 4.0 toxicity grade, and 
relationship to study drug will be provided.  Comparisons of the percentages of subjects 
experiencing an adverse event between veliparib + TMZ and placebo + carboplatin + 
paclitaxel as well as 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 drug in this study, 2) for deaths occurring off treatment 
within 30 days after the last dose of study drug, and 3) for all deaths in this study 
regardless of the number of days after the last dose of study drug.
8.1.10.5
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline will be analyzed for each scheduled postbaseline 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 


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measurement for that day.  Postbaseline measurements more than 30 days after the last 
dose of study drug will not be included.  Subjects that do not have a baseline 
measurement or do not have any postbaseline measurements will not be included.  
Comparisons of the differences in mean changes from baseline between veliparib + TMZ 
and placebo + carboplatin + paclitaxel as well as between veliparib + carboplatin + 
paclitaxel and placebo + carboplatin + paclitaxel will be made using ANCOVA with 
treatment group as the factor and baseline as a covariate.
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 drug, and as the grade of the last postbaseline 
measurement collected no more than 30 days after the last dose of study drug.  If multiple 
values are available for a postbaseline measurement, then the value with the highest 
NCI CTCAE grade will be used in the assessment of shift.  Comparisons of the number of 
subjects experiencing a shift from baseline grades of 0 to 2 or no grade to maximum 
postbaseline grades of 3 to 4, and from baseline grades of 0 to 2 or no grade to final 
postbaseline grades of 3 to 4 between veliparib + TMZ and placebo + carboplatin + 
paclitaxel as well as between veliparib + carboplatin + paclitaxel and placebo + 
carboplatin + paclitaxel will be performed using Fisher's exact tests.  Additional analyses 
including all measurements collected, regardless of the number of days after the last dose 
of study drug, will be performed.
Detailed listings of data for subjects experiencing NCI CTCAE Grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug, will be included in these 
listings.


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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 
drug, will be included in these listings.
8.1.10.8
Multiplicity Adjustments
The Hochberg testing procedure will be used to preserve the family-wise error rate for 
multiple comparisons.  For the primary endpoint PFS, a Hochberg testing procedure will 
be used where the larger P value for the comparisons of veliparib + TMZ and placebo + 
carboplatin + paclitaxel as well as veliparib + carboplatin + paclitaxel and placebo + 
carboplatin + paclitaxel will be compared to an α = 0.05.  If statistically significant, 
(P ≤0.05) then both comparisons will be considered significant.  If the larger P value is 
not statistically significant, then the smaller P value will be compared to an α = 0.025.  
Nominal P values will be reported.  Furthermore, if both veliparib treatment groups are 
statistically better than the placebo group for primary efficacy endpoint PFS, 
fixed-sequence testing method and Hochberg testing procedure will be used for the 
secondary endpoints.
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 183 deaths).  
Statistical significance for OS will be declared if a significant result is obtained for either 
analysis, consistent with group-sequential testing methods.


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8.1.10.9
Censoring Dates for Subjects that had the Blind Broken
All subjects that had the study blind broken prior to an event of disease progression or 
prior to the last date of evaluation will be censored on the last date of evaluation or on the 
day the study blind was broken, whichever was earlier.
8.2
Determination of Sample Size
Assuming the true hazard ratio in favor of the veliparib 40 mg BID + TMZ or veliparib 
120 mg BID + carboplatin + paclitaxel treatment group is 0.58 for PFS, a total of 159 PFS 
events will be needed for the study to have at least 80% power at 2-sided α level of 0.05 to 
detect a statistically significant treatment effect for the veliparib 40 mg BID + TMZ
treatment group or the veliparib 120 mg BID + carboplatin + paclitaxel treatment group 
using the log-rank test for PFS.  If the veliparib 40 mg BID + TMZ treatment group is 
terminated for reasons of futility, a total of 112 PFS events in the double-blind portion of 
the study will provide at least 80% power at 2-sided α level of 0.05 (or 74% power at 
2-sided α level of 0.025) to detect a statistically significant treatment effect for the 
veliparib 120 mg BID + carboplatin + paclitaxel treatment group using the log-rank test 
for PFS.
In addition, assuming the true hazard ratio in favor of the veliparib 40 mg BID + TMZ or 
veliparib 120 mg BID + carboplatin + paclitaxel treatment group is 0.61 for OS, a total of 
194 death events will be needed for the study to have at least 80% power at 2-sided 
α level of 0.05 to detect a statistically significant treatment effect for the veliparib 40 mg 
BID + TMZ treatment group or the veliparib 120 mg BID + carboplatin + paclitaxel 
treatment group using the log-rank test for OS.  If the veliparib 40 mg BID + TMZ 
treatment group is terminated for reasons of futility, a total of 136 death events in the 
double-blind portion of the study will provide approximately 80% power at 2-sided 
α level of 0.05 (or 74% power at 2-sided α level of 0.025) to detect a statistically 
significant treatment effect for the veliparib + carboplatin + paclitaxel treatment group 
using the log-rank test for OS.


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Accounting for the number (4) of subjects enrolled under the original protocol (Group 1 
of the study), a total of approximately 290 subjects with BRCA mutation as documented 
by the Sponsor core laboratory will be enrolled into the entire study.  
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 the subject's Study Day 1 and a unique randomization number 
will be provided.  The randomization numbers for Group 1 of the study will assign 
subjects in 1:1:1 ratio to veliparib 40 mg BID + TMZ, veliparib 80 mg BID + carboplatin 
paclitaxel, or placebo BID + carboplatin + paclitaxel.  The randomization numbers for 
Group 2 of the study will assign subjects in 1:1:1 ratio to veliparib 40 mg BID + TMZ, 
veliparib 120 mg BID + carboplatin + paclitaxel, or placebo BID + carboplatin + 
paclitaxel.  The randomization will be stratified by ER/PgR (ER and/or PgR positive 
versus ER and PgR negative), prior cytotoxic therapy use (yes versus no), and ECOG 0-1 
versus 2.
Two sets of subject randomization schedules will be generated by the Clinical Statistics 
Department at AbbVie prior to the start of the study — one for Group 1 of the study and 
the other for Group 2 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 


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ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The Investigator will be required to submit, 
maintain and archive study essential documents according to 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.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed, 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 


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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.
PG analysis, needle/excisional/punch biopsy and archived tissue sample collection will 
only be performed if the subject has voluntarily consented to participate after the nature of 
the testing has been explained and the subject has had the opportunity to ask questions.  
Informed consent for PG sample, needle/excisional/punch biopsy and archived tissue 
collection must be signed before testing is performed.  If the subject does not consent to 
the PG and/or tissue sample collection it will not impact the subject's participation in the 
study.
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-C15/BR23 and CIPN20) 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 


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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.
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.


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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.
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.


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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
12.1
Use of Information
Any PG research that may be done using DNA samples from this study will be 
experimental in nature and the results will not be suitable for clinical decision-making or 
subject management.  Hence, neither the Investigator, the subject, nor the subject's 
physician (if different than the Investigator) will be informed of individual subject
PG results, should analyses be performed, nor will anyone not directly involved in this 
research.  Correspondingly, genetic researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate PG information from this study may be 
used in scientific publications or presented at medical conventions.  PG information will 
be published or presented only in a way that does not identify any individual subject.
12.2
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.


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13.0
Completion of the Study
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 Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
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 TMZ, 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 Randomized, Phase 2 Study of the Efficacy and Tolerability of 
Veliparib in Combination with Temozolomide or Veliparib in 
Combination with Carboplatin and Paclitaxel Versus Placebo Plus 
Carboplatin and Paclitaxel in Subjects with BRCA1 or BRCA2 
Mutation and Metastatic Breast Cancer
Protocol Date:
07 June 2019
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
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Gronwald J, Byrski T, Huzarski T, Dent R, Bielicka V, Zuziak D, et al.  
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metastatic breast cancer.  J Clin Oncol.  2010;28:15s (Suppl; abstr 1019).
23.
Chiarugi A.  Poly(ADP-ribose) polymerase:  killer or conspirator?  The 'suicide 
hypothesis' revisited.  Trends Pharmacol Sci.  2002;23(3):122-9.
24.
Virág L, Szabó C.  The therapeutic potential of poly(ADP-Ribose) polymerase 
inhibitors.  Pharmacol Rev.  2002;54(3):375-429.
25.
DePinho RA, Polyak K.  Cancer chromosomes in crisis.  Nat Genet.  
2004;36(9):932-4.
26.
Sharpless NE, DePinho RA.  Telomeres, stem cells, senescence, and cancer.  J Clin 
Invest.  2004;113(2):160-8.
27.
Curtin NJ, Wang LZ, Yiakouvaki A, Kyle S, Arris CA, Canan-Koch S, 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.
28.
Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al.  
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) 
polymerase.  Nature.  2005;434(7035):913-7.
29.
Wielckens K, Garbrecht M, Kittler M, Hilz H.  ADP-ribosylation of nuclear 
proteins in normal lymphocytes and in low-grade malignant non-Hodgkin 
lymphoma cells.  Eur J Biochem.  1980;104(1):279-87.
30.
Hirai K, Ueda K, Hayaishi O.  Aberration of poly(adenosine diphosphate-ribose) 
metabolism in human colon adenomatous polyps and cancers.  Cancer Res.  
1983;43(7):3441-6.


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31.
Tomoda T, Kurashige T, Moriki T, Yamamoto H, Fujimoto S, Taniguchi T.  
Enhanced expression of poly(ADP-ribose) synthetase gene in malignant 
lymphoma.  Am J Hematol.  1991;37(4):223-7.
32.
Shiobara M, Miyazaki M, Ito H, Togawa A, Nakajima N, Nomura F, et al.  
Enhanced polyadenosine diphosphate-ribosylation in cirrhotic liver and carcinoma 
tissues in patients with hepatocellular carcinoma.  J Gastroenterol Hepatol.  
2001;16(3):338-44.
33.
AbbVie.  ABT-888 Investigator's Brochure Edition 6.  22 June 2012.
34.
Kummar S, Kinders R, Gutierrez ME, Rubinstein L, Parchment RE, Phillips LR, 
et al.  Phase 0 clinical trial of the poly(AEP-ribose) polymerase inhibitor ABT-888 
in patients with advanced malignancies.  J Clin Oncol.  2009;27:2705-11.  
Epub 2009 Apr 13.
35.
Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, et al.  
Secondary mutations as a mechanism of cisplatin resistance in BRCA2- mutated 
cancers.  Nature.  2008;451:1116-20.
36.
Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al.  
Poly(ADP)-ribose polymerase inhibition:  frequent durable responses in BRCA 
carrier ovarian cancer correlating with platinum-free interval.  J Clin Oncol.  
2010;28:2512-9.
37.
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 Oncol.  2012;30 (suppl):abstract 3049.
38.
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 3):abstract PD09-06.


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39.
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, 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.
40.
Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn 
KM, 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.
41.
Stachelek GC, Dalal S, Donigan KA, Campisi Hegan DC, Sweasy JB, Glazer PM.  
Potentiation of temozolomide cytotoxicity by inhibition of DNA polymerase β is 
accentuated by BRCA2 mutation.  Cancer Res.  2010;70(1):409-17.  Epub 
2009 Dec 22.
42.
Palma JP, Wang YC, Rodriguez LE, Montgomery D, Ellis PA, Bukofzer G, et al.  
ABT-888 confers broad in vivo activity in combination with temozolomide in 
diverse tumors.  Clin Cancer Res.  2009;15(23):7277-90.  Epub 2009 Nov 24.
43.
Trudeau ME, Crump M, Charpentier D, Yelle L, Bordeleau L, Matthews S, et al.  
Temozolomide in metastatic breast cancer (MBC):  a phase 2 trial of the National 
Cancer Institute of Canada – Clinical Trials Group (NCIC-CTG).  Ann of Oncol.  
2006;17:952-6.  Epub 2006 Mar 24.
44.
Siena S, Crinò L, Danova M, Del Prete S, Cascinu S, Salvagni S, et al.  Dose dense 
temozolomide regimen for the treatment of brain metastases from melanoma, 
breast cancer, or lung cancer not amenable to surgery or radiosurgery:  a 
multicenter phase 2 study.  Ann of Oncol.  2010;21:655-61.  Epub 2009 Sep 18.
45.
Langer CJ, Leighton JC, Comis RL, O'Dwyer PJ, McAleer CA.  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.


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46.
Gennari A, Sockler M, Puntoni M, Sormani M, Nanni O, Amadori D, et al.  
Duration of chemotherapy for metastatic breast cancer; a systematic review and 
meta-analysis of randomized clinical trials.  J Clin Oncol.  2011:29(16);2144-9.
47.
Paclitaxel [package insert].  Lake Forest, IL; Hospira Worldwide Inc.
48.
Carboplatin [package insert].  Lake Forest, IL; Hospira Worldwide Inc.
49.
Basch E, Prestrud AA, Hesketh PJ, Kris MG, Feyer PC, Somerfield MR, et al.  
Antiemetics:  American Society of Clinical Oncology practice guideline update.  
J Clin Oncol.  2011;29(31):4189-98.
50.
National Comprehensive Cancer Network.  NCCN clinical practice guidelines in 
oncology:  genetic/familial high-risk assessment:  breast and ovarian, version 1.  
2012.
51.
Eisenhauer EA, Therasse P, Bogaerts B, Schwartz LH, Sargent D, Ford R, et al.  
New response evaluation criteria in solid tumors:  Revised RECIST guideline 
version 1.1.  Eur J Cancer.  2009;45(2):228-47.
52.
Groenvold M and Petersen MA on behalf of the EORTC Quality of Life Group.  
Scoring of the EORTC QLQ-C15-PAL.  2006.
53.
Common Terminology Criteria for Adverse Events, Version 4.0, DCTD, NCI, 
NIH, DHHS.  28 May 2009.  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.p
df.  Accessed 29 July 2009.
54.
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.


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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.


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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.
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
Clinical
Statistics


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Appendix C.
EORTC QLQ-C15-PAL (Version 1)
We are interested in some things about you and your health.  Please answer all of the 
questions yourself by circling the number that best applies to you.  There are no "right" or 
"wrong" answers.  The information that you provide will remain strictly confidential.
Your year of birth (Year):
Today's date (Day, Month, Year):
Not at All
A Little
Quite a 
Bit
Very Much
1.
Do you have any trouble taking a short walk outside 
of the house?
1
2
3
4
2.
Do you need to stay in bed or a chair during the day?
1
2
3
4
3.
Do you need help with eating, dressing, washing 
yourself or using the toilet?
1
2
3
4
During the past week:
Not at All
A Little
Quite a 
Bit
Very Much
4.
Were you short of breath?
1
2
3
4
5.
Have you had pain?
1
2
3
4
6.
Have you had trouble sleeping?
1
2
3
4
7.
Have you felt weak?
1
2
3
4
8.
Have you lacked appetite?
1
2
3
4
9.
Have you felt nauseated?
1
2
3
4
During the past week:
Not at All
A Little
Quite a 
Bit
Very Much
10. Have you been constipated?
1
2
3
4
11. Were you tired?
1
2
3
4
12. Did pain interfere with your daily activities?
1
2
3
4
13. Did you feel tense?
1
2
3
4
14. Did you feel depressed?
1
2
3
4


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For the following question please circle the number between 1 and 7 that best applies to you.
15. How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
© Copyright 1995 and 2005 EORTC Quality of Life Group.  All rights reserved.  Version 1


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Appendix D.
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
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


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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 E.
EORTC QLQ-CIPN20
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.  Please answer by circling the number that best applies to you.
During the past week:
Not at All
A Little
Quite a Bit
Very Much
31. Did you have tingling fingers or hands? 
1
2
3
4
32. Did you have tingling toes or feet?
1
2
3
4
33. Did you have numbness in your fingers or 
hands?
1
2
3
4
34. Did you have numbness in your toes or feet?
1
2
3
4
35. Did you have shooting or burning pain in 
your fingers or hands?
1
2
3
4
36. Did you have shooting or burning pain in 
your toes or feet? 
1
2
3
4
37. Did you have cramps in your hands?
1
2
3
4
38. Did you have cramps in your feet? 
1
2
3
4
39. Did you have problems standing or walking 
because of difficulty feeling the ground 
under your feet?
1
2
3
4
40. Did you have difficulty distinguishing 
between hot and cold water?
1
2
3
4
41. Did you have a problem holding a pen, 
which made writing difficult? 
1
2
3
4
42. Did you have difficulty manipulating small 
objects with your fingers (for example, 
fastening small buttons)?
1
2
3
4
43
Did you have difficulty opening a jar or 
bottle because of weakness in your hands?
1
2
3
4
44. Did you have difficulty walking because 
your feet dropped downwards?
1
2
3
4
Please go on to the next page


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During the past week:
Not at All
A Little
Quite a Bit
Very Much
45. Did you have difficulty climbing stairs or 
getting up out of a chair because of weakness 
in your legs? 
1
2
3
4
46. Were you dizzy when standing up from a 
sitting or lying position? 
1
2
3
4
47. Did you have blurred vision?
1
2
3
4
48. Did you have difficulty hearing?
1
2
3
4
Please answer the following question only if you drive a car
49. Did you have difficulty using the pedals?
1
2
3
4
Please answer the following question only if you are a man
50. Did you have difficulty getting or 
maintaining an erection?
1
2
3
4
© QLQ-CIPN20 Copyright 2003 EORTC Quality of life Group.  All rights reserved


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Appendix F.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor/Emergency Contact:" previously read:
Sponsor/Emergency 
  Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Fax:
Has been changed to read:
Sponsor/Emergency 
  Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Fax:
Section 1.2  Synopsis
Subsection Methodology:
Second paragraph
Add:  new third sentence
For subjects on study treatment more than 5 years, Day 1 visit is not required.
Section 1.2  Synopsis
Subsection Methodology:
Last paragraph
Add:  new last sentence
For subjects on study treatment more than 5 years, there will be no post-treatment follow-
up.


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Table 5.  Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin 
+ Paclitaxel Treatment Arms)
Header row, column "Day 3 of Each Cycle" previously read:
Day 3 of Each Cycle
Has been changed to read:
Day 3 of Each Cycler
Table 5.  Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin 
+ Paclitaxel Treatment Arms)
Table note "g." 
Add:  new last sentence
For subjects on study treatment for more than 5 years, central laboratory testing is no 
longer required.
Table 5.  Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin 
+ Paclitaxel Treatment Arms)
Table note "j." 
Add:  new last sentence
For subjects on study treatment more than 5 years, tumor assessments will be conducted 
every 6 months.
Table 5.  Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin 
+ Paclitaxel Treatment Arms)
Table note "n." 
Add:  new last sentence
For subjects on study treatment more than 5 years, 12-lead ECG, urinalysis, CIPN 
Assessment (QLQ-CIPN20), EORTC QLQ-C15/BR23, and tumor assessments do not 
need to be performed at Final Visit.


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Table 5.  Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin 
+ Paclitaxel Treatment Arms)
Table note "o." 
Add:  new last sentence
For subjects on study treatment more than 5 years, CIPN Assessment (QLQ-CIPN20) and 
EORTC QLQ-C15/BR23 do not need to be performed at the Follow-up Visit.
Table 5.  Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin 
+ Paclitaxel Treatment Arms)
Table note "p." 
Add:  new last sentence
For subjects on study treatment more than 5 years, there will be no post-treatment follow-
up.
Table 5.  Study Activities (Subjects Randomized to Veliparib/Placebo + Carboplatin 
+ Paclitaxel Treatment Arms)
Table note "r." 
Add:  new second, third, and fourth sentence
For subjects on study treatment more than 5 years, Day 1 visit is not required. Physical 
Exam, Hematology, Chemistry, Performance Status (ECOG), AE assessment, and 
Dispense Veliparib/Placebo can be performed on Day 3 instead. Urinalysis, CIPN 
Assessment (QLQ-CIPN20), and EORTC QLQ-C15/BR23 no longer need to be 
performed on either Day 1 or Day 3 for these subjects.
Table 6.  Schedule Pharmacodynamic and Pharmacogenetic Assessments
Header row, column "Visit Schedule" previously read:
Visit Schedule
Has been changed to read:
Visit Schedulef


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Table 6.  Schedule Pharmacodynamic and Pharmacogenetic Assessments
Add:  new table note "f."
For subjects on study treatment more than 5 years, any sampling scheduled for Day 1 of 
every 10th cycle or Final Visit will no longer be required.
Section 5.3.1.1  Study Procedures
Last paragraph
Add:  new last sentence
For subjects on study treatment more than 5 years, laboratory samples may be collected 
up to 4 days prior to dosing carboplatin/paclitaxel on Day 3.
Section 5.3.1.1  Study Procedures
Subsection 12-lead Electrocardiogram (ECG)
Add:  new last sentence
Final Visit ECG will not be required for subjects on study treatment more than 5 years.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Add:  new fourth paragraph
For subjects remaining on study treatment for more than 5 years, use of the certified 
central laboratory will be discontinued. A certified local reference laboratory will 
perform CBC and chemistry test prior to dosing carboplatin/paclitaxel. Local laboratory 
results should be documented in the source and the electronic data capture (EDC) system 
as appropriate. Samples will no longer be sent to the central laboratory for analysis.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Fourth paragraph
Add:  new last sentence
For subjects on study treatment more than 5 years, lab samples may be collected up to 
4 days prior to dosing carboplatin/paclitaxel.


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Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Fourth paragraph, first bullet
Add:  new last sentence
Urinalysis will no longer be required for subjects on study treatment more than 5 years.
Table 9.  Clinical Laboratory Tests
Add:  new table note "***"
For subjects on study treatment for more than 5 years, hematology and chemistry 
laboratory tests should be per local standard of care/institutional guidelines, and should 
include neutrophils, platelets, SGOT/AST, SGPT/ALT, total bilirubin, and alkaline 
phosphatase.
Section 5.3.1.1  Study Procedures
Subsection Tumor Assessments (Radiologic)
Second paragraph 
Add:  new second sentence
For subjects on study treatment more than 5 years, tumor assessments will be conducted 
every 6 months (± 6 weeks) from C1D1 instead of every 9 weeks from C1D1, and will not 
be required at Final Visit.
Section 5.3.1.1  Study Procedures
Subsection Tumor Assessments (Radiologic)
Fourth paragraph 
Add:  new last sentence
For subjects on study treatment more than 5 years, tumor assessments will be 
discontinued if subject discontinues treatment for any reason.


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Section 5.3.1.1  Study Procedures
Subsection Tumor Assessments (Radiologic)
Fifth paragraph 
Add:  new last sentnece
For subjects on study treatment more than 5 years, radiology scans will not be sent to the 
central imaging vendor.
Section 5.3.1.1  Study Procedures
Subsection Tumor Assessments (Radiologic)
Last paragraph first sentence previously read:
All events of disease progression must be confirmed by the central imaging center.
Has been changed to read:
All events of disease progression must be confirmed by the central imaging center (except 
for subjects on study treatment more than 5 years).
Section 5.3.1.1  Study Procedures
Subsection CIPN Assessment
Add:  new last sentence 
CIPN assessment will no longer be required at any visit for subjects on study treatment
for more than 5 years.
Section 5.3.1.1  Study Procedures
Subsection Quality of Life
First paragraph
Add:  new last sentence 
EORTC QLQ-C15/BR23 questionnaires will no longer be administered at any visit for 
subjects on study treatment for more than 5 years.


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Section 5.3.1.1  Study Procedures
Subsection Dispensation of Study Drug
Second paragraph
Add:  new fourth, fifth, sixth, and seventh sentence 
For subjects on study treatment more than 5 years, veliparib/placebo may be dispensed at 
the Day 3 visit instead of the Day 1 visit.  Sufficient medication will be dispensed to cover 
an entire cycle.  The site is advised to contact the subject on the morning of Day 1 to 
reiterate the dosing instructions of veliparib/placebo.  It is recommended the site contact 
the subject on Day 7 to instruct about ceasing dosing.
Section 5.3.1.1  Study Procedures
Subsection Dispensation of Study Drug
Third paragraph, second sentence previously read:
Site personnel must contact the IVRS/IWRS for the bottle number assignments no more 
than 5 days before Day 1 of each cycle.
Has been changed to read:
Site personnel must contact the IVRS/IWRS for the bottle number assignments no more 
than 5 days before Day 1 of each cycle (or Day 3 for subjects on study treatment more 
than 5 years who are having veliparib/placebo dispensed at Day 3).
Section 5.3.1.1  Study Procedures
Subsection Post treatment Information
Add:  new fourth paragraph
No post-treatment information will be collected for subjects on study treatment for over 
5 years.
Section 5.3.1.3  Blood Samples for Pharmacodynamic Analysis
Subsection Blood Collection for Plasma Markers
Add:  new last sentence 
For subjects on study treatment more than 5 years, sampling scheduled for Day 1 of every 
10th cycle or Final Visit will no longer be required.


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Section 5.3.1.3  Blood Samples for Pharmacodynamic Analysis
Subsection Blood Collection for Serum Markers
Add:  new second sentence 
For subjects on study treatment more than 5 years, any sampling scheduled for Day 1 of 
every 10th cycle or Final Visit will no longer be required. 
Section 5.3.3  Efficacy Variables
First paragraph
Add:  new last sentence 
Assessments will be modified for subjects on study treatment more than 5 years as 
indicated in Section 5.3.1.1.
Section 5.4.1  Discontinuation of Individual Subjects
Fourth paragraph
Add:  new last sentence 
For subjects on study treatment more than 5 years, 12-lead ECG, urinalysis, CIPN 
Assessment (QLQ-CIPN20), and EORTC QLQ-C15/BR23, and tumor assesement do not 
need to be performed at Final Visit.
Section 5.4.1  Discontinuation of Individual Subjects
Fifth paragraph
Add:  new last sentence 
For subjects on study treatment more than 5 years, CIPN Assessment (QLQ-CIPN20) and 
EORTC QLQ-C15/BR23 do not need to be performed at the Follow-up Visit.
Section 5.4.1  Discontinuation of Individual Subjects
Seventh paragraph
Add:  new last sentence 
For subjects on study treatment more than 5 years, the subject will be discontinued from 
study if discontinuing treatment for any reason.


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Section 5.4.1  Discontinuation of Individual Subjects
Eighth paragraph
Add:  new last sentence 
For subjects on study treatment for more than 5 years, overall survival and post treatment 
information are not required.
Section 5.4.2  Discontinuation of Entire Study
First paragraph
Add:  new last sentence 
For subjects on study treatment for more than 5 years, survival follow-up is not required.
Section 5.7  Dose Reductions or Delays
First paragraph, last sentence previously read:
All toxicities, with the exception of anemia, alopecia, neuropathy, 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.
Has been changed to read:
All toxicities, with the exception of anemia, alopecia, neuropathy, 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 chemotherapy.


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Section 6.5  Adverse Event Reporting
Third and fourth paragraph previously read:
For any emergent safety concerns, please contact the AbbVie Medical Monitor.
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Office:
Mobile:
Fax:
Email:
Should in case of subject safety concerns or medical emergencies the Primary Study 
Designated Physician be unavailable, please call the following central back-up number:
Has been changed to read:
For any emergent safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Office:
Mobile:
Fax:
Email:


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In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director (TA MD) is not available by phone, please contact the 24-hour AbbVie 
Medical Escalation Hotline where your call will be re-directed to a designated backup 
AbbVie TA MD:
Section 6.5  Adverse Event Reporting
Last paragraph previously read:
The Sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The safety reference material used for SUSAR reporting will be 
the most current version of the Investigator's Brochure for veliparib or SmPC for TMZ, 
carboplatin, and paclitaxel.
Has been changed to read:
AbbVie will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
global and local guidelines. Appendix A of the Investigator Brochure will serve as the 
Reference Safety Information (RSI) for veliparib and Summary of Product Characteristics 
(SmPC) will be the RSI for carbloplatin, paclitaxel, and temozolomide.  The RSI in effect 
at the start of a DSUR reporting period serves as the RSI during the reporting period.  For 
follow-up reports, the RSI in place at the time of occurrence of the 'suspected' Serious 
Adverse Reaction will be used to assess expectedness.
Section 6.6  Pregnancy
First paragraph, first sentence previously read:
In the event of a positive pregnancy test, subjects must immediately discontinue study 
drug and must be discontinued from the study.
Has been changed to read:
In the event of a positive pregnancy test, subjects must immediately discontinue study 
drug and must be discontinued from the study (Section 5.4).


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Section 7.0  Protocol Deviations
Contact information previously read:
Clinical Team Lead:
Clinical Field Operations, GPRD
Knollstr. 50
67061 Ludwigshafen
Germany
Office:
Mobile:
Fax:
Email:
Medical Monitor:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Office:
Mobile:
Fax:
Email:
Has been changed to read:
Clinical Team Lead:
AbbVie Corporation
8401 Trans-Canada Highway
Saint-Laurent, Québec
H4S 1Z1
Canada
Office:
Fax:
Email:
Scientific Director:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Office:
Fax:
Email:


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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Global Drug Supply
Clinical
Statistics
Clinical
Clinical
Pharmacokinetics
Has been changed to read:
Name
Title
Functional Area
Clinical
Clinical
Clinical
Statistics

SAP_001.pdf: 
Veliparib
M12-895 – Statistical Analysis Plan
Version 5.0 – 07 Apr 2019
1
1.0
Title Page
Statistical Analysis Plan
Study M12-895
A Randomized, Phase 2 Study of the Efficacy and 
Tolerability of Veliparib in Combination with 
Temozolomide or Veliparib in Combination with 
Carboplatin and Paclitaxel Versus Placebo Plus 
Carboplatin and Paclitaxel in Subjects with BRCA1 
or BRCA2 Mutation and Metastatic Breast Cancer
Date:  07 Apr 2019
Version 5.0
NCT01506609


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1.1
SAP Update: Summary of Changes
The purpose of this update is to:
●
Remove statistical comparisons for demographic and baseline characteristics 
among treatment groups in Section 7.0 and Section 11.0.
●
Refine summary of study drug exposure and remove statistical comparisons on 
study drug exposure among treatment groups and summary of compliance in 
Section 9.0.
●
Remove cutoff date for OS analysis and include all deaths in the OS analysis 
in Section 10.0.
●
Add efficacy analysis of duration of response in Section 10.0.
●
Specify the number of days in censoring rules for modified PFS analysis in 
Section 10.0.
●
Remove censoring 30 days post last dose for PFS and OS analyses in 
Section 10.0.
●
Clarify definition of treatment-emergent AE and remove statistical 
comparisons of AE among treatment groups in Section 11.0.
●
Clarify and simply AE listings and remove subgroup analyses of AE in 
Section 11.0.
●
Clarify summary of number of deaths in Section 11.0.
●
Present only descriptive statistics for the mean change and mean difference of 
change from baseline to scheduled visits and final observation for laboratory 
and vital sign data in Section 11.0.
●
Remove statistical comparisons of shifts from baseline NCI CICTAE 
version 4.0 grades to maximum and final post-baseline grades in Section 11.0.
●
Remove analyses of vital signs using criteria for potentially clinically 
significant vital sign values in Section 11.0.


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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 Diagram .........................................................................................6
4.3
Sample Size................................................................................................9
4.4
Interim Analysis.......................................................................................10
5.0
Analysis Populations .............................................................11
5.1
Definition for Analysis Populations.........................................................11
5.2
Variables Used for Stratification of Randomization................................11
6.0
Analysis Conventions ............................................................12
7.0
Demographics, Baseline Characteristics, Medical 
History, Previous/Concomitant Medications, and 
Prior Oncology Therapies.....................................................15
7.1
Demographic and Baseline Characteristics .............................................16
7.2
Medical History .......................................................................................16
7.3
Prior/Concomitant Medications and Prior Oncology Therapies..............16
8.0
Patient Disposition.................................................................17
9.0
Study Drug Exposure and Compliance...............................17
9.1
Study Drug Exposure...............................................................................17
10.0
Efficacy Analysis....................................................................18
10.1
General Considerations............................................................................18
10.2
Primary Efficacy Analysis .......................................................................19
10.3
Secondary Efficacy Analyses...................................................................20
10.3.1
Overall Survival.......................................................................................21
10.3.2
Clinical Benefit Rate................................................................................21
10.3.3
Objective Response Rate .........................................................................22
10.3.4
Duration of Overall Response (DoR) ......................................................22
10.3.5
Chemotherapy-Induced Peripheral Neuropathy (CIPN)..........................23


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10.4
Tertiary Efficacy Analyses.......................................................................23
10.4.1
Analysis of Chemotherapy-Induced Peripheral Neuropathy by 
NCI CTCAE 4.0 Grading ........................................................................24
10.4.2
Quality of Life..........................................................................................24
10.4.3
Performance Status ..................................................................................30
10.5
Additional Efficacy Analyses ..................................................................30
10.6
Handling of Multiplicity ..........................................................................32
11.0
Safety Analysis.......................................................................33
11.1
General Considerations............................................................................33
11.2
Analysis of Adverse Events.....................................................................33
11.2.1
Analysis of Treatment-Emergent Adverse Events...................................33
11.3
Death........................................................................................................35
11.4
Longitudinal Analysis of Laboratory and Vital Signs Data.....................35
11.5
Analysis of Laboratory Data Using NCI CTCAE Criteria ......................35
List of Tables
Table 1.
Treatment Schema for Subjects Randomized to Veliparib + TMZ 
Treatment Arm...........................................................................................7
Table 2.
Treatment Schema for Subjects Randomized to Veliparib + 
Carboplatin + Paclitaxel or Placebo + Carboplatin + Paclitaxel 
Treatment Arm...........................................................................................7
Table 3.
Time Windows for Visit-Wise Analysis (QoL, ECOG, Lab, and 
Vital Signs) – Veliparib + TMZ Treatment Arm.....................................14
Table 4.
Time Windows for Visit-Wise Analysis for Vital Signs –
Veliparib/Placebo + Carboplatin + Paclitaxel Treatment Arm................15
Table 5.
Time Windows for Visit-Wise Analysis (EORTC QLQ-CIPN20, 
QoL, ECOG, and Lab) – Veliparib/Placebo + Carboplatin + 
Paclitaxel Treatment Arm........................................................................15


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3.0
Introduction
Veliparib is a potent PARP inhibitor that delays the repair of DNA damage induced by 
chemotherapeutic agents.  Veliparib increases sensitivity of tumor cells to DNA-damaging 
agents in vitro and in vivo and inhibits PARP in murine tumors in vivo and human 
peripheral blood mononuclear cells (PBMCs) and human tumors ex vivo.
This study is to evaluate the efficacy and tolerability of veliparib in combination with 
temozolomide (TMZ) or veliparib in combination with carboplatin and paclitaxel 
compared to placebo plus carboplatin and paclitaxel in subjects with BRCA1 or BRCA2 
mutated locally recurrent (and not amenable to therapy with curative intent) or metastatic 
breast cancer, who have received no more than two prior lines of cytotoxic therapy for 
metastatic disease.
This statistical analysis plan will provide details to further elaborate statistical methods as 
outlined in the protocol Study M12-895 and will describe analysis conventions to guide 
the statistical programming work.  The SAP will be signed off before the study database is 
locked.
Analysis will be performed using SAS Version 9.2 or upper (SAS Institute, Inc., Cary, 
NC  27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
This study is to evaluate the efficacy and tolerability of veliparib in combination with 
temozolomide (TMZ) or veliparib in combination with carboplatin and paclitaxel 
compared to placebo plus carboplatin and paclitaxel.
The primary objective of the study is to assess the progression-free survival (PFS) of oral 
veliparib in combination with temozolomide (TMZ) or in combination with carboplatin 
and paclitaxel compared to placebo plus carboplatin and paclitaxel in subjects with 


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BRCA1 or BRCA2 mutated locally recurrent (and not amenable to therapy with curative
intent) or metastatic breast cancer.
The secondary objectives of the study are to assess overall survival (OS), clinical benefit 
rate (CBR) through the end of Week 18 and objective response rate (ORR) in those 
subjects treated with veliparib in combination with TMZ or treated with veliparib plus 
carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel.  In addition, 
CIPN as assessed by the change from baseline in sensory scale at Week 18 from EORTC 
QLQ-CIPN20 will be assessed in those subjects treated with veliparib in combination 
with carboplatin and paclitaxel versus placebo in combination with carboplatin and 
paclitaxel.
The tertiary objectives are to assess Eastern Cooperative Oncology Group (ECOG) 
performance status, quality of life (QoL), CIPN assessed by the other EORTC QLQ-CIPN 
20 scales and NCI-CTCAE 4.0 grading for peripheral neuropathy, and exploratory 
correlative endpoints.
4.2
Design Diagram
This is a Phase 2, randomized, partially blinded, multinational, multicenter study to 
evaluate the efficacy and tolerability of veliparib in combination with TMZ or veliparib in 
combination with carboplatin and paclitaxel compared to placebo plus carboplatin and 
paclitaxel in approximately 290 subjects with BRCA1 or BRCA2 germline mutation (as 
documented by the Sponsor core laboratory) and with locally recurrent or metastatic 
breast cancer who have received no more than two prior lines of cytotoxic therapy for 
metastatic disease.  Approximately 120 research sites will participate.
Subjects will be randomized in a 1:1:1 ratio to one of the three treatment arms described 
below.  Subject randomization will be stratified by ER-positive and/or PgR-positive 
versus ER-negative and PgR-negative status, prior cytotoxic therapy versus no prior 
cytotoxic therapy, and ECOG 0 – 1 versus 2.


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Under the original protocol, 4 subjects were randomized in a 1:1:1 ratio (Group 1) to one 
of the three treatment arms (veliparib 40 mg BID + TMZ; veliparib 80 mg BID + 
carboplatin + paclitaxel; or placebo BID + carboplatin + paclitaxel).
Following protocol Amendment 1, approximately 290 subjects will be randomized in a 
1:1:1 ratio (Group 2) to one of the three treatment arms (veliparib 40 mg BID + TMZ; 
veliparib 120 mg BID + carboplatin + paclitaxel; or placebo BID + carboplatin + 
paclitaxel) at all study centers.
The dose schedules for all three groups of the study are detailed below.
Table 1.
Treatment Schema for Subjects Randomized to Veliparib + TMZ 
Treatment Arm
Days
1
2
3
4
5
6
7
8 – 28
Veliparib
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice 
a day
Twice 
a day
No drug 
dosing
TMZ
Once a 
day with 
a m. 
Veliparib
Once a 
day with 
a m. 
Veliparib
Once a 
day with 
a m. 
Veliparib
Once a 
day with 
a m. 
Veliparib
Once a 
day with 
a m. 
Veliparib
No drug 
dosing
Note:
A maximum of 24 cycles of veliparib + TMZ (additional cycles may be given, if both the investigator and the 
AbbVie Medical Monitor confirm that the subject would benefit from continued treatment).
Table 2.
Treatment Schema for Subjects Randomized to Veliparib + 
Carboplatin + Paclitaxel or Placebo + Carboplatin + Paclitaxel 
Treatment Arm
Days
1
2
3
4
5
6
7
8 – 21
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
Paclitaxel
IV
No drug 
dosing
*
Veliparib or placebo morning dose should be administered orally in the clinic prior to paclitaxel/carboplatin 
infusion.


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Subjects with controlled disease (complete response [CR], partial response [PR], or stable 
disease [SD] per RECIST Version 1.1 as determined by the investigator at each clinical 
site) and with tolerable side effects may continue to receive treatment with veliparib + 
TMZ until reaching a protocol-defined event of disease progression, or experiencing 
unmanageable toxicity, or reaching a maximum of 24 cycles of veliparib + TMZ.  If TMZ 
has been discontinued, veliparib will also be discontinued.  If the subject has not 
progressed and the investigator feels there is benefit from continued treatment for longer 
than 24 cycles, a discussion between the investigator and the AbbVie Medical Monitor is 
required.  If both the investigator and the AbbVie Medical Monitor confirm that the 
subject would benefit from continued treatment, then the subject may continue to receive 
veliparib + TMZ until the subject has disease progression or experiences a toxicity that 
requires discontinuation of further treatment.
Subjects randomized to veliparib/placebo + carboplatin + paclitaxel with controlled 
disease and with tolerable side effects may continue to receive treatment until reaching a 
protocol-defined event of disease progression or experiencing unmanageable toxicity.  If 
both carboplatin and paclitaxel have been discontinued due to toxicity, veliparib will also 
be discontinued.
When an investigator has determined that a subject should discontinue 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 + TMZ or veliparib/placebo + carboplatin + 
paclitaxel.  This Follow-Up Visit does not need to be conducted if the Final Visit is 
≥30 days after the last dose of veliparib + TMZ or Veliparib + carboplatin + paclitaxel or 
placebo + carboplatin + paclitaxel.
Post-treatment and survival information (i.e., the date and cause of death) will be 
collected via Interactive Voice or Web Response System (IVRS/IWRS) at monthly 
intervals (or as requested by Sponsor to support data analysis) beginning on the date the 
subject is registered off study and continuing for up to three (3) years for all subjects until 
the endpoint of death, the subject has become lost to follow-up, or AbbVie terminates the 
study.


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4.3
Sample Size
Assuming the true hazard ratio in favor of the veliparib 40 mg BID + TMZ or veliparib 
120 mg BID + carboplatin + paclitaxel treatment group is 0.58 for PFS, a total of 159 PFS 
events will be needed for the study to have at least 80% power at two-sided α level of 0.05 
to detect a statistically significant treatment effect for the veliparib 40 mg BID + TMZ 
treatment group or the veliparib 120 mg BID + carboplatin + paclitaxel treatment group 
using the log-rank test for PFS.  If the veliparib 40 mg BID + TMZ treatment group is 
terminated for reasons of futility, a total of 112 PFS events will be needed for the 
double-blind portion of the study to have at least 80% power at two-sided α level of 0.05 
(or 74% power at 2-sided α level of 0.025) to detect a statistically significant treatment 
effect for the veliparib 120 mg BID + carboplatin + paclitaxel treatment group using the 
log-rank test for PFS.
In addition, assuming the true hazard ratio in favor of the veliparib 40 mg BID + TMZ or 
veliparib 120 mg BID + carboplatin + paclitaxel treatment group is 0.61 for OS, a total of 
194 death events will be needed for the study to have at least 80% power at two-sided α 
level of 0.05 to detect a statistically significant treatment effect for the veliparib 40 mg 
BID + TMZ treatment group or the veliparib 120 mg BID + carboplatin + paclitaxel 
treatment group using the log-rank test for OS.  If the veliparib 40 mg BID + TMZ 
treatment group is terminated for reasons of futility, a total of 136 death events will be 
needed for double-blind portion of the study to have approximately 80% power at 
two-sided α level of 0.05 (or 74% power at 2-sided α level of 0.025) 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 290 subjects with BRCA mutation as documented by the 
Sponsor core laboratory will be enrolled into Group 2 of the study to accrue the required 
PFS events in a reasonable study duration.


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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 36 subjects in Group 2 of the study have met at least one of the following 
criteria:
●
Received two 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.
In addition, an interim futility analysis will be conducted and will be reviewed by the 
IDMC after the first 30 subjects with deleterious mutations (as determined by the sponsor 
core lab) with at least one measurable lesion at baseline are randomized to the veliparib + 
TMZ treatment group (across both Group 1 and Group 2) and complete the Week 27 
tumor assessment or discontinue the study prior to the Week 27 tumor assessment.
The pre-specified futility criteria are as follows:  If there are less than 5 responders (CR + 
PR) in the 30 subjects, then futility will be declared for the veliparib + TMZ treatment 
group.  This futility criterion corresponds to Bayesian posterior probability of at least 90% 
that the true objective response is ≤ 25%.
If futility is declared at the time of the futility analysis, any remaining subjects on 
veliparib + TMZ will be given the option either to receive veliparib 120 mg BID + 
carboplatin + paclitaxel or discontinue therapy.  These subjects will not be included in the 
efficacy analysis comparing veliparib 120 mg BID + carboplatin + paclitaxel treatment 
group to placebo + carboplatin + paclitaxel treatment group in order to avoid the 
crossover effects.


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The planned unblinded safety interim was performed in August 2013.  The IDMC 
recommended having another safety interim when approximately 80 subjects in Group 2 
of study have met at least one of the above safety interim analysis criteria.
The interim futility analysis and the second safety interim analysis (as recommended by 
the IDMC) were conducted by the IDMC in July 2014.  The IDMC recommended that 
TMZ treatment group could continue and there were no safety concerns.  The detailed 
IDMC recommendation can be found in the study document file.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
Two study populations will be analyzed as defined below.
Intent-To-Treat (ITT) population – consists of all subjects randomized by IVRS/IWRS.  
The data from the ITT population will be analyzed by the treatment group assignment 
given at the time of randomization, even if the subject does not receive the correct 
treatment, or does not follow the protocol until completion.
As Treated (AST) population – consists of all subjects randomized by IVRS/IWRS and 
took at least 1 dose of study drug (veliparib/placebo).  The data from AST population will 
be analyzed by the actual treatment that subject received.
5.2
Variables Used for Stratification of Randomization
The randomization will be stratified by ER/PgR (ER and/or PgR positive versus ER and 
PgR negative), prior cytotoxic therapy use (yes versus no), and ECOG 0 – 1 versus 2.
Randomization schedules will be generated using a stratified permuted block with mixed 
block size of 3 and 6.  The mixed block size of 2 and 4 will be used if the veliparib 40 mg 
BID + TMZ treatment group is terminated at the interim futility analysis.


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6.0
Analysis Conventions
General Considerations
Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a two-sided P value ≤ 0.05.  The date of randomization is defined as the 
date that the IVRS/IWRS issues a randomization number.
All analyses (except for efficacy endpoints) will be summarized by each treatment group 
for Group 1 and Group 2 of the study separately.
The analyses of all efficacy endpoints will include only randomized subjects in Group 2 
of the study who have been documented to have deleterious mutations by the sponsor core 
lab.  Sensitivity analyses will be conducted using all randomized subjects' data in Group 2 
of the study to evaluate 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 drug veliparib or placebo (AST 
population) will be included in the safety analysis.
Comparisons will be performed between veliparib 40 mg BID + TMZ and placebo BID + 
carboplatin + paclitaxel as well as between veliparib 120 mg BID + carboplatin + 
paclitaxel and placebo BID + carboplatin + paclitaxel in Group 2 of the study.
Definition of Study Drug
Unless otherwise specified, the study drug in this document refers to veliparib or placebo.
Dealing with Multiple Values on the Same Day
In cases where multiple values are collected on the same day (including baseline visit and 
post-baseline visits), the maximum grade/value representing the worse outcome will be 
selected as the grade/value for that day for the shift analysis of lab parameters, EORTC 
QLQ-CIPN20 scores, QoL, and performance status (ECOG); the arithmetic average will 


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be calculated and used as the value for that day for mean changes in laboratory and vital 
signs parameters.
Definition of Baseline
Unless otherwise specified, the baseline is defined as the last non-missing observation 
collected on or prior to the date of the first dose of study drug for treated subjects (or the 
date of randomization for non-treated subjects).
Definition of Final Observation
For EORTC QLQ-CIPN20, EORTC QLQ-C15/BR23, ECOG, lab, and vital signs 
variables, the Final Observation is defined as the last non-missing observation collected 
after first dose study drug but up to 30 days of last dose of study drug (veliparib/placebo).
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).  They are defined as the number of days between the day of the 
first dose of study drug and the specific time point.  Rx days are negative values when the 
time point of interest is prior to the first study drug dose day.  Rx days are positive values 
when the time point of interest is after the first study drug dose day.  The day of the 
first dose of study drug is defined as Study Rx Day 1, while the day prior to the first study 
drug dose is defined as Study Rx Day –1 (there is no Study Rx Day 0).
Definition of Cycle Rx Days in Each Cycle
Cycle Rx Days for each cycle are calculated for each time point relative to the first dose 
of treatment combination (veliparib/placebo + carboplatin/paclitaxel or veliparib + TMZ) 
in each cycle.
Definition of Analysis Windows
During the treatment period, all time points and corresponding time windows are based on 
Cycle Rx Days.


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For visit-wise longitudinal analyses such as mean change in EORTC QLQ-CIPN20, QoL, 
ECOG, laboratory, and vital signs values, the time windows specified in Table 3, Table 4, 
and Table 5 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, Table 4, and Table 5.
●
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 Visit-Wise Analysis (QoL, ECOG, Lab, and 
Vital Signs) – Veliparib + TMZ Treatment Arm
Scheduled Visit
Nominal Cycle Rx Day
Time Window
(Cycle Rx Day Range)
Cycle 1 Day 1
Baseline
As Baseline definition
Cycle 1 Day 15
15
(> 1, 18)
Cycle 1 Day 22
22
(19, 25)
Cycle 2 Day 1
1
(–3, 4)
Cycle 2 Day 15
15
(12, 18)
Cycle 2 Day 22
22
(19, 25)
Cycle X Day 1
1
(–3, 4)
Note:
Hematology, ECOG and Vital Signs will be assessed on C1D1, C1D15, C1D22, C2D1, C2D15, C2D22, on 
Day 1 of each subsequent cycle and the Final Visit.  Chemistry will be assessed on C1D1, C1D15, C2D1, 
C2D15, on Day 1 of each subsequent cycle and the Final Visit.  Urinalysis sample will be collected on Day 1 
of each cycle, and the Final Visit.  QoL will be assessed at C1D1 and C2D1, on Day 1 of every other cycle 
starting with Cycle 4, and the Final Visit.


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Table 4.
Time Windows for Visit-Wise Analysis for Vital Signs –
Veliparib/Placebo + Carboplatin + Paclitaxel Treatment Arm
Scheduled Visit
Nominal Cycle Rx Day
Time Window
(Cycle Rx Day Range)
Cycle 1 Day 1
Baseline
As Baseline definition
Cycle 1 Day 3
3
(2, 6)
Cycle 1 Day 17
17
(14, 18)
Cycle X Day 1
1
(–3, 1)
Cycle X Day 3
3
(2, 6)
Note:
Vital Signs will be assessed on C1D1, C1D3, C1D17, on Day 1 and Day 3 of each subsequent cycle and at the 
Final Visit.
Table 5.
Time Windows for Visit-Wise Analysis (EORTC QLQ-CIPN20, 
QoL, ECOG, and Lab) – Veliparib/Placebo + Carboplatin + 
Paclitaxel Treatment Arm
Scheduled Visit
Nominal Cycle Rx Day
Time Window
(Cycle Rx Day Range)
Cycle 1 Day 1
Baseline
As Baseline definition
Cycle 1 Day 17
17
(14, 18)
Cycle X Day 1
1
(–3, 4)
Note:
Hematology, chemistry and ECOG will be assessed on C1D1, C1D17, on Day 1 of each subsequent cycle and 
the Final Visit.  Urinalysis sample will be collected on Day 1 of each cycle, and the Final Visit.  EORTC 
QLQ-CIPN20 and QoL will be assessed at C1D1, on Day 1 of every other cycle starting with Cycle 2, and the 
Final Visit.
7.0
Demographics, Baseline Characteristics, Medical 
History, Previous/Concomitant Medications, and 
Prior Oncology Therapies
ITT population will be used in the demographic, baseline characteristics, medical history, 
and previous/concomitant medication and prior oncology therapies.
There will be no statistical comparison for the demographic and baseline characteristics 
between the treatment groups.


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7.1
Demographic and Baseline Characteristics
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
mean, standard deviation, and range.  Frequencies and percentages will be computed for 
the following parameters (but not limited to):  gender, race, BRCA1 status, BRCA2 
status, ER/PgR status, HER2 status, triple negative breast cancer, disease status 
(measurable versus non-measurable disease), number and sites of metastases including 
visceral (lung or liver), prior oncology therapy regimens including cytotoxic therapy use, 
hormonal therapy use, and other agents, and ECOG performance status.
In addition, demographic and baseline characteristics will also be summarized by 
stratification variables (ER/PgR, prior cytotoxic therapy use, and ECOG) under which 
subjects are randomized in IVRS/IWRS and by stratification variables entered on the 
electronic Case Report Forms (eCRF).
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.  There will be no statistical comparison for the medical history between 
treatment groups.
7.3
Prior/Concomitant Medications and Prior Oncology 
Therapies
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.


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The frequency and percentage of subjects who have 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.
There will be no statistical comparison for the prior and concomitant medications and 
prior oncology therapies between treatment groups.
8.0
Patient Disposition
All ITT subjects will be included in the analyses.  The treatment groups assigned by 
IVRS/IWRS will be used in the summaries of patient disposition and there will be no 
statistical comparison for the patient disposition between treatment groups.  The screen 
failure reasons will be summarized for the screen failure subjects.
The number of randomized subjects and the number of treated subjects will be 
summarized by treatment group and by investigator site/country.
In addition, the study drug discontinuation reasons and study discontinuation will be 
summarized by treatment group.
9.0
Study Drug Exposure and Compliance
9.1
Study Drug Exposure
Analyses for the study drug exposure will be performed on the AST population.  Subjects 
who were randomized but did not receive study drug (veliparib or placebo) will not be 
included in the analyses.
Duration of exposure is defined as total number of days a subject received study drugs.  
Average dose days per cycle is defined as total number of days a subject received study 
drugs dividing by the total number of cycles a subject actually received.  Duration of 
exposure is summarized for study drugs, TMZ, carboplatin, and paclitaxel separately.  
Average dose days per cycle will be summarized for study drugs and TMZ.


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Descriptive statistics (mean, standard deviation, median, and range) will be presented for 
the duration of exposure, average dose days per cycle for study drugs (veliparib or 
placebo) as well as TMZ, and the number of cycles for study drugs (veliparib or placebo) 
as well as TMZ, carboplatin, and paclitaxel.
In addition, the frequencies and percentages of subjects having dose reduction, 
interruption will be summarized for each treatment group.
If a subject has any dose reduction from the previous dose of study drugs, TMZ, 
carboplatin, and paclitaxel, this subject will be considered as having dose reduction of 
study drug, TMZ, carboplatin and paclitaxel, respectively.  Carboplatin dose reduction 
will be based on AUC dose.  The body surface area dose (mg/m2) will be used to 
determine dose reduction of TMZ or paclitaxel.  If a subject receives only one dose in the 
study, this subject will not be included in the summary of dose reduction.
If a subject skips 2 or more consecutive days of dosing within a cycle, or number of days 
on study drug is less than 7 days in a cycle, or number of days on TMZ is less than 5 days 
in a cycle, this subject will be considered as having a dose interruption of study drug or 
TMZ.  If a subject receives only one dose in the study, this subject will not be included in 
the summary of dose interruption.  The summary of dose interruption will be summarized 
for study drugs (veliparib or placebo) as well as TMZ.
There will be no statistical comparison for summary of exposure.
10.0
Efficacy Analysis
10.1
General Considerations
Unless otherwise specified, all ITT subjects with deleterious mutations documented by the 
sponsor core lab for Group 2 of the study will be included in the efficacy analysis.
Comparisons will be performed between veliparib 40 mg BID + TMZ and placebo BID + 
carboplatin + paclitaxel as well as between veliparib 120 mg BID + carboplatin + 
paclitaxel and placebo BID + carboplatin + paclitaxel for Group 2 of study.


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The required number of PFS events for the study was expected to occur in February 2016.  
To operationalize the data retrieval and data cleaning efforts, the 'PFS Cutoff' date for the 
analysis of primary PFS endpoint is set as 04 March 2016.
The 'PFS Cutoff' date will be used for the analysis of all imaging related efficacy 
endpoints (PFS, CBR, ORR, and Duration of Response) and overall survival.
For PFS, ORR, Duration of Response and CBR analyses, if the subject has prematurely 
blind broken before 'PFS Cutoff' date, disease progression assessment data after 
prematurely blind broken will not be included.
10.2
Primary Efficacy Analysis
The primary efficacy analysis will be a comparison of progression-free survival (PFS) 
between veliparib + TMZ and placebo + carboplatin + paclitaxel as well as between 
veliparib + carboplatin + paclitaxel and placebo + carboplatin + paclitaxel.  Comparisons 
between treatments groups will be performed using a Hochberg testing procedure for 
multiplicity adjustment (see Section 10.6 for details).
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 an event of disease 
progression (as determined by the central imaging center), or to the date of death (all 
causes of mortality), if disease progression is not reached.  All events of disease 
progression (as determined by the central imaging center) occurring on or before the 'PFS 
Cutoff' date will be included, regardless of whether the event occurred while the subject 
was still taking study drug or had previously discontinued study drug.  Events of death 
will be included for subjects who had not experienced an event of disease progression (by 
central imaging center), provided the death occurred within 9 weeks (63 days) of the last 
evaluable disease progression assessment (by central imaging center).  If the subject does 
not have an event of disease progression (by central imaging center) and the subject has 
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censored at the date of the subject's last evaluable disease progression assessment (by 
central imaging center) on or before the 'PFS Cutoff' date.
If the randomized subject did not have any post-baseline disease progression assessment, 
the subject's data will be censored on the date of randomization.  If the subject has 
prematurely blind broken before 'PFS Cutoff' date, disease progression assessment data 
after prematurely blind broken will not be included.
The distribution of PFS (by central imaging center) will be estimated for each treatment 
group using Kaplan-Meier methodology and compared between veliparib + TMZ and 
placebo + carboplatin + paclitaxel as well as between veliparib + carboplatin + paclitaxel 
and placebo + carboplatin + paclitaxel treatment groups using the log-rank test, stratified 
by ER/PgR (ER and/or PgR positive versus ER and PgR negative) and prior cytotoxic 
therapy use (yes versus no).
10.3
Secondary Efficacy Analyses
Secondary efficacy analyses comparing the effects of veliparib + TMZ and placebo + 
carboplatin + paclitaxel as well as 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 18 (CBR), objective 
response rate (ORR), and Chemotherapy-Induced Peripheral Neuropathy (CIPN).
If only one veliparib treatment group is statistically significantly better than the placebo 
group for the primary endpoint of PFS, then 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, ORR, 
CBR, and CIPN.  For each secondary endpoint, Hochberg testing procedure will be used 
to preserve the family-wise error rate for multiple comparisons.


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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 will be included, regardless of whether the event occurred while the subject was still 
taking study drug or after the subject discontinued study drug.  If a subject has not died, 
the data will be censored at the date last known to be alive.
The distribution of overall survival will be estimated for each treatment group using 
Kaplan-Meier methodology and compared between veliparib + TMZ and placebo + 
carboplatin + paclitaxel as well as between veliparib + carboplatin + paclitaxel and 
placebo + carboplatin + paclitaxel using the log-rank test, stratified by ER/PgR (ER 
and/or PgR positive versus ER and PgR negative) and prior cytotoxic therapy use (yes 
versus no).
All deaths collected in the extracted clinical database will be included in the final OS 
analysis.
10.3.2
Clinical Benefit Rate
Clinical benefit rate (CR, PR, SD or Non-CR/Non-PD) at Week 18 will be defined as the 
progression-free rate at 18 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 central imaging center).  A test statistic based on Kaplan-Meier estimates 
of the progression-free probability at 18 weeks (Rx Day 126) and the estimated variance 
will be constructed to test the null hypothesis that the clinical benefit rate at Week 18 for 
the two treatment groups (between veliparib + TMZ and placebo + carboplatin + 
paclitaxel as well as between veliparib + carboplatin + paclitaxel and placebo + 
carboplatin + paclitaxel) are the same.
For a given subject, time to progression-free will be defined as the number of days from 
the date the subject was randomized to the date the subject experiences a confirmed event 
of disease progression (as determined by the central imaging center).  All confirmed 


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events of disease progression occurring on or before the 'PFS Cutoff' date will be 
included, regardless of whether the event occurred while the subject was still taking study 
drug or had previously discontinued study drug.  If the subject does not have an event of 
disease progression on or before the 'PFS Cutoff' date, the subject's data will be censored 
at the date of the subject's last evaluable disease progression assessment (by central 
imaging center) on or before the 'PFS Cutoff' date.  If the randomized subject did not have 
any post-baseline disease progression assessment, the subject's data will be censored on 
the date of randomization.
If the subject has prematurely blind broken before 'PFS Cutoff' date, disease progression 
assessment data after prematurely blind broken will not be included.
10.3.3
Objective Response Rate
Objective response rate is calculated as the proportion of subjects who have confirmed PR 
or CR based on assessment by the central imaging center per RECIST (version 1.1).  All 
ITT subjects with deleterious mutations documented by the sponsor core lab who had at 
least one measurable lesion at baseline will be included in the analysis.  If the subject has 
prematurely blind broken before 'PFS Cutoff' date, disease progression assessment data 
after prematurely blind broken will not be included.
The proportion of subjects with a confirmed complete or partial objective response based 
on RECIST (version 1.1) will be estimated for each treatment group and compared 
between the treatment groups (veliparib + TMZ and placebo + carboplatin + paclitaxel as 
well as veliparib + carboplatin + paclitaxel and placebo + carboplatin + paclitaxel) using 
CMH test stratified by ER/PgR (ER and/or PgR positive versus ER and PgR negative) and 
prior cytotoxic therapy use (yes versus no).  In addition, 95% confidence interval will be 
constructed for ORR.
10.3.4
Duration of Overall Response (DoR)
DoR for a given subject will be defined as the number of days from the day the criteria are 
met for confirmed CR or PR (whichever is recorded first) based on assessment by the 


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central imaging center per RECIST (version 1.1) to the date that PD or death, whichever 
is early.  If a subject is still responding on or before the "PFS Cutoff" date then the 
subject's data will be censored at date of the last available disease progression assessment 
on or before the "PFS Cutoff."  All events of death occurring on or before "PFS Cutoff" 
date will be included for subjects who had not experienced disease progression provided 
the death occurred within provided the death occurred within 9 weeks (63 days) of the last 
evaluable disease progression assessment.  If the subject does not have an event of disease 
progression (by central imaging center) and the subject has not died as defined above on 
or before the 'PFS Cutoff' date, the subject's data will be censored at the date of the 
subject's last evaluable disease progression assessment on or before the 'PFS Cutoff' date.
The distribution of DoR as well as the median DoR with corresponding 95% CI will be 
estimated for each group using the Kaplan-Meier methodolody.
10.3.5
Chemotherapy-Induced Peripheral Neuropathy (CIPN)
Chemotherapy-Induced Peripheral Neuropathy (CIPN) as assessed by the change from 
baseline in sensory scale at Week 18 in EORTC QLQ-CIPN20 will be assessed in those 
subjects treated with veliparib in combination with carboplatin and paclitaxel versus 
placebo in combination with carboplatin and paclitaxel.  The definition of sensory scale is 
described in Section 10.6.
Change from baseline in sensory scale at Week 18 will be summarized and compared 
between two treatment groups, using an analysis of covariance (ANCOVA) model with 
treatment group as the factor and the corresponding baseline value as a covariate.
10.4
Tertiary Efficacy Analyses
In addition to the primary and secondary efficacy analyses, tertiary efficacy analyses will 
be performed comparing the effects of veliparib + TMZ and placebo + carboplatin + 
paclitaxel as well as veliparib + carboplatin + paclitaxel and placebo + carboplatin + 
paclitaxel on chemotherapy-induced peripheral neuropathy assessed by NCI CTC AE 4.0 


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Grading, QoL, and performance status.  For analyses of QoL and performance status, the 
data will be analyzed at visits with at least 5 subjects overall for each treatment group.
10.4.1
Analysis of Chemotherapy-Induced Peripheral Neuropathy 
by NCI CTCAE 4.0 Grading
Chemotherapy-Induced Peripheral Neuropathy (CIPN) as assessed by AE 4.0 grading for 
peripheral neuropathy will be analyzed in those subjects treated with veliparib/placebo in 
combination with carboplatin + paclitaxel.
The frequencies and percentages of subjects experiencing a treatment emergent grade 3 or 
4 peripheral neuropathy (SMQ 20000034 broad) will be summarized.  Comparisons of the 
percentages of subjects experiencing grade 3 or 4 peripheral neuropathy between veliparib 
+ carboplatin + paclitaxel and placebo + carboplatin + paclitaxel will be performed using 
Fisher's exact test.
10.4.2
Quality of Life
All subjects who do not have baseline measurement or any post-baseline measurements 
on ITT population will not be included in QoL analyses.  Post-baseline measurements will 
be obtained according to the visit window as in Table 3 and Table 5.  Post-baseline 
measurements more than 30 days after the last study visit will not be included.
EORTC-QLQ-CIPN20 Questionnaire
At the scheduled post-baseline visits, the EORTC QLQ-CIPN20, a 20-item questionnaire 
module developed to evaluate various aspects of CIPN, will be obtained according to the 
visit window as Table 5. This questionnaire provides 3 different scores for 3 domain 
scales – sensory scale (Item 31 – 36, 39, 40, and 48), motor scale (Item 37 – 38, 41 – 45, 
and 49), and autonomous scale (Item 46 – 47, 50).  The individual items and the 
multi-item scale should be scored such that the higher scores represent more 
symptoms/problems (i.e., higher score = worse).


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Scale
Number of Items
Item Range
Item Numbers 
(According CRF)
Sensory Scale
SS
9
3
31 – 36, 39, 40, 48
Motor Scale
MS
8
3
37, 38, 41 – 45, 49
Autonomic Scale
AS
3
3
46, 47, 50
Overall Scale
Overall
20
3
31 – 50
Scoring algorithms for scales are as follows:
If items I1, I2,…, In are included in a scale, the procedure are as follows:
Raw Score (RS) = (I1+I2+…+In)/(number of non-missing items)
Score = (RS-1)/range*100, where range is 3.
For each of the 4 scales, note that, if a subject completed more than 50% of the items in a 
scale, then the raw score of that subject will contribute to the summary statistics of that 
scale.  If a subject completed less than 50% of the items in a scale, then the raw score of 
that subject will be dropped from the calculation of the summary statistics of that scale.
Descriptive statistics will be presented for baseline, each scheduled post-baseline visit and 
the Final Observation.  Changes from baseline to each visit in each of the 3 scores will be 
summarized and compared between two treatment groups, using an analysis of covariance 
(ANCOVA) model with treatment group as the factor and the corresponding baseline 
value as a covariate.
Addition exploratory analyses may be performed, such as 1) including treatment duration 
as a covariate in the ANCOVA model to adjust for the confounding factor of treatment 
duration; 2) performing a repeated measures mixed model to evaluate the overall mean 
change from baseline in EORTC QLQ-CIPN20.


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EORTC QLQ-C15-PAL
The overall and domain specific scores will be calculated from the 15 items in EORTC 
QLQ-C15-PAL for each subject based on the QLQ-C15-PAL instruction.  The items and 
scales of the QLQ-C15-PAL are as follows.
Scale
Number of Items
Item Range
Item Numbers
Global Health Status/Quality of Life
Global Health Status/Quality of Life
QL
1
6
15
Functional Scales
Physical Functioning
PF2
3
3
1 – 3
Emotional Functioning
EF
2
3
13, 14
Symptom Scales
Fatigue
FA
2
3
7, 11
Nausea and Vomiting
NV
1
3
9
Pain
PA
2
3
5, 12
Dyspnoea
DY
1
3
4
Insomnia
SL
1
3
6
Appetite Loss
AP
1
3
8
Constipation
CO
1
3
10
Scoring algorithms for the scales are as follows:
For QL, PA, DY, SL, AP, and CO:
If items I1, I2,…,In are included in a scale, the procedure are as follows:  Raw Score 
(RS) = (I1 + I2+…+In)/n, Score = (RS-1)/range*100, where range is provided by the table 
above.


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For PF2, EF, FA, and NV:
Physical Functioning
Emotional Functioning
Fatigue
Nausea and Vomiting
Sum of Items 1 – 3a
PF2 Score
Item 13
Item 14
EF Score
Item 7
Item 11
FA Score
Item 9
NV Score
3
0.0
'Not at all'
'Not at all'
100.0
'Not at all'
'Not at all'
0.0
'Not at all'
0.0
4
6.7
'Not at all'
'A little'
83.3
'Not at all'
'A little'
22.2
'A little'
16.7
5
13.3
'Not at all'
'Quite a bit'
66.7
'Not at all'
'Quite a bit'
33.3
'Quite a bit'
50.0
6
20.0
'Not at all'
'Very much'
50.0
'Not at all'
'Very much'
55.6
'Very much'
100.0
7
26.7
'A little'
'Not at all'
83.3
'A little'
'Not at all'
22.2
8
33.3
'A little'
'A little'
66.7
'A little'
'A little'
33.3
9
46.7
'A little'
'Quite a bit'
50.0
'A little'
'Quite a bit'
55.6
10
60.0
'A little'
'Very much'
41.7
'A little'
'Very much'
66.7
11
73.3
'Quite a bit'
'Not at all'
66.7
'Quite a bit'
'Not at all'
33.3
12
93.3
'Quite a bit'
'A little'
50.0
'Quite a bit'
'A little'
44.4
'Quite a bit'
'Quite a bit'
41.7
'Quite a bit'
'Quite a bit'
66.7
'Quite a bit'
'Very much'
16.7
'Quite a bit'
'Very much'
88.9
'Very much'
'Not at all'
50.0
'Very much'
'Not at all'
44.4
'Very much'
'A little'
41.7
'Very much'
'A little'
66.7
'Very much'
'Quite a bit'
16.7
'Very much'
'Quite a bit'
88.9
'Very much'
'Very much'
0.0
'Very much'
'Very much'
100.0
a.
Items 1 – 3 are scored:  0 = 'Very much,' 1 = 'Quite a bit,' 2 = 'A little,' 3 = 'Not at all.'


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If a subject completed more than 50% of the items in a scale, then the raw score of that 
subject will contribute to the summary statistics of that scale.  If a subject completed less 
than 50% of the items in a scale, then the raw score of that subject will be dropped from 
the calculation of the summary statistics of that scale.
Descriptive statistics will be presented for the baseline, each scheduled post-baseline visit, 
and the Final Observation of both overall and domain specific scores by each treatment 
group.  Mean change (95% CI) from baseline to each scheduled post-baseline visit and the 
Final Observation within each treatment group and the mean difference of change (95% 
CI) from baseline to each scheduled post-baseline visit and the Final Observation between 
treatment groups will be obtained from the ANCOVA model with treatment group as the 
factor and baseline value as a covariate.
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 instruction.  The items and scales of the QLQ-BR23 are as follows.
Scale 
Name
Number of 
Items
Item 
Range
Item Numbers in 
Study M12-895 CRF
Function scales
Body Image
BRBI
4
3
39 – 42
Sexual* Function
BRSEF
2
3
44, 45
Sexual* Enjoyment
BRSEE
1
3
46
Future Perspective
BRFU
1
3
43
Symptom Scales/Items
Systemic Therapy Side Effects
BRST
7
3
31 – 34, 36, 37, 38
Breast Symptoms
BRBS
4
3
50 – 53
Arm Symptoms
BRAS
3
3
47, 48, 49
Upset by Hair Loss
BRHL
1
3
35


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Items for scales marked as* are scored positively (i.e., "very much" is best) and therefor 
use the same algebraic equation as for symptom scales.
BRSEE, sexual enjoyment, is not applicable if item 45 is 'not all all.'
BRHL, upset by hair loos, is not applicable if item 34 is 'not all all.'  The 'not applicable' 
item is considered as missing item.
For all scales, the Raw Score, RS, is the mean of component items:
Raw Score (RS) = (I1 + I2 +…+ In)/n
For Function Scales (BRBI, BRFU):
Score = (1-(RS-1)/range) × 100
For all Symptom Scales and Function Scales (BRSEF, BRSEE):
Score = (RS-1)/range) × 100
A high score for a function scale represents a high/health level of functioning.  A high 
score for a symptom scale/item represents a high level of symptomatology/problems.
If a subject completed more than 50% of the items in a scale, then the raw score of that 
subject will contribute to the summary statistics of that scale.  If a subject completed less 
than 50% of the items in a scale, then the raw score of that subject will be dropped from 
the calculation of the summary statistics of that scale.
Descriptive statistics will be presented for baseline, each scheduled post-baseline visit, 
and the Final Observation of individual item score and domain specific scores by each 
treatment group.  Mean change (95% CI) from baseline to each scheduled post-baseline 
visit and the Final Observation within each treatment group and the mean difference of 
change (95% CI) from baseline to each scheduled post-baseline visit and the Final 
Observation between treatment groups will be obtained from the ANCOVA model with 


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treatment group as the factor and baseline value as a covariate.  Male subjects may be 
excluded from the analyses for some questionnaires specifically for women.
10.4.3
Performance Status
All subjects who do not have baseline measurement or any post-baseline measurements 
on ITT population will not be included in ECOG analyses.  ECOG at the scheduled 
post-baseline visits will be obtained according to the visit window.  Post-baseline 
measurements more than 30 days after the last study visit will not be included.
Descriptive statistics will be presented for baseline, each scheduled post-baseline visit, 
and the Final Observation of ECOG by each treatment group.  Mean change (95% CI) 
from baseline to each scheduled post-baseline visit and the Final Observation within each 
treatment group and the mean difference of change (95% CI) from baseline to each 
scheduled post-baseline visit and the Final Observation between treatment groups will be 
obtained from the ANCOVA model with treatment group as the factor and baseline 
ECOG as a covariate.
10.5
Additional Efficacy Analyses
The primary and secondary efficacy endpoints may also be analyzed using all ITT 
subjects' data, regardless whether or not the subject has 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 + TMZ and 
placebo + carboplatin + paclitaxel as well as between veliparib + carboplatin + paclitaxel 
and placebo + carboplatin + paclitaxel.
PFS, ORR, and CBR at Week 18 based on radiological and clinical assessment by 
Investigator will also be analyzed using the same statistical methodology as that for the 
corresponding primary and secondary efficacy endpoints.


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For those subjects who take other anti-cancer therapies after discontinuation of the study 
drug, the PFS will be censored at the date of subject's initiation of other anti-cancer 
therapies.  In addition, the following modified PFS endpoints may be performed, such as 
1) including all PFS events regardless of early blind break; 2) PFS events will be censored 
at last tumor assessments prior to the PFS events if the PFS events occurred immediately 
after more than one missed tumor assessments (e.g., the disease progression event 
occurred more than 140 days (126 days + 14 days)).  The 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) using a Cox 
proportional hazard model to explore the effect of baseline factors including (but not 
limited to) the following:  ER/PgR status, prior cytotoxic therapy use and line of therapy, 
ECOG performance status, and stage of the disease; 2) subgroup analysis by ER/PgR 
status, by prior cytotoxic therapy use and line of therapy, by ECOG performance status, 
by stage of the disease, by region, by subsequent therapy type (including other PARP 
inhibitor use); and 3) using interval censoring methods to analyze PFS.
In addition, time to the first subsequent therapy (TTFST) and time to the 
second subsequent therapy (TTSST) defined in below may be analyzed.  The same 
methodology as used in the analysis of PFS will be used in the analysis of TTFST and 
TTSST.
Time to the first subsequent therapy (TTFST) is defined as the number of days from when 
the subject is randomized to the start of the first subsequent therapy or death of any cause 
whichever occurs first.  If the subject does not have an event of TTFST, the subject's data 
will be censored at the date of subject's last known alive date.
Time to the second subsequent therapy (TTSST) is defined as the number of days from 
when the subject is randomized to the start of the second subsequent therapy or death of 
any cause whichever occurs first.  If the subject does not have an event of TTSST, the 
subject's data will be censored at the date of subject's last known alive date.


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In addition, grade 3 or 4 peripheral neuropathy leading to study drug dose 
reduction/interruption may be performed.  Time to the first G3/G4 peripheral neuropathy 
and time to grade 3 or 4 peripheral neuropathy leading to study drug dose 
reduction/interruption may be performed if the event rate is high enough to allow such an 
analysis.  Number and percent of subjects with CNS progression may be summarized.
10.6
Handling of Multiplicity
The Hochberg testing procedure will be used to preserve the family-wise error rate for 
multiple comparisons.  For the primary endpoint PFS, a Hochberg testing procedure will 
be used where the larger P value for the comparisons of veliparib + TMZ and placebo + 
carboplatin + paclitaxel as well as veliparib + carboplatin + paclitaxel and placebo + 
carboplatin + paclitaxel will be compared to an α = 0.05.  If statistically significant, then 
both comparisons will be considered significant.  If the larger P value is not statistically 
significant, then the smaller P value will be compared to an α = 0.025.  Nominal P values 
will be reported.  Furthermore, if both veliparib treatment groups are statistically 
significantly better than the placebo group for primary efficacy endpoint PFS, 
fixed-sequence testing method and Hochberg testing procedure will be used for the 
secondary endpoints.  If only one of the two veliparib treatment groups is statistically 
significantly better than the placebo group for PFS, then statistical significance will not be 
declared for any secondary endpoints, regardless of the observed P values.
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 "PFS Final Analysis" database, 
and the second one based on the "OS Final Analysis" database.  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 two-sided false positive rate 
will be 0.05 or less for overall survival.


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11.0
Safety Analysis
11.1
General Considerations
Safety analyses will be performed on AST population.  Subjects who were randomized 
but did not receive study drug (veliparib or placebo) will not be included in the analyses 
of safety.
Safety summaries will be presented by treatment group (veliparib 40 mg BID + TMZ, 
veliparib BID + carboplatin + paclitaxel or placebo BID + carboplatin + paclitaxel).
In addition, the safety data from the veliparib 40 mg BID + TMZ group in both Group 1 
and Group 2 of the study may be combined.
Statistical comparisons will only be made for Group 2 of the study.  There will be no 
statistical comparison for the demographic and baseline characteristics between the 
treatment groups.
11.2
Analysis of 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) and 
within 30 days after the last dose of study drug.
11.2.1
Analysis of Treatment-Emergent Adverse Events
Treatment-emergent adverse events will be coded and summarized by system organ class 
and preferred term according to the Medical Dictionary for Regulatory Activities 
(MedDRA) adverse event coding dictionary.  The percentage of subjects experiencing an 
adverse event at a given severity, NCI CTCAE version 4.0 toxicity grade, and relationship 
to study drug will be provided.  There will be no statistical comparison for above 
analyses.
The frequencies and percentages of subjects experiencing treatment-emergent adverse 
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●
Any treatment-emergent adverse event
●
Any treatment-emergent adverse event that is rated at least possibly related to 
study drug/TMZ/Carboplatin/paclitaxel by the investigator (Probably Related 
or Possibly Related)
●
Any treatment-emergent NCI toxicity grade ≥ 3
●
Any treatment-emergent NCI toxicity grade ≥ 3 and with probably related or 
possibility related to study drug/TMZ/Carboplatin/paclitaxel
●
Any treatment-emergent NCI toxicity grades 3 or 4
●
Any treatment-emergent NCI toxicity grade 3 or 4 and with probably related or 
possibility related to study drug/TMZ/Carboplatin/paclitaxel
●
Any treatment-emergent serious adverse event
●
Any treatment-emergent serious adverse events with and with probably related 
or possibility related to study drug/TMZ/Carboplatin/paclitaxel
●
Any treatment-emergent adverse event leading to discontinuation of study 
either due to disease progression or not due to disease progression
●
Any treatment-emergent adverse event leading to discontinuation of study 
drug/TMZ/Carboplatin/paclitaxel either due to disease progression or not due 
to disease progression
●
Any treatment-emergent adverse event leading to study 
drug/TMZ/Carboplatin/paclitaxel interruption or dose reduction
●
Any treatment-emergent adverse event leading to death
●
Any treatment-emergent adverse event leading to death rated at least possibly 
related to study drug by the investigator (Probably Related or Possibly
Related)
In addition, the treatment-emergent adverse events and serious adverse events of special 
interest based on SMQ (broad) or CMQ (broad) may be summarized.  There will be no 
statistical comparison for above analyses.


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11.3
Death
The number of subject deaths will be summarized 1) for deaths occurring within 30 days 
after the last dose of study drug 2) for deaths occurring more than 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
Longitudinal Analysis of Laboratory and Vital Signs Data
Changes from baseline are analyzed for each scheduled post-baseline visit and the Final 
Observation for blood chemistry and hematology parameters, as well as urinalysis and 
vital sign parameters including diastolic/systolic blood pressure, heart rate, and body 
temperature.  If more than one measurement exists for a subject on a particular day, an 
arithmetic average will be calculated.  The average will be considered to be that subject's 
measurement of that day.  Post-baseline measurement more than 30 days after the last 
dose of study drug will not be included.  Subjects that do not have a baseline visit or do 
not have any post-baseline visits will not be included.  The data will be analyzed at visits 
with at least 5 subjects overall for each treatment group.
Descriptive statistics will be presented for baseline, each scheduled post-baseline, and the 
Final Observation by each treatment group.  Mean change from baseline to each 
scheduled post-baseline visit and the Final Observation within each treatment group and 
the mean difference of change from baseline to each scheduled post baseline visit and the 
Final Observation between treatment groups will be obtained by the descriptive statistics.
11.5
Analysis of Laboratory Data Using NCI CTCAE Criteria
Blood chemistry and hematology determinations will be categorized according to NCI 
CTCAE version 4.0 grades, and shifts from baseline NCI CTCAE version 4.0 grades to 
maximum and final post-baseline grades will be assessed.  The baseline and final grades 
will be defined respectively as the grade of the last measurement collected prior to the 
first dose of study drug, and as the grade of the last post-baseline measurement collected 


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no more than 30 days after the last dose of study drug.  If multiple values are available for 
a post-baseline measurement, then the value with the highest NCI CTCAE grade will be 
used in the assessment of shift.
Detailed listings of data for subjects experiencing NCI CTCAE grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug, will be included in these 
listings.