Clinical trial NCT02470585
Conditions: Ovarian Cancer Ovarian Neoplasm
Keywords: Veliparib Carboplatin Paclitaxel Overall Survival ABT-888 Randomized Poly Adenosine Diphosphate (ADP) - Ribose Polymerase (PARP) Ovarian BRCA VELIA
Sponsor: AbbVie
Start date: 2015-07-14; Completion date: 2023-10-05
Enrollment: 1140 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study was to evaluate whether progression-free survival (PFS) was prolonged with the addition of veliparib to standard platinum-based chemotherapy (carboplatin/paclitaxel \[C/P\]) and continued as maintenance therapy compared with chemotherapy alone.

Detailed description:
Participants were randomized in a 1:1:1 ratio to one of three arms. Randomization in the entire population was stratified according to the timing of surgery and residual disease status (any residual disease after primary surgery vs. no residual disease after primary surgery vs. interval surgery) and the paclitaxel schedule (weekly vs. every 3 -weeks), stage of disease (III vs. IV), geographic region (Japan vs. North America and rest of world \[ROW\]), and germline breast cancer susceptibility gene (BRCA) mutation status (positive versus negative or Unknown).

Cytoreductive surgery could be performed before randomization and the initiation of study treatment (primary) or after 3 cycles of study treatment (interval). The weekly or every-3-week paclitaxel schedule and the choice of primary or interval cytoreductive surgery were determined at the discretion of the investigator.

The primary objective was evaluated in the BRCA-deficient cohort, participants with homologous recombination deficiency (HRD), and the intention-to-treat (ITT) population. These populations were sequentially inclusive, with the HRD population including the BRCA-deficient population, and the ITT population including the HRD and BRCA-deficient populations. The BRCA-deficient population was defined as participants with either a germline (gBRCA) and/or tissue-based (tBRCA) deleterious or suspected deleterious mutation in BRCA1 or BRCA2 confirmed by centralized testing. The HRD population was defined as participants with HRD tumors based on HRD score or presence of a deleterious or suspected deleterious mutation in BRCA1 or BRCA2 as determined by centralized testing.

Arms: arm 1: Participants will receive placebo to veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles. arm 2: Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by placebo monotherapy continuous dosing for an additional thirty 21-day cycles. arm 3: Participants will receive 150 mg veliparib orally twice a day in combination with carboplatin/paclitaxel for six 21-day cycles followed by 300/400 mg veliparib monotherapy orally twice a day for an additional thirty 21-day cycles.
Interventions: intervention 1: Veliparib intervention 2: Paclitaxel intervention 3: Carboplatin intervention 4: Placebo to Veliparib
Intervention descriptions: intervention 1: Capsules for oral administration intervention 2: Administered by intravenous infusion, either 80 mg/m² of body-surface area (BSA) on Days 1, 8, and 15 of each 21-day cycle (weekly dosing), or 175 mg/m² of BSA on Day 1 of each 21-day cycle (3-week dosing). intervention 3: Administered by intravenous infusion at an area under the curve (AUC) of 6 mg/mL/min every 3 weeks. intervention 4: Capsules for oral administration

Protocol documents:
Prot_002.pdf: 
Veliparib (ABT-888)
M13-694 Protocol Amendment 8
EudraCT 2014-005070-11
1
1.0
Title Page
Clinical Study Protocol M13-694
A Phase 3 Placebo-Controlled Study of 
Carboplatin/Paclitaxel With or Without Concurrent 
and Continuation Maintenance Veliparib (PARP 
inhibitor) in Subjects with Previously Untreated 
Stages III or IV High-Grade Serous Epithelial 
Ovarian, Fallopian Tube, or Primary Peritoneal 
Cancer
Incorporating Administrative Changes 1, 2, and 3 
(Japan Only) and Amendments 1, 2, 3, 4, 5, 6, 7, 
and 8
AbbVie 
Investigational
  Product:
Veliparib (ABT-888)
Date:
08 March 2021
Development Phase:
3
Study Design:
This is a Phase 3, placebo-controlled, randomized study of veliparib in 
combination with carboplatin and paclitaxel and as continuation maintenance 
therapy in subjects with untreated Stage III or IV high-grade serous epithelial 
ovarian, fallopian tube, or primary peritoneal cancer.
EudraCT Number:
2014-005070-11
Investigator:
Multicenter Study:  Site Investigator information is on file at AbbVie Inc. 
(AbbVie)
Sponsor:
AbbVie Inc. (AbbVie)*
Collaborative 
Partners:
This protocol was designed and developed in collaboration with the 
Gynecologic Oncology Group (GOG) Foundation.  The study is also being 
conducted in collaboration with the Australia New Zealand Gynecologic 
Oncology Group (ANZGOG).  
 
NCT02470585


Veliparib (ABT-888)
M13-694 Protocol Amendment 8
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GOG Study Number:
PROTOCOL GOG-3005
Sponsor/Emergency 
  Contact:
 MD, PhD., FACP
AbbVie TA MD
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Mobile:
Email:
M13-694-MedMonitors@abbvie.com
 PhD
AbbVie TA SD
1 North Waukegan Road
North Chicago, IL  60064
Phone:
Mobile:
Email:
Medical Monitor:
 MD
US Oncology Research
The Woodlands, TX
Mobile:
Email:
M13-694-MedMonitors@abbvie.com
*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 (ABT-888)
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
18 December 2014
Amendment 1
26 May 2016
Administrative Change 1
30 June 2016
Administrative Change 2
13 September 2016
Amendment 2
21 September 2016
Amendment 3
14 November 2016
Amendment 4
24 March 2017
Administrative Change 3 (Japan Only)
17 May 2018
Amendment 5
10 December 2018
Amendment 6
24 April 2019
Amendment 7
01 May 2020
The purpose of this amendment is to:
●
Add benefits and risks evaluation information and updated study procedures in 
the context of the ongoing COVID-19 pandemic (Section 3.2, Section 9.2, and 
Section 9.3).
Rationale:  To confirm that the current pandemic situation does not change 
the benefit risk of study participation as COVID-19 related risks are not 
expected to differ substantially between trial participants and the broader 
population of subjects being treated for Ovarian, Fallopian or Peritoneal
cancer, as well as allow for procedure modification in response to the 
COVID-19 pandemic(including local labs, Adverse Event reporting and 
consent procedures).
●
Remove select study procedures for patients in survival and long-term follow-
up (Table 2, Section 5.1, and Section 5.3.1.1)
Rationale:  Primary analysis has already been completed.  Removal of select 
procedures allows for reduced burden on subjects and sites.
 


Veliparib (ABT-888)
M13-694 Protocol Amendment 8
EudraCT 2014-005070-11
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●
Remove the requirement to send scans performed after the primary analysis 
cut-off date to the central imaging vendor (Table 2 and Section 5.3.1.1)
Rationale:  Concordance between central imaging vendor and site was shown 
to be high at the primary analysis, which has already been completed.  
Removal of this requirement allows for reduced burden on sites.
●
Indicate that unblinding requests can be confirmed by either the TA MD or TA 
SD
Rationale:  To reflect staffing changes on the trial
●
Update study contact information (Section 1.0, Section 6.6.3 and Section 7.0)
Rationale:  To reflect changes in staffing and contact information
●
Added language indicating that the stated months at which endpoints will 
mature are estimates (Section 8.2.1)
Rationale:  For clarity 
●
Added language indicating that the final OS analyses will occur when required 
OS events have accrued in all populations (Section 8.3)
Rationale:  For clarity
 


Veliparib (ABT-888)
M13-694 Protocol Amendment 8
EudraCT 2014-005070-11
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M13-694
Name of Study Drug:  Veliparib (ABT-888)
Phase of Development:  3
Name of Active Ingredient:  Veliparib
Date of Protocol Synopsis:  08 March 2021
Protocol Title:  A Phase 3 Placebo-Controlled Study of Carboplatin/Paclitaxel With or Without 
Concurrent and Continuation Maintenance Veliparib (PARP inhibitor) in Subjects with Previously 
Untreated Stages III or IV High-Grade Serous Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal 
Cancer
Objectives:
The primary objective of the study is to evaluate whether progression-free survival (PFS) is prolonged 
when veliparib is added to carboplatin/paclitaxel and then continued as maintenance.  Progression-free 
survival as the primary study endpoint will be evaluated in three populations:  the BRCA-deficient 
(gBRCA and/or tBRCA), homologous recombination deficient (HRD), and whole population, as multiple 
primary endpoints.  Secondary objectives include PFS with veliparib in combination with chemotherapy 
versus chemotherapy alone, overall survival (OS), safety of all three arms, and disease related symptom 
(DRS) scores in the BRCA-deficient, HRD, and whole population.
Investigator:  Multicenter
Study Sites:  Approximately 300 sites
Study Population:  Female subjects with previously untreated Stage III or IV high grade serous 
epithelial ovarian, fallopian tube, or primary peritoneal cancer.
Number of Subjects to be Enrolled:  Approximately 1100
Methodology:
This is a Phase 3, randomized, placebo-controlled study to evaluate the efficacy and tolerability of 
veliparib in combination with carboplatin and paclitaxel and as continuation maintenance therapy in the 
above stated study population.  The study will consist of five phases:  the Pre-Therapy Phase 
(Screening), a Combination Therapy Phase, a Maintenance Therapy Phase, a Long-Term Follow-Up 
Phase, and a Survival Phase.
Pre-therapy (screening) procedures will be performed within 28 days prior to randomization and Cycle 1 
Day 1.  A computerized tomography (CT) of the abdomen and pelvis (and chest if metastases are 
present) will be used by Investigators to evaluate disease status per RECIST 1.1.  In addition to being 
reviewed by the Investigator and/or qualified site staff, radiographic scans will be sent to a central 
imaging center.  During the Pre-Therapy Phase, Investigators will be allowed the choice of either 
carboplatin AUC 6 in combination with weekly paclitaxel (Q-week) or carboplatin AUC 6 in 
combination with every 3 weeks paclitaxel (Q3-weeks).  Either of these chemotherapy regimens will be 
administered with either primary or interval cytoreductive surgery.  The Investigator's treatment decision 
will be documented prior to proceeding to randomization.
 


Veliparib (ABT-888)
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Methodology (Continued):
Once pre-therapy procedures are complete and eligibility is confirmed, subjects will be randomized 1:1:1 
to one of the following three arms.  Subjects will be stratified by stage of disease (Stage III versus IV), 
residual disease and choice of regimen, region of the world (Japan versus North America or Rest of 
World), and gBRCA mutation status (gBRCA positive versus gBRCA negative or Unknown).
Arm 1: Carboplatin/paclitaxel plus placebo for six 21-day cycles followed by placebo maintenance 
therapy for 30 additional 21-day cycles;
Arm 2: Carboplatin/paclitaxel plus veliparib for six 21-day cycles followed by placebo maintenance 
therapy for 30 additional 21-day cycles;
Arm 3: Carboplatin/paclitaxel plus veliparib for six 21-day cycles followed by veliparib maintenance 
therapy for 30 additional 21-day cycles.
During the Combination Therapy Phase, subjects will receive veliparib/placebo orally (PO) twice daily 
(BID) in combination with intravenous (IV) carboplatin/paclitaxel for six cycles (Cycle 1 through 
Cycle 6).
Subjects who complete the Combination Therapy Phase and who have not progressed will receive 
single-agent veliparib/placebo for an additional 30 cycles (Cycles 7 – 36) starting at 300 mg BID.  If the 
subject tolerates 300 mg BID for 2 weeks, veliparib/placebo should be increased to 400 mg BID during 
the Maintenance Phase.  Prior to increasing the dose of veliparib/placebo, at a minimum, vital signs and 
adverse event(s) must be assessed if escalation occurs outside of a routine study visit.  A Therapy 
Completion Visit will be performed for all subjects upon completion of the Maintenance Phase, when 
therapy is discontinued, or if the subject is discontinued prior to therapy completion.  All subjects will 
have one Follow-Up Visit approximately 30 days after the Therapy Completion Visit.  After the Therapy 
Completion Visit, subjects will enter the Long-Term Follow-Up Phase.
Long Term Follow-Up assessments are conducted as follows:
Subjects who have not progressed but have discontinued or completed study therapy will remain on 
study.  Subject status will be monitored via the collection of assessments as described in Section 5.3.1.1 
and Table 2 of the protocol.  Post-therapy information will be assessed every 3 months and new onset 
malignancy will be assessed every 6 months (or as requested by the sponsor).
Post baseline tumor assessments for all subjects randomized who have not progressed will be collected 
every 9 weeks, then at the end of the Combination Phase, then every 12 weeks for 2 years, then every 
6 months for up to 3 years, then annually until disease progression per RECIST 1.1.
Once a subject meets an event of progression, survival and post therapy information will be collected at 
3 month intervals and new-onset malignancy will be collected at 6 month intervals (or as requested by 
the sponsor) until the endpoint of death, the subject is lost to follow-up or until study termination by 
AbbVie.
Post baseline PRO assessments for all subjects will be collected according to the schedule of procedures 
for up to 2 years from C1D1 or until disease progression per RECIST 1.1, whichever is later.  Following 
the primary analysis and implementation of Protocol Amendment 8, PRO collection will no longer be 
required.
Subjects will be followed for up to 10 years for collection of new onset malignancy.
Pharmacogenetic and Pharmacodynamic samples will be collected for biomarker research and 
exploratory research at designated time points throughout the study.
A detailed description of the study visits and procedures are provided in the protocol.
 


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Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:
1.
Subjects with a histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal 
carcinoma, International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV with 
appropriate tissue available for histologic evaluation.
2.
Subjects will be required to have high-grade serous adenocarcinoma to be eligible.
3. Subject is willing to undergo testing for gBRCA.
4.
Subject must have adequate hematologic, renal, and hepatic function as follows:

Hemoglobin ≥ 9.5 g/dL (5.89 mmol/L);

Absolute neutrophil count greater than or equal to 1,500/µL;

Platelet count greater than or equal to 100,000/µL;

Serum creatinine ≤ 1.0 × ULN range; subjects with a serum creatinine > 1.0 × ULN range must 
have a creatinine clearance ≥ 60 mL/min (according to the Cockcroft-Gault equation);

Total bilirubin ≤ 1.5× ULN.  Subjects with Gilbert's Syndrome may have a bilirubin ≥ 1.5 × the 
ULN range if no evidence of biliary obstruction exists;

Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase 
must be less than or equal to 2.5 × ULN;

Albumin ≥ 3.0 g/dL.
5.
Subjects with neuropathy (sensory and motor) less than or equal to Grade 1.
6.
Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 
or 2.
7.
Subject is able to swallow and retain oral medication and does not have uncontrolled emesis.
8.
Subjects who undergo primary cytoreductive surgery must be randomized between 1 and 12 weeks 
after surgery.  Subjects undergoing interval surgery must have a tumor sample confirming the 
histological diagnosis prior to enrollment.
9.
Subjects with measurable disease or non-measurable disease are eligible.  Subjects may or may not 
have cancer-related symptoms.
10. Subject has one of the following available for PD analyses including tissue-based BRCA testing:

Archived diagnostic formalin-fixed paraffin embedded (FFPE) tumor tissue; or tumor tissue 
biopsy collected prior to Cycle 1 Day 1.
 


Veliparib (ABT-888)
M13-694 Protocol Amendment 8
EudraCT 2014-005070-11
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion:
1.
Subjects with the following histologic cell types are ineligible:  endometrioid adenocarcinoma, 
carcinosarcoma, undifferentiated carcinoma, mixed epithelial adenocarcinoma, adenocarcinoma not 
otherwise specified, mucinous adenocarcinoma, clear cell adenocarcinoma, low-grade serous 
adenocarcinoma, or malignant Brenner's tumor.
2.
Subjects with synchronous primary endometrial cancer, or a past history of endometrial cancer 
unless all of the following conditions are met:  endometrial cancer stage not greater than IA, no 
vascular or lymphatic invasion, no poorly differentiated subtypes including serous, clear cell, or 
other FIGO grade 3 lesions.
3.
Subjects with any evidence of other invasive malignancy being present within the last 3 years (with 
the exception of non-melanoma skin cancer).  Subjects are also excluded if their previous cancer 
treatment contraindicates this protocol's therapy.

Subjects may not receive any non-protocol specified anti-cancer therapy during the study, 
including maintenance therapy or hormonal therapy for breast cancer.  Subjects receiving 
hormonal therapy (such as tamoxifen or aromatase inhibitors) will require a 7 day (1 week) 
washout prior to randomization.
4.
Subjects who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are 
excluded.
5.
Subjects who have received prior chemotherapy for any abdominal or pelvic tumor are excluded.
6.
Subject has a clinically significant uncontrolled condition(s), including but not limited to:

Uncontrolled seizure disorder, or focal or generalized seizure within the last 12 months;

Active infection that requires parenteral antibiotics;

Known active hepatitis B or hepatitis C with abnormal liver function test or organ dysfunction;

Symptomatic congestive heart failure; unstable angina pectoris; serious ventricular cardiac 
arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation) or serious cardiac arrhythmia 
requiring medication (this does not include asymptomatic atrial fibrillation with controlled 
ventricular rate); or myocardial infarction within the last 6 months;

Uncontrolled hypertension (sustained systolic blood pressure > 150 mmHg or diastolic pressure 
> 100 mmHg despite optimal medical management);

Bowel obstruction or gastric outlet obstruction.  Note:  Subjects requiring drainage gastrostomy 
tube and/or parental hydration and/or nutrition are not eligible;

Psychiatric illness/social situations that would limit compliance with study requirements;

Any medical condition which in the opinion of the Investigator places the subject at an 
unacceptably high risk for toxicities.
7.
Known history of allergic reaction to Cremophor-paclitaxel, carboplatin, Azo-Colourant Tartrazine 
(also known as FD&C Yellow 5 or E102), Azo-Colourant Orange Yellow-S (also known as FD&C 
Yellow 6 or E110) or known contraindications to any study supplied drug.
8.
Subjects with history or evidence upon physical examination of central nervous system (CNS) 
disease, including primary brain tumor, any brain metastases, or history of cerebrovascular accident 
(CVA, stroke), transient ischemic attack (TIA) within 6 months of Cycle 1 Day 1.
9.
Subjects under the age of 18.
 


Veliparib (ABT-888)
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EudraCT 2014-005070-11
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Investigational Product:
Veliparib (ABT-888) 50 mg or 100 mg
Doses:
Veliparib 150 mg BID with carboplatin/paclitaxel for six 21-day cycles
Starting dose of 300 mg BID Days 1 through 21 of 21-day cycle as 
maintenance therapy, if tolerated, escalate to 400 mg BID (Cycle 7 
through Cycle 36)
Mode of Administration:
Oral
Reference Therapy:
Placebo (matching 50 mg or 100 mg)
Doses:
Placebo BID with carboplatin/paclitaxel for six 21-day cycles
Placebo BID maintenance therapy for up to 30 additional 21-day cycles
Mode of Administration:
Oral
Duration of Treatment:  Subjects will receive veliparib/placebo PO BID in combination with 
carboplatin/paclitaxel for six 21-day cycles of therapy.  Subjects who have not progressed per 
RECIST 1.1 will then receive maintenance therapy with veliparib/placebo PO BID for a maximum of an 
additional thirty 21-day cycles.
Criteria for Evaluation:
Efficacy:
The primary objective of the study is to evaluate whether PFS is prolonged when veliparib is added to 
carboplatin/paclitaxel and then continued as maintenance (Arm 3 versus Arm 1).  PFS as the primary 
study endpoint will be evaluated in three populations: the BRCA-deficient (gBRCA and/or tBRCA), 
HRD, and whole population, as multiple primary objectives.
Secondary objectives include PFS with veliparib in combination with chemotherapy versus 
chemotherapy alone (no maintenance; Arm 2 versus 1), OS (Arm 3 versus Arm 1 and Arm 2 versus 
Arm 1), safety of all three arms, and DRS scores (Arm 3 versus Arm 1 and Arm 2 versus Arm 1) in the 
BRCA-deficient, HRD, and whole populations.
Pharmacokinetic:
Sparse pharmacokinetic (PK) samples will be collected for the estimate of population PK parameters of 
veliparib such as apparent oral clearance (CL/F) and volume of distribution (V/F).
Pharmacodynamic:
All subjects must have a pre-therapy tumor biopsy (archived or fresh biopsy) for inclusion in the study.  
Genetic analysis to determine BRCA mutation status will be conducted using tissue and blood specimens 
to support efficacy endpoints.
Biospecimens will be collected at designated time points throughout the study to conduct research with 
the intent of identifying biomarkers associated with subject outcome or to better characterize the disease.
Safety:
AbbVie will assess adverse events, laboratory data, ECGs and vital signs throughout the study.  Adverse 
events intensity and laboratory evaluation changes will be assessed by utilizing National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
 


Veliparib (ABT-888)
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Statistical Methods:
Efficacy:
Primary Efficacy Endpoint
The primary efficacy endpoint is progression-free survival (PFS).  PFS will be defined as the number of 
days from the date that the subject was randomized to the date the subject experiences an event of 
disease progression, according to RECIST criteria version 1.1 (as determined by the Investigator) or to 
the date of death (all causes of mortality) if disease progression is not reached.  All events of disease 
progression will be included, regardless of whether the event occurred while the subject was still taking 
study drug or had previously discontinued study drug.  However, if a disease progression event occurs 
after a subject misses two or more consecutive disease progression assessments this subject will be 
censored at the last disease progression assessment prior to the missing disease progression assessments.  
All events of death will be included for subjects who had not experienced disease progression provided 
the death occurred within a time window defined according to the underlying disease assessment 
interval.  If the subject does not have an event of disease progression nor has the subject died, the 
subject's data will be censored at the date of the subject's last disease assessment.
The primary efficacy analyses are defined by comparing PFS in Arm 3 versus Arm 1 in the BRCA-
deficient, HRD, and whole population.  
Secondary Efficacy Endpoints
Overall Survival
Overall survival (OS) will be defined as the number of days from the day the subject is randomized to 
the date of the subject's death.  All events of death will be included, regardless of whether the event 
occurs while the subject is still taking study drug, or after the subject discontinues study drug.  If a 
subject has not died, then the data will be censored at the date when the subject is last known to be alive. 
The secondary efficacy analyses for OS are defined by comparing OS in Arm 3 versus Arm 1 and Arm 2 
versus Arm 1, in the BRCA-deficient, HRD, and whole population. 
PFS will also be compared between Arm 2 and Arm 1 as a secondary analysis.
Disease Related Symptoms
The overall mean change from baseline for the DRS scores measured at each assessment point up to 
2 years or disease progression will be a secondary endpoint of the study.  The overall mean change from 
baseline for the total DRS scores between the treatment groups will be compared using a longitudinal 
repeated measures model that takes into account the DRS scores measured at each assessment point up 
to 2 years.  This analysis will include all available data, from baseline out to 2 years or disease 
progression.
 


Veliparib (ABT-888)
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EudraCT 2014-005070-11
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Statistical Methods (Continued)
Efficacy (Continued):
Interim Analyses
For the OS hypotheses (Arm 3 versus Arm 1, or Arm 2 versus Arm 1) in the BRCA-deficient population, 
the HRD population, and the whole population, at least one efficacy interim analyses will be performed.  
The first interim analysis will occur at the time of the final PFS analysis. The alpha of the final OS 
analyses will depend on prior interim analyses as described in the statistical analysis plan (SAP).  
Additional details regarding the secondary analyses, including any interim efficacy analyses (e.g., at the 
request of a regulatory agency), will be specified in the SAP.
Sample Size Calculation
The trial will enroll approximately 1100 subjects (with 1:1:1 randomization ratio for 
Arm 1:Arm 2:Arm 3) in the whole population, including approximately 264 subjects with 
BRCA-deficient status (assuming 24% of the subjects in the whole population are BRCA deficient) to 
power the hypotheses specified in the whole and BRCA-deficient populations.  Detailed sample size 
calculation information for each endpoint of the BRCA-deficient, HRD, and whole populations is 
provided in Section 8.2.
Multiplicity Control
Multiple testing strategies and multiplicity control are detailed in Section 8.1.4.
 


Veliparib (ABT-888)
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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATEMS
AbbVie Temperature Excursion Management System
AUC
area under the plasma concentration-time curve
BCS
Biopharmaceutics Classification System
BID
twice daily
BMI
body mass index
BRCA1/2
breast cancer genes 1 and 2
BRCA-deficient
germline or tissue-based mutation in BRCA1 or BRCA2
BSA
Body Surface Area
C1D1
Cycle 1 Day 1
C3D1
Cycle 3 Day 1
C5D1
Cycle 5 Day 1
CL/F
oral clearance
Cmax
maximum observed plasma concentration
CNS
central nervous system
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CVA
cerebrovascular accident
CYP
cytochrome P450
DLT
dose-limiting toxicity
DNA
Deoxyribonucleic acid
DRS
disease-related symptoms
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EQ-5D-5L
EuroQOL five dimensions, five levels
ESMO
European Society for Medical Oncology
 


Veliparib (ABT-888)
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FACT
Functional Assessment of Cancer Therapy
FDA
US Food and Drug Administration
FFPE
formalin-fixed paraffin embedded
FIGO
International Federation of Gynecology and Obstetrics
gBRCA
germline BRCA1 or BRCA2 mutation
G-CSF
granulocyte colony-stimulating factor
GM-CSF
granulocyte macrophage colony-stimulating factor
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GOG
Gynecologic Oncology Group Foundation
GPRD
Global Pharmaceutical Research & Development
HDPE
high-density polyethylene
HR
hazard ratio
HRD
Homologous Recombination Deficiency
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
INR
international normalized ratio
IP
intraperitoneal
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intent-to-treat
IUD
intra-uterine device
IV
intravenous or intravenously
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NFOSI-18
NCCN FACT Ovarian Symptom Index-18
NSCLC
non-small cell lung cancer
OS
Overall Survival
PARP
poly-(ADP-ribose)-polymerase
PARPi
PARP inhibitor
 


Veliparib (ABT-888)
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PFS
progression-free survival
PLT
platelet
PO
by mouth
POR
Proof of Receipt
PR
partial response
PRO
patient-reported outcome
PT
prothrombin time
PTT
partial thromboplastin time
RECIST
Response Evaluation Criteria In Solid Tumors
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA MD
Therapeutic Area Medical Director
TA SD
Therapeutic Area Scientific Director
tBRCA
tissue-based BRCA1 or BRCA2 mutation
TCGA
The Cancer Genome Atlas
TIA
transient ischemic attack
Tmax
time to maximum observed plasma concentration
TTFST
time to the first subsequent therapy
TTSST
time to the second subsequent therapy
ULN
upper limit of normal
VAS
visual analog scale
V/F
volume of distribution
WBC
white blood cell
 


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................5
1.3
List of Abbreviations and Definition of Terms........................................12
2.0
Table of Contents...................................................................15
3.0
Introduction ...........................................................................21
3.1
Differences Statement..............................................................................28
3.2
Benefits and Risks....................................................................................28
4.0
Study Objective......................................................................31
5.0
Investigational Plan...............................................................31
5.1
Overall Study Design and Plan:  Description ..........................................31
5.2
Selection of Study Population..................................................................39
5.2.1
Inclusion Criteria .....................................................................................39
5.2.2
Exclusion Criteria ....................................................................................41
5.2.3
Prior and Concomitant Therapy...............................................................43
5.2.3.1
Prior Therapy ...........................................................................................44
5.2.3.2
Concomitant Therapy...............................................................................44
5.3
Efficacy Pharmacokinetic, Pharmacodynamic Pharmacogenetic 
and Safety Assessments/Variables...........................................................46
5.3.1
Efficacy Pharmacokinetic, Pharmacodynamic Pharmacogenetic 
and Safety Measurements Assessed and Flow Chart...............................46
5.3.1.1
Study Procedures .....................................................................................55
5.3.1.2
Collection and Handling of Biomarker and Optional Exploratory 
Research Samples ....................................................................................66
5.3.2
Drug Concentration Measurements .........................................................70
5.3.2.1
Collection of Samples for Analysis .........................................................70
5.3.2.2
Measurement Methods.............................................................................71
5.3.3
Efficacy Variables....................................................................................71
5.3.3.1
RECIST 1.1 for Disease Status................................................................71
5.3.4
Safety Variables.......................................................................................79
5.3.5
Pharmacokinetic Variables ......................................................................80
 


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5.3.6
Biomarker and Optional Exploratory Research Variables.......................80
5.3.7
Pharmacogenetic Variables......................................................................81
5.4
Removal of Subjects from Therapy or Assessment.................................82
5.4.1
Discontinuation of Individual Subjects....................................................82
5.4.2
Discontinuation of Carboplatin/Paclitaxel and Veliparib/Placebo ..........83
5.4.3
Discontinuation of Entire Study...............................................................83
5.5
Treatments................................................................................................84
5.5.1
Treatments Administered.........................................................................84
5.5.1.1
Administration of Veliparib/Placebo .......................................................85
5.5.1.2
Administration of Carboplatin/Paclitaxel ................................................85
5.5.1.2.1
Paclitaxel..................................................................................................86
5.5.1.2.2
Carboplatin...............................................................................................87
5.5.2
Identity of Investigational Products.........................................................87
5.5.2.1
Standard of Care Medicinal Products ......................................................87
5.5.2.2
Packaging and Labeling...........................................................................88
5.5.2.3
Storage and Disposition of Study Drugs..................................................88
5.5.3
Method of Assigning Subjects to Treatment Groups...............................90
5.5.4
Selection and Timing of Dose for Each Subject......................................90
5.5.5
Blinding....................................................................................................91
5.5.5.1
Blinding of Investigational Product.........................................................92
5.5.5.2
Blinding of Data for Independent Data Monitoring Committee 
(IDMC) ....................................................................................................92
5.5.5.2.1
Requested Unblinding Following Progression for Subsequent 
Treatment .................................................................................................92
5.5.6
Treatment Compliance.............................................................................93
5.5.7
Drug Accountability.................................................................................94
5.6
Discussion and Justification of Study Design..........................................95
5.6.1
Discussion of Study Design and Choice of Control Groups....................95
5.6.2
Appropriateness of Measurements...........................................................96
5.6.3
Suitability of Subject Population .............................................................97
5.6.4
Selection of Doses in the Study ...............................................................97
5.7
Dose Reductions or Delays......................................................................98
 


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5.7.1
Dose Reductions or Delays for Carboplatin and Paclitaxel with 
Placebo/Veliparib (Cycles 1 – 6) .............................................................99
5.7.1.1
Guidelines for Hematologic Toxicity During Combination Phase..........99
5.7.1.2
Guidelines for Non-Hematologic Toxicity ............................................105
5.7.2
Veliparib/Placebo Monotherapy Dose Reductions and Delays 
(Cycles 7 – 36).......................................................................................109
6.0
Adverse Events.....................................................................112
6.1
Definitions..............................................................................................112
6.1.1
Adverse Event........................................................................................112
6.1.2
Serious Adverse Events .........................................................................113
6.2
Adverse Events Expected Due to Ovarian, Fallopian Tube, or 
Primary Peritoneal Cancer or Progression of Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer.......................................................115
6.3
Adverse Event Severity..........................................................................115
6.4
Relationship to Study Drug....................................................................116
6.5
Adverse Event Collection Period...........................................................116
6.6
Adverse Event Reporting.......................................................................117
6.6.1
Deaths ....................................................................................................117
6.6.2
Lack of Efficacy or Worsening of Disease ............................................118
6.6.3
Reporting Serious Adverse Events ........................................................118
6.7
Pregnancy...............................................................................................120
6.8
Toxicity Management ............................................................................121
7.0
Protocol Deviations..............................................................121
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................122
8.1
Statistical and Analytical Plans..............................................................123
8.1.1
Baseline Characteristics.........................................................................123
8.1.1.1
Demographics ........................................................................................123
8.1.1.2
Medical History .....................................................................................123
8.1.2
Efficacy Endpoints.................................................................................123
8.1.2.1
Primary Efficacy Endpoint ....................................................................123
8.1.2.2
Secondary Efficacy Endpoints...............................................................125
8.1.2.2.1
Progression Free Survival (PFS)............................................................125
 


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8.1.2.2.2
Overall Survival (OS) ............................................................................125
8.1.2.2.3
Patient Reported Outcomes....................................................................125
8.1.2.3
Tertiary Efficacy Endpoints...................................................................126
8.1.2.3.1
PFS2, TTFST, and TTSST.....................................................................126
8.1.2.3.2
Additional PRO Endpoints ....................................................................126
8.1.3
Interim Efficacy Analyses for OS..........................................................127
8.1.4
Multiplicity Adjustment.........................................................................127
8.1.5
Safety .....................................................................................................129
8.1.5.1
Duration of Study Drug .........................................................................129
8.1.5.2
Adverse Events ......................................................................................129
8.1.5.3
Serious Adverse Events .........................................................................130
8.1.5.4
Deaths ....................................................................................................130
8.1.5.5
Analyses of Laboratory and Vital Signs Data........................................130
8.1.5.6
Analyses of Laboratory Data Using NCI CTCAE.................................131
8.1.6
Pharmacokinetic Analysis......................................................................131
8.2
Determination of Sample Size ...............................................................132
8.2.1
Total Sample Size ..................................................................................132
8.2.2
For the Hypotheses in the Whole Population.........................................132
8.2.3
For the Hypotheses in the BRCA-Deficient Population.........................135
8.2.4
For the Hypotheses in the HRD Population...........................................137
8.3
Timing for Analyses and Unblinding of the Study................................143
8.4
Randomization Methods ........................................................................143
9.0
Ethics.....................................................................................145
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................145
9.2
Ethical Conduct of the Study.................................................................146
9.3
Subject Information and Consent...........................................................146
9.3.1
Informed Consent Form and Explanatory Material ...............................147
9.3.2
Revision of the Consent Form and Explanatory Material .....................148
10.0
Source Documents and Case Report Form 
Completion ...........................................................................148
10.1
Source Documents .................................................................................148
10.2
Case Report Forms.................................................................................148
 


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11.0
Data Quality Assurance ......................................................149
12.0
Use of Information...............................................................150
12.1
Publication .............................................................................................150
13.0
Completion of the Study .....................................................150
14.0
Investigator's Agreement....................................................152
15.0
Reference List ......................................................................153
List of Tables
Table 1.
Study Procedures for Pre-Therapy, Combination and Maintenance 
Phases.......................................................................................................47
Table 2.
Study Procedures for Long Term Follow-Up and Survival Phase...........51
Table 3.
Schedule of Pharmacogenetic and Pharmacodynamic Procedures..........53
Table 4.
Schedule of Pharmacokinetic Sampling ..................................................54
Table 5.
Clinical Laboratory Tests.........................................................................60
Table 6.
Calculating Final Response for Subjects with No Radiographic or 
Clinical Evidence of Disease (ND) on the Post-Surgical Baseline 
Tumor Assessment...................................................................................78
Table 7.
Identity of Investigational Product...........................................................87
Table 8.
Standard of Care Medicinal Products ......................................................88
Table 9.
Study Drug Storage Conditions ...............................................................89
Table 10.
Dose Limiting Hematological Toxicities.................................................98
Table 11.
Q3-Week Schedule Dose Modifications for Dose Limiting 
Hematologic Toxicity, Reduced ANC (1000 – 1499/mm3) or 
Reduced Platelets (75,000 – 99,000/mm3) on Day 1, or Cycle 
Delay > 7 Days due to Hematologic Toxicity .......................................102
Table 12.
Q-Week Schedule Dose Modifications for Dose-Limiting 
Hematologic Toxicity, Reduced ANC (1000 – 1499/mm3) or 
Reduced Platelets (75,000 – 99,000/mm3) on Day 1, or Cycle 
Delay > 7 Days due to Hematologic Toxicity .......................................102
Table 13.
Q-Week Dosing Schedule Modifications for Hematologic 
Toxicity on Day 8 or 15 .........................................................................103
Table 14.
Dose Levels for Modifications for Non-Hematologic Toxicity.............106
Table 15.
Veliparib/Placebo Monotherapy Dose Levels .......................................111
 


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Table 16.
Study Treatment Arms...........................................................................127
Table 17.
The Null Hypotheses of Interest in Each Population.............................128
Table 18.
Power and Sample Size Calculation for Testing Scenario 1..................141
Table 19.
Power and Sample Size Calculation for Testing Scenario 2..................142
List of Figures
Figure 1.
Study Design............................................................................................32
Figure 2.
Overall Study Design...............................................................................34
Figure 3.
Adverse Event Collection ......................................................................117
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................158
Appendix B.
List of Protocol Signatories....................................................................160
Appendix C.
Ovarian Surgical Procedure ...................................................................161
Appendix D.
General Chemotherapy Guidelines ........................................................163
Appendix E.
Carboplatin Dose Calculation Instructions ............................................164
Appendix F.
FIGO Stage Grouping for Primary Carcinoma of the Ovary.................167
Appendix G.
Guidance for Identifying High Grade Serous Carcinoma......................169
Appendix H.
Adverse Events Expected Due to Ovarian, Fallopian Tube, or 
Primary Peritoneal Cancer or Progression of Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer.......................................................170
 


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3.0
Introduction
This Phase 3 study is designed to test whether the integration of concurrent and 
continuation maintenance veliparib (ABT-888), a poly-(ADP-ribose)-polymerase (PARP) 
inhibitor, with carboplatin/paclitaxel chemotherapy for high grade serous epithelial, 
ovarian, fallopian tube, or primary peritoneal cancer will improve clinical outcomes.
In this context, it is important to recognize that the potential mechanisms of PARP 
inhibition differ when directly integrated with platinum-based chemotherapy (enhanced 
cytotoxicity or therapeutic synergy) compared to use as a single agent after completion of 
chemotherapy (synthetic lethality in tumors with defective homologous deoxyribonucleic 
acid [DNA] repair).  This Phase 3 study incorporates both of these approaches in the 
experimental arms.
While significant strides have been made to tailor the primary treatment of ovarian cancer 
to improve efficacy and tolerability, the mortality of advanced-stage ovarian cancer has 
not changed, and additional improvements are needed.  The discovery and development of 
new molecular targeted agents may lead to more effective combination regimens and 
improved outcomes for patients.  Currently, the standard of care for the primary treatment 
of ovarian, fallopian tube, or primary peritoneal cancer is a combination of platinum and 
taxane chemotherapy.1,2  For patients with early-stage disease, as well as advanced 
suboptimal Stage III and Stage IV disease, intravenous (IV) carboplatin and paclitaxel is 
given on an every-3-week (Q3-weeks) cycle for 6 cycles.  Weekly administration of 
paclitaxel has shown a survival benefit compared to every-3-weeks paclitaxel 
administration for patients with Stage II – IV disease.3  For Stage II/III patients with 
small-volume (optimal) residual disease after primary cytoreductive surgery, a regimen 
combining intraperitoneal (IP) cisplatin and paclitaxel with IV paclitaxel is often used.2  
Despite the majority of patients entering a clinical complete remission following initial 
cytoreductive surgery and chemotherapy, most recur and eventually develop treatment 
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The clinical development of PARP inhibitors offers promising activity in both breast 
cancer genes 1 and 2 (BRCA1/2) mutation carriers and sporadic ovarian cancer 
patients.4-11  The Cancer Genome Atlas (TCGA) project has identified that approximately 
50% high grade serous ovarian cancers exhibit defects in homologous recombination and 
DNA repair pathways and many of these defects could be susceptible to targeting with 
PARP inhibition.12  In addition, groups have looked at ways to identify homologous 
recombination-repair-deficient (HRD) tumors using primary cultures from ascites or 
genomic profiles of loss of heterozygosity to identify subgroups of ovarian cancer patients 
who may be more responsive to chemotherapy and PARP inhibitors.13,14  Homologous 
recombination deficiency assays have been evaluated in clinical trials of the PARP 
inhibitors rucaparib and niraparib.15-17  This Phase 3 study incorporates this new 
knowledge regarding the biological subtypes of ovarian, fallopian tube, and primary 
peritoneal cancer and concepts of synthetic lethality and therapeutic synergy to improve 
the outcomes for women with high-grade serous ovarian cancer.
PARP Inhibitors
PARP-1 and PARP-2 are nuclear enzymes that recognize DNA damage and facilitate 
DNA repair.18  Activation of PARP-1 and PARP-2 enzymes is an essential step in the 
recognition of DNA damage that results in the poly(ADP-ribosyl)ation of many nuclear 
target proteins, including those that facilitate DNA repair.  Preclinical and clinical data 
indicate that PARP inhibitors enhance and prolong the effects of DNA-damaging 
therapies such as carboplatin (enhanced cytotoxicity or therapeutic synergy) and that 
tumors with DNA-repair deficiencies are particularly sensitive to PARP inhibition, even 
in the absence of any other DNA-damaging insults (synthetic lethality).
Therapeutic Synergy:  Combination with Cytotoxic Chemotherapy
In a variety of preclinical tumor models, including melanoma, prostate, colon, glioma, and 
BRCA-mutated breast and pancreatic carcinoma, veliparib significantly enhanced the 
antitumor activity when dosed on a schedule that overlapped the administration of a 
DNA-damaging agent.  Significant inhibition of tumor PARP levels at doses similar to 
 


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those with antitumor effect was observed, which is consistent with veliparib potentiation 
of DNA-damaging agents being mediated through mechanistic inhibition of PARP.
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.19  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.20  In 
particular, tumor cells with BRCA1 or BRCA2 deficiencies are exquisitely sensitive to 
PARP inhibition, even in the absence of any other insults.21  Deficiencies in homologous 
recombination, caused by low expression of BRCA1 have also been observed in tumors 
not associated with germline BRCA deficiency (e.g., ovarian cancer, non-small cell lung 
cancer [NSCLC], and gastric cancer).22-24  These tumors would be expected to be sensitive 
to PARP inhibition.
Platinum agents such as carboplatin and cisplatin cause DNA damage through the 
formation of interstrand crosslinks.  These crosslinks initially cause single-strand DNA 
breaks that lead to the recruitment and activation of PARP1 and PARP2 to facilitate DNA 
repair.  Thus, PARP inhibitors can augment the DNA damage caused by carboplatin 
leading to greater tumor cell death, in both BRCA-proficient and BRCA-deficient 
tumors.18,25  This is further supported by the Phase 2 study in women with platinum 
sensitive recurrent serous ovarian cancer receiving either olaparib (200 mg BID) in 
combination with carboplatin (area under the plasma concentration-time curve [AUC] 4) 
and paclitaxel followed by olaparib monotherapy maintenance (400 mg BID) versus 
carboplatin (AUC 6) and paclitaxel with no further therapy in which the olaparib arm 
showed an improvement in PFS (HR = 0.51, 95% CI 0.34 – 0.77; P = 0.0012; median PFS 
12.2 versus 9.6 months).11
 


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Comparative data from a placebo-controlled, randomized, double-blind Phase 2 study in 
subjects with advanced NSCLC (Study M10-898) further support the concept of 
therapeutic synergy in a DNA-repair proficient population.  In this study, veliparib 
120 mg BID on Days 1 to 7 added to standard therapy (carboplatin AUC 6 and paclitaxel 
200 mg/m2 on Day 3 on 21-day cycles) improved the median PFS by approximately 
1.6 months (HR 0.737; P = 0.14) and improved median OS by approximately 2 months 
(HR 0.769; P = 0.229).26  Comparative safety data demonstrated a modest increase in 
neutropenia and leukopenia in the veliparib arm without other remarkable differences in 
treatment toxicity.  Leukopenia (all grades) was increased in frequency by < 15% for 
veliparib- versus placebo-treated subjects, and neutropenia (all grades) was increased in 
frequency by < 10% for veliparib- versus placebo-treated subjects.  No other adverse 
event was increased by > 5%.  Adverse events led to reduction or discontinuation of 
backbone therapies at similar rates (± 3%) with or without veliparib.  These data support 
the tolerability of the combination and are consistent with a toxicity profile similar in 
nature to that anticipated for the backbone regimen, with some increase in hematological 
toxicities and hematological toxicities being the most commonly observed dose limiting 
toxicity.
Approximately 375 subjects with advanced cancer have been treated with veliparib in 
combination with carboplatin and paclitaxel in Phase 1 and Phase 2 studies to date.  The 
most commonly observed toxicities in these studies (> 30% of subjects) have included 
anemia (49.2%), nausea (42.9%), fatigue (40.9%), decreased neutrophil count/neutropenia 
(40.9% and 20.1%, respectively), decreased white blood cell count (35.8%), alopecia 
(32.7%), and decreased platelet count (30.3%).  Less frequent, but potentially serious 
events included fever (6.3%), embolism (4.3%), allergic reaction (drug hypersensitivity 
3.5%; hypersensitivity 3.1%), and febrile neutropenia (2.8%).
To best elucidate the dose in the intended Phase 3 study population, the GOG has 
conducted an ongoing Phase 1 dose-escalation study to evaluate the safety and maximum 
tolerated dose (MTD) of the combination of carboplatin (AUC 6, Q3-weeks), paclitaxel 
(175 mg/m2 Q3-weeks or 80 mg/m2 weekly [Q-week]), and bevacizumab (15 mg/kg, 
 


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Q3 weeks; initiated in Cycle 2 followed by bevacizumab maintenance) with escalating 
doses of either intermittent or continuous veliparib (Study GOG 9923; N = 300).  The 
most common toxicities in all subjects to date (veliparib 30 – 400 mg BID) have been 
those commonly observed with the backbone therapy and include myelosuppression 
(anemia, decreased white blood cell count, neutrophil count, and platelet count (96.3% 
each); fatigue (81.5%); alopecia (77.8%); nausea (59.3%); constipation and diarrhea 
(55.6% each); peripheral sensory neuropathy (51.9%); hypertension (40.7%); headache 
(37.0%), and dyspnea and epistaxis (33.3% each).  As expected for carboplatin and 
paclitaxel, myelosuppression has also been the most commonly observed Grade 3 and 4 
toxicities.
With consideration that subjects in the Phase 3 Study M13-694 will have untreated 
disease, Study GOG 9923 includes a stringent tolerability assessment in the expansion 
cohorts, with feasibility determined based upon DLTs through 4 cycles in a minimum of 
17 subjects at the recommended dose that confirms the ability to deliver multiple cycles of 
chemotherapy per standard of care.  Veliparib 150 mg BID continuous is the 
recommended dose in combination with both the Q3-weeks paclitaxel and carboplatin and 
the Q-week paclitaxel and carboplatin regimens.  Seventeen evaluable subjects were 
treated at this dose level in combination with Q3-weeks paclitaxel and carboplatin with 
2 DLTs (Grade 3 febrile neutropenia and Grade 3 hyponatremia).  One DLT (Grade 3 
headache) was observed in the 17 evaluable subjects treated with Q-week paclitaxel and 
carboplatin at this dose level.  The dose for this Phase 3 study is veliparib 150 mg BID 
administered continuously on Days 1 to 21 of a 21 day cycle for both regimens.
Synthetic Lethality:  Single-Agent Therapy
The TCGA project has identified that at least 50% of high-grade serous ovarian tumors 
exhibit defects in homologous recombination pathways that may result in increased 
sensitivity to PARP inhibitors.12  This includes approximately 15% to 20% of high-grade 
serous epithelial ovarian cancers with gBRCA and an estimated additional 7% with 
tBRCA.  Defects in homologous repair secondary to mutations in the BRCA genes result in 
DNA repair via more error prone mechanisms.  The combination of defective homologous 
 


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recombination due to mutations in BRCA1/2 and suppressed base excision repair due to 
PARP inhibition results in targeted cell death in the tumor cells,12 and has been called 
"synthetic lethality."28,29  Durable responses have been observed with veliparib 
monotherapy in both gBRCA advanced breast cancer30 and gBRCA recurrent ovarian 
cancer31 supporting the mechanism of synthetic lethality in BRCA1/2-mutated tumors.
Monotherapy Studies
Studies showing responses to monotherapy with PARP inhibitors in ovarian cancer have 
been presented and/or published with veliparib, olaparib, niraparib, and talazoparib.  In 
the initial Phase 1 study of olaparib, a cohort of BRCA mutation carriers and patients with 
a strong family history had a favorable response rate of 28%.4  Olaparib was studied 
further in the BRCA population in a Phase 2 dose-finding proof-of-concept study of 
100 mg twice daily (BID) and 400 mg BID.5  Again, a 33% response rate was seen at the 
400 mg BID dose, but only one third of that was seen at the 100 mg BID dose.  This is 
interesting in light of the pharmacodynamic data from the Phase 1 study that showed that 
90% inhibition of the PARP enzyme was reached at 100 mg BID.  Inhibition did not seem 
to increase further with higher doses when studying peripheral blood mononuclear cells as 
a surrogate tissue.
Olaparib has also been studied as monotherapy in a group of recurrent high-grade serous 
ovarian cancer patients or triple-negative breast cancer patients, stratified by whether they 
had a BRCA1 or BRCA2 mutation or not.  Of the subjects with ovarian cancer, an 
objective response rate of 41% (7/17; 95% confidence interval [CI] 22 – 64%) was 
observed in those with a BRCA1/BRCA2 mutation and of 24% (11/46; 95% 
CI 14 – 38%) in those without, supporting that underlying defects in DNA damage repair 
occur in ovarian tumors in the absence of BRCA1/BRCA2 mutations and that these lead to 
sensitivity to PARP inhibitor single-agent therapy.  Similarly, in a randomized, placebo 
controlled Phase 2 study evaluating olaparib maintenance monotherapy after carboplatin 
and paclitaxel treatment for platinum-sensitive recurrent serous ovarian cancer, PFS was 
significantly longer in the olaparib-treated group compared to placebo (hazard ratio 
[HR] = 0.35; 95% CI 0.25 – 0.49; P < 0.00001; median 8.4 versus 4.8 months) with 
 


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clinical benefit observed in BRCA-deficient patients (HR = 0.18, P < 0.00001) and in 
patients without a BRCA mutation (BRCA wild type) (HR = 0.54, P = 0.0075).32
In Cancer Therapy Evaluation Program (CTEP) Study 8282, a Phase 1 study in subjects 
with gBRCA-mutated cancer (germline BRCA1 or BRCA2 mutation), platinum refractory 
ovarian, fallopian tube, primary peritoneal cancer, or basal-like cancer, the recommended 
Phase 2 dose was 400 mg BID, with 500 mg BID declared intolerable due to nausea and 
fatigue.  Dose limiting toxicities included Grade 3 nausea and vomiting (400 mg BID) and 
Grade 2 seizures (400 mg BID and 500 mg BID).  Most common all-grade toxicities 
included fatigue, nausea, and lymphopenia.  Durable responses have been observed in the 
highest dose levels (300 to 500 mg BID) and enrollment in the expansion cohort is 
ongoing.
In GOG 280, a Phase 2 study evaluating veliparib 400 mg BID in gBRCA subjects with 
recurrent high-grade serous ovarian cancer and a maximum of 3 prior therapies, 
demonstrated two confirmed complete responses, 11 confirmed partial responses, and 
24 subjects with stable disease (N = 50).  The most notable toxicities have been 
gastrointestinal, with 18 subjects experiencing Grade 1 nausea, 23 subjects experiencing 
Grade 2 nausea, and 2 subjects experiencing Grade 3 nausea (50 subjects evaluable for 
toxicity).31  These toxicities, although not severe, were a common reason for dose delay 
and dose reduction.  Grade 3 and 4 treatment-emergent adverse events that occurred in 
more than 2 or more subjects (≥ 3%) included nausea (4%), small intestinal obstruction 
(8%), fatigue (6%), decreased lymphocyte count (4%), and hyponatremia (4%).
In total, approximately 400 subjects have been treated with veliparib monotherapy to date, 
either as single-agent therapy or as maintenance therapy, and the most common toxicities 
across these studies included nausea, fatigue, anemia, vomiting, decreased white blood 
cell count, and lymphocyte count.  In subjects receiving veliparib for greater than 
6 months, no increase in toxicity is observed over time.  The safety and efficacy of 
monotherapy with veliparib from these studies support the further evaluation of 
maintenance therapy (400 mg BID continuous) in subjects with previously untreated high 
grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer.
 


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3.1
Differences Statement
This is the first randomized, Phase 3 study evaluating the addition of veliparib to standard 
therapy in subjects with previously untreated high-grade serous epithelial ovarian cancer, 
fallopian tube, or primary peritoneal cancer.  
Other Phase 3 veliparib studies include:
●
Study M11-089:  Randomized, Double-Blind, Multicenter, Phase 3 Study 
Comparing Veliparib Plus Carboplatin and Paclitaxel Versus Placebo Plus 
Carboplatin and Paclitaxel in Previously Untreated Advanced or Metastatic 
Squamous Non-Small Cell Lung Cancer (NSCLC).
●
Study M14-011:  A Randomized, Placebo-Controlled, Double-Blind, Phase 3 
Study Evaluating Safety and Efficacy of the Addition of Veliparib Plus 
Carboplatin Versus the Addition of Carboplatin to Standard Neoadjuvant 
Chemotherapy Versus Standard Neoadjuvant Chemotherapy in Subjects with 
Early Stage Triple Negative Breast Cancer (TNBC).
●
Study M12-914: A Phase 3 Randomized, Placebo-Controlled Trial of 
Carboplatin and Paclitaxel with or without the PARP Inhibitor Veliparib 
(ABT-888) in HER2-Negative Metastatic or Locally Advanced Unresectable 
BRCA-Associated Breast Cancer.
3.2
Benefits and Risks
Preclinical data demonstrated two areas that warrant caution in the design and execution 
of human clinical trials:  1) as monotherapy, veliparib induced seizures in beagle dogs at 
exposures approximately 4-fold above anticipated efficacious clinical exposures at the 
MTD for veliparib in combination with platinum/paclitaxel (150 mg BID); and 2) in rats, 
veliparib administration resulted in a reversible and non-lethal exacerbation of 
temozolomide hematologic toxicity at doses that, in previous studies, resulted in 
exposures that were similar to or greater than the maximally efficacious exposure (AUC) 
in the melanoma murine model.  In addition to these two risk areas, a trend towards QTc 
prolongation was observed in anesthetized dogs, albeit at concentrations > 10-fold the 
 


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anticipated human efficacious maximum observed plasma concentration (Cmax).  As 
anticipated, hematological toxicity has been the dose-limiting toxicity for veliparib in 
combination with cytotoxic chemotherapy in the clinic, occurring at doses and exposures
well below those at which seizures have been observed.
Multiple clinical studies are currently evaluating veliparib in combination with cytotoxic 
chemotherapy in subjects with various solid tumors.  The main toxicities observed in 
these studies are consistent with those known for each background therapy, with 
myelosuppression being the most common dose-limiting toxicities.  Subjects who 
participate in Study M13-694 will be monitored for hematologic toxicities as well as for 
potentiation of any toxicity in combination therapy.
Gastrointestinal toxicities such as nausea and vomiting are the most common toxicities 
with veliparib single-agent therapy and have occurred in some subjects following a single 
dose.  Antiemetics may be used as per standard of care for nausea during the course of the 
study.  Anemia has been observed in clinical studies with continuously dosed single agent 
PARP inhibitors, including veliparib.
To date, over 3,000 subjects have been treated with veliparib and uncommon events of 
seizure have been observed.  The majority of cases have occurred with various 
confounding factors, primarily associated with underlying malignancy.  In this study, 
subjects with an uncontrolled seizure disorder or brain metastases will be excluded.
Best supportive care and treatment will be given as appropriate to each subject.  
Specifically, biologic response modifiers for erythropoiesis (e.g., erythropoietin, 
darbepoetin alpha) and colony-stimulating factors (e.g., neulasta, G-CSF, GM CSF, etc.) 
may be administered according to institutional or clinical practice guidelines 
(e.g., American Society of Clinical Oncology [ASCO], European Society for Medical 
Oncology [ESMO]).  Prophylactic antiemetics may also be given per National 
Comprehensive Cancer Network (NCCN), ESMO, or institutional practice guidelines.
 


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The lack of significant interaction with major cytochrome P450 (CYP) enzymes (either 
inhibition or induction), suggests that potential pharmacokinetic drug interactions with 
veliparib are unlikely.  For this reason, the Phase 3 study does not limit use of other 
medications on the basis of their CYP interactions.  As a Biopharmaceutics Classification 
System (BCS) Class 1 compound, veliparib exhibits rapid absorption and high solubility.  
In addition, food does not have a significant effect on veliparib bioavailability.  The 
administration of a high-fat meal had no significant effect on AUC and only caused a 
slight decrease in veliparib Cmax (17%) and a delay of approximately 1 hour in time to 
Cmax (peak time, Tmax).  For these reasons, veliparib may be administered with or without 
food.  As veliparib is predicted to be predominately excreted in urine, the Phase 3 study 
will be limited to subjects with adequate renal function (e.g., creatinine clearance 
≥60 mL/min). 
In summary, veliparib is an orally available PARP inhibitor that has been shown to 
significantly potentiate the effects of platinum/paclitaxel in multiple preclinical models of 
tumor progression.  Potential risks, as identified above, will be minimized by careful 
patient selection and monitoring to mitigate potential risks to subjects with previously 
untreated ovarian cancer.  The above scientific rationale supports the initiation of the 
proposed Phase 3 study of veliparib in combination with standard therapy.
The benefits and risks of study participation have been evaluated in the context of the
ongoing COVID-19 pandemic. No data are available to characterize the risk of
participation in this trial specific to COVID-19. COVID-19-related risks are not expected
to differ substantially between trial participants and the broader population of individuals
receiving treatment for untreated Stage III or IV high-grade serous epithelial ovarian, 
fallopian tube, or primary peritoneal cancer. In consideration of the life-threatening
nature of the disease under study, the benefit/risk balance for participation in this trial is
not changed.
 


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4.0
Study Objective
The primary objective of the study is to evaluate whether PFS is prolonged with the 
addition of veliparib to standard platinum-based chemotherapy (carboplatin/paclitaxel) 
and then continued as maintenance therapy when compared to chemotherapy alone.  This 
will be evaluated in the BRCA-deficient, HRD, and whole populations.  The BRCA-
deficient population will be defined as subjects with either a germ-line (gBRCA) and/or 
tissue-based (tBRCA) deleterious or suspected deleterious mutation in BRCA1 or BRCA2 
using centralized testing.  The HRD population will be defined as subjects with 
homologous recombination deficiency based on HRD score or presence of a deleterious or 
suspected deleterious mutation in BRCA1 or BRCA2 as determined using centralized 
testing.
Secondary objectives include evaluations of PFS (Arm 2 versus Arm 1), OS (Arm 3 
versus Arm 1 and Arm 2 versus Arm 1), safety of all three arms, and Disease Related 
Symptom (DRS) scores (Arm 3 versus Arm 1 and Arm 2 versus Arm 1) in the BRCA-
deficient, HRD, and whole population.
The tertiary objectives include PFS to the second objective radiographic progression 
(PFS2), time to first subsequent therapy (TTFST), time to second subsequent therapy 
(TTSST), and other PRO endpoints (which will be specified in a separate analysis plan).
5.0
Investigational Plan
This protocol was designed in collaboration between AbbVie and the Gynecologic 
Oncology Group Foundation.  
5.1
Overall Study Design and Plan:  Description
This is a randomized, placebo-controlled, double-blind, stratified, multicenter, 
multi-country Phase 3 study designed to evaluate if PFS is prolonged when veliparib is 
added to carboplatin/paclitaxel and continued as maintenance therapy in subjects with 
 


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previously untreated high-grade serous ovarian epithelial ovarian, fallopian tube, or 
primary peritoneal cancer. 
Approximately 1100 subjects at approximately 300 sites will be randomized to receive 
oral veliparib 150 mg/placebo BID in combination with standard first-line chemotherapy 
(paclitaxel and carboplatin) followed by oral veliparib/placebo BID maintenance therapy 
(Figure 1).  The study was designed to enroll 1100 subjects to meet scientific and 
regulatory objectives without enrolling an undue number of subjects in alignment with 
ethical considerations.  Therefore, if the target number of subjects has been enrolled, there 
is a possibility that additional subjects in screening will not be enrolled.
Figure 1.
Study Design
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 


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The study will consist of five phases:  a Pre-Therapy Phase (Screening), a Combination 
Therapy Phase, a Maintenance Therapy Phase, a Long-Term Follow-Up Phase, and a 
Survival Phase.  An overview of the study design is shown in Figure 2 followed by a 
description of each phase.
Study visits and procedures are detailed in Table 1, Table 2 and Section 5.3.1.1.
 


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Figure 2.
Overall Study Design
 
 
    
 
   
   
 
  
  
   
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Pre-Therapy Phase
During the Pre-Therapy Phase, Investigators will be allowed the choice of either 
carboplatin AUC 6 in combination with weekly paclitaxel (Q-week) or carboplatin AUC 6 
in combination with paclitaxel every 3 weeks (Q3-weeks).  Either of these chemotherapy 
regimens will be administered with primary or interval cytoreductive surgery such that 
there are the following treatment choices prior to randomization: 
1.
Primary cytoreductive surgery with carboplatin AUC 6 and weekly paclitaxel;
2.
Carboplatin AUC 6 and weekly paclitaxel with interval cytoreductive surgery 
between Cycle 3 and Cycle 4;
3.
Primary cytoreductive surgery with carboplatin AUC 6 and every 3 weeks 
paclitaxel;
4.
Carboplatin AUC 6 and every 3 weeks paclitaxel with interval cytoreductive 
surgery between Cycle 3 and Cycle 4.
The Investigator's treatment decision will be documented prior to proceeding to 
randomization.
Pre-therapy (screening) procedures will be performed within 28 days prior to 
randomization and Cycle 1 Day 1, except where noted in Table 1 and Section 5.3.1.1.
For subjects undergoing primary cytoreductive surgery, surgical outcomes including 
residual disease following primary cytoreductive surgery will be recorded on electronic 
case report forms (eCRFs).
Subjects must be willing (and consent) to undergo BRCA1/BRCA2 testing in order to 
participate on the study.  Both germline and tissue-based BRCA mutation status will be 
documented for all subjects by the central laboratory (Myriad).
Once pre-therapy procedures are complete and eligibility is confirmed, subjects will be 
randomized 1:1:1 to one of the following three arms.  Subjects will be stratified by stage 
 


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of disease (Stage III versus Stage IV), residual disease and choice of regimen, region of 
the world (Japan versus North America or Rest of World), and gBRCA mutation status 
(gBRCA positive versus gBRCA negative or Unknown).  Subject randomization is detailed 
in Section 8.4.
Arm 1:
Carboplatin/paclitaxel plus placebo for six 21-day cycles followed by 
placebo maintenance therapy for 30 additional 21-day cycles;
Arm 2:
Carboplatin/paclitaxel plus veliparib for six 21-day cycles followed by 
placebo maintenance therapy for 30 additional 21-day cycles;
Arm 3:
Carboplatin/paclitaxel plus veliparib for six 21-day cycles followed by 
veliparib BID maintenance therapy for 30 additional 21-day cycles.
Combination Therapy and Maintenance Phases
During the Combination Therapy Phase, subjects will receive veliparib/placebo by mouth 
(PO) in combination with intravenous (IV) carboplatin and paclitaxel (Q-week or 
Q3-weeks) for 6 cycles.  Subjects will self-administer veliparib 150 mg/placebo PO BID 
(approximately 8 to 12 hours apart; with or without food) continuously (Days 1 – 21) 
within each cycle of Cycles 1 – 6.  The morning dose of veliparib/placebo should be 
administered in the clinic prior to carboplatin and paclitaxel on C1D1, C2D1, C3D1 and 
C4D1 to facilitate pre-dose PK sampling.
Q-Week Paclitaxel Dosing Schedule:
●
Paclitaxel 80 mg/m2 IV over approximately 1-hour on Days 1 (prior to 
carboplatin), 8, and 15;
●
Carboplatin AUC 6 IV over approximately 30 minutes on Day 1;
●
Veliparib 150 mg/Placebo PO BID, continuously on Days 1 – 21.
Q3-Weeks Paclitaxel Dosing Schedule:
●
Paclitaxel 175 mg/m2 IV over approximately 3 hours on Day 1 prior to 
Carboplatin;
●
Carboplatin AUC 6 IV over approximately 30 minutes on Day 1;
 


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●
Veliparib 150 mg/Placebo PO BID, continuously on Days 1 – 21.
Subjects who complete the Combination Therapy Phase and who have not progressed per 
RECIST 1.1 will receive single-agent veliparib/placebo for an additional 30 cycles 
(Cycles 7 – 36) starting at 300 mg BID.  If the subject tolerates 300 mg BID for 2 weeks, 
veliparib/placebo may be increased to 400 mg BID at the Investigator's discretion during 
the Maintenance Phase.  Prior to increasing the dose of veliparib/placebo, at a minimum, 
vital signs and adverse event(s) must be assessed if escalation occurs outside of a routine 
study visit.
If subjects have discontinued veliparib/placebo during the Combination Therapy Phase, 
veliparib/placebo may be reinitiated at 300 mg to begin the Maintenance Phase once all 
therapy related toxicities have resolved to ≤ Grade 1 or baseline.
A Therapy Completion Visit will be conducted when the subject completes the 
Combination and the Maintenance Therapy Phase or when the Investigator determines a 
subject should discontinue all study treatments.  All subjects will have one Follow-Up 
Visit approximately 30 days after the Therapy Completion Visit.
Additional details regarding dosing with veliparib/placebo, carboplatin, and paclitaxel are 
provided in Section 5.5.1, Appendix D and Appendix E.  Guidelines for dose reductions 
or delays and toxicity management are provided in Section 5.7.
Subjects Undergoing Interval Cytoreductive Surgery
After adequate tissue biopsy to establish diagnosis, subjects will receive 3 cycles of 
therapy with interval cytoreductive surgery between Cycle 3 and Cycle 4, followed by 
3 additional cycles of therapy.  The specimen obtained to establish diagnosis must be 
processed locally as formalin-fixed paraffin embedded (FFPE) tissue.  Before sending to 
the central laboratory the tissue must be confirmed as adequate (at least 20% tumor 
content with a minimum of 80% nucleated cellular content) for planned analyses prior to 
enrollment.  To ensure sufficient viable tumor tissue is obtained, image-guided biopsies 
 


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should be achieved with 14 to 18 gauge cutting needles to provide 1 to 2 cores measuring 
1 to 1.5 cm in length.  Biopsy must be of solid tumor tissues; ascites is not acceptable for 
inclusion.
Veliparib/placebo should be discontinued 3 – 4 days prior to surgery.  Surgery must be 
performed after the third course of therapy, as soon as nadir counts permit, but within 
6 weeks after the completion of the third cycle.  The fourth cycle of therapy should be 
administered as soon as possible, but no more than 6 weeks after surgery.  Subjects may 
restart veliparib/placebo once recovered from surgery, with adequate hematological 
counts (ANC ≥ 1,500, PLT ≥ 100,000).  Hematological parameters must be assessed at a 
minimum of every 4 weeks if the monotherapy extends longer than this prior to resuming 
chemotherapy.
Cytoreductive surgery should be performed in accordance with the surgical procedures 
outlined in Appendix C.  Surgical outcomes including residual disease following interval 
cytoreductive surgery will be recorded on the eCRF.
Long-Term Follow-Up Phase
Subjects who have not progressed but have discontinued or completed study therapy will 
remain on study and will continue to be followed for standard of care assessments, PROs, 
and tumor assessments per the protocol schedule. Further details surrounding the 
assessments and activities in the Long Term Follow-Up Phase can be found in Table 2
and Section 5.3.1.1.  Subsequent to the primary analysis and implementation of Protocol 
Amendment 8, PROs and some standard of care assessments are no longer required. This 
is detailed in Table 2 and Section 5.3.1.1.
Survival Phase
Once a subject meets an event of progression, survival and post therapy information 
(subsequent therapy and progression/PFS2) will be collected at 3 month intervals and 
new-onset malignancy will be collected at 6 month intervals (or as requested by the 
 


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sponsor) until the endpoint of death, the subject is lost to follow-up or until study 
termination by AbbVie. 
Subjects will be followed for up to 10 years for collection of new onset malignancy.
5.2
Selection of Study Population
Women 18 years of age and older with previously untreated (no prior systemic therapy), 
International Federation of Gynecology and Obstetrics (FIGO) Stage III or IV high-grade 
serous epithelial ovarian, fallopian tube, or primary peritoneal carcinoma who meet the 
inclusion criteria and who do not meet any of the exclusion criteria will be eligible for 
enrollment into the study.  
Subjects must also have had or be willing to undergo radiographic imaging within 
28 days prior to randomization and Cycle 1 Day 1 (baseline).
5.2.1
Inclusion Criteria
1.
Subjects with a histologic diagnosis of epithelial ovarian, fallopian tube, or primary 
peritoneal carcinoma, FIGO Stage III or IV with appropriate tissue available for 
histologic evaluation.  FIGO staging is outlined in Appendix F.
2.
Subjects will be required to have high-grade serous adenocarcinoma to be eligible.  
Guidance for identifying high grade serous carcinoma is provided in Appendix G.
3.
Subject is willing to undergo testing for gBRCA.
4.
Subjects must have adequate hematologic, renal, and hepatic function as follows:
●
Hemoglobin ≥ 9.5 g/dL (5.89 mmol/L);
●
Absolute neutrophil count (ANC) greater than or equal to 1500/µL;
●
Platelet count greater than or equal to 100,000/µL;
●
Serum creatinine ≤ 1.0 × ULN range; subjects with a serum creatinine >1.0 × 
ULN range must have a creatinine clearance ≥ 60 mL/min (according to the 
Cockcroft-Gault equation);
 


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●
Total bilirubin ≤ 1.5 × ULN.  Subjects with Gilbert's Syndrome may have a 
bilirubin ≥ 1.5 × the ULN range if no evidence of biliary obstruction exists;
●
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and 
alkaline phosphatase must be less than or equal to 2.5 × ULN;
●
Albumin ≥ 3.0 g/dL.
5.
Subjects with neuropathy (sensory and motor) less than or equal to Grade 1.
6.
Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0, 1, or 2.
7.
Subject is able to swallow and retain oral medication and does not have 
uncontrolled emesis.
8.
Subjects who undergo primary cytoreductive surgery must be randomized between 
1 and 12 weeks after surgery.  Subjects undergoing interval cytoreductive surgery 
must have a tumor tissue sample confirming histological diagnosis prior to 
enrollment.
9.
Subjects with measurable disease or non-measurable disease are eligible.  Subjects 
may or may not have cancer-related symptoms.
10.
Subject has one of the following available for PD analyses including tissue-based 
BRCA testing:
●
Archived diagnostic formalin-fixed paraffin embedded (FFPE) tumor tissue; or
●
Tumor tissue biopsy collected prior to Cycle 1 Day 1.
11.
Women of childbearing potential must have a negative serum pregnancy test within 
7 days prior to initiation of study drug/placebo and a negative urine pregnancy test 
at Cycle 1 Day 1 and agree to use adequate contraception (one of the bullet points 
listed below) prior to study entry, and until permanently surgically sterile.  Women 
not of childbearing potential (permanently surgically sterile or postmenopausal 
defined as amenorrheic for at least 12 months without an alternative medical cause) 
at Screening do not require pregnancy testing:
 


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●
Total abstinence from sexual intercourse as the preferred lifestyle of the 
subject;
●
Double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal 
ring with spermicidal jellies or cream);
●
Intra-uterine device (IUD).
●
Vasectomized male partner of a female subject, provided the partner is sole 
sexual partner.
12.
Subject is 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.
Rationale for Inclusion Criteria
1 – 2, 5, 8 – 10
To select the subject population with appropriate disease severity for 
the evaluation
3 – 4, 6 – 7
For the safety of the subjects
11
The impact of veliparib and carboplatin or paclitaxel on pregnancies 
or breastfeeding is unknown
12
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Subjects with the following histologic cell types are ineligible:  endometrioid 
adenocarcinoma, carcinosarcoma, undifferentiated carcinoma, mixed epithelial 
adenocarcinoma, adenocarcinoma not otherwise specified, mucinous 
adenocarcinoma, clear cell adenocarcinoma, low-grade serous adenocarcinoma, 
transitional cell carcinoma, or malignant Brenner's tumor.
2.
Subjects with synchronous primary endometrial cancer, or a past history of 
endometrial cancer unless all of the following conditions are met:  endometrial 
 


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cancer stage not greater than IA, no vascular or lymphatic invasion, no poorly 
differentiated subtypes including serous, clear cell, or other FIGO grade 3 lesions.
3.
Subjects with any evidence of other invasive malignancy being present within the 
last 3 years (with the exception of non-melanoma skin cancer).  Subjects are also 
excluded if their previous cancer treatment contraindicates this protocol's therapy.
Subjects may not receive any non-protocol specified anti-cancer therapy during the 
study, including maintenance therapy or hormonal therapy for breast cancer.  
Subjects receiving hormonal therapy (such as tamoxifen or aromatase inhibitors) 
will require a 7 day (1 week) washout period prior to randomization.
4.
Subjects who have received prior radiotherapy to any portion of the abdominal 
cavity or pelvis are excluded.
5.
Subjects who have received prior chemotherapy for any abdominal or pelvic tumor 
are excluded.
6.
Subject has a clinically significant uncontrolled condition(s), including but not 
limited to:
●
Uncontrolled seizure disorder, or focal or generalized seizure within the last 
12 months;
●
Active infection that requires parenteral antibiotics;
●
Known active hepatitis B or hepatitis C with abnormal liver function test or 
organ dysfunction;
●
Symptomatic congestive heart failure; unstable angina pectoris; serious 
ventricular cardiac arrhythmia (i.e., ventricular tachycardia or ventricular 
fibrillation) or serious cardiac arrhythmia requiring medication (this does not 
include asymptomatic atrial fibrillation with controlled ventricular rate); or 
myocardial infarction within the last 6 months;
●
Uncontrolled hypertension (sustained systolic blood pressure > 150 mmHg or 
diastolic pressure > 100 mmHg despite optimal medical management);
 


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●
Bowel obstruction or gastric outlet obstruction.  Note:  Subjects requiring 
drainage gastrostomy tube and/or parental hydration and/or nutrition are not 
eligible;
●
Psychiatric illness/social situations that would limit compliance with study 
requirements;
●
Any medical condition which in the opinion of the Investigator places the 
subject at an unacceptably high risk for toxicities.
7.
Known history of allergic reaction to Cremophor-paclitaxel, carboplatin, 
Azo-Colourant Tartrazine (also known as FD&C Yellow 5 or E102), 
Azo-Colourant Orange Yellow-S (also known as FD&C Yellow 6 or E110) or 
known contraindications to any study supplied drug.
8.
Subjects with history or evidence upon physical examination of central nervous 
system (CNS) disease, including primary brain tumor, any brain metastases, or 
history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) 
within 6 months of Cycle 1 Day 1.
9.
Subjects who are pregnant or nursing.
10.
Subjects under the age of 18.
11.
In the opinion of the Investigator, the subject is an unsuitable candidate to receive 
veliparib or combination therapy.
Rationale for Exclusion Criteria
1 – 5, 10
To select the subject population with appropriate severity for the 
evaluation
6 – 9, 11
For the safety of the subjects
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements), except medications administered during primary or 
 


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interval cytoreductive surgery (e.g., anesthesia), that the subject is receiving at the time of 
enrollment, or receives during the study, must be recorded along with the reason for use, 
date(s) of administration including start and end dates, and dosage information including 
dose, route and frequency.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapies.
5.2.3.1
Prior Therapy
For the purposes of this protocol, prior antitumor treatment may be defined as, but is not 
limited to, anticancer agents (cytotoxic chemotherapy, hormonal therapy, immunotherapy, 
biologic therapy), radiotherapy, and investigational agents.  An investigational agent is 
any drug or therapy not currently approved for use in humans.
Anticancer Agents:
Subject must have received no prior chemotherapy for any 
abdominal or pelvic tumor.
Radiation:
Subject must have received no prior radiotherapy to any portion 
of the abdominal cavity or pelvis.
5.2.3.2
Concomitant Therapy
Premedication:
Refer to Section 5.5.1.2.
Anticancer 
Agents:
Any anti-cancer therapy including chemotherapy or biological 
therapy (maintenance therapy) will not be allowed until an event 
of disease progression per RECIST 1.1 has occurred, with the 
exception of docetaxel as noted in Section 5.7.1.2.  Subjects 
receiving hormonal therapy such as tamoxifen will require a 
7 day (1 week) washout prior to randomization.
 


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Supportive Care:
Best supportive care and treatment will be given as appropriate 
to each subject (antibiotics, transfusions, nutritional support, 
non-radiation palliative treatment for pain) according to 
institutional guidelines or ASCO or NCCN guidelines.
Antiemetic treatment for chemotherapy induced nausea and 
vomiting and veliparib/placebo monotherapy is outlined in 
Section 5.7.1.1 and Section 5.7.2.
Growth Factors:
Guidelines for the use of hematopoietic cytokines are outlined in 
Section 5.7.1.1.  
Radiation:
Concomitant radiation therapy will not be allowed.
Surgery:
If the subject requires surgery during the study other than that 
specified by protocol, then this needs to be discussed with the 
AbbVie TA MD.  Generally, veliparib/placebo should be 
discontinued 3 days prior to surgery, and subjects may restart 
veliparib/placebo once the subject has adequate hematological 
counts (ANC ≥ 1,500, PLT ≥ 100,000) and the investigator 
determines the subject has recovered from surgery.  
Secondary 
Surgery:
The performance of non-emergent abdominal surgery, other than 
that specified by protocol (such as interval or secondary 
cytoreductive surgery or second look surgery), prior to 
documentation of disease progression is not permitted.  
Non-emergent surgery for other indications, such as ostomy 
reversal, should be discussed with the AbbVie TA MD.
Alternative 
Therapy:
No anti-cancer Chinese medicine/herbal remedies may be taken 
concurrently with veliparib (a 14-day washout period must be 
documented).
 


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5.3
Efficacy Pharmacokinetic, Pharmacodynamic 
Pharmacogenetic and Safety Assessments/Variables
5.3.1
Efficacy Pharmacokinetic, Pharmacodynamic 
Pharmacogenetic and Safety Measurements Assessed and 
Flow Chart
The study visit and procedure schedule is outlined in Table 1 and Table 2.  The schedule 
for pharmacogenetic and pharmacodynamic sampling (translational research) and 
pharmacokinetic sampling is presented in Table 3 and Table 4 respectively.
 


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Table 1.
Study Procedures for Pre-Therapy, Combination and Maintenance Phases
Combination Phase (Cycles 1 – 6)
Maintenance Phase (Cycles 7 – 36)
Therapy 
Completion 
Visit
Follow-
Up Visite
Procedure
Pre-Therapy 
Phase 
(Screening)a
C1D1
Day 8 
and 
Day 15b
Cycle 
2 –
Cycle 
6
Every 9 Weeks 
from C1D1 then 
End of the 
Combination 
Phasec
Every 
Other 
Cycle 
(C7, C9, 
C11, etc.)
Study Drug 
Evaluationd
Every 12 Weeks 
for 2 Years, then 
Every 6 Months 
for 3 Years, Then 
Annuallyc
Informed Consent
X
Medical and Cancer 
History
X
Physical Examf
Xf
Xg
X
X
Xh
X
X
ECG
X
Vital Signs
X
X
X
X
X
Xh
X
X
ECOG PS
X
X
X
X
X
X
Serum Pregnancy Test
Xi
Xi
Xi
X
X
Hematologyj,k,l
X
Xj,k
Xj,k
Xj,k
Xj,k
X
X
Chemistryj,k
X
Xj,k
Xj,k
Xj,k
Xj,k
X
X
Urinalysisj
X
PT/INR, PTTm
Xm
Xm
Xm
Xm
CA-125 Blood Drawn
X
X
X
X
X
X
Randomizationo
X
Tumor Assessmentp
Xq
Xr
X
Xs
Chest X-Ray
Xt
NFOSI-18u,v
X
X
X
X
X
X
EQ-5D-5Lu,v
X
X
X
X
X
X
 


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Table 1.
Study Procedures for Pre-Therapy, Combination and Maintenance Phases (Continued)
Combination Phase (Cycles 1 – 6)
Maintenance Phase (Cycles 7 – 36)
Therapy 
Completion 
Visit
Follow-
Up Visite
Procedure
Pre-Therapy 
Phase 
(Screening)a
C1D1
Day 8 
and 
Day 
15b
Cycle 
2 –
Cycle 
6
Every 9 Weeks 
from C1D1 then 
End of the 
Combination 
Phasec
Every 
Other 
Cycle 
(C7, C9, 
C11, etc.)
Study Drug 
Evaluationd
Every 12 Weeks 
for 2 Years, then 
Every 6 Months 
for 3 Years, Then 
Annuallyc
Review Subject 
Calendar
X
X
X
Veliparib/Placebo 
Dispensing
Xw
Xw
Xw
Xw
Monitor AEs
X
X
Xx
X
X
Xx
X
X
Prior and Concomitant 
Medication Assessment
X
X
X
X
X
X
X
PS = Performance Status; C=Cycle; AEs = Adverse Events
a.
Perform within 28 days prior to randomization and Cycle 1 Day 1.
b.
Procedures in this column are only required for subjects being treated with weekly paclitaxel (Cycles 1 – 6 only).  If dose modification results in discontinuation of the Day 15
paclitaxel infusion, the Day 15 visit may be omitted.
c.
Can be performed ± 7 days of the scheduled visit.  Note, the end of Combination Therapy Phase tumor assessment scan is not required if the prior scan was completed within 
the last 6 weeks.  Intervals are as follows:  Every 9 weeks from C1D1, then end of the combination phase, then every 12 weeks for 2 years (from the start of maintenance 
phase), then every 6 months for 3 years (from the last scan on the every 12 week schedule), then annually.
d.
Approximately 2 weeks after beginning maintenance therapy at 300 mg BID, subjects will be evaluated for escalation to 400 mg at a Study Drug Evaluation Visit.  The 
procedures noted in this column will be performed.  If the PI determines the subject is not eligible to increase veliparib/placebo to 400 mg BID at this visit, the PI may 
reassess the subject's tolerability at any future visit.  Note, the procedures in this column will be required when determining if a subject can escalate to 400 mg BID.
e.
Perform within 30 days of the Therapy Completion Visit.
f.
All exams should include weight.  Height is obtained at the Pre-Therapy Visit only.
g.
If the physical examination is performed within 7 days prior to Cycle 1 Day 1, it is not required to repeat the exam on Cycle 1 Day 1 unless clinically indicated.
 


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Table 1.
Study Procedures for Pre-Therapy, Combination and Maintenance Phases (Continued)
h.
Procedures can be performed by PI or delegated to qualified medical staff (e.g., a nurse, sub-investigator, etc.).
i.
Subjects of childbearing potential:  a serum pregnancy test will be performed within 7 days of Cycle 1 Day 1.  A serum or urine pregnancy test should also be performed prior 
to randomization or Cycle 1 Day 1 if > 7 days since obtaining screening serum test results.  Subjects of childbearing potential who have prolonged interruption of therapy 
(> 3 months), a pregnancy test (urine or serum) must be performed and confirmed to be negative prior to resuming therapy.
j.
Refer to Table 5 for the complete listing of required clinical laboratory tests.
k.
Must be obtained within 4 days prior to therapy.  Any subject whose therapy is delayed must be evaluated on a weekly basis until adequate hematologic and non-hematologic 
parameters have been met.
l.
Non-Protocol Specified Surgery:  Subject may restart veliparib/placebo when ANC ≥ 1,500 and PLT ≥ 100,000.  Hematological parameters will be assessed as determined 
by the investigator.
Interval Surgery:  Subject may restart veliparib/placebo when ANC ≥ 1,500 and PLT ≥ 100,000.  Hematological parameters must be assessed at a minimum of every 4 
weeks if the monotherapy extends longer than this prior to resuming carboplatin/paclitaxel.
m.
For subjects on prophylactic or therapeutic anticoagulation with warfarin, PT/INR should be monitored at screening and with additional assessments as clinical indicated.  
Therapy should be held for PT/INR of > 1.5 × ULN on prophylactic warfarin or > therapeutic range if on full dose warfarin.
n.
A baseline (prior to initiating therapy) value is required.  CA-125 levels should then be drawn prior to each cycle during Cycles 1 – 6 only.  Additional CA-125 levels drawn 
over the course the study will be collected on the appropriate eCRF.
o.
Randomization should occur as close as possible to Cycle 1 Day 1.
p.
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.  Tumor 
assessments may also be done as clinically indicated at any time based on symptoms or physical signs suggestive of progressive disease.  All scan dates should be calculated 
from Cycle 1 Day 1.  In addition to being reviewed by the Investigator, imaging scans should be sent within 5 business days of imaging acquisition to the central imaging 
vendor. Subsequent to the primary analysis and implementation of Protocol Amendment 8, imaging scans are not required to be sent to the independent central imaging 
vendor.
q.
Primary surgery subjects:  The post-operative baseline scan must be performed within 28 days prior to randomization and Cycle 1 Day 1. Interval surgery subjects:  A 
baseline scan (prior to initiating therapy) must be completed within 28 days prior to randomization and Cycle 1 Day 1.
r.
Interval surgery subjects:  Pre-operative scan data will be collected after the completion of Cycle 3 on the appropriate eCRF to evaluate disease per RECIST 1.1.  A scan of 
at least the abdomen and pelvis is required to establish post-surgical baseline for the extent of residual disease prior to re-starting therapy on C4D1.  The post-operative scan 
should be performed as close as possible to resuming therapy at C4D1 and no more than 4 weeks prior to C4D1.
 


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Table 1.
Study Procedures for Pre-Therapy, Combination and Maintenance Phases (Continued)
s.
For subjects who discontinue therapy for reasons other than progression, a tumor scan will not be required at the time of discontinuation if completed within 4 weeks prior to 
the Therapy Completion Visit.
t.
Not required if CT of chest already performed at screening.
u.
PRO questionnaires administered at the Screening visit are considered baseline.  PROs do not need to be repeated at C1D1 if completed ≤ 7 days prior to C1D1.  Subsequent 
administration of the PROs to continue at odd numbered cycles, after the baseline PRO has been completed.
v.
Complete the NFOSI-18 first followed by the EQ-5D-5L.  Both questionnaires should be administered before discussing imaging scan results or disease status changes with 
the subject.
w.
Review each subject's calendar and document compliance with veliparib/placebo prior to the start of each cycle.
x.
Perform weekly for subjects receiving weekly paclitaxel.  Weekly AE assessments can be performed by the PI or delegated to qualified medical staff (e.g., a nurse, 
sub-investigator).
Note:
For procedures performed during the Pre-Therapy Phase (screening) and repeated, the later procedure performed prior to dosing will serve as a baseline for clinical 
assessment.  For C1D1 and subsequent study procedures (excluding tumor assessments), assessments should be performed within 4 days prior to the scheduled study 
visit.
 


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Table 2.
Study Procedures for Long Term Follow-Up and Survival Phase
Completion or Discontinuation of Therapy Without Disease Progression
(Long Term Follow-Up Phase)
Discontinuation of Therapy due to 
Disease Progression
(Survival Phase)
Procedure
Every 9 Weeks Until the End of 
Combination, then Every 12 Weeks 
for 2 Years, then Every 6 Months 
for 3 Years, then Annually, Until 
Disease Progressionc
At Least Every 
3 Months Until 
Disease Progression
Every 6 Months 
Until Disease 
Progression
Every 3 Months 
Beginning on Date 
of Progression
Every 6 Months 
Beginning on Date 
of Progression
Physical Exam
Xa
Vital Signs
Xa
ECOG PS
Xa
CA-125 Blood Draw
X
Tumor Assessmenth
X
NFOSI-18b
Xb
Xb
EQ-5D-5Lb
Xb
Xb
Monitor AEs
Xd
Survival Informatione,f
X
X
Post-Therapy Informatione,f
X
X
Review for New Onset Malignancyg
X
X
a.
Assessments (except for PROs) may be performed according to standard of care or every 3 months for up to 3 years (from C1D1).  As of Amendment 8, all patients are 
beyond 3 years post C1D1, therefore these assessments are no longer required.
b.
Both PROs will be completed for up to 2 years from C1D1, or until disease progression, whichever is later.  If disease progression occurs prior to 2 years from C1D1, both 
PROs should continue to be collected until 2 years from C1D1.  Complete the NFOSI-18 first followed by the EQ-5D-5L.  Both questionnaires should be administered before 
discussing imaging scan results or disease status changes with the subject.  Subsequent to the primary analysis and implementation of Protocol Amendment 8, these PRO 
assessments are no longer required.
 


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Table 2.
Study Procedures for Long Term Follow-Up and Survival Phase (Continued)
c.
Every 12 weeks for 2 years (from the start of maintenance phase), then every 6 months for 3 years (from the last scan on the every 12 week schedule), then annually.
d.
Subjects will be monitored for SAEs only per Section 6.5.  
e.
Survival information and post-therapy information will be collected every 3 months (i.e., 3, 6, 9, 12 etc.) or as requested by the Sponsor to support data analysis, beginning on 
the date of disease progression per RECIST 1.1 until the endpoint of death, or until the subject becomes lost to follow-up, or until study termination by AbbVie.
f.
Section 5.3.1.1 outlines the data being collected for survival and post-therapy information.
g.
New onset malignancy will be assessed every 6 months for up to 10 years.
h.
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.  Tumor 
assessments may also be done as clinically indicated at any time based on symptoms or physical signs suggestive of progressive disease.  All scan dates should be calculated 
from Cycle 1 Day 1.  In addition to being reviewed by the Investigator, imaging scans should be sent within 5 business days of imaging acquisition to the central imaging 
vendor. Subsequent to the primary analysis and implementation of Protocol Amendment 8, imaging scans are not required to be sent to the independent central imaging 
vendor.
 


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Table 3.
Schedule of Pharmacogenetic and Pharmacodynamic Procedures 
Procedure
Visit Schedule
Timing of Sample Collection
Sampling Plan
Specimen Matrix
Optional Pharmacogenomic Sample
C1D1, C3D1
Prior to Dosing
Blood
Frozen –20°C or colder
BRCA Sequencing:  Bridging Sample
C1D1
Prior to Dosing
Blood
Frozen –20°C or colder
Germline BRCA Sample
Screening
Prior to Dosing
Blood
Ambient
Plasma Markersa
C1D1, C3D1, C5D1
Prior to Dosing
Blood →Plasmab
Frozen –20°C or colder
Therapy Completion Visit
Anytime during the clinic visit
Serum Markers
C1D1, C3D1, C5D1
Prior to Dosing
Blood →Serumb
Frozen –20°C or colder
Therapy Completion Visit
Anytime during the clinic visit
Pre-therapy tumor biopsy sample (Required):  
Archival Tissue or Newly Collected Biopsy
Pre-therapy Phasec
Pre-Study Treatment FFPE tissue blocks 
(Room Temperature or 
Refrigerated-FFPE)
Optional tissue sample 
C1D1 – Therapy Completion Visitd
Anytime over the course of the 
study, including the Therapy 
Completion Visit
Archived FFPE tissue blocks (Room 
Temperature or Refrigerated-FFPE)
a.
An additional sample may be collected at the time of discontinuation due to an adverse event.
b.
Plasma and serum samples should be sent to the central lab within 4 weeks.  Samples that require storage longer than 4 weeks should be stored in –70 degree Celsius.
c.
All subjects must have a pre-therapy tumor biopsy for inclusion on the study.
d.
Post-therapy biopsy can be taken from any consenting subjects at any time over the course of the study, including at the Therapy Completion Visit.  The collection of this 
tissue sample does not require a separate biopsy procedure and may be collected during routine procedures including interval surgery or during a biopsy at the time disease 
progression is suspected.
Note:
If a drug interruption is needed, the subject will continue to have study visits as planned; however, the above samples will not be drawn during the time of study drug 
interruption.
 


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Table 4.
Schedule of Pharmacokinetic Sampling
Procedure
Visit Schedule
Before Drug Administration
After Veliparib AM Dosea
Sampling Plan
Specimen Matrix
Veliparib PK Sampling
C1D1
0-hourb
1, 2, 3 hours
Blood →Plasma
Frozen –20°C or colder
Veliparib PK Sampling
C2D1, C3D1, 
C4D1
0-hourb
Blood →Plasma
Frozen –20°C or colder
a.
The Veliparib PK sampling draws may be completed within a window of ± 10%.
b.
Before the administration of the morning dose of veliparib/placebo.  The morning dose of veliparib/placebo should be dosed in clinic prior to carboplatin and paclitaxel on 
C1D1, C2D1, C3D1 and C4D1.
Notes:
If a drug interruption is needed, the subject will continue to have study visits as planned; however PK samples will not be drawn during the time of study drug 
interruption.
The date and time of sample collection and the date and time of the last two doses of veliparib/placebo will be captured on the eCRF.
If an indwelling catheter of any type is used, approximately 3 mL volume of blood must be collected and discarded prior to collection of the veliparib sample.  The use of 
indwelling catheter for the collection of pharmacokinetic samples is discouraged unless it is absolutely necessary.
 


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5.3.1.1
Study Procedures
The study procedures outlined in Table 1 and Table 2 are discussed in further detail in this 
section, with the exception of prior and concomitant therapy (Section 5.2.3), tumor 
assessment criteria (RECIST 1.1; Section 5.3.3.1), administration of veliparib/placebo 
(Section 5.5.1.1), the monitoring of treatment compliance (Section 5.5.6) and adverse 
event information (Section 6.1.1).  All study data will be recorded on electronic case 
report forms (eCRFs) with supporting source documentation.
Pre-Therapy, Combination, Maintenance, and Long-Term Follow-Up Phases
Study Visits
For procedures performed during the Pre-Therapy Phase (screening) and repeated, the 
later procedure performed prior to dosing on Cycle 1 Day 1 will serve as a baseline for 
clinical assessment.  Assessments obtained as standard practice for management of the 
underlying disease may be accepted for eligibility, provided the assessments were 
collected within the specified eligibility window.  Please refer to Table 1 for specified 
windows.  Cycle 1 Day 1 and subsequent study procedures (excluding tumor assessments) 
should be performed within 4 days prior to the scheduled study visit date.
During the Combination Phase (Cycles 1 – 6), the frequency of study visits will vary 
depending on the dosing schedule chosen for paclitaxel.  Subjects receiving weekly 
paclitaxel will have weekly study visits.  Subjects receiving Q3-weeks paclitaxel will have 
study visits on Day 1 of every cycle.  
During the Maintenance Therapy Phase, all subjects will have study visits on Day 1 of 
every other cycle except for the Study Drug Evaluation visit (conducted approximately 
2 weeks after starting maintenance therapy).  At this visit, the PI or designated qualified 
staff will evaluate whether a subject is tolerating therapy at 300 mg BID and is suitable to 
escalate veliparib/placebo to 400 mg BID.  If the PI determines a subject is not suitable to 
escalate to 400 mg BID at the Study Drug Evaluation visit, the PI may reassess the 
 


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subject's tolerability at any future visit.  Procedures for the Study Drug Evaluation visit 
and any future visits where escalation is considered, are outlined in Table 1.
Baseline scans for primary and interval cytoreductive surgery are discussed in this section 
under the Tumor Assessment subheading.  All post-baseline tumor assessments can be 
performed ± 7 days of the scheduled visit.
Informed Consent
Signed informed consent will be obtained from the subject or the subject's legally 
acceptable representative before any study procedures are undertaken or before any 
prohibited medications are withheld from the subject in order to participate in this study.  
Informed consent will be required for the optional research tests.  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 a 
study-specific procedure has been performed (e.g., local laboratories drawn), but subject 
does not randomize into the study.  The reason for screen failure will be documented in 
the source documents and will be captured in the eCRF.
Medical History
A complete medical history includes documentation of any clinically significant medical 
condition(s); history of tobacco and alcohol use; presence and severity of any 
symptoms/conditions associated with ovarian cancer and detailed ovarian oncology 
history (histology, tumor staging, residual disease at the completion of surgery [if 
applicable], date of diagnosis, tumor burden, metastatic sites, any previous BRCA status 
testing (US only) and results of tumor molecular analysis/profiling, if available).
On Cycle 1 Day 1 any changes observed from the pre-therapy procedures (prior to dosing) 
will be recorded in the subject's medical history.  At each subsequent visit, the subject's 
medical history will be reviewed and any clinically significant changes from baseline will 
be recorded in the source documents and on the adverse event eCRF.
 


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Physical Examination
Physical examinations, including body weight, will be performed per Table 1 and Table 2.  
If the pre therapy physical examination is performed within 7 days of Cycle 1 Day 1, it is 
not required to repeat the exam on Cycle 1 Day 1 unless clinically indicated.  Clinically 
significant changes from baseline will be documented in the source documentation and 
eCRFs as adverse events.
Height will be measured at the Pre-Therapy Visit only.  For height and weight, subject 
should not wear shoes.
Vital Signs
Vital signs will be performed per Table 1 and Table 2.  Vital sign determinations include 
sitting blood pressure, heart rate and body temperature.  If possible, blood pressure and 
heart rate measurements should not immediately follow scheduled blood collections.
Weekly Paclitaxel Dosing Schedule:  During weekly study visits, vital signs can be 
performed by PI or delegated to qualified medical staff (e.g., a nurse, sub-investigator, 
etc.).
Adverse Event Assessment
AE assessments will be performed per Table 1 and Table 2.
Weekly Paclitaxel Dosing Schedule:  During weekly study visits, AE assessments can 
be performed by the PI or delegated to qualified medical staff (e.g., a nurse, 
sub-investigator, etc.).
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed per Table 1.  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 
 


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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.
ECOG Performance Status
The ECOG performance status will be assessed per Table 1 and Table 2 as follows:
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.
Pregnancy Test (In Women of Childbearing Potential)
For female subjects of childbearing potential, a serum pregnancy test will be performed 
within 7 days of Cycle 1 Day 1.  A serum or urine pregnancy test at day of randomization 
should also be performed and reviewed prior to randomization, if a serum pregnancy test 
is completed more than 7 days prior to randomization.  If a serum pregnancy test is 
performed on the day of randomization, a urine pregnancy test does not need to be 
completed.  Pregnancy tests may also be repeated during the study according to country 
requirements.
If pregnancy results are equivocal (e.g., false positive due to B-hCG being a tumor 
marker) in subjects with evidence to support lack of pregnancy (e.g., surgically sterile), 
the results should be discussed with the AbbVie TA MD and the Investigator's 
interpretation along with supporting information documented in the source documents.
 


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The urine or serum pregnancy test results must be reviewed and determined to be negative 
prior to randomization.  If the urine pregnancy test is positive, it should be confirmed by a 
serum pregnancy test or additional testing and dosing should be delayed.
For female subjects of childbearing potential, who have prolonged interruption of study 
drugs (> 3 months), a pregnancy test (urine or serum) must be performed and confirmed 
to be negative prior to resuming study drugs.  In situations of suspected pregnancy, 
pregnancy testing will be performed as soon as possible.  In addition, pregnancy testing 
may be repeated at the discretion of the investigator at any time during the study.
Should a female study subject become pregnant or suspect she is pregnant while 
participating in this study, she should inform the treating Investigator immediately 
(Section 6.7).
Females of non-childbearing potential (either postmenopausal or permanently surgically 
sterile) at Screening do not require pregnancy testing.
Clinical Laboratory Tests
Samples for chemistry, hematology, and urinalysis will be collected per Table 1 and 
Table 2 using a certified local laboratory.  Specific laboratory tests are outlined in Table 5.
All laboratory samples will be assessed using a certified local reference laboratory and 
these data will be used for all data analysis.  The appropriate certifications will be 
collected from the local laboratories, as needed.
Qualified medical staff at the site will review, initial and date all local laboratory results.  
Any laboratory value outside the reference range that is considered clinically significant 
by the Investigator will be followed as appropriate.  Clinically significant laboratory 
values will be recorded as adverse events if they meet the criteria as specified in 
Section 6.1.1.
 


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Table 5.
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
Blood urea nitrogen (BUN)
Serum creatinine
Total bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic 
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Chloride
Calcium
Inorganic phosphorus2
Total protein
Glucose
Albumin
Magnesium2
Bicarbonate (if available, Japan 
only)
Specific gravity
Ketones
pH
Protein
Blood
Glucose 
Serum Pregnancy Tests
Human Chorionic 
Gonadotropin (hCG)4
Coagulation
Special Chemistry
Tumor Markers
Activated Partial 
Thromboplastin Time (aPTT)1
International Normalized Ratio 
(INR)1
BRCA1 and BRCA2 germline 
mutation3
CA-125
1.
Collected per Table 1.
2.
Not required on Day 8 and Day 15 assessments during Cycles 1 – 6 for subjects receiving carboplatin and weekly 
paclitaxel.
3.
Collected during screening.
4.
Collected and reviewed prior to Randomization.
Tumor Assessments
Tumor assessments will be performed per Table 1 and Table 2.  A CT scan of the 
abdomen and pelvis (and chest, if metastases are present) using RECIST 1.1 will be used 
in the evaluation of tumor responses, as appropriate.33  Subjects will continue to be 
monitored by the same diagnostic method as outlined in Section 5.3.3.1 (Methods for 
Evaluation of Disease).
 


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Primary surgical subjects:  The post-operative (baseline) scan must be performed within 
28 days prior to randomization and Cycle 1 Day 1.
Interval surgery subjects:  A pre-therapy (screening) baseline scan is required to be 
performed on interval surgery subjects within 28 days prior to randomization and Cycle 1 
Day 1.  Pre-operative scan data will be collected after the completion of Cycle 3 on the 
appropriate eCRF to evaluate disease per RECIST 1.1.  A scan of at least the abdomen 
and pelvis is required to establish post-surgical baseline for the extent of disease 
evaluation prior to re-starting therapy on Cycle 4 Day 1.  The post-operative scan should 
be performed as close as possible to resuming therapy at Cycle 4 Day 1 and no more than 
4 weeks prior to Cycle 4 Day 1.  
Scheduled tumor assessments will not be affected by delays in therapy and/or drug 
holidays.  The end of Combination Therapy Phase tumor assessment scan is not required 
if the prior scan was completed within the last 6 weeks.  Subjects who discontinue therapy 
for reasons other than disease progression will continue to be followed as per the 
scheduled tumor assessments to determine the extent of tumor burden, until disease 
progression occurs.
In addition to being reviewed by the Investigator and/or qualified medical site staff, 
imaging scans should be sent within 5 business days of imaging acquisition to an 
independent central imaging vendor.  AbbVie may discontinue this requirement at any 
time during the course of the study.  The central imaging vendor will provide instructions 
regarding the preparation and shipment of the images.  Imaging scans will be assessed for 
quality by the central imaging vendor and archived.  Interpretations from the central 
imaging vendor will not be sent to the study site.  Blinded independent central reviews 
will be performed as a sensitivity analysis as described in the SAP.  Subsequent to the 
primary analysis and implementation of Protocol Amendment 8, imaging scans are not 
required to be sent to the independent central imaging vendor.
 


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Randomization and Subject Number Assignment
Interactive Response Technology (IRT) will be utilized to register (screen and randomize) 
subjects on study.  The site will contact the IRT to obtain a screening (subject) number 
once the subject has signed the informed consent and a study-specific procedure has been 
performed (i.e., labs are drawn).  Once the screening number is assigned, if the subject is 
not randomized into the study, the reason for screen failure will be documented in the 
source document and will be captured in the eCRF.
Subjects who meet the eligibility criteria, agree to participate, and complete all pre-
therapy (screening) procedures will proceed to randomization.  Randomization is to occur 
as close as possible to Cycle 1 Day 1.  The site will need to also access the IRT system 
and a unique randomization number will be provided.  During the randomization process, 
subjects will be randomized in a 1:1:1 ratio to one of 3 treatment arms:
Arm 1:
Carboplatin/paclitaxel plus placebo for six 21-day cycles followed by 
placebo maintenance therapy for 30 additional 21-day cycles.
Arm 2:
Carboplatin/paclitaxel plus veliparib for six 21-day cycles followed by 
placebo maintenance therapy for 30 additional 21-day cycles.
Arm 3:
Carboplatin/paclitaxel plus veliparib for six 21-day cycles followed by 
veliparib maintenance therapy for 30 additional 21-day cycles.
A bottle number randomization schedule and a subject randomization schedule will be 
generated by the Clinical Statistics Department at AbbVie prior to the start of the study.  
A copy of all randomization schedules will be kept by the Clinical Statistics Department 
at AbbVie and a copy will be forwarded to the IRT vendor.
Dispensing Study Drug
Randomized subjects will receive sufficient quantities of veliparib/placebo for 21 days in 
each 21 day cycle during the Combination Phase, and 42 days for 2 cycles, during the 
Maintenance Phase.  The IRT will assign every bottle of veliparib/placebo to be dispensed 
to a subject.  Prior to each cycle (per Table 1), site personnel must contact IRT for the 
 


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next bottle number assignment.  Veliparib/Placebo cannot be dispensed without 
contacting the IRT.  AbbVie or designee will provide specific instructions on the use of 
IRT.  During the combination and maintenance phase, IRT will allow additional kits to be 
dispensed during scheduled clinic visits, if needed.
Trained site personnel will administer IV carboplatin and paclitaxel.  Subjects will be 
supervised at the time of the infusion.
Subjects will be provided with veliparib/placebo self-administration instructions and 
subject dosing cards.  Subjects will be instructed to store veliparib/placebo according to 
specific directions included in Section 5.5.2.3.  Subjects should return bottles of veliparib 
or placebo (empty, partially filled, or full) to the study site prior to each cycle and at the 
Therapy Completion Visit.
Disease Related Symptom Scores
Two PRO questionnaires will be administered (per Table 1 and Table 2):  the NCCN 
Functional Assessment of Cancer Therapy (FACT) Ovarian Symptom Index-18 
(NFOSI-18) questionnaire, and the EQ-5D-5L/VAS.34,35
The NFOSI-18 consists of 18 items and separates disease related symptoms from 
treatment related side effects.  Four subscale scores will be constructed:  a 9-item based
disease related symptoms (DRS) score, a 1-item based disease related emotional 
well-being (DRS-E) score, a 5-item based treatment side effect (TSE) subscale, and a 
3-item based functional well-being (FWB) subscale score.36  The DRS score will be used 
as a secondary endpoint of the study.
The EuroQol 5 Dimensions (EQ-5D-5L) is a generic preference instrument that has been 
validated in numerous populations.  The EQ-5D-5L has five dimensions:  mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression.  These dimensions are 
measured on a five level scale:  no problems, slight problems, moderate problems, severe 
problems, and extreme problems.  The EQ-5D-5L also contains a visual analog scale 
(VAS) to assess the subject's overall health.  
 


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Order of Administration
Subjects will be asked to complete the NFOSI-18 first, followed by the EQ-5D-5L.  To 
minimize response bias, the questionnaires should be administered before discussing 
imaging scan results or disease related clinical changes with the subject.  Subjects should 
be encouraged to respond to all of the questions.  Clarification can be given regarding the 
intention of each question even when the question(s) do not seem relevant to their 
situation.  While the subject is still at the site, the Investigator or a designee will need to 
check the forms returned by the subject for completeness.  If a subject is unable to a 
complete form(s) for any reason, it should be documented in the source.
Subjects Who Cannot Come to the Site
In the event a subject is unable to come to the site (e.g., physical condition is a barrier) or 
have moved to long-term follow-up, the questionnaires may be sent (e.g., mail, courier, 
email, electronically, etc.) with a request to complete them and return to the site as 
instructed by site staff. 
Questionnaires collected outside the clinic should be reviewed by qualified site staff for 
missing information and follow-up with subject may be required per investigator's 
discretion.  
Long-Term Follow-Up Phase
Completion or Discontinuation of Study-Therapy without Progression:
Subjects who have not progressed, but have discontinued or completed study therapy will 
remain on-study.  These subjects are followed for tumor assessments until unequivocal 
progression per RECIST 1.1.  Subjects will be monitored for SAEs according to 
Section 6.5.  Assessments will be completed in the following timeframes:
●
PRO questionnaires will be collected every 3 months for 2 years from C1D1 or 
until disease progression, whichever is later.  If disease progression occurs 
prior to 2 years from C1D1, both PROs should continue to be collected until 
 


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2 years from C1D1.  PRO time points are calculated from Cycle 1 Day 1.  
Following the primary analysis and implementation of Protocol Amendment 8, 
PRO collection will no longer be required.
●
Tumor assessments will be collected every 9 weeks from C1D1, then end of 
the combination phase, then every 12 weeks for 2 years (from the start of 
maintenance phase), then every 6 months for 3 years (from the last scan on the 
every 12 week schedule), then annually, until progression is noted.  Tumor 
assessment timepoints are calculated from Cycle 1 Day 1.
●
Subject status will be monitored via the collection of standard of care 
assessments, including physical exam, vital signs, and ECOG. The 
assessments will be completed per a standard of care schedule or every 
3 months (whichever is sooner), for a maximum of 3 years from C1D1 and 
documented on the appropriate eCRF. As of Amendment 8, all patients are 
beyond 3 years post C1D1, therefore these assessments are no longer required.
●
All subsequent therapies will be documented on the appropriate eCRF.
●
New onset malignancy will be assessed every 6 months for up to 10 years.
Discontinuation of Study-Therapy due to Progression
●
Survival and post-therapy information will be assessed every 3 months.
●
New onset malignancy will be assessed every 6 months for up to 10 years.
Assessment for New Onset Malignancy
All subjects will be followed for any occurrence and outcome of a second primary cancer, 
including myelodysplastic syndrome or acute myeloid leukemia.  New onset malignancy 
may be spontaneously reported at any time.  
Survival Information and Post-Therapy Information
Once an event of progression occurs, subjects will be registered as "off-study" in IRT and 
will continue to be followed for survival, post-therapy information, including date of 
progression on first and second subsequent therapy, PROs (as applicable), and new onset 
 


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malignancy, per Table 2.  Following the primary analysis and implementation of Protocol 
Amendment 8, PRO collection will no longer be required.
Survival (i.e., the date and cause of death) and post-therapy information will be collected 
on the appropriate eCRF at 3-month intervals (or as requested by sponsor to support data 
analysis) beginning on the date of disease progression and continuing either until the 
endpoint of death, until the subject is lost to follow-up, or until the study termination by 
AbbVie.  If the subject withdraws from survival 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.
The following will be collected for post-therapy information: 
●
Name(s) of post-therapy regimens;
●
Post-therapy dates of initiation and completion;
●
Date of progression to the first post-study therapy (PFS2);
●
Response to subsequent therapies and reason for discontinuation.
Subject must request to be withdrawn specifically from survival follow-up; this request 
must be documented in the subject's medical record and signed by the investigator.  If the 
subject withdraws from survival follow-up, the site staff may use a public information 
source (such as county records) to obtain information about survival status only, as 
appropriate per local regulations.
5.3.1.2
Collection and Handling of Biomarker and Optional 
Exploratory Research Samples
Blood, plasma, serum, and tumor tissue will be collected and may be utilized to evaluate 
known and/or novel markers (nucleic acids, peptides/proteins and/or metabolites) of 
disease status, related conditions or to evaluate the association with pharmacokinetics, 
safety or efficacy.  The biomarker rationale will be discussed in the Biomarker Research 
Variables Section (Section 5.3.6).
 


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All samples should be labeled and shipped as outlined in the study-specific laboratory 
manual.
AbbVie (or people or companies working with AbbVie) will store the samples in a secure 
storage space with adequate measures to protect confidentiality.  The samples may be 
retained while research on veliparib (or drugs of this class) or this disease and related 
conditions continues, but for no longer than 20 years after study completion, or per local 
requirement.  The procedure for obtaining and documenting informed consent for 
exploratory research samples is discussed in Section 9.3.
Biomarker Samples (Mandatory Sampling)
Blood and tumor tissue will be used to determine germline and tissue-based BRCA
mutation status respectively.  Other exploratory pharmacodynamic correlative studies will 
be performed.  Serum, plasma and tissue specimens may be utilized to evaluate known 
and novel markers (nucleic acids, peptides/proteins and/or metabolites) of disease status.  
Pharmacodynamic variables will be further discussed in Section 5.3.6.
Germline BRCA Sample (gBRCA)
Each subject will have blood collected (7 mL) as described in Table 3 for gBRCA testing.  
The gBRCA status of each patient will be determined using the sponsor core laboratory.  
Genetic risk assessment and counseling should proceed per NCCN guidelines or the 
standard policy of the institution.  
BRCA Sequencing 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 (7 mL 
per tube) must be obtained from all subjects per Table 3 to be tested at a future date.
 


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Blood Collection for Plasma Markers
Approximately 12 mL (Cycle 1 Day 1 and Therapy Completion Visit) or 6 mL (Cycle 3 
Day 1 and Cycle 5 Day 1) of blood will be collected pre-dose by venipuncture at time 
points outlined in conjunction with PK samples, if possible, as outlined in Table 4.  The 
collection, processing and storage should be performed as described in the study-specific 
laboratory manual.  The complete process of centrifugation, transfer to cryovial and 
freezing should be accomplished in less than 1 hour from the time of blood draw.
Blood Collection for Serum Markers
Approximately 5 mL of blood will be collected pre-dose by venipuncture as outlined in 
Table 3.  The collection should be performed as described in the study-specific laboratory 
manual.  The complete process of clot formation, centrifugation, transfer to cryovials and 
freezing should be accomplished in less than 2 hours from the time of blood draw.
Tumor Biopsy Tissue Collection
Pre-Therapy Tumor Biopsy Sample (Archived or Newly Collected Biopsy) (Required for 
Randomization)
Subjects must consent to provide available archival tissue.  A portion of this biopsy will 
be used to assess BRCA status therefore all subjects must have a pre-therapy biopsy for 
inclusion on the study.  Only one of the following forms of pre-therapy tumor tissue 
(archived tissue or newly collected biopsy) is required:
●
Archived biopsy:  The most recent archived biopsy is preferred and should be 
obtained during Screening, if possible.  If no archived material is available, a 
fresh biopsy should be collected from subjects according to institutional 
procedures for subjects willing to participate on study.
●
Newly Collected biopsy:  Sample should be collected during Screening 
period, and fixed in formalin and embedded in paraffin according to 
institutional procedures.  Tumor samples should be stored according to 
Institutional procedures until shipment to AbbVie or an AbbVie-designated 
 


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contract research organization (CRO).  AbbVie or a designated CRO will 
prepare the samples for analysis.
While sending FFPE blocks is preferred, slides prepared by the local pathology laboratory 
are acceptable and should be prepared as described in the study-specific laboratory 
manual.
Exploratory Research Samples (Optional Sampling)
Subjects will have the option to provide samples for exploratory research.  Subjects may 
still participate in the main study even if they decide not to participate in this optional 
exploratory research.
Samples for Pharmacogenetic Exploratory Research
An optional whole blood sample for DNA isolation will be collected on Cycle 1 Day 1 
and Cycle 3 Day 1 from each subject who consents to provide samples for exploratory 
research.  
Samples will be shipped frozen to AbbVie or a designated laboratory for DNA extraction 
and long-term storage.  Instructions for the preparation and shipment of the 
pharmacogenetic exploratory research samples will be provided in a laboratory manual.
Samples for Biomarker Exploratory Research
For subjects who consent, additional samples may be collected for exploratory research to 
potentially help identify biomarkers associated with subjects' response to the study drug or 
to better characterize the disease.  All subjects will have the following samples collected 
as described in the Table 3:
●
An optional post-therapy tumor tissue biopsy should be collected at the time 
point outlined in Table 3 from subjects who are willing to consent.  
Institutional procedures should be followed to fix and embed the collected 
biopsy in paraffin.  While tissue blocks are preferred, slides prepared by the 
 


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local pathology laboratory are acceptable, and should be prepared as described 
in the study-specific laboratory manual.
Optional Tissue Sample Collection
An optional post-therapy tumor tissue biopsy should be collected at the time point 
outlined in Table 3 from subjects who are willing to consent.  Collection of this tissue 
sample does not require a separate biopsy procedure and may be collected during routine 
procedures including interval surgery or during progression.  Institutional procedures 
should be followed to fix and embed the collected biopsy in paraffin.  While tissue blocks 
are preferred, slides prepared by the local pathology laboratory are acceptable, and should 
be prepared as described in the study-specific laboratory manual.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Veliparib Pharmacokinetic Specimen Collection
Approximately 3 mL of blood will be collected by venipuncture for veliparib 
concentrations at 0 hours (just before morning dose of veliparib) and other time points as 
specified per Table 4.  The date/time of collection of each blood sample and the last 
two doses of veliparib/placebo taken prior to the blood sample collection will be recorded.
If an indwelling catheter of any type is used, approximately 3 mL volume of blood must 
be collected and discarded prior to collection of the veliparib sample.  The use of 
indwelling catheter for the collection of pharmacokinetic samples is discouraged unless it 
is absolutely necessary.
Refer to the study-specific laboratory manual for detailed instructions on sample 
collection, processing and shipment.
 


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5.3.2.2
Measurement Methods
Plasma concentrations of veliparib will be determined using validated method in the Drug 
Analysis Department at AbbVie.  Plasma concentrations of veliparib metabolite(s) may be 
determined using validated or non-validated methods.
5.3.3
Efficacy Variables
The primary efficacy endpoint is PFS.  The secondary efficacy endpoints are OS and 
DRS.  The tertiary efficacy endpoints are PFS2, time from randomization to 
first subsequent therapy or death (TTFST), and time from randomization to second 
subsequent therapy or death (TTSST), and additional PRO endpoints.
5.3.3.1
RECIST 1.1 for Disease Status
Overall tumor assessment will be assessed using RECIST 1.1.  Changes in the overall 
tumor assessment over the course of therapy must be evaluated using the criteria listed 
below:
Eligibility
Subjects with measurable or non-measurable disease prior to cytoreductive surgery are 
eligible.  Subjects with measurable disease will have objective tumor response evaluated 
by RECIST 1.1.  Measurable disease is defined by the presence of at least one measurable 
lesion.  All subjects will be followed to determine the overall assessment according to 
RECIST 1.1, including subjects with no radiographically evaluable disease following 
cytoreductive surgery.
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
 


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Non-Measurable Lesions
All other lesions, including small lesions (longest 
diameter < 10 mm) as well as truly non-measurable 
lesions.  Lesions considered truly non-measurable 
include:  leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung and also 
abdominal masses that are not confirmed and followed by 
imaging techniques.
Measurable Malignant 
Lymph Nodes
To be considered pathologically enlarged and measurable, 
a lymph node must be ≥ 15 mm in short axis when 
assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline 
and in follow-up, only the short axis will be measured and 
followed.
Non-Measurable 
Malignant Lymph Nodes
Pathological lymph nodes with ≥ 10 to < 15 mm short 
axis.
 


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Special Considerations 
Regarding Lesion 
Measurability
Bone lesions
Lytic bone lesions or mixed lytic-blastic lesions, with 
identifiable soft tissue components, that can be evaluated 
by cross sectional imaging techniques such as MRI/CT 
can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability 
described above.
Blastic bone lesions are non-measurable.
Cystic lesions
Lesions that meet the criteria for radiographically defined 
simple cysts should not be considered as malignant 
lesions (neither measurable nor non measurable) since 
they are, by definition, simple cysts.
'Cystic lesions' thought to represent cystic metastases can 
be considered as measurable lesions, if they meet the 
definition of measurability described above.
However, if non-cystic lesions are present in the same 
subject, these are preferred for selection as target lesions.
Lesions with prior local treatment
Tumor lesions situated in a previously irradiated area, or 
in an area subjected to other loco-regional therapy, are 
usually not considered measurable unless there has been 
demonstrated progression in the lesion.
Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation, using calipers if 
clinically assessed.
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 
 


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(e.g., skin nodules).  For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is recommended.
Conventional CT should be performed with cuts of 5 mm or less in slice thickness 
contiguously.  This applies to tumors of the chest and abdomen.  A scale should be 
incorporated into all radiographic measurements.  MRI can be performed if required by 
local law, but should have sponsor approval.
If prior to enrollment, it is known a subject is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, MRI may be substituted.  Alternatively, a 
contrast dye preparation protocol may be used in consultation with the AbbVie TA MD.37  
The use of non-contrast CTs, which may affect how tumor progression is evaluated, is 
discouraged.  For subjects who develop contraindications to contrast after baseline 
contrast CT is done, the decision as to whether non-contrast CT or MRI should be made 
based upon discussion with the AbbVie TA MD.
For accurate objective response evaluation, PET scans and ultrasound (US) should not be 
used to measure tumor lesions.
The utilization of endoscopy and laparoscopy for objective tumor evaluation is not 
advised.  However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained.
Cytology and histology can be used to differentiate between partial response (PR) and 
complete response (CR) in rare cases.
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.
CA-125 levels:  CA-125 alone cannot be used to assess response.  If CA-125 is initially 
above the upper normal limit, it must normalize for a subject to be considered in complete 
response.
 


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


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these lesions are not required, but the presence (stable, increasing or decreasing) or 
absence of each should be noted throughout follow-up.
Re-Baseline for Interval Surgery Subjects
Interval surgery subjects will have a second baseline timepoint with imaging.  
Post-surgical imaging should be performed as close as possible to resuming therapy at 
Cycle 4 Day 1 and no more than 4 weeks prior to Cycle 4 Day 1.  The post-surgical scan 
is considered a re-baseline for the subject.  Overall tumor response assessments will be 
determined by comparing follow-up visit scans to the post-surgical baseline (re-baseline) 
scan and/or post-surgery nadir.  Adequate assessment of tumor persistence and resection 
should be made during interval surgery.
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 SOD of target lesions, 
taking as reference the baseline SOD.
Progressive Disease (PD):
At least a 20% increase in the SOD 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 
 


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examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the 'sum' of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm.  For PR, SD and PD, the actual short axis measurement of the nodes is 
to be included in the sum of target lesions.
All lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (< 5 mm).  
However, sometimes target lesions or lymph nodes become too small to measure.  If it is 
in the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present, but too small to 
measure, a default value of 5 mm should be assigned (as derived from the 5 mm CT slice 
thickness).  The measurement of these lesions is potentially non-reproducible; therefore 
providing this default value will prevent false responses or progression based upon 
measurement error.
Evaluation of Non-Target Lesions
Complete Response (CR):
The disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes 
must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s).
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.
In this setting, to achieve 'unequivocal progression' on the basis of non-target disease, 
there must be an overall level of substantial worsening in non-target disease such that, 
even in the presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest 'increase' in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare.  
 


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In the absence of radiographic or clinical evidence of progressive disease, a rise in 
CA-125 alone is not sufficient to declare progression.
New Lesions
The appearance of new malignant lesions denotes disease progression.  While there are no 
specific criteria for the identification of new radiographic lesions, the findings of a new 
lesion should be unequivocal; i.e., not attributable to differences in scanning technique, 
timing of scanning, phase of contrast administration, change in imaging modality or 
finding thought to represent something other than tumor (e.g., some 'new' bone lesions 
may be simply healing or flare of pre-existing lesions).  A lesion identified on a follow-up 
study in an anatomical location that was not scanned at baseline is considered a new 
lesion and will indicate disease progression.
If a new lesion is equivocal (e.g., too small to measure), continued therapy and follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is a 
new lesion, then progression should be declared using the date of the initial scan.
Overall Response:
If a patient has neither measurable nor non-measurable lesions evident on the baseline 
(post-surgical) tumor assessment, the overall responses for post base-line scan should be 
PD, Non-PD, or not evaluable, as follows.
Table 6.
Calculating Final Response for Subjects with No Radiographic or 
Clinical Evidence of Disease (ND) on the Post-Surgical Baseline 
Tumor Assessment
New Lesion
Overall Response
No (Absent)
nonPD (No disease)
Yes (Present)
PD (Progressive Disease)
Not Evaluated
NE*
*
NE will be used in exceptional cases where insufficient data exist, unless progressive disease is identified.
 


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The overall assessment of the tumor burden will include assessment of target (for subjects 
with measurable disease) and non-target lesion as follows:
Calculating Final Response:
Overall Response for Subjects with Measurable Disease at Baseline
Target Lesion
Non-Target Lesion
Unequivocal New Lesion*
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not evaluated
No
PR
SD
Non-PD or not evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
*
Equivocal new lesions will not allow for CR but will otherwise not impact the overall response.
Calculating Final Response for Non-Measurable Disease:
Overall Response for Subjects with Non-Measurable Disease at Baseline
Non-Target Lesion
New Lesion
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/Non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Note:
If CA-125 is initially above the upper normal limit, it must normalize for a subject to be considered in 
complete response.
5.3.4
Safety Variables
AbbVie will assess adverse events, laboratory data, and vital signs throughout the study.  
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National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) Version 4.0 Published:  May 28, 2009 (v4.03:  June 14, 2010).43
During the conduct of the study, the AbbVie medical and safety team will be monitoring 
blinded, subject laboratory results and serious adverse event data as they are reported.
5.3.5
Pharmacokinetic Variables
A nonlinear mixed effect modeling analysis will be conducted to estimate the population 
pharmacokinetic parameters of veliparib such as apparent oral clearance (CL/F) and 
volume of distribution (V/F).  The results of pharmacokinetic analyses may be reported in 
a separate report.
AbbVie or a designated laboratory will store the pharmacokinetic samples in a secure 
storage space with adequate measures to protect confidentiality.  To increase confidence 
in trends, remaining sample aliquots may be used to perform replicate tests, or sample 
analysis at additional time points for tests currently identified in the protocol.  Upon 
completion of this research AbbVie or a designated laboratory will destroy the samples.
5.3.6
Biomarker and Optional Exploratory Research Variables
Biomarker (blood, plasma, serum, and tissue) and optional pharmacogenetic samples will 
be collected to investigate and conduct exploratory analyses of biomarkers including, but 
not limited to, nucleic acids, proteins, lipids or metabolites.  
Biomarker and pharmacogenetic research samples may be analyzed with the intent of 
identifying potential associations with subject outcome or to better characterize the 
disease.  These characterizations may include genetic and non-genetic assessment of DNA 
repair pathways, pathway(s) targeted by the study drug (veliparib/placebo) or those 
believed to be related to the disease or to drug response.  Specifically, biomarker samples 
will be used to determine germline and tissue-based BRCA status.  Additional analysis 
aimed at identifying underlying defects in the homologous recombination pathway, 
regardless of etiology, may be performed and associated with response.  The information 
 


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learned from analyzing biomarker and pharmacogenetic samples may be used to 
investigate factors influencing response to treatment, scientific questions related to cancer, 
and/or in the development of new therapies and diagnostic tests.  The results of biomarker 
and pharmacogenetic testing may not be included with the study summary.
Biomarker and exploratory research samples may be anonymized and used for diagnostic 
test development.  
5.3.7
Pharmacogenetic Variables
Biomarker (blood, plasma, serum, and tissue) and optional pharmacogenetic samples will 
be collected to investigate and conduct exploratory analyses of biomarkers including, but 
not limited to, nucleic acids, proteins, lipids or metabolites.  
Biomarker and pharmacogenetic research samples may be analyzed with the intent of 
identifying potential associations with subject outcome or to better characterize the 
disease.  These characterizations may include genetic and non-genetic assessment of DNA 
repair pathways, pathway(s) targeted by the study drug (veliparib/placebo) or those 
believed to be related to the disease or to drug response.  Specifically, biomarker samples 
will be used to determine germline and tissue-based BRCA status.  Additional analysis 
aimed at identifying underlying defects in the homologous recombination pathway, 
regardless of etiology, may be performed and associated with response.  The information 
learned from analyzing biomarker and pharmacogenetic samples may be used to 
investigate factors influencing response to treatment, scientific questions related to cancer, 
and/or in the development of new therapies and diagnostic tests.  The results of biomarker 
and pharmacogenetic testing may not be included with the study summary.
Biomarker and exploratory research samples may be anonymized and used for diagnostic 
test development.  AbbVie (or a designated laboratory) will store the samples in a secure 
storage space with adequate measures to protect confidentiality.  The samples will be 
retained while research on veliparib (or drugs of this class) continues for up to but no 
longer than 20 years.
 


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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Subjects will receive therapy until disease progression according to Section 5.3.3.1, 
RECIST 1.1., completion of therapy, or unmanageable toxicity (per discussion with the 
AbbVie TA MD).  Subjects who discontinue therapy for reasons other than disease 
progression will continue to be followed as per the schedule of assessments in Table 2, 
until disease progression occurs.
Each subject also has the right to withdraw from therapy at any time.  Additionally, the 
Investigator may discontinue a subject from therapy at any time for any reason if he/she 
considers it necessary, including the occurrence of noncompliance with the protocol.
Each subject will discontinue therapy (as applicable) if any of the following occur:
●
The subject experiences an unmanageable toxicity or requires an alternate 
anticancer agent(s) that is not specified in the protocol.
●
Subject requires cancer-directed radiotherapy or surgery related to clinical 
disease progression.  
●
Subject is suspected to be pregnant; pregnancy is confirmed or begins 
breastfeeding during the combination and maintenance therapy phases of the 
study.
●
The subject or subject's legally acceptable representative decides to withdraw 
consent for any reason.
●
Any other medical reason that AbbVie or the study Investigator deems 
appropriate.
Discontinued subjects will not be replaced.
A Therapy Completion Visit will be conducted for all subjects when therapy is 
discontinued.  All subjects will have one Follow-Up Visit approximately 30 days after the 
Therapy Completion Visit.  Subjects starting any new cancer therapy within the 30 days 
after the last dose of study drug (veliparib/placebo) must complete the 30-day follow-up 
 


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assessments in advance of starting any anti-cancer therapy.  This Follow-Up Visit does 
not need to be performed for subjects who have had a Therapy Completion Visit 
conducted ≥ 30 days after the last dose of study drug (veliparib/placebo).  For subjects 
who discontinue therapy for reasons other than progression, a tumor scan will not be 
required if completed within 4 weeks prior to the Therapy Completion Visit.
Once an event of progression occurs, subjects will be registered as "off-study" within IRT 
and continue to be followed during the Long-Term Follow-Up Phase (per Table 2 and 
Section 5.3.1.1).
If a subject completes study therapy 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.
In the event that a subject becomes pregnant during the study, the administration of study 
drugs to that subject must be discontinued immediately.  The site must report the 
pregnancy by telephone within 24 hours to one of the AbbVie representatives listed in 
Section 7.0.
5.4.2
Discontinuation of Carboplatin/Paclitaxel and 
Veliparib/Placebo 
Carboplatin, paclitaxel, and veliparib/placebo, dose reductions or delays and 
discontinuation will occur as outlined in Section 5.7.
5.4.3
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.
 


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The following procedures for study discontinuation will be followed:
●
If the Sponsor has decided to prematurely discontinue the study, the Sponsor 
will promptly notify in writing each Investigator as well as regulatory 
authorities of the decision and give detailed reasons for the discontinuation.
●
Each Investigator must promptly notify the IRB/IEC and give detailed reasons 
for the discontinuation.
●
Each Investigator must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments such as replacement of 
therapy, if applicable, by other appropriate regimens.
5.5
Treatments
5.5.1
Treatments Administered
Subjects will receive the following:
●
Carboplatin/Paclitaxel plus placebo PO BID for six 21-day cycles, followed by 
maintenance therapy with placebo PO BID for up to an additional 
thirty 21-day cycles;
●
Carboplatin/Paclitaxel plus veliparib 150 mg PO BID for six 21-day cycles, 
followed by maintenance therapy with placebo PO BID for up to an additional 
thirty 21-day cycles; or
●
Carboplatin/Paclitaxel plus veliparib 150 mg PO BID for six 21-day cycles, 
followed by maintenance therapy with veliparib 400 mg PO BID for up to an 
additional thirty 21-day cycles.
●
For subjects switching to docetaxel due to discontinuation of paclitaxel, 
following the 7-day washout period of veliparib, docetaxel in combination 
with carboplatin is to be administered per institutional guidelines, including 
modifications for toxicity.
General chemotherapy guidelines are found in Appendix D.
 


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5.5.1.1
Administration of Veliparib/Placebo
Subjects will self-administer the morning dose of veliparib/placebo and the evening doses 
of veliparib/placebo approximately 8 to 12 hours after the morning dose with or without 
food in the same calendar day, starting on Day 1 of each cycle.  Veliparib/placebo will be 
taken 1 hour prior to paclitaxel for Day 1 of Cycle 1, 2, 3, and 4 and in the case of 
veliparib/placebo interruptions during the Combination Phase.
During the maintenance phase (Cycles 7 – 36) standard anti emetic therapy may be 
administered as appropriate, including a combination of standard antiemetics 
(i.e., 5-HT3 receptor antagonists, steroids, and prochlorperazine, and/or promethazine).
It is recommended that if a subject misses a scheduled dose of veliparib/placebo and less 
than 6 hours have passed since the scheduled dosing time, the dose should be immediately 
taken.  It is recommended that if more than 6 hours have passed since the scheduled 
dosing time, the subject should not take the missed dose but should wait and take the next 
regularly scheduled dose.
If the subject vomits within 15 minutes of taking veliparib/placebo, another dose will be 
administered.  The dose may only be repeated once.  If more than 15 minutes has passed 
from the time of oral dosing then no additional doses will be taken.
5.5.1.2
Administration of Carboplatin/Paclitaxel
Investigators should evaluate subjects for carboplatin and paclitaxel treatment per the 
locally approved product label, local practice, or applicable SmPC.  Due to the risk of 
immediate hypersensitivity reaction, paclitaxel should always be administered before 
carboplatin.
Best supportive care and treatment for nausea and vomiting can be provided according to 
institutional guidelines or American Society of Clinical Oncology (ASCO) or NCCN 
guidelines.
 


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For example, 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 mg IV OR 0.50 mg oral, Day 1 only
●
Dexamethasone 8 mg (IV or oral), Days 1 to 3
NK1 antagonist 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 or Fosaprepitant 150 mg 
IV Day 1
●
5-HT3 receptor antagonist dosing
Dexamethasone:  12 mg (IV or oral) on Day 1 and 8 mg (IV or oral) Days 2 and 3 or 
Days 2 – 4 (with aprepitant) or Dexamethasone:  12 mg (IV or oral) on Day 1 and 8 mg 
(IV or oral) on Day 2 and 8 mg (IV or oral) twice per day on Days 3 and 4 (with 
fosaprepitant).38
5.5.1.2.1
Paclitaxel
Pre-Medication for Paclitaxel
To reduce the severity of hypersensitivity reactions due to treatment with paclitaxel, 
manage according to institutional guidelines, the locally approved product label, local 
practice, or applicable Summary of Product Characteristics (SmPC, i.e., premedication 
with corticosteroids, diphenhydramine, and H2 antagonists).  Pre-medications are to be 
documented in the appropriate forms in EDC.
 


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Weekly Paclitaxel
For subjects receiving paclitaxel 80 mg/m2, paclitaxel will be administered over 
approximately 1-hour as an IV infusion on Days 1, 8, and 15 of each 21-day cycle × 
6 cycles.
Every 3-Weeks Paclitaxel
For subjects receiving paclitaxel 175 mg/m2, paclitaxel will be administered as an IV 
infusion over approximately 3 hours on Day 1 of each 21-day cycle × 6 cycles.
5.5.1.2.2
Carboplatin
Carboplatin AUC 6 will be administered as a 30-minute IV infusion, following paclitaxel 
administration on Day 1 of each 21-day cycle × 6 cycles.  Carboplatin dose calculation 
instructions can be found in Appendix E.
5.5.2
Identity of Investigational Products
Information regarding the veliparib formulation to be used in this study is presented in 
Table 7.
Table 7.
Identity of Investigational Product
Study Drug
Dosage 
Form
Strength
Route of 
Administration
Manufacturer
Veliparib (ABT-888)
Capsule
50 mg or 100 mg
Oral
AbbVie
Placebo
Capsule
Placebo to match 50 mg 
and 100 mg
Oral
AbbVie
5.5.2.1
Standard of Care Medicinal Products
Information regarding carboplatin, paclitaxel, and docetaxel to be used in this study is 
presented in Table 8.
 


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Table 8.
Standard of Care Medicinal Products
Standard of Care Products
Dosage Form
Route of Administration
Carboplatin 
(commercially available)*
Solution in a vial
Intravenously
Paclitaxel
(commercially available)*
Solution in a vial
Intravenously
Docetaxel
(commercially available)*
Solution in a vial
Intravenously
*
Carboplatin, docetaxel and paclitaxel formulations may vary based on the source.  Each investigational site will be 
responsible for tracking the lot numbers for all non-investigational medicinal products (e.g., carboplatin, paclitaxel 
and docetaxel) dispensed.
Note:
AbbVie will not be providing carboplatin, paclitaxel, or docetaxel during the study.
5.5.2.2
Packaging and Labeling
Veliparib (ABT-888) will be packaged in high-density polyethylene (HDPE) bottles 
containing either 50 mg, 100 mg, or matching placebo capsules.  Bottles of 50 mg and 
matching placebo will contain 44 capsules (this includes 2 additional capsules in each 
bottle dispensed per cycle to cover loss, spillage or replacement due to vomiting within 
15 minutes).  Bottles of 100 mg and matching placebo will contain 44 capsules (this 
includes 2 additional capsules in each bottle dispensed per cycle to cover loss, spillage or 
replacement due to vomiting within 15 minutes).  Each bottle label will include all 
information as required by local regulations and must remain affixed to the bottle.  All 
blank spaces on the label will be completed by site staff prior to dispensing to the subject.
AbbVie will provide detailed instructions and training for the handling of study supplies 
to the study site.
5.5.2.3
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 9, until they are dispensed for subject use or are 
returned to AbbVie.
 


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Table 9.
Study Drug Storage Conditions
Study Drug
Country
Storage Conditions
Veliparib (ABT-888) or placebo
All countries, except 
Australia/New Zealand
Store at 15° to 25°C (59° to 77°F)
Veliparib (ABT-888) or placebo
Australia/New Zealand
Store below 25°C
Investigational products are for investigational use only, and are to be used only within 
the context of this study.  The clinical supplies for this study must be maintained under 
adequate security and stored under conditions specified on the label.
The controlled storage area should have a temperature recording device.  A storage 
temperature log is to be maintained to document proper storage conditions.  The room 
temperature storage must be recorded each business day to document proper function.
Malfunctions or temperature excursions outside the specified storage range for veliparib 
or matching placebo must be reported to the sponsor immediately.  Sites should use the 
AbbVie Temperature Excursion Management System (ATEMS) module via IRT, if 
available, or fax copies of the temperature log indicating the extent of the excursion (time, 
duration of the temperature excursion, min/max values and study drugs affected) to 
AbbVie Global Drug Supply Management including the Storage Temperature Excursion 
Reporting Form.
This information will be used to determine the continued acceptability of the drug.
In case of a temperature excursion, study medication should be quarantined and not 
dispensed until AbbVie Global Pharmaceutical Research & Development (GPRD) or 
ATEMS deems the medication as acceptable.
Storage and Disposition of Carboplatin and Paclitaxel
Paclitaxel
Vials must be stored between 15° to 25°C (59° to 77°F) (or per locally approved label or 
SmPC) in the provided cartons to protect from light. 
 


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Carboplatin
Vials must be stored between 15° to 25°C (59° to 77°F) (or per locally approved label or 
SmPC) in the provided cartons to protect from light.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects in the study will be randomized using an IRT.  Before the study is initiated, 
directions for the IRT will be provided to each site.  The site will contact the IRT to obtain 
a Screening (subject) number once the subject has signed the informed consent and a 
study-specific procedure has been performed (i.e., laboratory samples 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.  For 
others, the site will access the system and a unique randomization number will be 
provided.  Note:  The Investigator's treatment decision must be documented prior to 
accessing the IRT for subject randomization.
The IRT will randomize subjects into the 3 treatment arms in a 1:1:1 ratio.  Subject 
randomization will be stratified by stage of disease (III versus IV), residual disease and 
choice of regimen, and region of the world (Japan versus North America or Rest of the 
World), and germline BRCA mutation status (gBRCA positive versus gBRCA negative or 
Unknown).  The stratification factors used for the randomization should be the last values 
on the date of randomization and should be consistent with those on the eCRF.
A bottle number randomization schedule and a subject randomization schedule will be 
generated by the Clinical Statistics Department at AbbVie prior to the start of the study.  
A copy of all randomization schedules will be kept by the Clinical Statistics Department 
at AbbVie and a copy will be forwarded to the IRT vendor.
5.5.4
Selection and Timing of Dose for Each Subject
All randomized subjects will receive veliparib 150 mg/placebo PO BID in combination 
with chemotherapy (carboplatin/paclitaxel) for 6 cycles.  Subjects who complete the 
Combination Therapy Phase and who have not progressed will receive single-agent 
 


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veliparib/placebo for an additional 30 cycles (Cycles 7 – 36) starting at 300 mg BID.  If 
the subject tolerates 300 mg BID, veliparib/placebo should be increased to 400 mg BID 
during the Maintenance Phase.  Veliparib/placebo will be dosed starting on Day 1 of each 
cycle and dosed continuously (21/21 days).  One dose will be taken in the morning and 
the second dose will be taken in the evening.  The morning dose of veliparib/placebo
should be dosed in clinic prior to carboplatin and paclitaxel on Day 1 of Cycles 1, 2, 3, 
and 4 for PK sampling purposes.
All randomized subjects will also receive carboplatin (AUC 6) on Day 1 of each cycle and 
paclitaxel (80 mg/m2 on Days 1, 8, and 15 of each cycle, or 175 mg/m2 on Day 1 of each 
cycle) (unless a delay is required per locally approved product labels or SmPCs).  The 
paclitaxel infusion should be given first.
5.5.5
Blinding
AbbVie (with the exception of AbbVie Drug Supply Management), the Investigator, the 
study site personnel and subject will remain blinded to each subject's therapy with 
veliparib or placebo throughout the course of the study.
All subjects will be treated with open-label carboplatin and paclitaxel.
The IRT will provide access to blinded subject therapy information during the double 
blind period.
AbbVie must be notified before the blind is broken unless identification of the 
investigational product is required for medical emergency, i.e., situation in which the 
knowledge of the specific blinded therapy will affect the immediate management of the 
subject's conditions (e.g., antidote is available).  AbbVie must then be notified within 
24 hours of the blind being broken.  The date and reason that the blind was broken must 
be recorded in the source documentation and eCRF, as applicable.
 


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5.5.5.1
Blinding of Investigational Product
The IRT will provide access to blinded subject therapy 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 treatment is required, every effort must 
be made to contact the AbbVie TA MD (listed in Section 6.7) prior to contacting the IRT 
for 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.
5.5.5.2
Blinding of Data for Independent Data Monitoring 
Committee (IDMC)
An Independent Data Monitoring Committee (IDMC) will review safety data for this 
study in an un-blinded fashion approximately 12 months and 24 months from the date the 
first subject is randomized.  Details of the IDMC review will be outlined in the IDMC 
Charter.  Aggregate clinical safety data will be reviewed on a real-time basis throughout 
the course of the study.
5.5.5.2.1
Requested Unblinding Following Progression for 
Subsequent Treatment
For subjects who have completed Study M13-694 and for whom the treatment assignment 
is necessary for immediate patient management and treatment decisions, unblinding may 
be considered on a case-by-case basis.  Unequivocal disease progression per RECIST 1.1 
must be documented and the data must be complete prior to unblinding the case, to ensure 
that the data integrity is maintained.  In addition, these requests would be anticipated to be 
either consistent with the indication for PARP inhibitors or for patients for whom this 
information is necessary for participation in other clinical studies.  
Patients who undergo optional treatment unblinding and are found to have been 
randomized to "placebo" will not continue to receive veliparib.
 


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a.
Criteria for Requested Unblinding: 
The unblinding procedure applies to patients who experience progression as 
defined in Section 5.3.3.1.  It is vital to properly apply the protocol specified 
definition of progression.  In addition, the treatment assignment must be needed 
for immediate treatment decisions.  If any questions arise with regard to 
progression for a patient, please contact the AbbVie TA MD/SD.
Prior to unblinding, a separate document requesting unblinding with rationale
must be submitted and processed.  The AbbVie TA MD/SD will provide written 
confirmation to the site that the patient has an adequately documented progression.  
This documentation must be archived properly in the appropriate site files.
b. Unblinding Procedures 
Patients who meet the criteria for requested unblinding will be unblinded by 
AbbVie and the treatment assignment provided to the site.  Please allow 3 – 5 days 
for unblinding.
5.5.6
Treatment Compliance
The Investigator or his/her designated and qualified representatives will 
administer/dispense study drugs only to subjects enrolled in the study in accordance with 
the protocol.  The study drugs must not be used for reasons other than that described in 
the protocol.
Veliparib/Placebo should be taken as directed by the Investigator.  Carboplatin and 
paclitaxel will be administered intravenously by trained site personnel.
Subjects will be instructed to return all veliparib/placebo bottles (empty, partially filled or 
full) to the study site personnel prior to each cycle and at the Therapy Completion Visit.  
The site staff will document the bottles returned and the number of capsules per bottle on 
the appropriate form.  
 


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Upon completion or termination of the study, all original bottles/cartons containing 
unused veliparib/placebo (empty containers will be defaced and discarded on site) will be 
returned to AbbVie according to AbbVie's instructions, or if pre-arranged between the 
sponsor and site, destruction of used and unused bottles will be performed at the site.
Unless otherwise directed by the Investigator, a subject will be considered compliant with 
veliparib/placebo if 80% of the assigned dose is taken during a cycle.  Compliance below 
80% will require counseling of the subject by study site personnel.
5.5.7
Drug Accountability
The site will record the dose of carboplatin and paclitaxel (and docetaxel, if applicable) 
given to each subject in the source documents and on the eCRF.  As the Investigator will 
obtain carboplatin, paclitaxel and docetaxel commercially, site inventory and 
accountability of carboplatin, paclitaxel and docetaxel will not be performed, and drug 
accountability forms will not be provided.  Each investigational site will be responsible 
for tracking the lot numbers for all non-investigational medicinal products 
(e.g., carboplatin, paclitaxel and docetaxel) dispensed.
Upon receipt of a shipment of veliparib/placebo, the representative at each site will 
1) open and inspect the shipment; 2) verify that the veliparib/placebo has been received 
intact, in the correct amounts and at the correct address; 3) sign and date the Proof of 
Receipt (POR) or similar documentation accompanying the shipment; 4) register the 
shipment as received via the IRT.  All 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 IRT.
An overall accountability of the study drugs will be performed and verified by the site 
monitor throughout the study and at the study site closeout visit.  An accurate running 
inventory of veliparib/placebo will be maintained utilizing the IRT drug accountability 
module and, if required, according to your institutional policy and will include the lot 
 


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number, POR number(s), the bottle/kit numbers, and the date veliparib/placebo was 
dispensed for each subject.
Upon completion or termination of the study, all original containers containing unused 
study drug (veliparib/placebo, empty containers will be defaced and discarded on site) 
will be returned to a destruction facility according to instructions from AbbVie or if 
prearranged between the sponsor and site, destruction of used and unused 
veliparib/placebo in bottles will be performed at the site.
The study Investigator or his/her designated representative agrees not to supply study 
medication to any persons not enrolled in the study or not named as a sub-investigator 
listed on the FDA 1572 or Investigator Information and Agreement (IIA) form.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The proposed Phase 3 study will evaluate the efficacy and tolerability of veliparib in 
combination with standard chemotherapy compared to chemotherapy alone in women 
with previously untreated, Stage III or IV high-grade serous epithelial ovarian, fallopian 
tube, or primary peritoneal cancer.  Treating physicians will be allowed the choice of 
treating with either paclitaxel on a weekly schedule or every 3 weeks schedule in 
combination with carboplatin AUC 6 such that there are the following treatment choices 
prior to randomization:  
1.
Primary cytoreductive surgery with carboplatin and weekly paclitaxel (21-day 
cycle)
2.
Carboplatin and weekly paclitaxel (21-day cycle) with interval cytoreductive 
surgery after Cycle 3
3.
Primary cytoreductive surgery with carboplatin and Q3-weeks paclitaxel (21-day 
cycle)
 


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4.
Carboplatin and Q3-weeks paclitaxel (21-day cycle) with interval cytoreductive 
surgery after Cycle 3
Following the Investigator's choice of therapy, subjects will be randomized in a 1:1:1 ratio 
to one of the following:
●
Carboplatin/paclitaxel plus placebo for 6 cycles followed by placebo 
maintenance therapy for up to an additional 30 cycles (Cycles 7 – 36)
●
Carboplatin/paclitaxel plus veliparib for 6 cycles followed by placebo 
maintenance therapy for up to an additional 30 cycles (Cycles 7 – 36)
●
Carboplatin/paclitaxel plus veliparib for 6 cycles followed by veliparib 
maintenance therapy for up to an additional 30 cycles (Cycles 7 – 36)
These regimens are supported as category 1 level of evidence by NCCN guidelines and 
consistent with current standard of care.39  This design will allow the effect of adding 
veliparib to standard chemotherapy to be assessed separately from the effect of adding 
veliparib as induction therapy and maintenance therapy.  A pre-specified alpha allocation 
rule is used to control the overall type I error rate.
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be used in 
this study.
The efficacy measurements in this study are standard and validated.  Progression-free 
survival is a widely accepted endpoint of clinical importance for the evaluation of subjects 
with previously untreated ovarian cancer.  Additionally, RECIST 1.1 is a validated 
guideline for the measurement of responses in subjects with advanced or metastatic solid 
tumors.
 


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5.6.3
Suitability of Subject Population
The proposed Phase 3 study will evaluate the efficacy and tolerability of veliparib in 
combination with standard chemotherapy compared to chemotherapy alone in subjects 
with previously untreated Stage III or IV high-grade serous epithelial ovarian, fallopian 
tube, or primary peritoneal cancer.  The study will enroll subjects ≥ 18 years of age with a 
histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma 
FIGO Stage III or IV, with appropriate tissue available for histologic evaluation.  The 
proposed inclusion and exclusion criteria are anticipated to result in a study subject 
population representative of ovarian cancer patients who are receiving front line systemic 
therapy with carboplatin and paclitaxel according to current practice guidelines.
5.6.4
Selection of Doses in the Study
The doses of standard chemotherapy (carboplatin and paclitaxel) are identical to those 
used as standard first-line therapy for the treatment of ovarian cancer39 and to those used 
in the GOG 9923 study.  The dose of veliparib in combination with carboplatin and 
paclitaxel is based upon the GOG 9923 study in subjects with newly diagnosed ovarian 
cancer in which the recommended dose of veliparib in combination with carboplatin and 
paclitaxel was determined to be 150 mg PO BID, and as verified by assessment of 
tolerability beyond Cycle 1 during the expansion phase.  This Phase 3 study will allow 
subjects to receive veliparib 300 – 400 mg PO BID maintenance therapy following the 
completion of 6 cycles of chemotherapy with veliparib/placebo.  This dose has been 
selected based upon the recommended Phase 2 dose (CTEP 8282) and additional safety 
and efficacy data in Phase 2 studies in gBRCA breast cancer (CTEP 8264) and ovarian 
cancer (GOG 280) in which durable responses were observed to single-agent therapy.40
The maximum dose of veliparib for any subject in this study is 150 mg BID in 
combination with carboplatin and paclitaxel for 21 of 21 days per cycle over 6 cycles and 
400 mg BID as single-agent therapy for 21 of 21 days per cycle over 30 cycles.
 


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5.7
Dose Reductions or Delays
In order to maintain dose-intensity and cumulative dose-delivery on this study, reasonable 
efforts will be made to minimize dose reduction and therapy delays as specified.  Any 
subject whose therapy is delayed must be evaluated on a weekly basis until adequate 
hematologic and non-hematologic parameters have been met.  The therapy schedule will 
then proceed in the usual sequence.  For the purposes of this section, therapy refers to 
veliparib/placebo and chemotherapy.
Dose-Limiting Hematologic Toxicities
Dose-limiting hematological toxicities will include only those listed in Table 10.  Dose-
limiting toxicities will be handled according to Table 11 (Q3-weeks) and Table 12
(Q-week).
Table 10.
Dose Limiting Hematological Toxicities
Febrile neutropenia
Prolonged Grade 4 neutropenia persisting for greater than 7 days
Grade 4 thrombocytopenia (< 25,000/mm3)
Bleeding associated with Grade 3 thrombocytopenia (25,000 to < 50,000/mm3)
Grade 4 neutropenia with severe infection
No dose modifications will be made for anemia.  Subjects may receive red blood cell 
transfusions and/or erythropoiesis stimulating agents using standard supportive care 
guidelines.  In cases of profound anemia where additional intervention or dose 
modification may be considered appropriate please contact the AbbVie TA MD.
For dose-limiting hematological toxicity the cycle should be delayed until the ANC 
recovers to ≥1,000 cells/mm3 and the platelet count recovers to ≥ 75,000/mm3 (Grade 1).  
For dose-limiting neutropenia, veliparib/placebo should be held until the ANC recovers to 
≥1,000 cells/mm3.  For dose-limiting thrombocytopenia, veliparib/placebo should be held 
 


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until the platelet count recovers to ≥ 75,000/mm3.  Once veliparib/placebo is reinstituted, 
the dose will remain the same.
Unless required per the Investigator, there should be no modifications for uncomplicated 
Grade 4 neutropenia lasting ≤ 7 days or for uncomplicated Grade 3 thrombocytopenia.
5.7.1
Dose Reductions or Delays for Carboplatin and Paclitaxel 
with Placebo/Veliparib (Cycles 1 – 6)
If a subject experiences an adverse event that results in a delay in starting a cycle or 
requires that therapy be delayed or interrupted during a cycle, the subject will complete 
the planned activities per Table 1 and Section 5.3.1.1.  For subjects receiving carboplatin 
and paclitaxel with veliparib/placebo (Cycles 1 – 6), re-escalation of the dose following 
dose reductions is not allowed.
5.7.1.1
Guidelines for Hematologic Toxicity During Combination 
Phase
Initial therapy modifications may consist of cycle delay and/or dose reduction.  Treatment 
decisions will be based on the ANC rather than the total white cell count.
Administration of chemotherapy in Cycles 1 – 6 should not begin until the ANC is 
≥1000 cells/mm3 and the platelet count is ≥75,000/mm3.  While subjects with an ANC 
1000 – 1499/mm3 or platelet count 75,000 – 99,000/mm3 may be able to proceed with 
therapy; recommended dose modifications are outlined in Table 11 and Table 12.
For the weekly regimen, the Day 8 and 15 weekly paclitaxel doses should not be given 
unless the ANC ≥ 500 cells/mm3 and the platelet count ≥ 50,000 cells/mm3.  For subjects 
with an ANC < 500 cells/mm3 or platelets < 50,000 cells/mm3, the dose should be omitted 
and dose reductions should be used for the following cycle.  Day 8 and/or Day 15 cycle 
days should be omitted in their entirety in the event of delays due to hematological 
toxicity.  Within a given cycle, if the Day 8 dose is held and the counts recover by 
Day 15, the Day 15 dose may be given.
 


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During the Combination Phase in the event of chemotherapy delays/interruptions 
veliparib/placebo is continued in the absence of a dose-limiting toxicity as part of the 
same cycle.  A new cycle (subsequent cycle) is started when chemotherapy is restarted.
Guidelines for dose modifications and delays for hematological toxicity during the 
Combination Phase are summarized as follows:
 


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Table
Brief Table Title
Summary of Guidance
Note:
Table 10
Dose Limiting Hematological 
Toxicities
Hold study therapy until recovered (including veliparib/placebo) 
Dose modification per Table 11 or Table 12
If a subject experiences both a DLT and a delay for the 
same hematologic parameter (i.e., ANC) within a given 
cycle, only one dose modification is indicated
Table 11
Q3-Week Dose Modifications 
for Dose Limiting Hematologic 
Toxicity, Reduced ANC or 
Platelets on D1, or Cycle Delay 
> 7 Days due to Hematologic 
Toxicity
Modifications should occur for the following:
1.
Dose limiting hematological toxicities (Table 10)
2.
Reduced ANC or Platelets on Day 1  

Delay of cycle Day 1 therapy if ANC < 1000/mm3 or 
Platelets < 75,000/mm3;

If ANC 1001 – 1499/mm3 or Platelets 75,000 –
99,000/mm3, the patient can be immediately treated 
with a dose reduction OR treatment can be delayed 
1 week, to allow for hematologic recovery, and 
treatment resumed without dose reduction (per the 
investigator's discretion).
3.
Delayed hematological recovery for > 7 days.
If ANC recovers to ≥ 1500/mm3 and Platelets recover to 
≥100,000/mm3 within 7 days, no dose modification may be 
needed and cycle Day 1 can be reattempted.
Veliparib/Placebo is continued despite chemotherapy 
delays in the absence of a DLT.  Following a DLT, 
veliparib/placebo may be restarted when the ANC 
≥1000/mm3 and Platelets ≥ 75,000/mm3
Table 12
Q-Week Dose Modifications 
for Dose-Limiting Hematologic 
Toxicity, Reduced ANC 
Platelets on D1, or Cycle Delay 
> 7 Days due to Hematologic 
Toxicity
Modifications should occur for the following:
1.
Dose limiting hematological toxicities (Table 10)
2.
Reduced ANC or Platelets on Day 1  

Delay of cycle Day 1 therapy if ANC < 1000/mm3 or 
Platelets < 75,000/mm3;

Dose reduce OR delay therapy if ANC 1001 –
1499/mm3 or Platelets 75,000 – 99,000/mm3 (per the 
Investigator's discretion);

Delayed hematological recovery for > 7 days
If ANC recovers to ≥ 1500/mm3 and Platelets recover to 
≥100,000/mm3 within 7 days, no dose modification may be 
needed and cycle Day 1 can be reattempted.
Veliparib/Placebo is continued despite chemotherapy 
delays in the absence of a DLT.  Following a DLT, 
veliparib/placebo may be restarted when the ANC 
≥1000/mm3 and Platelets ≥ 75,000/mm3
Table 13
Q-Week Dose Modifications 
for Hematologic Toxicity on 
Day 8 or 15
Day 8 and/or Day 15 paclitaxel should be omitted when ANC or 
platelets are not adequate 'on that day' for treatment.
Not applicable
 


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Table 11.
Q3-Week Schedule Dose Modifications for Dose Limiting 
Hematologic Toxicity, Reduced ANC (1000 – 1499/mm3) or 
Reduced Platelets (75,000 – 99,000/mm3) on Day 1, or Cycle Delay 
> 7 Days due to Hematologic Toxicity
ANC
PLT
First Occurrence*
Second Occurrence
Third Occurrence**
Yes
No
Reduce carboplatin one 
AUC unit (AUC 5) and 
add G-CSF
Reduce carboplatin 
one AUC unit (AUC 4)
Discontinue 
veliparib/placebo and 
notify AbbVie TA MD
Yes
Yes
Reduce carboplatin one 
AUC unit (AUC 5) and 
add G-CSF
Reduce carboplatin 
one AUC unit (AUC 4)
Discontinue 
veliparib/placebo and 
notify AbbVie TA MD
No
Yes
Reduce carboplatin one 
AUC unit (AUC 5)
Reduce carboplatin 
one AUC unit (AUC 4)
Discontinue 
veliparib/placebo and 
notify AbbVie TA MD
*
GCSF should continue through the end of the Combination Phase, once initiated.  Refer to the Guidelines for the 
Use of Hematopoietic Cytokines.
**
If the subject has recovered within 7 days, dose modifications may not be needed and veliparib/placebo can be 
continued.  Following recovery, Day 1 of the cycle is reattempted.  
Note:
For cycle delays > 21 days, notify the AbbVie TA MD.
Table 12.
Q-Week Schedule Dose Modifications for Dose-Limiting 
Hematologic Toxicity, Reduced ANC (1000 – 1499/mm3) or 
Reduced Platelets (75,000 – 99,000/mm3) on Day 1, or Cycle Delay 
> 7 Days due to Hematologic Toxicity
ANC
PLT
First Occurrence*
Second Occurrence
Third Occurrence**
Yes
No
Reduce carboplatin 
one AUC unit (AUC 5) 
and add G-CSF
Discontinue Day 15 paclitaxel 
dose 
Discontinue 
veliparib/placebo and 
notify AbbVie TA MD
Yes
Yes
Reduce carboplatin 
one AUC unit (AUC 5) 
and add G-CSF
Reduce carboplatin one AUC 
unit (AUC 4) and discontinue 
Day 15 paclitaxel dose 
Discontinue 
veliparib/placebo and 
notify AbbVie TA MD
No
Yes
Reduce carboplatin 
one AUC unit (AUC 5)
Reduce carboplatin one AUC 
unit (AUC 4)
Discontinue 
veliparib/placebo and 
notify AbbVie TA MD
*
GCSF should continue through the end of the Combination Phase, once initiated.  Refer to the Guidelines for the 
Use of Hematopoietic Cytokines.
**
If the subject has recovered within 7 days, dose modifications may not be needed and veliparib/placebo can be 
continued.  Following recovery, Day 1 of the cycle is reattempted.
 


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Table 12.
Q-Week Schedule Dose Modifications for Dose-Limiting 
Hematologic Toxicity, Reduced ANC (1000 – 1499/mm3) or 
Reduced Platelets (75,000 – 99,000/mm3) on Day 1, or Cycle Delay 
> 7 Days due to Hematologic Toxicity (Continued)
Note:
For cycle delays > 21 days, notify the AbbVie TA MD.
For subjects who have had 2 dose reductions for reduced ANC, and then develop reduced platelets, an 
additional dose modification is allowed but should be discussed with the AbbVie TA MD.  Alternatively, for 
subjects who have had 2 dose reductions for reduced platelets, and then develop reduced ANC, an additional 
dose modification is allowed but should be discussed with the AbbVie TA MD.
Table 13.
Q-Week Dosing Schedule Modifications for Hematologic Toxicity 
on Day 8 or 15
ANC 
< 500
PLT 
< 50
First Occurrence*
Second Occurrence
Third Occurrence
Yes
No
Reduce carboplatin one 
AUC unit (AUC 5) and 
add G-CSF with the 
next cycle
Discontinue Day 15 
paclitaxel dose with the next 
cycle
Discontinue 
veliparib/placebo and 
notify AbbVie TA MD
Yes
Yes
Reduce carboplatin one 
AUC unit (AUC 5) and 
add G-CSF with the 
next cycle
Reduce carboplatin one AUC 
unit (AUC 4) and discontinue 
Day 15 paclitaxel dose with 
the next cycle
Discontinue 
veliparib/placebo and 
notify AbbVie TA MD
No
Yes
Reduce carboplatin one 
AUC unit (AUC 5) with 
the next cycle
Reduce carboplatin one AUC 
unit (AUC 4) with the next 
cycle
Discontinue 
veliparib/placebo and 
notify AbbVie TA MD
*
GCSF should continue through the end of the Combination Phase, once initiated.  Refer to the Guidelines for the 
Use of Hematopoietic Cytokines.
Note:
Day 8 and/or Day 15 cycle days should be omitted in their entirety in the event of delays due to hematological 
toxicity.
For subjects who have had 2 dose reductions for reduced ANC, and then develop reduced platelets, an 
additional dose modification is allowed but should be discussed with the AbbVie TA MD.  Alternatively, for 
subjects who have had 2 dose reductions for reduced platelets, and then develop reduced ANC, an additional 
dose modification is allowed but should be discussed with the AbbVie TA MD.
Modifications for Delayed Hematologic Recovery:
Dose modifications noted in Table 11 (Q3-weeks) and Table 12 (Q-week) should be 
considered for management of cycle Day 1 delays > 7 days for hematologic recovery 
(delays ≤ 7 days may not need a dose modification).  Delay on the basis of neutropenia is 
 


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defined if the ANC is < 1000 cells/mm3 within 24 hours prior to Day 1 of each cycle of 
scheduled therapy.
Delay on the basis of thrombocytopenia is defined if the platelet count is < 75,000/mm3
within 24 hours prior to Day 1 of each cycle of scheduled therapy.
If a subject experiences delays for the same hematologic parameter within a given cycle, 
these are considered to be one occurrence and only one dose modification is indicated.  If 
a subject experiences both a DLT and a delay for the same hematologic parameter 
(i.e., ANC) within a given cycle, only one dose modification is indicated.
Guidelines for the Use of Hematopoietic Cytokines
The use of hematopoietic cytokines is restricted as noted:
In general, subjects will NOT receive prophylactic filgrastim (G-CSF), PEG-filgrastim 
(Neulasta), or sargramostim (GM-CSF) unless they experience therapy delays, dose 
omissions, or neutropenic complications as specified.  In particular, hematopoietic growth 
factors should not be used to avoid initial chemotherapy dose modifications as stipulated 
in the protocol.  However, subjects may receive growth factors for the management of 
neutropenic complications in accordance with ASCO or institutional guidelines.  Subjects 
who may be at increased risk of febrile neutropenia for whom prophylactic growth factors 
may be indicated (such as age 65 or older) should be discussed with the AbbVie TA MD 
prior to randomization.
If needed per dose modifications guidelines, it is recommended that filgrastim (dosed 
according to institutional standard) be administered daily subcutaneously, separated from 
chemotherapy by at least 24 hours.  Pegfilgrastim should not be used for subjects 
receiving Day 15 paclitaxel as they do not have a 2-week chemotherapy-free interval.  For 
subjects receiving Day 15 paclitaxel who require the addition of filgrastim per dose 
modification guidelines, it is recommended that doses be given daily on Days 16 – 18 of 
the cycle.  If institutional guidelines allow for G-CSF to be administered at another time 
 


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during a cycle, this may be allowed per investigator discretion as long as it is given 
24 hours apart from chemotherapy.
Growth factors as part of a dose modification should continue and be given on the same 
cycle days through the end of the Combination Phase, once initiated.
Subjects will NOT receive prophylactic thrombopoietic agents.
Subjects may receive erythropoietin, iron supplements, and/or transfusions as clinically 
indicated for management of anemia.  
Treating physicians should be aware of the prescribing information for the erythropoiesis 
stimulating agents (including Aranesp, Epogen and Procrit) which note that there is a 
potential risk of shortening the time to tumor progression or disease-free survival, and that 
these agents are administered only to avoid red blood cell transfusions.  They do not 
alleviate fatigue or increase energy.  They should not be used in subjects with 
uncontrolled hypertension.  They can cause an increased incidence of thrombotic events in 
cancer patients on chemotherapy.  The updated package inserts should be consulted.  
Subjects may NOT receive amifostine or other protective reagents. 
5.7.1.2
Guidelines for Non-Hematologic Toxicity
Management of therapy related Grade 3 or Grade 4 non-hematological toxicity (excluding 
fatigue, nausea, vomiting, constipation, diarrhea, hypokalemia, hypomagnesemia, 
hypocalcemia, hyponatremia, and hypophosphatemia) should consider the dose level 
modifications as indicated specifically in this section.  Table 14 below provides guidance 
on the dose levels for modifications related to non-hematologic toxicity.  Dose 
modifications can be made for one drug at a time and do not require reducing all 
three drugs at once.
 


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Table 14.
Dose Levels for Modifications for Non-Hematologic Toxicity
Drug
Regimen –2 Level
Regimen –1 Level
Regimen Starting Dose
Paclitaxel (Q3-week)
110 mg/m2 Day 1
135 mg/m2 Day 1
175 mg/m2 Day 1
Paclitaxel (Q-week)
60 mg/m2 Days 1, 8
80 mg/m2 Days 1, 8
80 mg/m2 Days 1, 8, 15
Carboplatin (Q-week and 
Q3-week)
4
5
6
Veliparib/Placebo
50 mg BID
100 mg BID
150 mg BID
Note:
Refer to the text below to determine which study drug(s) should be modified.
Peripheral Neuropathy
For grade 2 (or greater) peripheral neuropathy, paclitaxel should be reduced one dose 
level (both dosing schedules) and chemotherapy can be delayed for a maximum of 
three weeks until recovered to Grade 1. 
Veliparib/Placebo is continued despite chemotherapy delays in the absence of a dose-
limiting toxicity.  
If peripheral neuropathy fails to recover to Grade 1 by a maximum delay of three weeks 
from time therapy is due, the AbbVie TA MD should be contacted.  If Grade 2 (or greater) 
neuropathy recurs after 2 dose reductions of paclitaxel, the AbbVie TA MD should be 
contacted.  Docetaxel may be substituted if neuropathy results in discontinuation of 
paclitaxel.  A washout of 7 days from veliparib/placebo is required before starting 
docetaxel.  Veliparib/Placebo is not permitted in combination with docetaxel.  
Subjects requiring a switch to docetaxel during Cycles 1 – 6 will be allowed to proceed 
with veliparib/placebo monotherapy beginning in Cycle 7.
Seizures
Any event of seizure, regardless of grade or attribution requires discontinuation of 
veliparib/placebo and discussion with the AbbVie TA MD regarding the decision to 
resume treatment.
 


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Renal Toxicity
Renal toxicity (associated with reduction in glomerular filtration rate [GFR]) is not 
expected from carboplatin as a direct complication of chemotherapy in this untreated 
patient population using the prescribed dose and schedule of the regimen.  As such, there 
are no specific dose modifications for renal toxicity.  However, the target AUC dose of 
carboplatin must be recalculated each cycle in any subject who develops renal 
insufficiency, defined by serum creatinine > 1.5 × ULN, Grade ≥ 2.
Hepatic Toxicity
Hepatic toxicity is not expected as a direct complication of chemotherapy in this untreated 
patient population using the prescribed dose and schedule for each regimen.  However, the 
development of Grade 3 (or greater) elevations in SGOT (AST), SGPT (ALT), alkaline 
phosphatase or bilirubin requires reduction of one dose level in paclitaxel and delay in 
subsequent therapy for a maximum of three weeks until recovered to ≤ Grade 1.  If 
Grade 3 (or greater) elevations do not recover within three weeks or recur despite dose 
modification, the AbbVie TA MD should be contacted.
Hypersensitivity Reaction
In general, the occurrence of a hypersensitivity reaction to carboplatin or paclitaxel is not 
considered a dose-limiting toxicity.  Subjects may be retreated at full doses after 
administration of medication to prevent hypersensitivity reactions, and adjustments in 
infusion rates should be made.  However, if despite these safety measures repeat attempt 
at infusion of the inciting drug results in a recurrent hypersensitivity reaction, the subject 
will discontinue this agent.  Severe hypersensitivity reactions to paclitaxel do not have to 
proceed with a rechallenge.  Docetaxel may be substituted for paclitaxel.  A washout of 
7 days from veliparib/placebo is required before starting docetaxel.  
Veliparib/Placebo is not permitted in combination with docetaxel.  Subjects requiring 
a switch to docetaxel during Cycles 1 – 6 will be allowed to proceed with 
veliparib/placebo monotherapy beginning in Cycle 7.
 


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Subjects receiving docetaxel who experience either febrile neutropenia, neutrophils 
< 500 cells/mm3 for more than 7 days or severe or cumulative cutaneous reactions during 
docetaxel therapy should have the docetaxel dose reduced.  If the subject continues to 
experience these reactions, the dosage should be discontinued.  Conversely, subjects who 
do not experience febrile neutropenia, neutrophils < 500 cells/mm3 for more than 7 days, 
severe or cumulative cutaneous reactions, or severe peripheral neuropathy during 
docetaxel therapy may be able to tolerate higher doses at the Investigator's discretion and 
careful monitoring.  Those subjects who experience grade 3 or greater peripheral 
neuropathy should discontinue docetaxel therapy.
Other Toxicity
There will be no dose modifications for alopecia, nausea, constipation, diarrhea, 
hypokalemia, hypocalcemia, hypomagnesemia, hyponatremia, hyponatremia, or 
hypophosphatemia.  It is recommended that routine medical measures be employed to 
manage nausea, constipation, diarrhea, and electrolyte abnormalities.
Nausea, Vomiting, or Fatigue
Nausea, vomiting, or fatigue ≥ Grade 3 which persists despite supportive medications 
with symptoms thought to be secondary to veliparib/placebo and not related to 
carboplatin, paclitaxel, or disease progression, veliparib/placebo should be held until 
symptoms resolve to ≤ Grade 1.  These cases should be discussed with the AbbVie TA 
MD, as it is unlikely for veliparib to be the predominant cause of nausea, vomiting, or 
fatigue during the combination phase.  Veliparib/Placebo should then be restarted at the 
next lower dose level.  No more than 2 dose reductions are allowed prior to 
discontinuation of veliparib/placebo.
If veliparib/placebo is discontinued during Cycles 1 – 6, the subject will resume 
veliparib/placebo dosing with Cycle 7 (the maintenance phase) if therapy toxicity resolves 
to ≤ Grade 1.
Dose modifications for other non-hematologic toxicities will occur as follows:
 


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●
For any Grade 3 non-hematologic adverse event (except controllable 
nausea/vomiting, constipation, diarrhea, hypokalemia, hypocalcemia, 
hypomagnesemia, hypophosphatemia, or hyponatremia) considered to be 
related to study treatment, therapy should be held until symptoms resolve to 
≤Grade 1 or to baseline and reduce the dose of the drug(s) most likely to have 
caused the toxicity by one dose level.  If a Grade 3 adverse event persists for 
> three weeks or recurs after resumption of therapy, the subject may be taken 
off therapy after discussing with the AbbVie TA MD.
●
Any Grade 4 non-hematologic adverse event (except controllable 
nausea/vomiting, constipation, diarrhea, hypokalemia, hypocalcemia, 
hypomagnesemia, hypophosphatemia, or hyponatremia) considered to be 
related to therapy should be discussed with the AbbVie TA MD and the 
subject may either be taken off therapy or dose reductions implemented.
5.7.2
Veliparib/Placebo Monotherapy Dose Reductions and 
Delays (Cycles 7 – 36)
Subjects who complete six cycles of carboplatin and paclitaxel and who have not 
progressed will receive single-agent, blinded veliparib/placebo starting at 300 mg.  If 
subjects have discontinued veliparib/placebo during the Combination Phase, 
veliparib/placebo may be reinitiated at 300 mg during the Maintenance Phase once 
therapy related toxicity resolve to ≤ Grade 1 or baseline.
Subjects should have an ANC ≥ 1,000/mm3 and a platelet count ≥ 75,000/mm3 prior to 
initiating all cycles during maintenance.
If the subject tolerates 300 mg BID, veliparib/placebo should be increased to 400 mg BID 
during the Maintenance Phase.  If the subject is not tolerating 300 mg BID, the AbbVie 
TA MD should be contacted.  Additionally, the following are guidelines for dose 
reductions, delays and discontinuation of veliparib/placebo monotherapy as needed for 
toxicities thought to be related to veliparib/placebo.  Subjects will follow the schedule of 
procedures outlined in Table 1.
 


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For any subject who experiences Grade 3 or 4 toxicity despite optimal supportive care 
(with the exception of anemia and non-treatment related clinically insignificant laboratory 
abnormalities), and the toxicity is not attributable to underlying disease, the 
veliparib/placebo dose will be held until the toxicity resolves to Grade 1 or lower or to 
baseline if Grade 2 is present at the time of study entry.
Interruptions of study drug for events that are clearly not related to therapy 
(e.g., underlying cancer, planned surgical procedures, or acute viral illnesses), do not 
necessitate a dose reduction.
The timing of the dose resumption should be at the Investigator's discretion.  In the cases 
of delays, tumor assessments should continue per Table 1.
The dose of veliparib/placebo may be reduced by one dose level (per Table 15) for 
subjects experiencing the following toxicities if attributed to veliparib/placebo:
Hematological Toxicities
●
Grade 3 or Grade 4 neutropenia persisting greater than 7 days
●
Grade 3 or 4 ANC with fever (ANC < 1.0 × 109/L, fever ≥ 38.5°C)
●
Grade 3 thrombocytopenia with active bleeding
●
Grade 4 thrombocytopenia
Non-Hematological Toxicities
●
Any CTCAE ≥ Grade 3 toxicity that represents at least 2 grade increase from 
baseline with the following clarifications:
○
Excludes nausea, vomiting, diarrhea, and tumor pain that have not received 
optimal treatment with antiemetics, antidiarrheals, or analgesics.
○
A rise in creatinine to Grade 3, only if not corrected to Grade 1 or baseline 
within 24 hours with IV fluids.
○
Metabolic toxicities, only if unable to be corrected to Grade 2 or less 
within 24 hours (such as glucose changes, hypokalemia, hypomagnesemia, 
hyperuricemia, hypophosphatemia, and hyponatremia).  Grade 4 metabolic 
 


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toxicities that are symptomatic will result in dose reduction regardless of 
duration or ability to correct.
○
For any > Grade 2 event of seizure attributed to veliparib/placebo, 
veliparib/placebo is to be interrupted, brain CT or MRI obtained, and the 
event should be discussed with the AbbVie TA MD.
Re-escalation may be permitted if toxicity has resolved to Grade 1 or lower and can be 
maintained with optimal supportive care.  In addition, temporary dose reductions or 
interruptions may be allowed for Grade 1 or 2 nausea or vomiting that remain intolerable 
despite optimal treatment.  This should be discussed with the AbbVie TA MD.
Table 15.
Veliparib/Placebo Monotherapy Dose Levels
Dose Level
Veliparib/Placebo
Starting Dose Level
300 mg BID 
(if unable to escalate dose due to toxicity then continue current dose)
Dose Level +1
400 mg BID
Dose Level –1
300 mg BID
Dose Level –2
250 mg BID*
*
If veliparib 250 mg/placebo BID is not tolerable, veliparib/placebo will be interrupted or discontinued.  There will 
be no dose reductions below the 250 mg BID dose.
Gastrointestinal Toxicities:  Nausea or Vomiting
Gastrointestinal toxicities, predominantly nausea and vomiting, are observed with 
veliparib as single-agent therapy (300 – 400 mg BID).  These toxicities most commonly 
occur within first few days or weeks of treatment and are most often Grade 2 or lesser 
severity.  In Phase 1 and Phase 2 studies, approximately 5% of subjects have experienced 
Grade 3 nausea during the first 4 weeks of treatment at 400 mg BID veliparib, and 
approximately 15% dose reduce, 2% discontinue and 5% delay or interrupt dosing due to 
nausea at 300 – 400 mg BID dose levels.
To optimize dose intensity and maintain subject quality of life, early initiation or 
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metoclopramide, prochlorperazine) and/or lorazepam should be considered when subjects 
begin the maintenance phase.  In addition, management should include counseling 
regarding these toxicities and may include brief interruption of dosing or dose 
modification.  As this is based upon a retrospective review of Phase 1 and 2 data, 
investigators should also rely on standard clinical practice and guidelines for nausea 
management.  
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 the study drugs, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with 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.
 


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Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, (meets protocol specific criteria [see Section 6.8 regarding toxicity 
management]) and/or if the Investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre-planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery performed 
earlier than planned), then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an adverse event.
All protocol-related nonserious AEs must be collected from the signing of the study 
specific informed consent until therapy administration.  In addition, adverse events with 
onset or worsening reported by a subject from the time that the first dose of study drug 
(veliparib or placebo) is administered until 30 days have elapsed following 
discontinuation of study drug administration will be considered as treatment-emergent 
adverse events.
6.1.2
Serious Adverse Events
If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a 
serious adverse event (SAE) within 24 hours of the site being made aware of the serious 
adverse event.
 


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Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had 
not been taken.  This does not include an event that would 
have been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay. This 
does not include an emergency room visit or admission to 
an outpatient facility hospitalization for respite care, or 
hospitalization due solely to progression of the underlying 
cancer.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, 
life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective 
or spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
For serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
 


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6.2
Adverse Events Expected Due to Ovarian, Fallopian Tube, 
or Primary Peritoneal Cancer or Progression of Ovarian, 
Fallopian Tube, or Primary Peritoneal Cancer
Events that are clearly consistent with ovarian cancer or the expected progression of 
ovarian cancer, including but not limited to abdominal pain, abdominal distension, ascites, 
intestinal obstruction, colonic obstruction, small intestinal obstruction, pleural effusion, 
and constipation should be considered as expected.  A list of expected adverse events is 
presented in Appendix H of the protocol.  These adverse events may occur alone or in 
various combinations and are considered expected adverse events in ovarian subjects.
6.3
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 Published:  May 28, 2009 (v4.03:  June 14, 2010).43
For adverse events not captured by the NCI CTCAE Version 4.0 Published:  
May 28, 2009 (v4.03:  June 14, 2010), 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.
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.
 


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For all reported serious adverse events that increase in severity, the supplemental eCRFs 
also need to be updated and need to include the new AE serial number.
6.4
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study therapies (for the purpose of this section, therapy is considered 
veliparib/placebo plus carboplatin/paclitaxel):
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.
The Investigator will assess the relationship of each adverse event to veliparib, to 
carboplatin, to paclitaxel, and to ovarian cancer.  Most events will be reasonably related to 
one treatment or to ovarian cancer, though some events may be reasonably related to more 
than one or to none.  For causality assessments, events assessed as having a reasonable 
possibility of being related to veliparib will be considered "associated."  Events assessed 
as having no reasonable possibility of being related to study drug will be considered "not 
associated."  In addition, when the Investigator has not reported causality or deemed it not 
assessable, AbbVie will consider the event associated.
If an Investigator's opinion of no reasonable possibility of being related to veliparib, to 
carboplatin, to paclitaxel, and to ovarian cancer is given, an Other cause of event must be 
provided by the Investigator for the serious adverse event.
6.5
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 therapy 
administration.
 


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In addition, all adverse events reported from the time of therapy administration until 
30 days following discontinuation of therapy administration have elapsed will be 
collected, whether solicited or spontaneously reported by the subject.
Serious and nonserious adverse events occurring after the study-specific informed consent 
is signed but prior to the initial dose of veliparib/placebo, carboplatin, paclitaxel will be 
collected only if they are considered by the Investigator to be causally related to the 
study-required procedures.
Adverse event information will be collected as shown in Figure 3.
Figure 3.
Adverse Event Collection
Protocol-Related 
SAEs* & AEs**
SAEs and Nonserious AEs
Elicited and/or Spontaneously Reported

      


Consent 
Signed
Study 
Drug Start
Study Drug 
Stopped
30 Days
After Study 
Drug Stopped
*
SAEs and AEs will be reported 30 days following the completion of veliparib/placebo and/or carboplatin/paclitaxel 
(whichever treatment occurs last).  Significant AEs (Grade 3/4) and SAEs considered by the Investigator as having 
a reasonable possibility of being related to veliparib/placebo and carboplatin/paclitaxel should be reported to 
AbbVie during the Long term Follow-up Period after the subject experiences progression, at the Investigator's 
discretion.
**
Only if considered by the Investigator to be causally related to study-required procedures.
6.6
Adverse Event Reporting
6.6.1
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol 
specified adverse event reporting period (Section 6.5) that are more likely related to 
disease progression will therefore be an expected adverse event and will not be an 
expedited report.
 


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Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be reported.  
The term "sudden death" should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a subject with or without pre-existing 
heart disease, within 1 hour of the onset of acute symptoms, or, in the case of an 
unwitnessed death, within 24 hours after the subject was last seen alive and stable.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be replaced 
by the established cause of death.
6.6.2
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease are also considered an expected outcome for this study and will not be 
subject to expedited reporting.  If there is uncertainty as to whether an event is due to 
disease progression, it should be reported as an adverse event.
6.6.3
Reporting Serious Adverse Events
In the event of a serious adverse event, whether associated with therapy or not, the 
Investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event by entering the serious adverse event data into the EDC 
system (RAVE®).  Serious adverse events that occur prior to the site having access to the 
RAVE® system or if RAVE® is not operable should use the SAE Non-CRF paper forms 
and send them to Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the serious adverse event.
Serious adverse events which are considered expected due to the underlying ovarian, 
fallopian tube, or primary peritoneal cancer as described in Section 6.2 would not be 
expedited as individual safety case reports to regulatory authorities.
 




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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
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure for veliparib or 
SmPC for carboplatin and paclitaxel.
In Japan, the principal investigator will provide documentation of all serious adverse 
events to the Director of the investigative site and the Sponsor.
6.7
Pregnancy
In the event of a positive pregnancy test, subjects must immediately discontinue study 
drugs and must be discontinued from the study.  The Investigator must report the positive 
pregnancy test to the appropriate contact listed in protocol Section 6.6 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 therapy (veliparib/placebo).  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.
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.
 






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8.1
Statistical and Analytical Plans
8.1.1
Baseline Characteristics
All baseline summary statistics and analyses will be based on characteristics obtained 
prior to randomization.  Unless otherwise stated, baseline for a given variable will be 
defined as the last value for that variable obtained prior to randomization.
Baseline characteristic data will be summarized with all randomized subjects for Arms 1, 
2, and 3 of the study separately.
8.1.1.1
Demographics
Continuous demographic variables such as age, height, and weight will be summarized 
with means, standard deviation and range.  Frequencies and percentages will be computed 
for the categorical parameters such as race, gender, BRCA-deficiency status, stage of the 
disease, residual disease, choice of regimen, and region.
8.1.1.2
Medical History
Frequencies and percentages will be computed for each medical history parameter.
8.1.2
Efficacy Endpoints
8.1.2.1
Primary Efficacy Endpoint
The primary efficacy endpoint is progression-free survival (PFS).  PFS will be defined as 
the number of days from the date that the subject was randomized to the date the subject 
experiences an event of disease progression, according to RECIST criteria version 1.1 (as 
determined by the investigator) or to the date of death (all causes of mortality) if disease 
progression is not reached.  All events of disease progression (as determined by the 
investigator) will be included, regardless of whether the event occurred while the subject 
was still taking study drug (veliparib or placebo containing regimen) or had previously 
discontinued study drug.  However, if a disease progression event occurs after a subject 
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censored at the last disease progression assessment prior to the missing disease 
progression assessments.  All events of death will be included for subjects who had not 
experienced disease progression provided the death occurred within the expected time 
windows defined according to the underlying disease assessment interval (every 9 weeks, 
then at the end of the Combination Phase, then every 12 weeks for 2 years, then every 
6 months for 3 years, and then annually).  If the subject does not have an event of disease 
progression (as determined by the investigator) nor has the subject died, the subject's data 
will be censored at the date of the subject's last disease assessment.
The primary efficacy analyses are defined by comparing PFS in Arm 3 versus Arm 1 in 
the BRCA-deficient population, HRD population and whole population.  The study will be 
successful if the first analysis in the multiplicity testing procedure described in 
Section 8.1.4 (comparison of PFS [Arm 3 vs. Arm 1] in the BRCA-deficient population) is 
statistically significant.  If this comparison is statistically significant, the other primary 
endpoints will be analyzed for statistical significance in the specified order.
The distribution of PFS will be estimated for each treatment arm using Kaplan-Meier 
methodology.  For the whole population, PFS will be compared between each of the 
treatment arms and the control arm using the log-rank test, stratified by residual disease 
and BRCA-deficient status.  For the BRCA-deficient population and HRD population, PFS 
will be compared between each of the treatment arms and the control arm using the log-
rank test, stratified by residual disease. 
Median PFS time will be estimated and 95% confidence interval for the estimated median 
PFS time will be presented for each treatment arm.
Additional details regarding the primary analyses including the final list of stratification 
factors to be used will be specified in the final SAP prior to unblinding of the data.
 


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8.1.2.2
Secondary Efficacy Endpoints
8.1.2.2.1
Progression Free Survival (PFS)
PFS will also be compared between Arm 2 and Arm 1 as a secondary analysis, following 
the same methodology as the primary analysis.
8.1.2.2.2
Overall Survival (OS)
OS 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 (veliparib or placebo containing 
regimen), or after the subject discontinues study drug.  If a subject has not died, then the 
data will be censored at the date when the subject is last known to be alive.
The secondary efficacy analyses for OS are defined by comparing OS in Arm 3 versus 
Arm 1 and Arm 2 versus Arm 1, in the BRCA-deficient, HRD, and whole population.  
The distribution of OS will be estimated for each treatment arm using Kaplan-Meier 
methodology.  For the whole population, OS will be compared between each of the 
treatment arms and the control arm using the log-rank test, stratified by residual disease 
and BRCA-deficient status.  For the BRCA-deficient population and HRD population, OS 
will be compared between each of the treatment arms and the control arm using the log-
rank test, stratified by residual disease.
Median OS time will be estimated and 95% confidence interval for the estimated median 
OS time will be presented for each treatment arm.
8.1.2.2.3
Patient Reported Outcomes
Disease Related Symptoms (DRS) Score
The overall mean change from baseline for the NFOSI-18 DRS scores measured at each 
assessment point up to 2 years or disease progression will be a secondary endpoint of the 
study.  The overall mean change from baseline for the total DRS scores between the 
 


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treatment groups will be compared using a longitudinal repeated measures model that 
takes into account the DRS scores measured at each assessment point up to 2 years or 
disease progression with analysis of appropriate timepoints as indicated.
8.1.2.3
Tertiary Efficacy Endpoints
8.1.2.3.1
PFS2, TTFST, and TTSST
PFS2 will be defined as the number of days from the day the subject is randomized to the 
date that the subject has disease progression on the subsequent therapy or death of any 
cause, whichever occurs first.  If the subject does not have an event of PFS2 (as 
determined by the Investigator), the subject's data will be censored at the subject's last 
known date of follow-up.
Time to the first subsequent therapy (TTFST) will be defined as the number of days from 
the day the subject is randomized to the start of the first subsequent therapy or death of 
any cause.  If the subject does not have an event of TTFST, the subject's data will be 
censored at the date of the subject's last visit or survival follow-up.
Time to the second subsequent therapy (TTSST) will be defined as the number of days 
from the day the subject is randomized to the start of the second subsequent therapy or 
death of any cause.  If the subject does not have an event of TTSST, the subject's data will 
be censored at the date of the subject's last visit or survival follow-up.
PFS2, TTFST, and TTSST will be summarized and analyzed using the same 
methodologies as PFS.
8.1.2.3.2
Additional PRO Endpoints 
Additional analyses based on other PRO endpoints will be specified either in the SAP or 
in a separate PRO analysis plan.
 


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8.1.3
Interim Efficacy Analyses for OS
Overall survival is expected to mature at month 58 in the whole population and at 
month 77 for the BRCA-deficient and HRD populations.
For the OS hypotheses (Arm 3 versus Arm 1, or Arm 2 versus Arm 1) in the BRCA-
deficient population, the HRD population, and the whole population, at least one efficacy 
interim analyses will be performed.
The first interim analysis will occur at the time of the final PFS analysis.
The alpha of the final OS analyses will depend on prior interim analyses as described in 
the SAP.  Additional details regarding the secondary analyses, including any interim 
efficacy analyses (e.g., at the request of a regulatory agency), will be specified in the SAP.
8.1.4
Multiplicity Adjustment
This is a three-arm, randomized, placebo-controlled Phase 3 clinical trial.  All subjects 
will receive six cycles of carboplatin and paclitaxel.  In addition to the chemotherapy, 
subjects will be randomly allotted to receive either placebo or veliparib.  While 6 cycles 
of chemotherapy are planned, the randomized treatment (placebo or veliparib) will be 
continued during a maintenance phase of treatment for a maximum of 36 total cycles of 
veliparib/placebo.
Table 16.
Study Treatment Arms
Arm
Description
Arm 1:  C/P + placebo  →placebo
Reference regimen
Arm 2:  C/P + veliparib →placebo
Veliparib administered in the combination therapy phase 
only
Arm 3:  C/P + veliparib →veliparib
Veliparib administered in both combination therapy and 
maintenance therapy phases
Note:
[+] indicates 'concurrent with;' [→] indicates ' followed by;' [C/P] indicates 'backbone chemotherapy' 
(i.e., carboplatin/paclitaxel).
 


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There are three populations of interest:  the BRCA-deficient population, HRD population, 
and whole population.
In each population, the hypotheses of interest are listed below in Table 17. 
Table 17.
The Null Hypotheses of Interest in Each Population
PFS (Arm 3 versus Arm 1)
PFS (Arm 2 versus Arm 1)
OS (Arm 3 versus Arm 1)
OS (Arm 2 versus Arm 1)
DRS (Arm 3 versus Arm 1)*
DRS (Arm 2 versus Arm 1)*
PFS = Progression Free Survival; OS = Overall Survival; DRS = Disease Related Symptom 
*
No alpha allocation on this test.
Note:
PFS (Arm 3 versus Arm 1) denotes the null hypothesis:  Arm 3 (C/P + veliparib →veliparib) does not 
increase PFS compared to Arm 1 (C/P + placebo →placebo).  Other PFS and OS notations in this table are 
defined similarly.  DRS (Arm 3 versus Arm 1) denotes the null hypothesis of no difference in DRS scores 
between Arm 3 and Arm 1. DRS (Arm 2 versus Arm 1) is defined similarly.
The expected proportion of BRCA-deficient subjects is approximately 24% in the whole 
population.  Test results will be available for all subjects during the trial.  
BRCA testing data available as of July 2018 suggest that the final proportion of subjects 
with BRCA-deficient status will be approximately 25%, thus meeting the criteria under the 
original protocol to include the BRCA-deficient population in the testing sequence.  
Therefore, an alternate testing sequence scenario to account for a low (< 18%) proportion 
of BRCA-deficient subjects, as proposed in the original protocol, will not be needed for 
the analyses.
Emerging data during the course of this trial has supported the increasing use of PARP 
inhibitors in patients with ovarian, fallopian tube, and primary peritoneal cancer.15-17  In 
2017, niraparib maintenance therapy was shown to provide improvement in outcomes 
(PFS) for all patients with platinum-sensitive, recurrent ovarian cancer.  While the largest 
improvement was seen in patients with gBRCA mutations (HR = 0.27, 95% CI = 0.17 -
0.41), a significant benefit was also observed in the HRD population (HR = 0.30, 95% 
CI = 0.22 - 0.41).  Similarly, rucaparib has also demonstrated benefit in patients with high 
loss of heterozygosity (LOH) scores (HR = 0.32, 95% CI = 0.24 - 0.42).  The addition of a 
 


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third subgroup analysis (HRD population) to the primary endpoint was thus incorporated 
into the study design to test the hypothesis that veliparib would also benefit patients with 
BRCA-like mutations.
Since subject randomization was not prospectively stratified by HRD status, two testing 
scenarios were proposed dependent on the level of the balance of treatment arms within 
the HRD population.  Further details on these testing scenarios are detailed in SAP v2.0.
The multiple testing procedure governing the analysis of data when the primary endpoint 
(PFS) matures are specified in the SAP v2.0, finalized before the database was unblinded.  
The appropriate control of overall type I error in the context of subsequent analyses, 
including interim analyses conducted at the behest of regulatory agencies, will be 
specified in subsequent SAP amendments, as warranted.
8.1.5
Safety
The safety of veliparib 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 were randomized but did not receive study drug 
(veliparib or placebo containing regime) will not be included in the analyses of safety.
8.1.5.1
Duration of Study Drug
A summarization of the number of days and/or cycles subjects were exposed to study drug 
will be provided.
8.1.5.2
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.
 


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Treatment-emergent adverse events will be summarized by preferred terms within a 
System and Organ Class according to the most current Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary.  In addition, the percentage of subjects experiencing an 
adverse event at a NCI CTCAE Version 4.0 Published:  May 28, 2009 (v4.03:  
June 14, 2010)43 toxicity grade, and relationship to study drug will be provided.  The 
percentages of subjects experiencing an adverse event will be compared between Arm 2 
and 3 versus Arm 1 using Fisher's exact test.
The frequencies and percentages of subjects experiencing a treatment-emergent Grade 3 
or Grade 4 peripheral neuropathy will be summarized and compared between the 
treatment arms using CMH test stratified by the stratification factors.
8.1.5.3
Serious Adverse Events
Serious adverse events will be summarized using the same methods as Adverse Events 
described above.
8.1.5.4
Deaths
The number of subject deaths will be summarized (1) for deaths occurring within 30 days 
of the last dose of study drug, (2) for deaths occurring more than 30 days of 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.
8.1.5.5
Analyses of Laboratory and Vital Signs Data
Changes from baseline will be analyzed for each scheduled post-baseline visit and for the 
final visit for blood chemistry and hematology parameters, as well as urinalysis and vital 
sign parameters.  If more than one measurement exists for a subject on a particular day, 
then an arithmetic average will be calculated.  This average will be considered to be that 
subject's measurement for that day.  Post-baseline measurements more than 30 days after 
the last dose of study drug will not be included.  Subjects that do not have a baseline 
measurement or do not have any post-baseline measurements will not be included.  
Comparisons of the differences in mean changes from baseline for Arm 2 and 3 versus 
 


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Arm 1 will be made using ANOVA with treatment group as the factor for each 
post-baseline visit.
8.1.5.6
Analyses of Laboratory Data Using NCI CTCAE
Where applicable, blood chemistry and hematology determinations will be categorized 
according to NCI CTCAE version 4.0 Published:  May 28, 2009 (v4.03:  June 14, 2010),43
and shifts from baseline NCI CTCAE 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 last post-baseline 
measurement collected no more than 30 days after the last dose of study drug.
The percentage of subjects experiencing a shift from baseline grades of 0 to 2 to 
maximum post-baseline grades of 3 to 4, and from baseline grades of 0 to 2 to final post 
baseline grades of 3 to 4 will be compared between Arm 2 and 3 and Arm 1 using Fisher's 
exact test.
Detailed listings of data for subjects experiencing NCI CTCAE Grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug, will be included in these 
listings.
8.1.6
Pharmacokinetic Analysis 
The pharmacokinetic parameters of rate of absorption (Ka), apparent volume of 
distribution (V/F) and oral clearance (CL/F) for veliparib may be estimated using a 
nonlinear mixed-effect population modeling approach with NONMEM software and 
reported in a separate pharmacokinetic report.
 


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8.2
Determination of Sample Size
The study originally aimed to power for the PFS and OS endpoints in both the whole and 
the BRCA-deficient populations.  The update to the multiplicity adjustment will change 
the power as described under the original protocol, particularly in the whole population.  
Hence, fewer events will be required for the primary analysis in the whole population as 
compared to original estimates (391 versus 446).
8.2.1
Total Sample Size
The trial will enroll approximately 1100 subjects (with 1:1:1 randomization ratio for 
Arm 1:Arm 2:Arm 3) in the whole population, including approximately 264 subjects with 
BRCA-deficient status (assuming 24% of the subjects in the whole population are 
BRCA-deficient) to power the hypotheses specified in the whole and BRCA-deficient 
populations.  Detailed sample size calculation information for each endpoint of the BRCA-
deficient, HRD, and whole populations is provided in Table 18 and Table 19.
Throughout the Protocol, the timing of maturity of each endpoint within each population 
is an estimate based on the original design assumptions and do not necessarily reflect the 
exact month on study the analysis will occur.  Therefore the "Month 36," "Month 48,"
etc… should be considered as surrogates only for the timing of each particular analysis.
8.2.2
For the Hypotheses in the Whole Population
PFS (Arm 3 Versus Arm 1):
Testing of PFS (Arm 3 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 3 (C/P + veliparib →veliparib) decreases the PFS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the whole population.  According to the 
original protocol, the power calculation for this hypothesis is based on the log-rank test at 
a one-sided alpha level of 0.0125.  Assuming a PFS hazard ratio of 0.7 in Arm 3 versus 
Arm 1, up to a total of 446 events would be needed for the test to have 94% power to 
detect a statistically significant treatment effect.  Assuming a median PFS of 15.5 months 
in Arm 1 and an enrollment period of 18 months, and taking into account a dropout rate of 
 


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10%, approximately 367 subjects were needed per arm in a 1:1 randomization ratio (Arm 
3 versus Arm 1) in order to have a matured PFS endpoint at around 36 months.
Based on the revised testing procedures, and keeping all other assumptions above the 
same, the power based on the log-rank test at a one-sided alpha level of 0.025 
(Scenario 1), 0.0224, and 0.0125 (Scenario 2) are 96.5%, 96.1%, 93.6%, respectively.  
The actual alpha level will depend on the testing scenario, and the ordering of the p-values 
between the HRD population and the Whole population if under Scenario 2.  Power 
calculations based on 391 events are provided in Table 18 and Table 19.
PFS (Arm 2 Versus Arm 1):  
Testing of PFS (Arm 2 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 2 (C/P + veliparib →placebo) decreases the PFS event rate relative to reference 
regimen in Arm 1 (C/P + placebo→placebo) in the whole population.  The original 
protocol specified that this hypothesis would be assessed with the stratified log-rank test 
at a one sided alpha level of 0.00625 or 0.0125 based on the Hochberg procedure.  The 
power calculation for this hypothesis was based on the log-rank test at a one-sided alpha 
level of 0.00625.  Assuming a PFS hazard ratio of 0.7 in Arm 2 versus Arm 1, up to a 
total of 446 events would be needed for the test to have 90% power to detect a statistically 
significant treatment effect based on the alpha level of 0.00625.  Assuming median PFS of 
15.5 months in Arm 1 and an enrollment period of 18 months, and taking into account of 
a dropout rate of 10%, approximately 367 subjects were needed per arm in a 1:1 
randomization ratio (Arm 2 versus Arm 1) to have a mature PFS endpoint at around 
36 months.  
Based on the revised testing procedures, and keeping all other assumptions above the 
same, the power based on the log-rank test at a one-sided alpha level of 0.025 is 96.5%.  
Using a one-sided alpha level of 0.0024, the power is 83.1%.  The actual alpha level will 
depend on the Testing Scenario, and on the outcome of testing PFS of 3vs1 in the HRD 
and Whole populations if under Scenario 2.  Power calculations based on 391 events are 
provided in Table 18 and Table 19.
 


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OS (Arm 3 Versus Arm 1):
Testing of OS (Arm 3 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 3 (C/P + veliparib →veliparib) decreases the OS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the whole population.  According to the 
original protocol, this hypothesis would be assessed with the stratified log-rank test at a 
one sided alpha level of 0.00625 or 0.0125.  The power calculation for this hypothesis was 
based on the log-rank test at a one-sided alpha level of 0.00625.  Assuming an OS hazard 
ratio of 0.7 in Arm 3 versus Arm 1, up to a total of 350 events would be needed for the 
test to have 80% power to detect a statistically significant treatment effect.  Assuming a 
median OS of 41.5 months in Arm 1 and an enrollment period of 18 months, and taking 
into account of a dropout rate of 10% and an efficacy interim analysis that occurs at the 
time of the PFS analysis, approximately 367 subjects were needed per arm in a 
1:1 randomization ratio (Arm 3 versus Arm 1) to have a mature OS endpoint at around 
58 months.  
Based on the revised testing procedures, and keeping all other assumptions above the 
same, the power based on the log-rank test at a one-sided alpha level of 0.025 is 91.5%.  
Using a one-sided alpha level of 0.0024, the power is 70%.  The actual alpha level will 
depend on the outcomes of the preceding tests in the testing sequence. 
OS (Arm 2 Versus Arm 1):
Testing of OS (Arm 2 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 2 (C/P + veliparib →placebo) decreases the OS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the whole population.  According to the 
original protocol, the power calculation for this hypothesis was based on the log-rank test 
at a one-sided alpha level of 0.0125.  Assuming an OS hazard ratio of 0.7 in Arm 2 versus 
Arm 1, up to a total of 350 events would be needed for the test to have 86% power to 
detect a statistically significant treatment effect.  Assuming a median OS of 41.5 months 
in Arm 1 and an enrollment period of 18 months, and taking into account of a dropout rate 
of 10% and an efficacy interim analysis that occurs at the time of the PFS analysis, 
 


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approximately 367 subjects were needed per arm in a 1:1 randomization ratio (Arm 2 
versus Arm 1) to have a mature OS endpoint at around 58 months.  
Based on the revised testing procedures, and keeping all other assumptions above the 
same, the power based on the log-rank test at a one-sided alpha level of 0.025 is 91.5%.  
Using a one-sided alpha level of 0.0024, the power is 70%.  The actual alpha level will 
depend on the outcomes of the preceding tests in the testing sequence. 
8.2.3
For the Hypotheses in the BRCA-Deficient Population
PFS (Arm 3 Versus Arm 1):
Testing of PFS (Arm 3 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 3 (C/P + veliparib →veliparib) decreases the PFS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the BRCA-deficient population.  
According to the original protocol, the power calculation for this hypothesis was based on 
the log-rank test at a one-sided alpha level of 0.0125.  Assuming a hazard ratio for PFS of 
0.5 in Arm 3 versus Arm 1, up to a total of 79 events would be needed for the test to have 
80% power to detect a statistically significant treatment effect.  Assuming median PFS of 
21 months in Arm 1 and an enrollment period of 18 months, approximately 88 subjects 
per arm in a 1:1 randomization ratio (Arm 3 versus Arm 1) were needed to have a matured 
PFS endpoint at around 36 months taking into account of a dropout rate of 10%.
Based on the revised testing procedures, and keeping all other assumptions above the 
same, the power based on the log-rank test at a one-sided alpha level of 0.025 is 87%.
PFS (Arm 2 Versus Arm 1):  
Testing of PFS (Arm 2 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 2 (C/P + veliparib →veliparib) decreases the PFS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the BRCA-deficient population.  
According to the original protocol, the power calculation for this hypothesis was based on 
the log-rank test at a one-sided alpha level of 0.0125.  Assuming a hazard ratio for PFS of 
0.5 in Arm 2 versus Arm 1, up to a total of 79 events would be needed for the test to have 
 


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80% power to detect a statistically significant treatment effect.  Assuming median PFS of 
21 months in Arm 1 and an enrollment period of 18 months, approximately 88 subjects 
per arm in a 1:1 randomization ratio (Arm 2 versus Arm 1) were needed to have a matured 
PFS endpoint at around 36 months taking into account of a dropout rate of 10%.
Based on the revised testing procedures, and keeping all other assumptions above the 
same, the power based on the log-rank test at a one-sided alpha level of 0.0248 is 87%.  If 
under Scenario 2, only one of HRD or Whole is significant, then the power based on the 
log-rank test at a one-sided alpha level of 0.0024 is 61%. 
OS (Arm 3 Versus Arm 1):
Testing of OS (Arm 3 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 3 (C/P + veliparib →veliparib) decreases the OS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the BRCA-deficient population.  
According to the original protocol, the power calculation for this hypothesis was based on 
the log-rank test at a one-sided alpha level of 0.0125.  Assuming a hazard ratio for OS of 
0.5 in Arm 3 versus Arm 1, up to a total of 79 events would be needed for the test to have 
80% power to detect a statistically significant treatment effect.  Assuming median OS of 
53 months in Arm 1 and an enrollment period of 18 months, approximately 88 subjects 
per arm in a 1:1 randomization ratio (Arm 3 versus Arm 1) were needed to have a matured 
OS endpoint at around 77 months, taking into account of a dropout rate of 10% and 2 
efficacy interim analyses that occur at the time of the PFS analysis and OS analysis for the 
whole population.
Based on the revised testing procedures, and keeping all other assumptions above the 
same, the power based on the log-rank test at a one-sided alpha level of 0.0248 is 87%.  
Using a one-sided alpha level of 0.0024, the power is 61%.  The actual alpha level will 
depend on the outcomes of the preceding tests in the testing sequence. 
 


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OS (Arm 2 Versus Arm 1):
Testing of OS (Arm 2 versus Arm 1) evaluates whether the veliparib containing regimen 
in Arm 2 (C/P + veliparib →placebo) decreases the OS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the BRCA-deficient population.  
According to the original protocol, the power calculation for this hypothesis was based on 
the log-rank test at a one-sided alpha level of 0.0125.  Assuming a hazard ratio for OS of 
0.5 in Arm 2 versus Arm 1, up to a total of 79 events would be needed for the test to have 
80% power to detect a statistically significant treatment effect.  Assuming median OS of 
53 months in Arm 1 and an enrollment period of 18 months, approximately 88 subjects 
per arm in a 1:1 randomization ratio (Arm 2 versus Arm 1) were needed to have a matured 
OS endpoint at around 77 months, taking into account of a dropout rate of 10% and 2 
efficacy interim analyses that occur at the time of the PFS analysis and OS analysis for the 
whole population.
Based on the revised testing procedures, and keeping all other assumptions above the 
same, the power based on the log-rank test at a one-sided alpha level of 0.0248 is 87%.  
Using a one-sided alpha level of 0.0024, the power is 61%.  The actual alpha level will 
depend on the outcomes of the preceding tests in the testing sequence. 
8.2.4
For the Hypotheses in the HRD Population
PFS (Arm 3 Versus Arm 1):
Testing of PFS (Arm 3 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 3 (C/P + veliparib →veliparib) decreases the PFS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the HRD population.  According to
Scenario 1 of the revised testing procedure, the power calculation for this hypothesis is 
based on the log-rank test at a one-sided alpha level of 0.025.  It is currently estimated that 
at the time of achieving the latter of 646 PFS events in the Whole Population and 109 in 
the BRCA deficient population, that at least 242 total events will accrue in the HRD 
population.  Assuming a HR = 0.60, we can expect a total of 170 events in Arm 3 and 
Arm 1 combined.  Assuming a hazard ratio for PFS of 0.6 in Arm 3 versus Arm 1, 
 


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242 events will provide 91.5% power to detect a statistically significant treatment effect.  
Assuming a median PFS of 18 months in Arm 1 and an enrollment period of 18 months, 
approximately 160 subjects per arm in a 1:1 randomization ratio (Arm 3 versus Arm 1) 
are needed to have a matured PFS endpoint at around 36 months taking into account of a 
dropout rate of 10%.
Based on Scenario 2 of the revised testing procedures, and keeping all other assumptions 
above the same, the power based on the log-rank test at a one-sided alpha level of 0.0224 
and 0.0125 is 90.8% and 86%, respectively. 
PFS (Arm 2 Versus Arm 1):
Testing of PFS (Arm 2 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 2 (C/P + veliparib →placebo) decreases the PFS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the HRD population.  According to 
Scenario 1 of the revised testing procedure, the power calculation for this hypothesis is 
based on the log-rank test at a one-sided alpha level of 0.025.  It is currently estimated that 
at the time of achieving the latter of 646 PFS events in the Whole Population and 109 in 
the BRCA deficient population, that at least 242 total events will accrue in the HRD 
population.  Assuming a HR = 0.60, we can expect a total of 170 events in Arm 2 and 
Arm 1 combined.  Assuming a hazard ratio for PFS of 0.6 in Arm 2 versus Arm 1, 
242 events will provide 91.5% power to detect a statistically significant treatment effect.  
Assuming a median PFS of 18 months in Arm 1 and an enrollment period of 18 months, 
approximately 160 subjects per arm in a 1:1 randomization ratio (Arm 2 versus Arm 1) 
are needed to have a matured PFS endpoint at around 36 months taking into account of a 
dropout rate of 10%.
Based on Scenario 2 of the revised testing procedures, and keeping all other assumptions 
above the same, the power based on the log-rank test at a one-sided alpha level of 0.0024 
is 70%. 
 


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OS (Arm 3 Versus Arm 1):
Testing of OS (Arm 3 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 3 (C/P + veliparib →veliparib) decreases the OS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the HRD population.  According to 
Scenario 1 of the revised testing procedure, the power calculation for this hypothesis is 
based on the log-rank test at a one-sided alpha level of 0.025.  Assuming a hazard ratio for 
OS of 0.6 in Arm 3 versus Arm 1, up to a total of 166 events will be needed for the test to 
have 90% power to detect a statistically significant treatment effect.  Assuming median 
OS of 47 months in Arm 1 and an enrollment period of 18 months, approximately 
160 subjects per arm in a 1:1 randomization ratio (Arm 3 versus Arm 1) are needed to 
have a matured OS endpoint at around 77 months, taking into account of a dropout rate of 
10% and 2 efficacy interim analyses that occur at the time of the PFS analysis and OS 
analysis for the whole population.
Based on Scenario 2 of the revised testing procedures, and keeping all other assumptions 
above the same, the power based on the log-rank test at a one-sided alpha level of 0.0024, 
the power is 68.6%.  The actual alpha level will depend on the outcomes of the preceding 
tests in the testing sequence. 
OS (Arm 2 Versus Arm 1):
Testing of OS (Arm 2 versus Arm 1) evaluates whether the veliparib containing regimen 
in Arm 2 (C/P + veliparib →placebo) decreases the OS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the HRD population.  Based on 
Scenario 1 of the revised testing procedure, the power calculation for this hypothesis is 
based on the log-rank test at a one-sided alpha level of 0.025.  Assuming a hazard ratio for 
OS of 0.6 in Arm 2 versus Arm 1, up to a total of 166 events will be needed for the test to 
have 90% power to detect a statistically significant treatment effect.  Assuming median 
OS of 47 months in Arm 1 and an enrollment period of 18 months, approximately 160 
subjects per arm in a 1:1 randomization ratio (Arm 2 versus Arm 1) are needed to have a 
matured OS endpoint at around 77 months, taking into account of a dropout rate of 10% 
 


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and 2 efficacy interim analyses that occur at the time of the PFS analysis and OS analysis 
for the whole population.
Based on Scenario 2 the revised testing procedures, and keeping all other assumptions 
above the same, the power based on the log-rank test at a one-sided alpha level of 0.0024, 
the power is 68.6%.  The actual alpha level will depend on the outcomes of the preceding 
tests in the testing sequence.
 


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Table 18.
Power and Sample Size Calculation for Testing Scenario 1
PFS
OS
Type I Error
Population
No. of 
Subjects per 
Arm (N)
Power
Expected 
Hazard
Ratio
No. of 
Events for 
2 Arm 
Comparison
Projected 
Endpoint 
Mature Time 
(Months)
Power
Expected 
Hazard 
Ratio
No. of Events
for 2 Arm 
Comparison
Projected 
Endpoint 
Mature 
Time 
(Months)
alpha = 0.025
BRCA-deficient
88
87%
0.50
79
36
87%a
0.50
79
77
HRD
160
91.5%
0.60
170
36
90%a
0.60
166
77
Whole
367
94.1%
0.70
391
36
91.5%b
0.70
350
58
PFS = progression-free survival; OS = overall survival
a.
Assumes 2 efficacy interim analyses (at month 36 and month 58, respectively) with alpha spending of 0.0001 at each of the 2 interim analyses.  The multiplicity adjusted 
alpha for the final analysis at month 77 is 0.0248, provided all preceding null hypotheses in the hierarchical testing sequence are rejected.
b.
Assumes an efficacy interim analysis at month 36 with alpha spending of 0.0001.  The nominal alpha for the final analysis at month 58 is 0.0248.  The multiplicity adjusted 
alpha for the analysis at month 77 is 0.0248, provided all preceding null hypotheses in the hierarchical testing sequence are rejected.
Note:
All calculations take into account a 10% dropout rate.  An enrollment period of 18 months with linear enrollment rate is assumed.  The actual endpoint mature time may 
vary depending on the true enrollment pattern.
 


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Table 19.
Power and Sample Size Calculation for Testing Scenario 2
PFS
OS
Type I Error
Population
No. of 
Subjects per 
Arm (N)
Power
Expected 
Hazard 
Ratio
No. of 
Events for 
2 Arm 
Comparison
Projected 
Endpoint 
Mature Time 
(Months)
Power
Expected 
Hazard 
Ratio
No. of Events 
for 2 Arm 
Comparison
Projected 
Endpoint 
Mature 
Time 
(Months)
alpha = 0.025
BRCA-
deficient
88
87%
0.50
79
36
87%a
0.50
79
77
HRD
160
91.5%
0.60
170
36
90%a
0.60
166
77
Whole
367
94.1%
0.70
391
36
91.5%b
0.70
350
58
alpha = 0.0224
HRD
160
90.8%
0.60
170
36
-
-
-
-
Whole
367
93.6%
0.70
391
36
-
-
-
-
alpha = 0.0125
HRD
160
86.2%
0.60
170
36
-
-
-
-
Whole
367
90.1%
0.70
391
36
-
-
-
-
alpha = 0.0024
HRD
160
70%
0.60
170
36
68.6%
0.60
166
77
Whole
367
76%
0.70
391
36
70%
0.70
350
58
PFS = progression-free survival; OS = overall survival
a.
Assumes 2 efficacy interim analyses (at month 36 and month 58, respectively) with alpha spending of 0.0001 at each of the 2 interim analyses.  The multiplicity adjusted 
alpha for the final analysis at month 77 is 0.0248, provided all preceding null hypotheses in the hierarchical testing sequence are rejected.
b.
Assumes an efficacy interim analysis at month 36 with alpha spending of 0.0001.  The nominal alpha for the final analysis at month 58 is 0.0248.  The multiplicity adjusted 
alpha for the analysis at month 77 is 0.0248, provided all preceding null hypotheses in the hierarchical testing sequence are rejected.
Note:
All calculations take into account a 10% dropout rate.  An enrollment period of 18 months with linear enrollment rate is assumed.  The actual endpoint mature time may 
vary depending on the true enrollment pattern.
 


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8.3
Timing for Analyses and Unblinding of the Study
As shown in Table 18 and Table 19, the estimated PFS endpoint mature time is 
approximately 36 months for both the whole and the BRCA-deficient population, as well 
as the HRD population, and the estimated OS endpoint mature time is approximately 
58 months for the whole population and 77 months for the BRCA-deficient and HRD 
populations.  AbbVie will unblind the data to perform the primary analyses when required 
numbers of PFS endpoints are accrued in the BRCA-deficient, HRD, and whole 
populations.  The data cutoff date for the primary analyses of PFS will be determined 
when the total number of PFS events in Arms 1 and 3 combined have reached at least 
79 in the BRCA-deficient population, at least 170 in the HRD population, and at least 
391 in the whole population.  Since this is a blinded study involving 3 arms, an 
independent statistical data analysis center will inform the sponsor when all criteria 
specified above have been met.  Subsequently all subjects will be followed as planned for 
survival and investigators and subjects will remain blinded to reduce bias.  The final OS 
analyses will occur when the required numbers of OS endpoints have accrued in all 
populations, and will be based on required events.  Additional analyses of efficacy and 
safety may be performed in Japanese subjects after the primary analyses to meet the 
Japanese regulatory requirements.  Additional details on these analyses will be specified 
in a separate SAP for the Japanese subjects.
8.4
Randomization Methods
An Interactive Response Technology (IRT) system will be utilized to randomize subjects.  
Before the study is initiated, directions for the IRT will be provided to each site.  The 
investigational site will contact the IRT on or prior the subject's Cycle 1 Day 1 visit and a 
unique randomization number will be provided.
Subject randomization will be stratified into 48 groups as defined by combining 
categories of the four randomization stratification factors listed as below:
1.
Stage of the disease:
 


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●
III
●
IV
2.
Residual disease and choice of regimen:
●
Q3-weeks carboplatin/paclitaxel, no residual disease
●
Q3-weeks carboplatin/paclitaxel, any residual disease
●
Q-week carboplatin/paclitaxel, no residual disease
●
Q-week carboplatin/paclitaxel, any residual disease
●
Interval cytoreductive surgery, Q3-weeks carboplatin/paclitaxel 
●
Interval cytoreductive surgery, Q-weeks carboplatin/paclitaxel 
3.
Region:
●
Japan
●
North America or Rest of World
4.
germline BRCA mutation status
●
gBRCA positive 
●
gBRCA negative or unknown
Cancer stage at diagnosis, maximal residual disease, and BRCA mutation status are major 
prognostic factors of survival.  Complete (no visible residual disease) and optimal 
(residual disease < 1 cm) primary surgical cytoreduction is also associated with prolonged 
survival in advanced epithelial ovarian cancer.40,42  To control for these known prognostic 
factors, randomization will be stratified by (Stage III versus IV), residual disease (any 
residual disease versus no visual residual disease) following initial cytoreductive surgery 
and germline BRCA mutation status (positive versus negative or unknown).  Residual 
disease following interval cytoreduction will be captured and recorded on electronic case 
report forms (eCRFs) for subjects receiving treatment with carboplatin and paclitaxel as 
the data will not be available at randomization but could still influence 
outcomes/prognosis.  Randomization will also be stratified by choice of therapy to 
minimize the impact of potential heterogeneity between these regimens and for region to 
account for regional differences in treatment decisions and surgical practices.
 


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During randomization, subjects within each of the 48 stratification groups will be 
randomized in a 1:1:1 ratio to treatment Arms 1, 2 and 3, respectively.
The stratification factors used for the randomization should be the last values on or prior 
to the date of randomization and should be consistent with those on the eCRF.
Randomization to Arms 1, 2, and 3 will occur until the required number of subjects is 
enrolled as defined in Section 8.2.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The Investigator will be required to submit, 
maintain and archive study essential documents according to International Conference 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 
 


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affect the conduct of the study and/or increase the risk to subjects.  Written documentation 
of the submission to the IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
In the event that the COVID-19 pandemic leads to difficulties in performing protocol 
specified procedures, AbbVie will engage with study site personnel in efforts to ensure
the safety of subjects, maintain protocol compliance, and minimize risks to the integrity of
the study while trying to best manage subject continuity of care. This may include
alternative methods for assessments (e.g., phone contacts or virtual site visits), and 
alternative locations for data collection (e.g., use of a local lab instead of a central lab. In 
all cases, these alternative measures must be allowed by local regulations and permitted 
by IRB/IEC. Investigators should notify AbbVie if any urgent safety measures are taken 
to protect the subjects against any immediate hazard.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the main study informed consent form will be given to the subject and the original will be 
placed in the subject's medical record.  An entry must also be made in the subject's dated 
source documents to confirm that informed consent was obtained prior to any 
study-related procedures and that the subject received a signed copy.
 


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An informed consent, approved by an IRB/IEC, must be voluntarily signed and dated 
before samples are collected for optional exploratory research.  The nature of the testing 
should be explained and the subject given an opportunity to ask questions.  The informed 
consent must be signed before the samples are collected and any testing is performed.  If 
the subject does not consent to provide samples for the optional exploratory research, it 
will not impact their participation in the study.
In the event a subject withdraws from the main study, stored biomarker and optional 
exploratory research samples will continue to be stored and analyzed unless the subject 
specifically withdraws consent for these samples (samples will not be stored for more than 
20 years).  If consent is withdrawn for the biomarker and optional sampling, the subject 
must inform their study doctor, and once AbbVie is informed, the samples will be 
destroyed.  In the event that destruction is not possible, they will no longer be linked to 
the subject.  However, if the subject withdraws his/her consent and the samples have 
already been tested, those results will still remain as part of the overall research data.
Due to the COVID-19 pandemic, modifications to the protocol may be necessary.  
Subjects should be informed of the changes to the conduct of the study relevant to their
participation (e.g., cancellation of visits, change in laboratory testing site, etc.). 
Documentation of this notification and verbal consent should be maintained at the site. A 
signed and dated informed consent form should be obtained from the subject afterwards as 
soon as possible, if required by local regulations.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the principal investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the sponsor.  Approval of the IRB 
will be obtained prior to use in the study.
 


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9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the principal investigator will revise the consent form and explanatory material 
based on the information without delay and will obtain the approval of the IRB prior to 
use in the study.  The investigator will provide the information, without delay, to each 
subject already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating 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 investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
 


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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 
principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
Investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
 


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12.0
Use of Information
Any research that may be done using optional exploratory research samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject, will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from optional exploratory research 
may be provided to investigators and used in scientific publications or presented at 
medical conventions.  Optional exploratory research information will be published or 
presented only in a way that does not identify any individual subject.
12.1
Publication
The Investigators have the right to publish the results of the study, but with due regard to 
the protection of confidential information.  Accordingly, AbbVie shall have the right to 
review and approve any paper for publication, including oral presentation and abstracts, 
which utilize data generated from this study.  At least 60 days before any such paper or 
abstract is presented or submitted for publication, a complete copy shall be given to 
AbbVie for review.  AbbVie shall review any such paper or abstract and give its 
comments to the author(s) promptly.  The Investigator shall comply with AbbVie's 
confidential information in any such paper and agrees to withhold publication of same for 
an additional 60 days in order to permit AbbVie to obtain patent or other proprietary 
rights protection, if AbbVie deems it necessary.
13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator (Director of 
the Site in Japan) and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the Investigator (Director of the Site in Japan) 
and AbbVie.  The investigator will provide a final report to the IEC/IRB following 
 


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conclusion of the study, and will forward a copy of this report to AbbVie or their 
representative.
The Investigator (Director of the Site in Japan) must retain any records related to the study 
according to local requirements.  If the Investigator (Director of the Site in Japan) is not 
able to retain the records, he/she must notify AbbVie to arrange alternative archiving 
options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this Investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory Investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The global end-of-study is defined as the date of the last subject's last visit, or the date of 
the last subject's last follow-up contact, whichever is later.  The sponsor may also end the 
study upon confirmation that the primary endpoint was statistically met.
 


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for veliparib and the 
product labeling for carboplatin and paclitaxel.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Phase 3 Placebo-Controlled Study of Carboplatin/Paclitaxel 
With or Without Concurrent and Continuation Maintenance 
Veliparib (PARP inhibitor) in Subjects with Previously Untreated 
Stages III or IV High-Grade Serous Epithelial Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer
Protocol Date:
08 March 2021
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
 


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15.0
Reference List
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Fong PC, Yap TA, Boss DS, et al.  Poly(ADP)-ribose polymerase inhibition:  
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9.
Gelmon KA, Tischkowitz M, Mackay H, et al.  Olaparib in patients with recurrent 
high-grade serous or poorly differentiated ovarian carcinoma or triple-negative 
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Ledermann J, Harter P, Gourley C, et al.  Olaparib maintenance therapy in 
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Oza AM, Cibula D, Oaknin A, et al.  Olaparib plus paclitaxel plus carboplatin 
(P/C) followed by olaparib maintenance treatment in patients (pts) with platinum 
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Cancer Genome Atlas Research Network.  Integrated genomic analyses of ovarian 
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Mukhopadhyay A, Plummer ER, Elattar A, et al.  Clinicopathological features of 
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Mirza MR, Monk BJ, Herrstedt J, et al.  Niraparib Maintenance Therapy in 
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Coleman RL, Oza AM, Lorusso D, et al.  Rucaparib maintenance treatment for 
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Swisher EM, Lin KK, Oza AM, et al.  Rucaparib in relapsed, platinum-sensitive 
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Donawho CK, Luo Y, Luo Y, et al.  ABT-888, an orally active poly(ADP-ribose) 
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Bryant HE, Schultz N, Thomas HD, et al.  Specific killing of BRCA2-deficient 
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Farmer H, McCabe N, Lord CJ, et al.  Targeting the DNA repair defect in BRCA 
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Huggins-Puhalla SL, Beumer JH, Appleman LJ, et al.  A phase I study of 
chronically dosed, single-agent veliparib (ABT-888) in patients with either BRCA 
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breast cancer (BRCA-wt).  J Clin Oncol.  2012;30 (15 suppl).  Abstract 3054.
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Rosell R, Skrzypski M, Jassem E, et al.  BRCA1:  a novel prognostic factor in 
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Wei L, Lan L, Yasui A, et al.  BRCA1 contributes to transcription-coupled repair 
of DNA damage through polyubiquitination and degradation of Cockayne 
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Ashworth A, Lord C, Reis-Filho JS.  Genetic interactions in cancer progression and 
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AbbVie.  R&D/10/098.  Effects of veliparib (ABT-888) in syngeneic and xenograft 
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Ramalingam SS, Blais N, Mazieres J, et al.  Randomized, Placebo-Controlled, 
Phase II Study of Veliparib in Combination with Carboplatin and Paclitaxel for 
Advanced/Metastatic Non-Small Cell Lung Cancer.  Clin Cancer Res.  
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Sherrill B, Wang J, Kotapati S, et al.  Q-TWiST analysis comparing 
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28.
Tutt A, Robson M, Garber JE, et al.  Phase II trial of the oral PARP inhibitor 
olaparib in BRCA-deficient advanced breast cancer.  J Clin Oncol.  
2009;27 (18 suppl).  Abstract CRA501.
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Audeh MW, Penson RT, Friedlander M, et al.  Phase II trial of the oral PARP 
inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer.  J Clin 
Oncol.  2009;27 (15 suppl).  Abstract 5500.
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Somlo G, Frankel PH, Luu TH, et al.  Phase II trial of single agent PARP inhibitor 
ABT-888 (veliparib [vel]) followed by postprogression therapy of vel with 
carboplatin (carb) in patients (pts) with stage BRCA-associated metastatic breast 
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Coleman RL, Sill MW, Bell-McGuinn K, et al.  A phase II evaluation of the potent, 
highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent 
epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry 
a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic 
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Steffensen, KD, Adimi, P, Jakobsen, A.  Veliparib monotherapy to patients with 
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Abstract 5532.
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Elattar A, Bryant A, Winter-Roach BA, et al.  Optimal primary surgical treatment 
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Bristow RE, Tomacruz RS, Armstrong DK, et al.  Survival effect of maximal 
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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.
 


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


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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical 
Clinical Program Development
Statistics
Pharmacokinetics
 


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Appendix C.
Ovarian Surgical Procedure
Purpose:
To obtain an accurate staging of ovarian cancer; to perform 
maximum resection of ovarian cancer; to optimize the selection 
of postoperative therapy.
Indications:
All cases of ovarian cancer, including borderline tumors of the 
ovary.
Contraindications:
Poor surgical risk.
Content of Procedure
1.
The procedure's exposure must be adequate to explore the entire abdominal cavity 
and allow safe cytoreductive surgery.  A vertical incision is recommended for 
celiotomy.  Endoscopic approaches should not compromise disease assessment nor 
feasibility of resection.  The goal for any resection attempt is no visible tumor 
residuum, or R0 resection.
2.
The volume of any free peritoneal fluid should be estimated.  Free peritoneal fluid 
is to be aspirated for cytology.  If no free peritoneal fluid is present, separate 
peritoneal washings will be obtained from the pelvis, paracolic gutters and 
infradiaphragmatic area.  These may be submitted separately or as a single 
specimen.  Subjects with Stage III or IV disease do not require cytologic 
assessment.
3.
All peritoneal surfaces including the undersurface of both diaphragms and the 
serosa and mesentery of the entire gastrointestinal tract will be visualized and 
palpated for evidence of metastatic disease.
4.
Careful inspection of the omentum and removal if possible of at least the infracolic 
omentum will be accomplished.  At minimum a biopsy of the omentum must be 
obtained.
5.
If possible an extrafascial total abdominal hysterectomy and bilateral salpingo 
oophorectomy will be performed.  If this is not possible or not indicated, a biopsy 
of the ovary and sampling of the endometrium must be performed.  The surgery 
 


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section (§4.1) in selected ovarian cancer protocols may permit a unilateral 
salpingo-oophorectomy and/or subtotal hysterectomy.
6.
If there is no evidence of disease beyond the ovary or pelvis, the following must be 
done. 
a.
Peritoneal biopsies from:
i.
Cul-de-sac
ii.
Vesical peritoneum
iii.
Right and left pelvic sidewalls
iv.
Right and left paracolic gutters
b. Biopsy or scraping of the right diaphragm
c.
Selective bilateral pelvic and periaortic lymph node sampling.
d. Infracolic omentectomy
7.
Selective pelvic and periaortic lymph node sampling must be done in the following 
situations:
a.
Subjects with tumor nodules outside the pelvis which are ≤ 2 cm (presumed 
Stage IIIB) must have bilateral pelvic and periaortic lymph node biopsies
b. Subjects with parenchymal Stage IV disease and those with tumor nodules 
outside the pelvis which are greater than 2 cm do not require pelvic or periaortic 
lymph node biopsies unless the only nodule greater than 2 cm is a lymph node 
in which case it must be at least biopsied, or preferentially, resected.
8.
Histologically confirmed metastatic nodal disease makes further node sampling 
unnecessary unless their resection would enable R0 resection.
Adequate assessment of tumor persistence and resection should be made during surgery.
 


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Appendix D.
General Chemotherapy Guidelines
●
A subject will be permitted to have a new cycle of chemotherapy delayed up to 
7 days (without this being considered to be a protocol violation) for major life 
events (e.g., serious illness in a family member, major holiday, vacation which 
is unable to be re-scheduled).  Documentation to justify this decision should be 
provided. 
●
It will be acceptable for individual chemotherapy doses to be delivered within 
a 24-hour window before and after the protocol-defined date for "Day 1" 
treatment.  If the treatment due date is a Friday, and the subject cannot be 
treated on that Friday, then the window for treatment would include the 
Thursday (1 day earlier than due) through the Monday (Day 3 past due). 
●
For weekly regimens, it will be acceptable for individual chemotherapy doses 
to be delivered within a "24-hour window," for example; "Day 8 
chemotherapy" can be delivered on Day 7, Day 8, or Day 9 and "Day 15 
chemotherapy" can be given on Day 14, Day 15, or Day 16. 
●
Chemotherapy doses can be "rounded" according to institutional standards 
without being considered a protocol violation (most institutions use a rule of 
approximately ± 5% of the calculated dose). 
●
Chemotherapy doses are required to be recalculated if the subject has a weight 
change of greater than or equal to 10%.  Subjects are permitted to have 
chemotherapy doses recalculated for < 10% weight changes.
●
The Fujimoto, DuBois, or institutional standard formulas may be used to 
calculate BSA.
●
It is acceptable for capping BSA at 2.0 for paclitaxel dosing, if it is site's 
institutional practice to do so.
 


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Appendix E.
Carboplatin Dose Calculation Instructions
Dosing of Carboplatin:
1.
The carboplatin dose will be calculated to reach a target area under the curve 
(AUC) according to the Calvert formula using an estimated glomerular filtration 
rate (GFR) from the Cockcroft-Gault formula.
2.
The initial dose of carboplatin must be calculated using GFR.  In the absence of 
renal toxicity greater than or equal to CTCAE Grade 2 (serum creatinine >1.5 × 
ULN) or toxicity requiring dose modification, the dose of carboplatin will not need 
to be recalculated for subsequent cycles, but will be subject to dose modification 
for toxicity as noted in the protocol.
3.
Carboplatin doses are required to be recalculated if the subject has a weight change 
of greater than or equal to 10%.  Subjects are permitted to have chemotherapy 
doses recalculated for < 10% weight changes.
4.
At the time of dose modification, if the subject's age had changed (the subject has 
had a birthday), the site can use the current age.
5.
In subjects with an abnormally low serum creatinine (less than 0.7 mg/dl), the 
creatinine clearance should be estimated using a minimum value of 0.7 mg/dl.  For 
trials where subjects enter and are treated within less than or equal to 12 weeks of 
surgery:  If a more appropriate (higher) baseline creatinine value is available from 
the pre-operative period (within 4 weeks of surgery date), that value may also be 
used for the initial estimation of GFR.
 


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CALVERT FORMULA:
Carboplatin dose (mg) = target AUC × (GFR + 25)
NOTE:  the GFR used in the Calvert formula should not exceed 125 ml/min.  Maximum
carboplatin dose (mg) = target AUC (mg/min) × 150 ml/min.  The maximum allowed 
doses of carboplatin are:
●
AUC 6 = 900 mg
●
AUC 5 = 750 mg
●
AUC 4 = 600 mg
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance.  The estimated creatinine clearance (ml/min) is calculated by the 
method of Cockcroft-Gault using the following formula:
Creatinine Clearance (mL/min) = [140-Age (years)] × Weight (kg) × 0.85
72 × serum creatinine (mg/dl)
Notes:
1.
Weight in kilograms (kg)
a.
Body Mass Index (BMI) should be calculated for each patient.  A BMI 
calculator is available at the following link:  
http://www.nhlbi.nih.gov/health/educational/lose_wt/BMI/bmicalc.htm
b. Actual weight should be used for estimation of GFR for patients with BMI of 
less than 25
c.
Adjusted weight should be used for estimation of GFR for patients with BMI 
of greater than or equal to 25
d. Adjusted weight calculation:
●
Ideal weight (kg) = (((Height (cm)/2.54) – 60) × 2.3) + 45.5
 


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●
Adjusted weight (kg) = (Actual weight – Ideal weight) × 0.40) + Ideal 
weight
2.
The Cockcroft-Gault formula above is specifically for women (it includes the 
0.85 factor).
3.
For sites in which the institutional practice is to estimate GFR using 
isotopic/EDTA clearance:  if the calculated carboplatin dose (using Cockcroft & 
Gault formula) is > 10% higher than the carboplatin calculated using the 
EDTA-based GFR, carboplatin dose may be administered as calculated per 
institutional guidelines.  GFR estimated using isotopic/EDTA clearance should 
then be used for subsequent doses and dose modifications.
At the time of a dose modification for toxicity:
If the creatinine at the time of a dose modification is lower than the creatinine used to 
calculate the previous dose, use the previous (higher) creatinine; if the creatinine at the 
time of a dose modification is higher than the creatinine used to calculate the previous 
dose, use the current (higher) creatinine.  This will ensure that the patient is actually 
receiving a dose reduction.
 


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Appendix F.
FIGO Stage Grouping for Primary Carcinoma of the Ovary
These categories are based on findings at clinical examination and/or surgical exploration.  
The histologic characteristics are to be considered in the staging, as are results of 
cytologic testing as far as effusions are concerned.  It is desirable that a biopsy be 
performed on suspicious areas outside the pelvis.
STAGE I:  Tumor confined to ovaries
IA
Tumor limited to one ovary, capsule intact, no tumor on surface, negative 
washings
IB
Tumor involves both ovaries, otherwise like 1A
IC Tumor limited to 1 or both ovaries
IC1
Surgical spill
IC2
Capsule rupture before surgery or tumor on ovarian surface
IC3
Malignant cells in the ascites or peritoneal washings
STAGE II:  Tumor involves 1 or both ovaries with pelvic extension (below the pelvic 
brim) or primary peritoneal cancer
IIA
Extension and/or implant on uterus and/or fallopian tubes
IIB
Extension to other pelvic intraperitoneal tissues
STAGE III:  Tumor involves 1 or both ovaries with cytologically or histologically 
confirmed spread to the peritoneum outside the pelvis and/or metastases to the 
retroperitoneal lymph nodes
IIIA (positive retroperitoneal lymph nodes and/or microscopic metastases beyond the 
pelvis
IIIA1
Positive retroperitoneal lymph nodes only
IIIA1 (i)
Metastases ≤ 10 mm
IIIA1 (ii)
Metastases > 10 mm
IIIA2
Microscopic, extrapelvic (above the brim) peritoneal involvement ± positive 
retroperitoneal nodes
IIIB
Macroscopic, extrapelvic, peritoneal metastases ≤ 2 cm ± retroperitoneal 
lymph nodes.  Includes extension to capsule of liver/spleen
 


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IIIC
Macroscopic, extrapelvic, peritoneal metastasis > 2 cm ± positive 
retroperitoneal lymph nodes.  Includes extension to capsule of liver/spleen
STAGE IV:  Distant metastases excluding peritoneal metastases
IVA
Pleural effusion with positive cytology
IVB
Hepatic and/or splenic parenchymal metastases, metastases to 
extraabdominal organs (including inguinal lymph nodes and lymph nodes 
outside of the abdominal cavity)
Other major recommendations are as follows:
●
Histologic type including grading should be designated at staging
●
Primary site (ovary, Fallopian tube or peritoneum) should be designated where 
possible
○
Tumors that may otherwise qualify for stage I but involved with dense 
adhesions justify upgrading to Stage II if tumor cells are histologically 
proven to be present in the adhesions
 


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Appendix G.
Guidance for Identifying High Grade Serous Carcinoma
The following should be considered when determining a diagnosis of high grade serous 
carcinoma:
●
Diagnosed as Grade 2 or Grade 3 serous carcinoma using Shimizu-Silverberg 
grading scheme.  
●
Wide spectrum of architectural patterns, including solid, glandular, and 
cribriform patterns, and patterns resembling transitional cell carcinoma.  At 
least focal papillae and micropapillae with gaping and slit-like architectural 
features are present.
●
Histologic variants such as transitional cell carcinoma or serous carcinoma 
with microcystic features.
●
High nuclear grade, with extreme nuclear size variability (> 5×).
●
More than 10 mitotic figures per 10 high power fields.
●
Typically disseminated at presentation.  WT1 expression should be sought for 
Stage I tumors.
●
WT1, p53, and/or p16 overexpression may be sought if the differential 
diagnosis includes low grade serous carcinoma, endometrioid carcinoma, or 
clear cell carcinoma.
●
Can be distinguished from serous borderline tumor by the presence of high 
nuclear grade if obvious stromal invasion is not identified after examination of 
multiple sections.
 


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Appendix H.
Adverse Events Expected Due to Ovarian, Fallopian Tube, or 
Primary Peritoneal Cancer or Progression of Ovarian, Fallopian 
Tube, or Primary Peritoneal Cancer
Adverse Events Expected Due to Ovarian Cancer or Progression of Ovarian Cancer*
Abdominal pain
Abdominal distension
Ascites
Intestinal obstruction
Colonic obstruction
Small intestinal obstruction
Pleural effusion
Constipation
*
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.
 

SAP_001.pdf: 
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M13-694 – Statistical Analysis Plan
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1.0
Title Page
Statistical Analysis Plan
Study M13-694
A Phase 3 Placebo-Controlled Study of 
Carboplatin/Paclitaxel With or Without Concurrent 
and Continuation Maintenance Veliparib (PARP 
inhibitor) in Subjects with Previously Untreated 
Stages III or IV High-Grade Serous Epithelial 
Ovarian, Fallopian Tube, or Primary Peritoneal 
Cancer
Date:  04 May 2020
Version 3.0
NCT02470585


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2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
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
4.3.1
Hypotheses related to PFS .......................................................................11
4.3.2
Hypotheses related to OS.........................................................................12
4.4
Interim Analysis.......................................................................................13
4.5
Analysis Timing.......................................................................................15
5.0
Analysis Populations .............................................................16
5.1
Definition for Analysis Populations.........................................................16
5.2
Variables Used for Stratification of Randomization................................16
6.0
Analysis Conventions ............................................................17
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications and 
Prior Oncology Therapies.....................................................25
7.1
Demographic and Baseline Characteristics .............................................25
7.2
Medical History .......................................................................................27
7.3
Prior and Concomitant Medications and Prior Oncology Therapies .......28
8.0
Subject Disposition................................................................28
9.0
Study Drug Exposure and Compliance...............................29
9.1
Study Treatment Exposure.......................................................................29
9.1.1
Dose Reductions, Interruptions, Delays and Intensity.............................30
10.0
Efficacy Analysis....................................................................32
10.1
General Considerations............................................................................32
10.2
Primary Efficacy Analysis .......................................................................33
10.3
Secondary Efficacy Analyses...................................................................36
10.3.1
Overall Survival.......................................................................................36
10.3.2
Progression-Free Survival........................................................................36


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10.3.3
Patient Reported Outcomes......................................................................37
10.4
Tertiary Efficacy Analyses.......................................................................38
10.4.1
Progression-Free Survival 2 (PFS2) ........................................................38
10.4.2
Time to the First Subsequent Therapy .....................................................39
10.4.3
Time to the Second Subsequent Therapy.................................................40
10.4.4
Additional PRO Endpoints ......................................................................41
10.5
Additional Efficacy Analyses ..................................................................41
10.6
Efficacy Subgroup Analyses....................................................................42
10.7
Multiplicity Adjustment...........................................................................43
11.0
Safety Analysis.......................................................................47
11.1
General Considerations............................................................................47
11.2
Analysis of Adverse Events.....................................................................47
11.2.1
Adverse Event Overview .........................................................................47
11.2.2
Adverse Event by SOC and PT................................................................49
11.2.3
Adverse Event by Frequency...................................................................50
11.2.4
Adverse Events of Special Interest ..........................................................50
11.2.4.1
Time to Onset of AESI ............................................................................52
11.2.4.2
Prevalence and Incidence Rates of AESI.................................................52
11.2.5
Adverse Event Subgroup Assessments....................................................53
11.3
Deaths ......................................................................................................53
11.4
Analysis of Laboratory and Vital Signs Data ..........................................53
11.5
Analyses of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values...................................................................57
12.0
References...............................................................................58
List of Tables
Table 1.
Power and Sample Size Calculation ........................................................10
Table 2.
Time Windows for Visit-Wise Analysis of DRS.....................................21
Table 3.
Dose Intensity for Carboplatin and Paclitaxel .........................................32
Table 4.
Study Treatment Arms.............................................................................44
Table 5.
The Null Hypotheses of Interest in each Population ...............................44
Table 6.
Adverse Events of Special Interest ..........................................................51


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Table 7.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values ......................................................................................................56
Table 8.
Potential Clinical Significance Criteria for Vital Signs...........................57
List of Figures
Figure 1.
Overall Study Design.................................................................................8
Figure 2.
Testing Procedure ....................................................................................45


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3.0
Introduction
This statistical analysis plan (SAP) is created based on Study Protocol M13-694, 
incorporating Amendments 1, 2, 3, 4, 5, 6 and 7.  Study M13-694 examines the safety and 
efficacy of veliparib (ABT-888) in combination with standard platinum-based 
chemotherapy (carboplatin/paclitaxel) and then as monotherapy in maintenance for high 
grade serous epithelial, ovarian, fallopian tube, or primary peritoneal cancer.
This SAP provides details to guide the analyses for baseline, efficacy, and safety variables 
and describes the populations and variables that will be analyzed and the statistical 
methods that will be used for primary and follow-up analyses for Study M13-694 
(Analysis timing is defined in Section 4.5).
Version 3.0 of the SAP was created after finalization of the interim CSR to add an 
additional interim analysis of Overall Survival per the request of the FDA and allow 
provision for additional interim analyses if warranted.  No changes to any analysis 
previously conducted will be made.
Analyses will be performed using SAS® Version 9.4 (SAS Institute, Inc., Cary, NC) or 
later under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective of the study is to evaluate whether PFS is prolonged with the 
addition of veliparib to standard platinum-based chemotherapy (carboplatin/paclitaxel) 
and then continued as maintenance therapy when compared to chemotherapy alone 
(Arm 3 versus Arm 1).  This will be evaluated in three nested cohorts defined in 
Section 5.1:  subjects with BRCA-deficient tumors, subjects with homologous 
recombination deficient (HRD) tumors, and the whole patient population.
Secondary objectives include evaluations of OS (Arm 3 versus Arm 1 and Arm 2 versus 
Arm 1), PFS (Arm 2 versus Arm 1), Disease Related Symptom (DRS) scores (Arm 3 


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versus Arm 1 and Arm 2 versus Arm 1), and safety of the 3 study arms.  These will be 
evaluated within the three patient populations.
The tertiary objectives include progression free survival 2 (PFS2), time to first subsequent 
therapy (TTFST), time to second subsequent therapy (TTSST), and other PRO endpoints 
(which will be specified in a separate analysis plan).  These will also be evaluated by 
comparing Arms 3 and 2 with Arm 1, within the three patient populations.
4.2
Design Diagram
This is a randomized, placebo-controlled, double-blind, stratified, multicenter, multi-
country Phase 3 study designed to evaluate if PFS is prolonged when veliparib is added to 
carboplatin/paclitaxel and continued as maintenance therapy when compared to 
chemotherapy alone in subjects with previously untreated high-grade serous epithelial 
ovarian, fallopian tube, or primary peritoneal cancer.
Subject randomization was stratified by stage of disease, residual disease and choice of 
regimen, region of the world, and gBRCA mutation status (gBRCA was added during the 
course of the study).  Approximately 1100 subjects were planned for enrollment, and 
1140 subjects were randomized in a 1:1:1 ratio to one of the following three treatment 
Arms:  
Arm 1:  
Carboplatin/paclitaxel plus placebo for six 21-day cycles followed by 
placebo maintenance therapy for 30 additional 21-day cycles;
Arm 2:  
Carboplatin/paclitaxel plus veliparib for six 21-day cycles followed by 
placebo maintenance therapy for 30 additional 21-day cycles;
Arm 3:  
Carboplatin/paclitaxel plus veliparib for six 21-day cycles followed by 
veliparib BID maintenance therapy for 30 additional 21-day cycles.
Subjects that were found not to tolerate paclitaxel, could instead receive docetaxel but had 
to temporarily discontinue veliparib due to lack of safety data for this combination.  
Subjects were allowed to restart veliparib in the maintenance phase once treatment with 
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The study consists of five phases:  a Pre-Therapy Phase (Screening), a Combination 
Therapy Phase, a Maintenance Therapy Phase, a Long-Term Follow-Up Phase, and a 
Survival Phase.  An overview of the study design is shown in Figure 1.


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Figure 1.
Overall Study Design


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4.3
Sample Size
The trial was planned to enroll approximately 1100 subjects (with 1:1:1 randomization 
ratio for Arm 1:Arm 2:Arm 3) in the whole population, including approximately 
264 subjects with BRCA-deficient status (assuming 24% of the subjects in the whole 
population are BRCA-deficient) to power the hypotheses specified in the BRCA-deficient 
and whole populations (Table 1).  Detailed sample size calculations for the PFS and OS 
endpoints of the BRCA-deficient, HRD and whole populations are described in 
Section 4.3.1 – Section 4.3.2.
In order to calculate the needed number of subjects in each of the 3 arms, the same 
statistical assumptions were used to power both the comparisons of PFS and OS between 
Arm 3 versus Arm 1 [3vs1], and between Arm 2 versus Arm 1 [2vs1], within each 
population.  
The associated power for the alpha level and population can be found in Table 1.
Throughout the SAP, 'Month 36' is used as the surrogate for the time of primary analysis 
of PFS for all three populations; 'Month 48' is used as the surrogate for the time of the 
additional interim analysis of OS for all three populations, conducted approximately 
one year after the primary analysis of PFS; 'Month 58' is used as the surrogate for the time 
of final analysis of OS in Whole population; and 'Month 77' is used as the surrogate for 
the time of final analysis of OS in both BRCA-deficient and HRD populations. 


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Table 1.
Power and Sample Size Calculation 
PFS
OS
Type I 
Error
Population
No. of 
Subjects 
per Arm 
(N)
Power
Median 
PFS in 
Arm 1
Hazard 
Ratio
No. of 
Events for 
2 Arm 
Comparison
Projected 
Endpoint 
Mature 
Time 
(Months)
Power
Median 
OS in 
Arm 1
Hazard 
Ratio
No. of 
Events for 
2 Arm 
Comparison
Projected 
Endpoint 
Mature 
Time 
(Months)
alpha = 
0.025  
BRCA-
deficient
88
87%
21
0.50
79
36
87%a
53
0.50
79
77
HRD
160
91.5%
18
0.60
170
36
90%a
47
0.60
166
77
Whole
367
96.5%
15.5
0.70
446
36
91.5%b
41.5
0.70
350
58
94.1%
15.5
0.7
391
36
PFS = progression-free survival; OS = overall survival
a.
Assumes 3 efficacy interim analyses (at Month 36, Month 48, and Month 58, respectively) with alpha spending of 0.000001 at each of the 3 interim analyses.  The 
multiplicity adjusted alpha for the final analysis at Month 77 is 0.025, provided all preceding null hypotheses in the hierarchical testing sequence are rejected.
b.
Assumes 2 efficacy interim analysis at Month 36 and Month 48 with alpha spending of 0.000001.  The alpha for the final analysis at Month 58 is 0.025.  The multiplicity 
adjusted alpha for the analysis at Month 77 is 0.025, provided all preceding null hypotheses in the hierarchical testing sequence are rejected.
Note:
All calculations take into account a 10% dropout rate.  An enrollment period of 18 months with linear enrollment rate is assumed.  The actual endpoint mature time may 
vary depending on the true enrollment pattern.


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4.3.1
Hypotheses related to PFS
PFS (Arm 3 versus Arm 1, and Arm 2 versus Arm 1):
Testing of PFS (Arm 3 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 3 (C/P + veliparib →veliparib) decreases the PFS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the population of interest.
Testing of PFS (Arm 2 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 2 (C/P + veliparib →placebo) decreases the PFS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the population of interest.
BRCA-deficient Population:  A total of 79 events would provide 87% power for a 
1-sided log-rank test at a 0.025 significance level to detect a statistically significant 
improvement in PFS assuming a true hazard ratio of 0.5 (between Arm 3 and Arm 1, or 
between Arm 2 and Arm 1). 
Assuming a median PFS of 21 months in Arm 1 and an enrollment period of 18 months, 
approximately 88 subjects per arm in a 1:1 randomization ratio (Arm 3:Arm 1 and 
Arm 2:Arm 1) were needed to have a matured PFS endpoint at around 36 months taking 
into account a dropout rate of 10%.
HRD Population:  This population was not in the original protocol design consideration.  
Assuming a HR = 0.6 between Arm 3 and Arm 1, or Arm 2 and Arm 1, we can expect at 
least a total of 170 PFS events in Arm 3 and Arm 1 combined, and Arm 2 and Arm 1 
combined at the time of primary analyses of PFS in BRCA-deficient and Whole 
populations.  A total of 170 events would provide 91.5% power with a 1-sided log-rank 
test at a 0.025 significance level to detect a statistically significant improvement in PFS 
assuming a true hazard ratio of 0.6 (between Arm 3 and Arm 1, and Arm 2 and Arm 1).  
Assuming a median PFS of 18 months in Arm 1 and an enrollment period of 18 months, 
approximately 160 subjects per arm in a 1:1 randomization ratio (Arm 3:Arm 1, and 


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Arm 2:Arm 1) are needed to have a matured PFS endpoint at around 36 months taking 
into account of a dropout rate of 10%.
Whole Population:  A total of events between 391 and 446 would provide power 
between 94.1% and 96.5%, with a 1-sided log-rank test at a 0.025 significance level to 
detect a statistically significant improvement in PFS assuming a true hazard ratio of 
0.7 (between Arm 3 and Arm 1, or between Arm 2 and Arm 1). 
Assuming a median PFS of 15.5 months in Arm 1 and an enrollment period of 18 months, 
and taking into account a dropout rate of 10%, approximately 367 subjects were needed 
per arm in a 1:1 randomization ratio (Arm 3:Arm 1, and Arm 2:Arm 1) in order to have a 
matured PFS endpoint at around 36 months.
4.3.2
Hypotheses related to OS
OS (Arm 3 versus Arm 1, and Arm 2 versus Arm 1):  
Testing of OS (Arm 3 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 3 (C/P + veliparib →veliparib) decreases the OS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the population of interest.
Testing of OS (Arm 2 versus Arm 1) evaluates whether the veliparib-containing regimen 
in Arm 2 (C/P + veliparib →placebo) decreases the OS event rate relative to reference 
regimen in Arm 1 (C/P + placebo →placebo) in the population of interest.  
BRCA-deficient Population:  A total of 79 events would provide 87% power with a 
1-sided log-rank test at a 0.025 significance level to detect a statistically significant 
improvement in OS, assuming a true hazard ratio of 0.5 (between Arm 3 and Arm 1, or 
between Arm 2 and Arm 1).  
Assuming a median OS of 53 months in Arm 1 and an enrollment period of 18 months, 
approximately 88 subjects per arm in a 1:1 randomization ratio (Arm 3:Arm 1, and 
Arm 2:Arm 1) were needed to have a matured OS endpoint at around 77 months, taking 


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into account of a dropout rate of 10% and 2 efficacy interim analyses that occur at the 
time of the primary analyses of PFS and final analysis of OS analysis for the whole 
population.
HRD Population:  A total of 166 events would provide 90% power with a 1-sided log-
rank test at a 0.025 significance level to detect a statistically significant improvement in 
OS, assuming a true hazard ratio of 0.6 (between Arm 3 and Arm 1, and Arm 2 and 
Arm 1). 
Assuming a median OS of 47 months in Arm 1 and an enrollment period of 18 months, 
approximately 160 subjects per arm in a 1:1 randomization ratio (Arm 3 versus Arm 1) 
are needed to have a matured OS endpoint at around 77 months, taking into account of a 
dropout rate of 10% and 2 efficacy interim analyses that occur at the time of the primary 
PFS and final analysis of OS for the whole population.
Whole Population:  Under the design considerations in the original protocol, a total of 
350 events would provide 91.5% power for a 1-sided log-rank test at a 0.025 significance 
level, respectively, to detect a statistically significant improvement in OS assuming a true 
hazard ratio of 0.7 (between Arm 3 and Arm 1, or between Arm 2 and Arm 1). 
Assuming a median OS of 41.5 months in Arm 1 and an enrollment period of 18 months, 
and taking into account of a dropout rate of 10% and an efficacy interim analysis that 
occurs at the time of the PFS analysis, approximately 367 subjects were needed per arm in 
a 1:1 randomization ratio (Arm 3 versus Arm 1) to have a mature OS endpoint at around 
58 months.
4.4
Interim Analysis
Interim Efficacy Analyses for Overall Survival
Overall survival is expected to mature at Month 58 in the whole population and at 
Month 77 for the BRCA-deficient and HRD populations.


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The Overall Survival hypotheses (Arm 3 versus Arm 1, or Arm 2 versus Arm 1) in the 
BRCA-deficient, HRD, and Whole populations will be tested at the following time points.  
The order of the testing sequence will follow that in Section 10.7. 
The first interim analysis for all three populations will occur at the time of the primary 
analyses of PFS (~Month 36) with an alpha of 0.000001.
The second interim OS analysis for all three populations will occur approximately 
one year after the first interim with an alpha of 0.000001.
The third interim OS analysis in the BRCA-deficient and HRD populations will occur at 
the time when the Whole population matures (~Month 58) with an alpha of 0.000001.
The final analyses of OS in each population will occur when the BRCA-deficient 
population matures (~Month 77) and will have an alpha of 0.025 if all null hypotheses 
tested previously according to the testing sequence are rejected. The final analysis for 
Whole Population, planned to be performed along with the analyses of mature OS data in 
BRCA-deficient and HRD populations, will still be based on the data from the time when 
the targeted number of OS data was achieved in the Whole Population (~Month 58). 
If future analyses need to be performed as requested by regulatory agencies, an alpha of 
0.000001 will be spent for each of those additional analyses without amending the SAP. 
Interim Safety Analyses
An Independent Data Monitoring Committee (IDMC) will review safety data in an un-
blinded fashion approximately 12 months from the date the first subject is randomized.  
Details of the IDMC review will be outlined in the IDMC Charter.  Aggregate clinical 
safety data will be reviewed on a real-time basis throughout the course of the study.
The first IDMC meeting reviewed safety data on July 29, 2016.  The IDMC saw no 
concerning safety signals and recommended continuing the study.  They also 
recommended an additional IDMC meeting in 6 months due to the fast enrollment rate.  In 


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addition, the IDMC noted a significant imbalance of gBRCA status across treatment 
groups, and recommended adding gBRCA status as a randomization stratification factor to 
potentially correct this imbalance.  This recommendation was based on the expectation 
that BRCA status is a strong prognostic and predictive factor for patients' responses to the 
study regimen.  AbbVie followed the IDMC's recommendation and added the gBRCA
stratification factor in September 2016.
The study proceeded to have three subsequent IDMC meetings to review safety data, on 
January 17, 2017, July 31, 2017, and May 04, 2018.  No further IDMC meetings are 
scheduled at the time of finalization of this SAP.
4.5
Analysis Timing
The 'data cutoff date' for the primary analyses of PFS will be determined when the total 
number of PFS events in Arms 1 and 3 combined have reached 79 in the BRCA-deficient 
population, 170 in the HRD population, and 391 in the whole population.  Since this is a 
blinded study involving 3 arms, an independent statistical data analysis center will be used 
to confirm that the above stated criteria for the total number of PFS events between 
Arms 1 and 3 have been reached.  
The first interim analysis of OS will occur in the BRCA-deficient, HRD and whole 
populations at the time of the primary analyses for PFS.
Per FDA request, a second interim analysis of OS for the three populations will be 
conducted, approximately one year after the primary analysis. 
For the whole population, the final analysis of OS will occur after the total number of 
deaths between Arms 1 and 3 have reached 350.  At the time of the final analysis of OS 
for the whole population, interim analysis of OS will be performed for BRCA-deficient 
and HRD populations. 


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For the BRCA-deficient and HRD populations, final analyses of OS will occur after the 
total number of deaths in Arms 1 and 3 reaches 79 in the BRCA-deficient population and 
166 in the HRD population. 
5.0
Analysis Populations
5.1
Definition for Analysis Populations
The study populations are defined as follows:  
●
Whole population (ITT population) – all subjects randomized by IRT.
●
BRCA-deficient population – all subjects in the ITT population with either a 
germline (gBRCA) and/or tissue (tBRCA) deleterious or suspected deleterious 
mutation in BRCA1 or BRCA2 as determined using centralized testing.
●
HRD population – all subjects in the BRCA-deficient population as well as 
those determined as having homologous repair deficiency tumors based on 
HRD score as determined using centralized testing.
●
As Treated (AST) population – all subjects who were randomized by IRT and 
took at least one dose of veliparib/placebo.  The data from the AST population 
will be analyzed by the actual treatment that subject received.
For all efficacy analyses, subjects in the Whole population, BRCA-deficient population, 
and HRD population will be analyzed by the treatment group assignment given at the time 
of randomization, regardless of actual treatment received, or failure to follow the protocol 
until completion.
5.2
Variables Used for Stratification of Randomization
Subject randomization was stratified into 48 groups as defined by combining categories of 
the four randomization stratification factors (gBRCA was added per the IDMC's 
recommendation during the course of the study) that follow:
1.
Stage of the disease
a.
III


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b.
IV
2.
Residual disease and choice of regimen
a.
Q3-weeks carboplatin/paclitaxel, no residual disease
b.
Q3-weeks carboplatin/paclitaxel, any residual disease
c.
Q-week carboplatin/paclitaxel, no residual disease
d.
Q-week carboplatin/paclitaxel, any residual disease
e.
Interval cytoreductive surgery, Q3-weeks carboplatin/paclitaxel
f.
Interval cytoreductive surgery, Q-week carboplatin/paclitaxel
3.
Region
a.
Japan
b.
North America or Rest of World
4.
Germline BRCA mutation status
a.
gBRCA positive (germline deleterious or suspected deleterious mutation in 
BRCA1 or BRCA2)
b.
gBRCA negative (wildtype or unknown)
Stratification factors to be used in stratified efficacy analyses are described below in 
Section 6.0.  
6.0
Analysis Conventions
General Considerations
The date of randomization is defined as the date that the IRT issues a randomization 
number.
All randomized subjects will be included in the efficacy analyses.  All subjects who 
receive at least one dose of veliparib/placebo will be included in the safety analysis.


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Data Cutoff Date
Only data occurring on or before the 'data cutoff date' will be used in all analyses and 
summaries of safety and efficacy data.  Unless otherwise specified, the same 'data cutoff 
date' will be used for all three populations.  Data occurring after the cutoff date may be 
used in determining end dates for calculation of exposure (e.g., exposure or adverse event 
duration) or last known alive dates.
Definition of Study Drug
Unless otherwise specified, the study drug in this document refers to veliparib/placebo.
Definition of Study Treatment
Unless otherwise specified, the study treatment in this document refers to 
veliparib/placebo, carboplatin, paclitaxel, and as applicable, docetaxel.
Stratification Variables to be Adjusted for in Stratified Efficacy Analyses
Due to suspected sparseness of data in some strata observed through blinded summaries, a 
subset of the randomization stratification factors will be used for all stratified efficacy 
analyses.  The subset was chosen based on the differences observed between the 
stratification levels in the efficacy data (pooled across three treatment groups).  
Additionally, based on the pooled data, Residual Disease was further collapsed as the 
Interval Surgery and Any Residual Disease after Primary Surgery showed similar 
efficacy.
Whole population:  Primary Plan: Residual Disease (2 levels:  No Residual Disease after 
Primary Surgery versus Any Residual Disease after Primary Surgery or Interval Surgery),
Stage of Disease (Stage III versus Stage IV), Choice of Paclitaxel Dosing Regimen (Q-
weekly versus Q3-weekly) and BRCA-deficient status (BRCA-deficient versus BRCA
wildtype or unknown) will be used in all stratified analyses of the efficacy endpoints for 
the whole population. However, if any of the 16 stratum cells due to the above strategy 


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result in 0 PFS events for Arms 1 and 3 combined, then Choice of Paclitaxel Dosing 
Regimen will be dropped from the set of factors. The set of factors will be consistent 
among all stratified efficacy analyses based on the whole population (unless specified 
otherwise).
BRCA-deficient and HRD populations:  Residual Disease (2 levels:  No Residual Disease 
after Primary Surgery versus Any Residual Disease after Primary Surgery or Interval 
Surgery) and Stage of Disease (Stage III versus Stage IV) will be used in all stratified 
analyses of the efficacy endpoints for the BRCA-deficient and HRD populations.  
The stratification factor value under which the subject is randomized by the IRT will be 
used in the efficacy analyses for all factors except BRCA-deficient status. Since tissue 
BRCA status was not a randomization factor, and not all subjects were randomized by 
germline BRCA status, the actual results from the central testing will be used for the 
analyses (i.e., not the gBRCA status used for stratification at randomization).
Dealing with Multiple Values on the Same Day
In cases where multiple values are collected on the same day (including baseline visit and 
post-baseline visits), the maximum grade value will be selected as the value for that day 
for the shift analysis of lab parameters; the worst score calculated for that day will be used 
for analysis of quality of life (QoL), and performance status (ECOG).
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 treatment for treated subjects (or
the date of randomization for non-treated subjects).
Definition of Final Visit
For laboratory and vital signs variables, Final Visit is defined as the last non-missing 
observation collected within 30 days following the last dose of study treatment.  All post-


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baseline assessments collected more than 30 days after the last dose of study treatment 
will not be included in the analyses of laboratory and vital signs variables.
Definition of Study Rx Day (Days Relative to the First Dose of Study Treatment)
Study Rx Days are calculated for each time point relative to the first dose date of any 
component of study treatment.  They are defined as the number of days between the day 
of the first dose of study treatment and the specific time point.  Rx days are negative 
values when the time point of interest is prior to the first study treatment dose day.  Rx 
days are positive values when the time point of interest is after the first study treatment 
dose day.  The day of the first dose of study treatment is defined as Study Rx Day 1, while 
the day prior to the first study treatment dose is defined as Study Rx Day –1 (there is no 
Study Rx Day 0). 
Definition of Cycle Rx Days in Each Cycle
During the combination phase (Cycles 1 through 6), Cycle Rx Days for each cycle are 
calculated for each time point relative to the first dose of 
veliparib/placebo/carboplatin/paclitaxel/docetaxel in each cycle.
During the maintenance phase (Cycles 7 through 36), Cycle Rx Days are calculated for 
each time point relative to the first dose of veliparib/placebo in each cycle. 
Subjects that have discontinued study therapy and are in the Long Term Follow Up 
without Disease Progression Phase will still have QoL data summarized as treatment 
cycles.  Cycle Rx Days will be calculated by taking the last available Cycle start date 
while on treatment, and iteratively adding 21 days to define the nominal day of each 
Cycle Rx Day up until Cycle 36.  
Definition of Analysis Windows for DRS
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 from baseline to all post-
baseline assessments in DRS, the time windows specified in 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 as in Table 2.
●
If more than one assessment is included in a time window, the assessment 
closest to the nominal day should be used.  If there are two observations 
equally distant to the nominal day, the later one will be used in analyses.
The data will only be analyzed for visits that have at least 5 subjects' observations for each 
treatment group.
Table 2.
Time Windows for Visit-Wise Analysis of DRS
Scheduled Visit
Nominal Cycle 
Rx Day
Time Window while On 
Study Therapy
(Study Rx Day Range)
Time Window when Off 
Study Therapy
(Study Rx Day Range)
Combination Phase:
Cycle 1
Baseline
As Baseline Definition
As Baseline Definition
Cycle 3
1
(–3, 4) 
(–21, 21)
Cycle 5
1
(–3, 4)
(–21, 21)
Maintenance Phase
Cycle 7
1
(–3, 4)
(–21, 21)
Cycle 9
1
(–3, 4)
(–21, 21)
Cycle XXa
1
(–3, 4)
(–21, 21)
a.
Every other cycle until Cycle 35.
Determination of Censoring Dates for OS, TTFST, and TTSST
The censoring date for overall survival, time to first subsequent therapy and time to 
second subsequent therapy for a subject will be the last assessment date from the 
following list of data record types:
●
Vital signs


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●
Physical exam
●
Lab variables, including SAE lab reports
●
ECOG performance status
●
Quality of life measures
●
Study drug administration
●
Tumor assessments scan date
●
Transfusions
●
Electrocardiogram
●
Adverse event
●
PK blood draws
●
Date of Cytoreductive Surgery
●
Concomitant Medications
●
Post treatment therapy
●
Survival follow-up (last-known-alive date)
●
Randomization Date
Records that indicate that the assessment was not done will not be used in determining the 
censoring date.
Partial Dates
The following rules will apply for partial start dates:
●
Missing day will be imputed as the first day of the month
●
Missing month and day will be imputed as January 1st
●
For partial adverse event start dates:  if the first dose date is available, and the 
adverse event end date is missing or after the first dose date, then the imputed 
start date would be the maximum of the first dose date and the imputed value 
under the above two criteria.
The following rules will apply for partial end dates:


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●
Missing day will be imputed as the last day of the month 
●
Missing month and day will be imputed as December 31st
●
For partial adverse event end dates:  the imputed value can never be set later 
than the subject death date, when the death date is available.
●
For partial exposure end dates: 
●
For veliparib records, missing day will be imputed as the maximum of the 
first day of the month and the exposure record start date
●
For veliparib records, missing month and day will be imputed as the maximum 
of January 1st of the provided year and the exposure record start date
●
For chemotherapy, if any part of the date is missing, the end date will be 
imputed as the record start date
●
For all study treatment, if the end date is completely missing, then the end date 
will be imputed as the exposure record start date
Definition of Treatment-Emergent Adverse Events
Adverse Events will be considered "treatment-emergent" when their onset is on or after 
the day of the first dose of study treatment and also are at most 30 days after the last dose 
of any study treatment (including docetaxel if applicable). 
If the onset date for an adverse event is reported with a month and year but without the 
day of the month, and the reported month matches that of the start of study treatment, then 
the adverse event will be treatment-emergent.  If the reported month matches the month in
which the 30 day follow-up period ends then the adverse event will be treatment-
emergent.  If an onset or end date for an adverse event is reported with a year only in such 
a way that it cannot be determined definitively if the adverse event is treatment-emergent 
by comparing with dosing data, the adverse event will be considered treatment-emergent.
NCI Grades for Laboratory Variables
Laboratory variable values will be graded using National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0 Published:  


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May 28, 2009 (v4.03:  June 14, 2010)1 for some analyses.  Criteria are specified for the 
assignment of grades with values between 1 and 4.  The criteria are unidirectional:  any 
one set of criteria constitute a screening either for low or high values of potential clinical 
significance. 
For laboratory tests for which a normal range limit is one end of the grade 1 range then 
values that are either within the normal range or outside it in the direction opposite to the 
test will be classified as grade 0 values.  For other tests, values outside the grade 1 range 
in the direction opposite to that of the test will be classified as grade 0.
There can be instances in which the criteria for more than one grade apply to a lab test 
value.  In those instances the highest applicable grade will be assigned to the value.
Definition of Safety Subgroups for Adverse Event and Laboratory Summaries
Adverse Events and Laboratory values may be summarized according to the following 
clinically important safety subgroups. 
●
Combination Period: defined as the first dose date of 
veliparib/carboplatin/paclitaxel to the day before the first dose date veliparib 
during Cycle 7.  For subjects not dosed after Cycle 6, the Combination Period 
is defined as the first dose date of veliparib/carboplatin/paclitaxel to the last 
dose date of any component of the study treatment + 30 days.  
●
Maintenance Period:  defined as the first dose date of veliparib that occurs 
after the end of Cycle 6 to the last dose date of veliparib + 30 days.  Only 
subjects that were dosed with veliparib after the end of Cycle 6 will be 
included in safety summaries regarding Maintenance Period.
●
Q-weekly Dosing: for AE and Lab summaries by choice of dosing schedule, 
the actual dosing schedule the subject was under will be used (not necessarily 
what the subject was randomized as).
●
Q3-weekly Dosing: for AE and Lab summaries by choice of dosing schedule, 
the actual dosing schedule the subject was under will be used (not necessarily 
what the subject was randomized as).


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●
Subjects Dosed With Docetaxel: All subjects that received at least one dose of 
docetaxel.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications 
and Prior Oncology Therapies
The ITT population will be used in the analyses of demographic, baseline characteristics, 
medical history, and previous/concomitant medication.  Prior oncology therapies will only 
be summarized for subjects with a history of another cancer.
All summaries and analyses will be presented by each treatment arm, and may also be 
summarized separately for the BRCA-deficient and HRD populations.
7.1
Demographic and Baseline Characteristics
The following demographic and baseline characteristics will be summarized:
●
Country
●
Region (as randomized) [North America vs. Japan vs. Rest of World].
●
Region (confirmed post randomization) [North America vs. Japan vs. Rest of 
World]
●
Race
●
Age (continuous and categorical [< 65 years vs. ≥ 65 years])
●
Height
●
Weight
●
Type of Ovarian Cancer [High-grade serous epithelial ovarian vs. High-grade 
serous epithelial fallopian tube vs. High-grade serous epithelial primary 
peritoneal]
●
History of Other Cancer [History vs. No History]
●
CA-125 level [≤ ULN vs. > ULN]
●
Germline BRCA status (as randomized) [gBRCA Positive vs. gBRCA Negative 
vs. Unknown vs. Not randomized by gBRCA]


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●
Germline BRCA status (central testing) [BRCA1/2 mutation vs. BRCA1/2 
wildtype]
●
Tissue BRCA status [BRCA1/2 mutation vs. BRCA1/2 wildtype]
●
BRCA-deficient status [germline or tissue BRCA1/2 mutation vs. BRCA1/2 
wildtype]
●
Type of BRCA-deficiency [germline BRCA1/2 mutation vs. tissue BRCA1/2 
mutation and germline BRCA1/2 wildtype vs. BRCA1/2 wildtype]
●
Type of BRCA1/2 mutation [BRCA1 vs. BRCA2 vs. BRCA1 and BRCA2 vs. 
BRCA1/2 wildtype]
●
HRD status [HRD vs. non-HRD]
●
HRD and BRCA-deficient status [HRD and BRCA1/2 mutation vs. HRD and 
BRCA1/2 wildtype vs. non-HRD]
●
Stage of Disease at randomization [III vs. IV]
●
Stage of Disease as confirmed by investigator after randomization [III vs. IV]
●
Residual Disease and Choice of Regimen at randomization
○
Q3-weekly paclitaxel, no residual disease
○
Q3-weekly paclitaxel, any residual disease
○
Q-weekly paclitaxel, no residual disease
○
Q-weekly paclitaxel, any residual disease
○
Interval cytoreductive surgery, Q3-weekly paclitaxel
○
Interval cytoreductive surgery, Q-weekly paclitaxel
●
Residual Disease and Choice of Regimen as confirmed by investigator after 
randomization (categories as above; where microscopic or any macroscopic 
residual disease is classified as any residual disease and no residual disease is 
classified as no residual disease)
●
Choice of Surgery at randomization [primary vs. interval] 
●
Choice of Surgery as confirmed by investigator after randomization [primary 
vs. interval vs. no surgery received] 
●
Residual Disease at randomization [no residual disease vs. any residual disease 
vs. interval surgery] 


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●
Residual Disease after primary surgery, as confirmed by investigator after 
randomization [no residual disease vs. microscopic residual disease only vs. 
any macroscopic residual disease] 
●
Residual Disease after interval surgery [no residual disease vs. microscopic 
residual disease only vs. any macroscopic residual disease] 
●
Choice of Dosing Regimen at randomization [Q-weekly vs. Q3-weekly] 
●
Choice of Dosing Regimen as confirmed by investigator after randomization 
[Q-weekly vs. Q3-weekly]
●
Smoking history [current smoker vs. past smoker vs. never smoked vs 
unknown]
●
Alcohol history [current user vs. past user vs. never vs. unknown]
●
ECOG performance status [0, 1, vs. 2]
The number of subjects with missing information will also be summarized.
Categorical data will be summarized by numbers and percentages in each category. 
Continuous data will be summarized by mean, standard deviation, median, IQR, 
minimum and maximum values.
7.2
Medical History
Medical history data will be summarized and presented using body systems and 
conditions/diagnoses as captured on the eCRF.  The body systems will be presented in 
alphabetical order and the conditions/diagnoses will be presented in alphabetical order 
within each body system.  The frequency 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 among 
the treatment groups.


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7.3
Prior and Concomitant Medications and Prior Oncology 
Therapies
The frequency and percentage of subjects who took at least one dose of medication other 
than study treatment will be summarized by the generic name coded by WHO dictionary.  
This analysis will be performed for prior and concomitant medications separately.  Any 
medication initiated before the first day of treatment with study therapy is a prior 
treatment.  Medications initiated during the study from the first day of study treatment, or 
else initiated before study treatment and continued into the study treatment period, are 
concomitant medications.  Prior Oncology Therapies will be presented in a separate 
summary for subjects treated for another type of cancer prior to entering the study.
There will be no statistical comparison for the prior and concomitant medications among 
the treatment groups.
8.0
Subject Disposition
Analyses for the subject disposition will be performed on the ITT population at the time 
of the primary analysis and final analysis as appropriate.  The treatment groups assigned 
by IRT will be used in the summaries of subject disposition and there will be no statistical 
comparison for the subject disposition.
The screen failure reasons will be summarized for the screen failure subjects.
The number of randomized subjects, the number of treated subjects, and final status will 
be summarized by treatment group and by investigator site/country.
The frequency and percentage of subjects who discontinued study, veliparib/placebo, 
carboplatin, or paclitaxel will be summarized for each treatment group.  All reasons for 
discontinuation and the primary reason for discontinuation of each drug (including 
docetaxel) will be summarized by treatment group.
The frequency and percentage of subjects who underwent primary or interval surgery will 
be summarized by randomized surgery type.  For subjects that did not undergo surgery, 


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the reasons may be summarized and a subject listing may be provided containing 
additional details.
9.0
Study Drug Exposure and Compliance
9.1
Study Treatment Exposure
Analyses for the exposure to study treatment will be performed on the AST population.  
The number of cycles that subjects are exposed to veliparib/placebo, carboplatin, 
paclitaxel, and docetaxel (for subjects dosed with docetaxel) will be summarized by 
treatment group.  Frequencies and percentages of the maximum cycle dosed will be 
displayed for each component of study treatment by treatment group.
In addition, the following will be summarized for veliparib/placebo only:  
Days exposed to study drug (days) is defined as the total number of individual days a 
subject received study drug. 
Days exposed to study drug (intervals):  the frequency and percentage of subjects 
exposed to veliparib/placebo will be summarized for each of the following duration 
intervals.
●
1 to 63 days [≤ 3 cycles]
●
64 to 126 days [3 < cycles ≤ 6]
●
127 to 252 days [6 < cycles ≤ 12]
●
253 to 378 days [12 < cycles ≤ 18]
●
379 to 504 days [18 < cycles ≤ 24]
●
505 to 630 days [24 < cycles ≤ 30]
●
≥ 631 days [> 30 cycles]


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Average dosed days per cycle of study drug is defined as the total number of days a 
subject received study drug divided by the number of cycles that the subject is exposed to 
study drug.  
For all summaries of all components of the study treatment, descriptive statistics (mean, 
standard deviation, median, and range) will be used to summarize duration of exposure 
and number of cycles exposed by treatment group.  
9.1.1
Dose Reductions, Interruptions, Delays and Intensity
The frequencies and percentages of subjects having dose reduction (all treatments), 
interruption (veliparib/placebo only), or delay (carboplatin, paclitaxel, docetaxel) will be 
summarized for each treatment group.  Summaries of veliparib will be done for the entire 
treatment period, and will also be separated by combination period (Cycle 1 through 
Cycle 6) and maintenance (Cycle 7 through Cycle 36). 
Dose Reductions
Carboplatin/paclitaxel/docetaxel:  If a subject has any dose reduction from the previous 
dose of carboplatin/paclitaxel/docetaxel, this subject will be considered as having
experienced dose reduction of carboplatin/paclitaxel/docetaxel, respectively.  For 
carboplatin, this is calculated using the AUC.  For paclitaxel and docetaxel, this 
calculation is done using the investigator-selected dose level (mg/m^2). 
Veliparib:  The data entry guidelines for BID dosing for veliparib instructs that each 
skipped dose is recorded into EDC.  To only summarize true dose reductions and not days 
when only a single dose was taken, the following convention will be used:  Dose 
reductions for veliparib will be calculated by first finding the maximum total daily dose 
per cycle.  If a subject has a reduction from the previous cycle's maximum total daily 
dose, then this subject will be considered as having experienced a dose reduction of 
veliparib.


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Dose Interruptions
Dose interruptions are defined for veliparib/placebo only.  If a subject skips 1 or more 
consecutive days, this subject will be considered as having experienced a dose 
interruption of veliparib/placebo.
By definition, all interval surgery subjects that undergo surgery will have a dose 
interruption of veliparib.  Therefore, the summary of dose interruptions will also be 
divided into primary versus interval surgery subjects, according to the surgery type the 
subject actually received. 
Dose Delays
Dose delays are defined for carboplatin, paclitaxel and docetaxel.
For carboplatin, Q3-weekly dosing of paclitaxel, and docetaxel, a dose delay is defined as 
more than 27 days between consecutive dose dates of the respective therapy.  For Q-
weekly dosing of paclitaxel, a dose delay is more than 13 days between consecutive dose 
dates. 
Dose Intensity for Chemotherapy
Dose intensity will be calculated for carboplatin and paclitaxel per Table 3.  For 
paclitaxel, intensities will be summarized by actual dosing schedule (weekly versus 
Q3 weekly).  There is no planned dose level of docetaxel, and so will not be summarized 
for subjects that switched to docetaxel.


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Table 3.
Dose Intensity for Carboplatin and Paclitaxel
Actual Total 
Dose (ATD)
Planned Total 
Dose (PTD)
Actual 
Dosing 
Days 
(ADD)a
Ideal Dosing Days 
(IDD)a
Dose 
Intensity (%)
Carboplatin
Actual total 
dose AUC 
(mg/mL/min)
AUC 6 
(mg/mL/min) * 
total number of 
administrations of 
carboplatin
Last dose 
date + 21 –
first dose 
date 
Number of 
administrations * 21
100* 
(ATD/PTD) * 
(IDD/ADD)
Paclitaxel 
(weekly)
Actual total 
dose (mg/m2)
80 mg/m2 * total 
number of 
administrations of 
paclitaxel
Last dose 
date + 7 –
first dose 
date 
Number of 
administrations * 7
100* 
(ATD/PTD) * 
(IDD/ADD)
Paclitaxel 
(Q3 weekly) 
Actual total 
dose (mg/m2)
175 mg/m2 * total 
number of 
administrations of 
paclitaxel
Last dose 
date + 21 –
first dose 
date 
Number of 
administrations * 21
100* 
(ATD/PTD) * 
(IDD/ADD)
a.
For interval surgery subjects, ADD and IDD will be calculated for Cycles 1 - 3 and 4 - 6 separately, and summed 
together to get a final total value of dosing days.
10.0
Efficacy Analysis
10.1
General Considerations
Efficacy analyses will be performed on all randomized subjects within the whole 
population, BRCA-deficient population and HRD populations.  The date of randomization 
is defined as the date when the randomization number is issued by IRT. 
All data occurring on or before the 'data cutoff date' (defined in Section 6.0) will be 
included in all efficacy analyses.  Data occurring after the 'data cutoff date' will be 
excluded for PFS, PFS2 and DRS.  For OS, TTFST and TTSST, it will be used in 
determining the censoring date (as described in Section 10.3.1, Section 10.4.2, and 
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For the final analyses of OS, the 'data cutoff date' will correspond to when data mature 
(~58 months for whole population, ~77 months for BRCA-deficient and HRD 
populations). 
For all time to event analyses (PFS, PFS2, OS, TTFST, TTSST), the following 
conventions will used:  
●
The distribution of the endpoint will be estimated for each treatment arm using 
Kaplan-Meier methodology.  
●
For both the BRCA-deficient population and the HRD population, the endpoint 
will be compared between each of the treatment arms (Arm 3 or Arm 2) and 
the control arm (Arm 1) using the log-rank test, stratified by the factors 
described in Section 6.0.
●
For the whole population, the endpoint will be compared between each of the 
treatment arms (Arm 3 or Arm 2) and the control arm (Arm 1) using the log-
rank test, stratified by the factors described in Section 6.0.
●
The Cox Proportional Hazard Model will be used to estimate the hazard ratio 
and 95% confidence interval comparing each of the treatment arms (Arm 3 or 
Arm 2) and the control arm (Arm 1) within each population, stratified by the 
factors described in Section 6.0. 
●
For all endpoints, the median time and its 95% confidence interval will be 
estimated for each treatment arm within each population.
10.2
Primary Efficacy Analysis
The primary efficacy endpoint is progression-free survival (PFS).  PFS will be defined as 
the number of days from the date that the subject was randomized to the date the subject 
experiences an event of disease progression, according to RECIST criteria version 1.1 (as 
determined by the investigator) or to the date of death (all causes of mortality) if disease 
progression is not reached.  If the subject does not have an event of disease progression 
according to RECIST criteria versions 1.1 (as determined by the investigator) nor has the 
subject died, the subject's data will be censored at the date of the subject's last evaluable 
disease assessment.  Data for subjects without any post-baseline radiographic assessments 


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and that did not die within 89 days (12 weeks + 5 days) of randomization, will be 
censored at the date of random assignment.
Handling of Intercurrent Events
●
The following events of PD/death will be included:
○
Events that occur after a subject discontinues or completes study treatment
○
Events that occur after a subject starts a new therapy (so long as the subject 
has not withdrawn consent from protocol tumor assessments)
●
The following events of PD/death will be censored
○
Events that occur after too much time has passed since the last valid 
radiologic assessment according to the below table
Disease Progression or Death after too much time between scans
Per the protocol, the scan schedule is as follows:  (every 9 weeks, then at the end of the 
Combination Phase, then every 12 weeks for 2 years, then every 6 months for 3 years, and 
then annually).  Due to the complexity of this scan schedule and to prevent the gap 
between valid assessments prior to PD from getting too wide for the later time periods, the 
following programming conventions are implemented:  


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Randomization ≤ last 
evaluable scan prior to 
PD/Death Date < 2.5 years*
2.5 ≤ last evaluable 
scan prior to PD/Death 
Date < 5.5 years*
5.5 ≤ last evaluable 
scan prior to 
PD/Death Date
Definition of 
Interval
12 weeks
6 months
1 year
Number of 
Intervals allowed 
missing prior to 
PD before event is 
censored
2
1.5
1.5
Skipped intervals 
prior to PD
24 weeks
(168 days + 5 days)
9 months
(270 days + 5 days)
18 months
(548 days + 5 days)
Number of 
Intervals allowed 
missing prior to 
death before event 
is censored
1
1
1
Skipped interval 
Prior to death
12 weeks + 5 days
6 months
(182 days + 5 days)
12 months
(365 days + 5 days)
*
2.5 years = 913.125 days; 5.5 years = 2,008.875 days.
The three primary efficacy analyses are defined by:
●
comparing PFS in Arm 3 versus Arm 1 in the BRCA-deficient population using 
the log-rank test, stratified by factors defined in Section 6.0, at the 1-sided 
0.025 α level;
●
comparing PFS in Arm 3 versus Arm 1 in the HRD population using the log-
rank test, stratified by factors defined in Section 6.0, at the 1-sided α level as 
specified in Section 10.7;
●
comparing PFS in Arm 3 versus Arm 1 in the whole population using the log-
rank test, stratified by factors defined in Section 6.0, at the 1-sided α level as 
specified in Section 10.7.
The distribution of PFS will be summarized per considerations in Section 10.1. 
The study will be successful if the first analysis in the multiplicity testing procedure 
described in Section 10.7 (comparison of PFS [Arm 3 v Arm 1] in the BRCA-deficient 


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population) is statistically significant.  If this comparison is statistically significant, the 
other two primary endpoints will be analyzed for statistical significance in the specified 
order.
10.3
Secondary Efficacy Analyses
10.3.1
Overall Survival
OS 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, using the data as specified in Section 6.0.  However, if a 
subject is known to either be alive or have had died after the 'data cutoff date,' then the 
subject's data will be censored at the 'data cutoff date.'
The six secondary efficacy analyses for OS include comparing OS in Arm 3 versus Arm 1 
and Arm 2 versus Arm 1 in the BRCA-deficient population, the HRD population, and the 
whole population.  Each comparison will be tested using the log-rank test, stratified by 
factors defined in Section 6.0, at the α level as specified in Section 10.7;
The distribution of OS will be summarized per considerations in Section 10.1.
10.3.2
Progression-Free Survival
The three secondary efficacy analyses of PFS include comparing PFS in Arm 2 versus 
Arm 1 in the BRCA-deficient population, the HRD population, and the whole population.  
Each comparison will be tested using the log-rank test, stratified by factors defined in 
Section 6.0, at the α level based on the pre-specified α allocation rule in Section 10.7.
The analyses of PFS will be performed per Section 10.1.


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10.3.3
Patient Reported Outcomes
Disease Related Symptoms
The overall mean change from baseline for the disease related symptom physical (DRS) 
scores measured at each assessment point up to disease progression or 2 years if 
progression has not been reached will be a secondary endpoint of the study.  No alpha will 
be spent on these endpoints.
DRS scores are collected at odd numbered cycles, and will be summarized through 
Cycle 35, which is approximately 2 years of study therapy assuming no interruptions.  
The visits windows are detailed in Section 6.0.
The secondary efficacy analyses for DRS are defined by the following comparisons, 
which will be performed in the BRCA-deficient population, HRD population and the 
whole population:  
●
The comparison of mean changes from baseline in total DRS score to each 
scheduled assessment until disease progression or death, for up to 2 years, 
between Arm 3 and Arm 1, and Arm 2 and Arm 1 using a mixed-model for 
repeated measures (MMRM) model with observed DRS score. 
A separate MMRM model will be used for each of the three populations.  Only subjects 
with a baseline and at least one post-baseline assessment will be included in the model.  
Each model will include the fixed categorical effects of treatment group, stratification 
factors (as specified per population in Section 6.0), time point (each scheduled assessment 
up to 2 years), and treatment group-by-time point interaction, and the continuous fixed 
covariate of baseline DRS score.  The REPEATED statement will be used for time point 
in PROC MIXED with blocks in the covariance matrix identified by subject nested within 
treatment group.  Restricted maximum likelihood estimation will be utilized and an 
unstructured covariance structure will be used to model the within-subject error.  In the 
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If AR(1) does not converge, compound symmetry structure will be used.  If convergence 
has still not been met, then a simple summary of ANCOVA by visit will be produced. 
Calculation of DRS at each timepoint
The score range of the FOSI-DRS Score is 0 – 36, where a high score is considered good 
and a score of 0 would be a severely symptomatic subject. 
Individual Item Scores:
Item Codes GP1, GP4, GP6, 03, HI7, Cx6 and O1 are considered "reverse" items and the 
subject's item response will be subtracted from 4 to correct for the direction as follows
Individual Item Score = (4 – Item Response)
For Item Codes C3 and GF5, no correction to the subject's item response is necessary:
Individual Item Score = Item Response
DRS Score
FOSI-DRS score = (Sum of Individual Item Scores × 9)/(number of items answered). 
10.4
Tertiary Efficacy Analyses
10.4.1
Progression-Free Survival 2 (PFS2)
Progression-Free Survival 2 (PFS2) is defined as the number of days from the day the 
subject is randomized to the earliest date of disease progression reported on any line of 
subsequent therapy or death by any cause.  This is regardless of the subject having a 
documented PD for the primary PFS analysis prior to starting a subsequent therapy.  
Therefore, the same event of progression may be used for both the primary PFS analysis 
and the analysis of PFS2, provided the subject has not withdrawn consent from the 
protocol tumor assessments.  Additionally, an event of PFS2 may be either radiographic 
or clinical progression, such as increase in CA-125, and will be documented by the 


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investigator.  Any death that occurs prior to either a documented first progression, or a 
documented second progression, will be considered as an event of PFS2. 
In summary, the following will be considered PFS2 events:
●
The earliest event of progression (of any type), as determined by the 
investigator, that occurs after the initiation of a subsequent therapy
●
Any death that occurs prior to the subject achieving the above described event 
of progressive disease, regardless if the subject started a subsequent therapy
If the subject does not have an event of PFS2, the following censoring rules will apply:
●
If the subject is still being followed per protocol scan schedule for a primary 
PFS event, PFS2 will be censored at the same date as for the primary PFS 
analysis. 
●
If the subject is no longer being followed for primary PFS (for any reason), 
PFS2 will be censored at the subject's most recent post-treatment therapy start 
date or end date as applicable
The tertiary efficacy analyses for PFS2 are defined by comparing PFS2 in Arm 3 versus 
Arm 1 and Arm 2 versus Arm 1, in the BRCA-deficient population, HRD population and 
the whole population.  PFS2 may also be compared between Arm 2 and Arm 3 as an 
exploratory analysis.  
The efficacy analyses of PFS2 will be summarized per guidelines in Section 10.1.
10.4.2
Time to the First Subsequent Therapy
Time to the First Subsequent Therapy (TTFST) will be defined as the number of days 
from the day the subject is randomized to the start of the first subsequent therapy (after 
discontinuation of protocol study treatment) or death of any cause.  If the subject does not 
have an event of TTFST, the subject's data will be censored at the date the subject was last 
known to be alive and not have received subsequent therapy, i.e., the subject's last visit 
(including on therapy study visit, long-term follow-up without disease progression visit) 


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or survival follow-up.  If the subject is known to have an event of TTFST after the 'data 
cutoff date,' or the subject is known to be alive and without an event of TTFST after the 
cutoff, then the subject's data will be censored at the 'data cutoff date.'  See Section 6.0 for 
more censoring details.  
The tertiary efficacy analyses for TTFST are defined by comparing TTFST in Arm 3 
versus Arm 1 and Arm 2 versus Arm 1, in the BRCA-deficient population, the HRD 
population, and the whole population.  TTFST may also be compared between Arm 2 and 
Arm 3 as an exploratory analysis.  
The efficacy analyses of TTFST will be summarized and analyzed per guidelines in 
Section 10.1.
10.4.3
Time to the Second Subsequent Therapy
Time to the Second Subsequent Therapy (TTSST) will be defined as the number of days 
from the day the subject is randomized to the start of the second subsequent therapy or 
death of any cause.  If the subject does not have an event of TTSST, the subject's data will 
be censored at the date the subject was last known to be alive and not have received a 
second subsequent therapy, i.e., the subject's last visit (including on therapy study visit, 
long-term follow-up without disease progression visit) or survival follow-up.  If the 
subject is known to have an event of TTSST after the 'data cutoff date,' or the subject is 
known to be alive and without an event of TTSST after the cutoff, then the subject's data 
will be censored at the 'data cutoff date'.  See Section 6.0 for more censoring details.
The tertiary efficacy analyses for TTSST are defined by comparing TTSST in Arm 3 
versus Arm 1 and Arm 2 versus Arm 1, in the BRCA-deficient population, the HRD 
population, and the whole population.  TTSST may also be compared between Arm 2 and 
Arm 3 as an exploratory analysis.  
The efficacy analyses of TTSST will be summarized and analyzed per guidelines in 
Section 10.1. 


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10.4.4
Additional PRO Endpoints
Additional analysis based on other PRO endpoints will be specified in a separate PRO 
analysis plan.
10.5
Additional Efficacy Analyses
In addition to the stratified log-rank test for the primary and secondary efficacy endpoints, 
the following analyses may be performed for the comparison of PFS, and OS, between the 
two treatment groups, and within the three analysis populations.
●
Un-stratified log-rank test and the Cox proportional hazards model for PFS, 
OS.
●
Modified PFS endpoint to examine sensitivity to different censoring methods, 
described in detail below under Supplemental Analyses for PFS Endpoint. 
●
Modified efficacy endpoint OS to censor at the date of subject's initiation of 
other post anti-cancer therapies.
●
Landmark analyses of PFS at end of Combination Phase (at 4.5 months), at 
10 months (~6 months after the end of chemotherapy), and at 24 months.
●
Landmark analyses of OS at 24, 30 and 36 months.
●
Median Follow-Up Time on Study, calculated via reverse K-M method. 
●
PFS per central review based on central review of tumor assessments for all
subjects, and analyzed following the same methodology as for the primary 
endpoint of PFS.  
●
Concordance of the investigator and central review evaluation of progression 
may also be summarized. 
Supplemental Analyses for PFS Endpoint
In addition to the Primary PFS analysis, modified PFS analyses will be performed to 
examine the sensitivity to various censoring methods.  A summary of these are in the 
following table.


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Type of Censoring
Name for Analysis
Primary
Mod 1
Mod 2
Mod 3
Mod 4
Mod 5
First Post-Treatment Anti-Cancer Therapy
No
Censor
No
No
No
No
Death window implementation
Censor
Censor
Censor
No
Censor
No
Blind Break
No
No
Censor
No
No
No
Missing Scans prior to PD
Censor
Censor
Censor
Censor
No
No
No means do not censor for the event.
First Post-Treatment Anti-Cancer Therapy:  PFS will be censored at the last evaluable tumor assessment prior to the 
date of subject's initiation of other anti-cancer therapies.  
Blind Break:  PFS will be censored at the last evaluable tumor assessment prior to the date of investigator blind break. 
Tumor Marker CA-125
CA-125 values will be presented as cross-tabulations of baseline versus maximum on 
treatment value within each of the cycle windows as follow:  Cycles 1 – 3 (not including 
value used as baseline), Cycles 4 – 6, Cycles 7 – 12, Cycles 13 – 18, Cycles 19 – 24, 
Cycles 25 – 30, Cycles 31 – 36.  The first dose date of the cycle defines the start of the 
window, and 1 day prior to the start date of the next cycle window defines the end of the 
cycle window.  Within each cycle window, the maximum CA-125 value will be 
categorized into 1 of 3 categories:  ≤ ULN, > ULN & < 2 × ULN, or ≥ 2 × ULN.  
Summaries will be presented within the BRCA-deficient, HRD, and whole populations.  
10.6
Efficacy Subgroup Analyses
Subgroup analyses will be performed for the endpoints of PFS and OS within each 
efficacy analysis population (BRCA-deficient, HRD, and whole, as appropriate) to 
evaluate the impact of the baseline characteristics on treatment effect.  Analyses 
performed in the whole population will be stratified by BRCA-deficient status.  Analyses 
performed within BRCA-deficient and HRD populations will be unstratified.
The subgroups will be (but not limited) as follows:
●
BRCA-deficient status [BRCA1/2 mutation vs. BRCA1/2 wildtype] (central 
testing) 


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●
Type of BRCA-deficiency [germline BRCA1/2 mutation vs. tissue BRCA1/2 
mutation and germline BRCA1/2 wildtype vs. BRCA1/2 wildtype].
●
Type of BRCA1/2 mutation [BRCA1 vs. BRCA2 vs. BRCA1 and BRCA2 vs. 
BRCA wildtype].
●
HRD status [HRD vs. non-HRD]
●
HRD and BRCA-deficient status [HRD and BRCA1/2 mutation vs. BRCA1/2 
wildtype vs. non-HRD vs. HRD].
●
Race [White, Black, Other]
●
Region [North America vs. Japan vs. Rest of World].
●
Stage of Disease [III vs. IV] (as randomized)
●
Residual Disease and Choice of Regimen (as randomized)
●
Residual Disease post Interval Surgery [No Disease (post interval surgery) vs. 
Any Disease (post interval surgery)] 
○
Note:  this only includes interval surgery subjects
●
Residual Disease (Efficacy Stratification Factor) [No Residual Disease After 
Primary Surgery vs. Any Residual Disease After Primary Surgery or Interval 
Surgery].
●
Age group [< 65 years vs. ≥ 65 years]
●
Smoking history [current smoker vs. past smoker vs. never smoked]
●
ECOG [0 vs. ≥ 1]
10.7
Multiplicity Adjustment
The multiplicity considerations of this study include three treatment arms, (two pairwise 
comparisons), three populations, and multiple endpoints. 
Three treatment arms are annotated in Table 4.


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Table 4.
Study Treatment Arms
Arm
Description
Arm 1:  C/P + placebo →placebo
Reference regimen
Arm 2:  C/P + veliparib →placebo
Veliparib administered in the combination therapy phase only
Arm 3:  C/P + veliparib →veliparib
Veliparib administered in both combination therapy and 
maintenance therapy phases
Note:
[+] indicates 'concurrent with;' [→] indicates ' followed by;' [C/P] indicates 'backbone chemotherapy'
(i.e., carboplatin/paclitaxel).
There are three populations of interest:  BRCA-deficient population, HRD population, and 
whole population.
The hypotheses of interest are listed below:  
Table 5.
The Null Hypotheses of Interest in each Population
PFS (Arm 3 versus Arm 1)
PFS (Arm 2 versus Arm 1)
OS (Arm 3 versus Arm 1)
OS (Arm 2 versus Arm 1)
DRS (Arm 3 versus Arm 1)
DRS (Arm 2 versus Arm 1)
PFS = Progression Free Survival; OS = Overall Survival; DRS = Disease Related Symptom 
Note:
PFS (Arm 3 versus Arm 1) denotes the null hypothesis:  Arm 3 (C/P + veliparib → veliparib) does not 
increase PFS compared to Arm 1 (C/P + placebo → placebo).  Other PFS and OS notations in this table are 
defined similarly.  DRS (Arm 3 versus Arm 1) denotes the null hypothesis of no difference in DRS scores 
between Arm 3 and Arm 1.  DRS (Arm 2 versus Arm 1) is defined similarly.  Note that no alpha will be spent 
on DRS analyses.
Criteria to Determine Testing Sequence
Since subject randomization was not prospectively stratified by HRD status, two testing 
scenarios were available and depended only on the balance of treatment arms within the 
HRD population.  Since upon unblinding at the time of the primary analysis, the treatment 
ratio between Arm 3 and Arm 1 was not greater than the previously defined ratio of 
2.53:1, the following Testing Sequence applies.


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Figure 2.
Testing Procedure 


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Testing Scenario:  
●
A fixed-sequence testing procedure will be used to control the Type I error rate 
at 0.05 from the primary efficacy endpoint sequentially through the secondary 
efficacy endpoints.  Each of the comparisons in this sequence will be tested at 
a 1-sided 0.025 level.  There will be no multiplicity adjustment on the DRS 
scores or the tertiary efficacy endpoints.  
At Month 36 (alpha = 0.025),
1.
Test PFS (Arm 3 versus Arm 1) in BRCA-deficient population,
2.
Test PFS (Arm 3 versus Arm 1) in HRD population,
3.
Test PFS (Arm 3 versus Arm 1) in whole population
●
In parallel, alpha = 0.000001 will be spent on interim OS analyses
At Month 48 per request of FDA, alpha = 0.000001 will be spent on the second interim 
OS analyses for BRCA-deficient, HRD and whole populations.
At Month 58 when OS matures in the whole population, alpha = 0.000001 will be spent 
on second interim OS analyses for BRCA-deficient and HRD populations.
At Month 77 (alpha = 0.025, provided all preceding null hypotheses in the hierarchical 
testing sequence at Month 36 are rejected)
4.
Test OS (Arm 3 versus Arm 1) in BRCA-deficient population,
5.
Test OS (Arm 3 versus Arm 1) in HRD population,
6.
Test OS (Arm 3 versus Arm 1) in whole population (based on data from Month 58)
7.
Test PFS (Arm 2 versus Arm 1) in BRCA-deficient population (based on data from 
Month 36),
8.
Test PFS (Arm 2 versus Arm 1) in HRD population (based on data from Month 
36),


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9.
Test PFS (Arm 2 versus Arm 1) in whole population (based on data from Month 
36)
10.
Test OS (Arm 2 versus Arm 1) in BRCA-deficient population (based on data from 
Month 77),
11.
Test OS (Arm 2 versus Arm 1) in HRD population (based on data from Month 77),
12.
Test OS (Arm 2 versus Arm 1) in whole population (based on data from Month 58)
11.0
Safety Analysis
11.1
General Considerations
Safety analyses will be performed on the AST population.  All subjects who took at least 
one dose of veliparib/placebo will be included.  Treatment groups in the safety summaries 
will be based on the actual treatment the subject receives.
Summaries involving docetaxel will only be performed on subjects who were dosed with 
docetaxel.
Where applicable, only P values ≤ 0.100 when rounded to three digits will be presented.
11.2
Analysis of Adverse Events
Analyses of adverse events will include only "treatment-emergent" events and are defined 
in Section 6.0.  Treatment-emergent adverse events will be summarized by preferred 
terms within a System and Organ Class according to the MedDRA adverse event coding 
dictionary.  Grading of treatment-emergent adverse events will be according to NCI 
CTCAE Version 4.0 terminology grade provided by the investigator.  
11.2.1
Adverse Event Overview
An overview of treatment emergent adverse events will be presented for each treatment 
arm consisting of the number and percentage of subjects experiencing at least one event 
for the following adverse event categories:


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●
Any adverse event
●
Any adverse event that is rated by the investigator as a reasonable possibility 
of being related to each of:  veliparib/placebo, carboplatin, paclitaxel, and 
docetaxel*
●
Any NCI terminology grade 3 or grade 4 adverse event
●
Any NCI terminology grade 3, grade 4, or grade 5 adverse event**
●
Any serious adverse event.
●
Any adverse event leading to discontinuation of each of:  veliparib/placebo, 
carboplatin, paclitaxel, and docetaxel.
●
Any adverse event leading to discontinuation of each of:  veliparib/placebo, 
carboplatin, paclitaxel, and docetaxel due to disease progression.
●
Any adverse event leading to discontinuation of each of:  veliparib/placebo, 
carboplatin, paclitaxel, and docetaxel not due to disease progression.
●
Any adverse event leading to interruption or reduction of veliparib/placebo
●
Any adverse event leading to dose interruption of veliparib/placebo
●
Any adverse event leading to dose reduction of each of:  veliparib/placebo, 
carboplatin, paclitaxel, and docetaxel
●
Any adverse event leading to dose reduction or delay of each of:  carboplatin, 
paclitaxel, and docetaxel
●
Any adverse event leading to dose delay of each of:  carboplatin, paclitaxel, 
and docetaxel 
●
Any adverse event of special interest (as listed in Table 6)
●
Any adverse event leading to death
●
Any adverse event leading to death with a reasonable possibility of being 
related to veliparib by the investigator
●
All deaths.
*
Only summaries for veliparib/placebo will be presented in the SOC/PT tables. 
**
No summary will be presented in the SOC/PT tables. 


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11.2.2
Adverse Event by SOC and PT
In addition to the AE categories listed under Adverse Event Overview (unless noted 
otherwise), the numbers and percentages of subjects experiencing treatment-emergent 
adverse events will be summarized by treatment group for the following adverse event 
categories:
●
Any adverse event with number broken down by maximum NCI terminology 
grade.
●
Any adverse event that is rated by the investigator as a reasonable possibility 
of being related to veliparib/placebo with NCI terminology grade 3 or grade 4 
adverse event
●
Any adverse event leading to discontinuation of veliparib/placebo with a 
reasonable possibility of being related to veliparib (as rated by investigator)
●
Any serious adverse event leading to discontinuation of veliparib/placebo with 
a reasonable possibility of being related to veliparib (as rated by investigator)
●
Any serious adverse event with number broken down by maximum NCI 
terminology grade. 
●
Any NCI terminology grade 3 or grade 4 serious adverse event
●
Any serious adverse event that is rated by the investigator as a reasonable 
possibility of being related to veliparib/placebo
●
Any serious adverse event that is rated by the investigator as a reasonable 
possibility of being related to veliparib/placebo with NCI terminology grade 3 
or grade 4 serious adverse event
For all adverse event summaries, the number and percentage of subjects experiencing 
treatment-emergent adverse events will be tabulated according to SOC and PT for each 
treatment arm.  Subjects reporting more than one AE for a given PT will only be 
counted once for that term.  Subjects reporting more than one adverse event within an 
SOC will only be counted once for that SOC.  Subjects reporting more than one AE will 
only be counted once in the overall total.  The SOCs will be presented in alphabetical 
order and the PTs will be presented in alphabetical order within each SOC.


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11.2.3
Adverse Event by Frequency
The number and percentage of subjects experiencing treatment-emergent adverse events
and treatment-emergent serious adverse events will be tabulated according to preferred 
term and sorted by overall frequency.  For adverse events with a frequency greater than 
10% in any treatment group, comparisons of the rates of subjects experiencing an adverse 
event will be done between Arm 3 versus Arm 1 and Arm 2 versus Arm 1 using Fisher's 
exact test.  For testing the rates of AEs experienced in the maintenance phase, a 5% cutoff 
will be applied.  
11.2.4
Adverse Events of Special Interest
Treatment-emergent adverse events and serious adverse events of special interest based on 
Standardized (SMQ-s) or Company (CMQ-s) MedDRA Queries, will be summarized. 
The search criteria for each event is located in Table 6.  The rates of these events will be 
summarized by MedDRA system organ class and preferred term.  The same overview 
summary as for TEAE, and listing of subjects' data, will be provided for each AESI.


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Table 6.
Adverse Events of Special Interest
Adverse Event of 
Special Interest
Search Criteria
Event Definition/Medical Concept
Nausea and vomiting
Nausea and vomiting preferred 
terms MedDRA preferred terms 
(PT code 10028813, 10047700)
Treatment-emergent adverse events coded 
to either of those two MedDRA preferred 
terms
Seizures
Convulsions SMQ 20000079 
(query for convulsions)
Treatment-emergent adverse events coded 
to MedDRA preferred terms on the broad 
search list.
Anemia
Haematopoietic erythropenia 
SMQ 20000029
Treatment-emergent adverse events coded 
to MedDRA preferred terms on the broad 
search list.
Thrombocytopenia
Haematopoietic thrombocytopenia 
SMQ 20000031
Treatment-emergent adverse events coded 
to MedDRA preferred terms on the broad 
search list.
Neutropenia
Hematological Toxicity-
Neutropenia CMQ 80000154
Treatment-emergent adverse events coded 
to MedDRA preferred terms on the broad 
search list.
Infection events 
within 14 days after 
neutropenia events
Infections CMQ 80000018 and 
hematological toxicity-
neutropenia CMQ 80000154
Treatment-emergent adverse events from 
the MedDRA preferred terms on the broad 
search list.
Myelodysplastic 
Syndromes (MDS)
Myelodysplastic syndrome SMQ 
(Narrow) 20000217
Treatment-emergent adverse events from 
the MedDRA terms on the search list.
Acute Myeloid 
Leukemia (AML)
Acute myeloid leukaemia 
PT (10000880)
Treatment-emergent adverse events from 
the MedDRA terms on the search list.
Haemorrhages events 
within 14 days after 
thrombocytopenia
Haemorrhage terms (excl 
laboratory terms) SMQ 20000039 
and hematopoietic 
thrombocytopenia SMQ 20000031
Treatment-emergent adverse events from 
the MedDRA terms on the broad search 
list.
Second/Secondary 
Malignancies
Secondary Malignancies SMQs, 
20000194 and 20000195
Treatment-emergent adverse events from 
the MedDRA terms on the narrow search 
list for malignancies are used as a starting 
point for medical review to search for 
secondary malignancies.
Changes in 
reproductive organ 
function
SMQ 20000210 (fertility 
disorders)
Treatment-emergent adverse events from 
the MedDRA terms on the search list.
Teratogenicity
Pregnancies and outcomes will be 
analyzed individually as they occur.


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11.2.4.1
Time to Onset of AESI
Summary statistics (N, mean, standard deviation, median, minimum, and maximum) will 
be generated for the time from first dose to onset (in days) using the first AESI event for 
each subject.
11.2.4.2
Prevalence and Incidence Rates of AESI
Prevalence and incidence of AESI for each PT, each SOC, and overall will be provided 
for time periods in groups of 3 cycles, relative to the first dose of any study treatment:  
Cycles 1 - 3, 4 - 6, 7 - 9, 10 - 12, 13 - 15, 16 - 18, 19 - 21, 22 - 24, 25 - 27, 28 - 30, 31 -
33, and 34 - 36.  The 30 day safety window will be applied and grouped into the last cycle 
for each subject.  For each time period, the incidence for any given PT will be calculated 
as follows:  
●
The numerator for each time period will be the number of subjects who had the 
first occurrence of an adverse event in that time period and are included in the 
denominator.
●
The denominator for each time period will be the number of subjects who took 
at least one dose of study treatment in the time period and did not experience 
an event within any previous period.
●
Incidence for each time period = numerator/denominator.
The numerator and the corresponding incidence for each PT will be presented for each of 
the time periods.
For each time period, the prevalence for any given PT will be calculated as follows:  
●
The numerator for each time period will be the number of subjects who had an 
occurrence of an adverse event in that time period or in a previous time period 
and that was ongoing in the current time period and are included in the 
denominator.
●
The denominator for each time period will be the number of subjects who took 
at least one dose of study treatment in the time period.


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●
Prevalence for each time period = numerator/denominator.
The numerator and the corresponding prevalence for the PT will be presented for each of 
the time periods.
11.2.5
Adverse Event Subgroup Assessments
The incidence of treatment emergent adverse events overview, TEAE by SOC and by PT 
of all treatment-emergent adverse events, grade 3 and 4 events, serious adverse events, 
leading to veliparib discontinuation, AEs leading to death, and AEs of special interest will 
be assessed for the subgroups defined below:  
●
Age categories [< 65 years, ≥ 65 years]
●
Region [US, Japan, Rest of World]
●
Combination Period (Cycles 1 through 6), 
●
Maintenance Period (Cycles 7 through 36), 
●
Q-weekly Dosing, 
●
Q3-weekly Dosing
●
Subjects Dosed with Docetaxel. 
Refer to Section 6.0 for more details on defining the latter 5 groups.
11.3
Deaths
The number of subject deaths will be summarized (1) for deaths occurring within 30 days 
of the last dose of study drug, (2) for deaths occurring more than 30 days of the last dose 
of study drug and (3) for all deaths in this study regardless of the number of days relative 
to the last dose of study drug.  There will be no statistical test for above analyses.
11.4
Analysis of Laboratory and Vital Signs Data
All of the below summaries will be summarized by for the entire AST population, as well 
as the following subgroups described in detail in Section 6.0:  Combination Period 


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(Cycles 1 through 6), Maintenance Period (Cycles 7 through 36), Q-weekly Dosing, 
Q3-weekly Dosing, and Subjects Dosed with Docetaxel.
See Section 6.0 for additional information regarding laboratory data conventions.
Analyses of Laboratory Data Using NCI CTCAE
For hematology and chemistry variables for which NCI CTCAE Version 4 (v4.03) criteria 
exist, baseline and post-baseline hematology and chemistry variable observations will be 
categorized as grade 0 to grade 4.
The percentage of subjects experiencing a shift from baseline to the maximum value post-
baseline, and from baseline to the final value, according to the categories below will be 
presented:  
●
Grade 0 or unknown at baseline, to Grade 1 to Grade 4 post-baseline, or 
worsened from an abnormal baseline value by at least one grade post-baseline
●
Grade 0 or unknown to Grade 2 at baseline, to Grade 3 or Grade 4 post-
baseline and from Grade 3 at baseline to Grade 4 post-baseline
Cross-tabulation of the frequency of categorized baseline grades versus maximum post-
baseline grades and baseline grades versus final value will be presented.  All treated 
subjects will be included in the cross tabulation regardless whether baseline or post-
baseline measurements are collected.  
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 veliparib/placebo, will be included 
in these listings.
Drug-Induced Liver Injury
Elevations relative to the upper limit of normal (ULN) in alanine transaminase (ALT), 
AST, total bilirubin, and alkaline phosphatase as outlined in the FDA Guidance for 


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Industry pertaining to premarketing clinical evaluations for drug-induced liver injury 
(DILI) will be summarized using the maximum post-baseline values:  
●
ALT:  > 3 × –, > 5 × –, > 10 × –, or > 20 × ULN
●
AST:  > 3 × –, > 5 × –, > 10 × –, or > 20 × ULN
●
Total bilirubin > 2 × ULN
●
Alkaline phosphatase > 1.5 × ULN
●
ALT or AST (> 3 × ULN) accompanied by total bilirubin (> 2 × ULN) at the 
same visit (potential Hy's Law criteria 3)
Plots will be generated for total bilirubin vs. ALT values and total bilirubin vs. AST 
values in the eDISH format.  For each subject, the visit with the maximum total bilirubin 
value relative to the ULN, then the maximum ALT (or AST) value relative to the ULN 
will be used in the plot.  A listing of lab data for subjects meeting potential Hy's law 
criteria will be provided.


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Table 7.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values
Test
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
ALT 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 –
20 × ULN
> 20 × ULN
Death
AST 
> ULN – 3 × ULN
> 3 – 5 × ULN
> 5 –
20 × ULN
> 20 × ULN
Death
Alkaline 
Phosphatase
> ULN – 2.5 × ULN
> 2.5 – 5 × ULN
> 5 –
20 × ULN
> 20 × ULN
Death
Total 
Bilirubin
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 –
10 × ULN
> 10 × ULN
Death
Hemoglobin 
(low)
< LLN – 100 g/L
< 100 – 80 g/L
< 80 g/L
--
Death
Hemoglobin 
(high)
CH > 0.0 – 20.0 g/L
CH > 20.0 –
40.0 g/L
CH > 40.0 g/L
--
Death
White blood 
cells
< LLN – 3.0 × 109/L
< 3.0 –
2.0 × 109/L
< 2.0 –
1.0 × 109/L
< 1.0 × 109/L
Death
Absolute 
Neutrophil 
Count
< LLN – 1.5 × 109/L
< 1.5 –
1.0 × 109/L
< 1.0 –
0.5 × 109/L
< 0.5 × 109/L
Death
Platelet 
count
< LLN –
75.0 × 109/L
< 75.0 –
50.0 × 109/L
< 50.0 –
25.0 × 109/L
< 25.0 × 109/L
Death
Glucose 
(high)
> ULN –
8.9 mmol/L
> 8.9 –
13.9 mmol/L
> 13.9 –
27.8 mmol/L
> 27.8 mmol/L
Death
Glucose 
(low)
< LLN –
3.0 mmol/L
< 3.0 –
2.2 mmol/L
< 2.2 –
1.7 mmol/L
< 1.7 mmol/L
Death
Creatinine
> ULN – 1.5 × ULN
> 1.5 – 3 × ULN
> 3 – 6 × ULN
> 6 × ULN
Death
Uric acid
> ULN –
590 mcmol/L
--
--
> 590 mcmol/L
Death
Inorganic 
phosphate
< LLN – 0.8 
mmol/L
< 0.8 – 0.6 
mmol/L 
< 0.6 – 0.3 
mmol/L
< 0.3 mmol/L
Death
Calcium 
(low)
< LLN –
2.0 mmol/L
< 2.0 –
1.75 mmol/L
< 1.75 –
1.5 mmol/L
< 1.5 mmol/L
Death
Calcium 
(high)
> ULN –
2.9 mmol/L
> 2.9 –
3.1 mmol/L
> 3.1 –
3.4 mmol/L
> 3.4 mmol/L
Death
Albumin
< LLN – 30 g/L
< 30 – 20 g/L
< 20 g/L
--
Death
Lymphocyte
< LLN – 0.8 × 109/L
< 0.8 –
0.5 × 109/L
< 0.5 –
0.2 × 109/L
< 0.2 × 109/L
Death


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Table 7.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory Values 
(Continued)
Test
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Sodium 
(low)
< LLN –
130 mmol/L
--
< 130 –
120 mmol/L
< 120 mmol/L
Death
Sodium 
(high)
> ULN –
150 mmol/L
> 150 –
155 mmol/L
> 155 –
160 mmol/L
> 160 mmol/L
Death
Potassium 
(low)
< LLN –
3.0 mmol/L
--
< 3.0 –
2.5 mmol/L
< 2.5 mmol/L
Death
Potassium 
(high)
> ULN –
5.5 mmol/L
> 5.5 –
6.0 mmol/L
> 6.0 –
7.0 mmol/L
> 7.0 mmol/L
Death
Magnesium 
(low)
< LLN –
0.5 mmol/L
< 0.5 –
0.4 mmol/L
< 0.4 –
0.3 mmol/L
< 0.3 mmol/L
Death
Magnesium 
(high)
> ULN –
1.23 mmol/L
--
> 1.23 –
3.30 mmol/L
> 3.30 mmol/L
Death
Bicarbonate
< LLN – 16 mmol/L
< 16 –
11 mmol/L
< 11 –
8 mmol/L
< 8 mmol/L
Death
11.5
Analyses of Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values
Vital signs values will be assessed for potential clinical significance through the 
application of criteria developed at AbbVie as detailed in Table 8 below.
Table 8.
Potential Clinical Significance Criteria for Vital Signs
Systolic Blood Pressure
> 150 mmHg and > 20 mmHg higher than baseline
< 70 mmHg and a decrease of ≥ 30 mmHg from baseline
Diastolic Blood Pressure
> 100 mmHg and higher than baseline
< 50 mmHg and a decrease of ≥ 20 mmHg from baseline
Pulse Rate
> 120 bpm and an increase of ≥ 30 bpm from baseline
< 50 bpm and a decrease of ≥ 30 bpm from baseline
Temperature
≥ 38.9°C
≤ 35.6°C
Weight
> 10% decrease from baseline


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The frequency and percentage of subjects with post-baseline values meeting Criteria for 
Potentially Clinically Significant Vital Signs values will be summarized.  All subjects 
who have at least one post-baseline measurement will be included in the summary.  If a 
subject does not have vital signs recorded at baseline, but has a post-baseline value which 
met the above criteria for blood pressure and pulse rate, this subject is considered as 
meeting the potentially clinically significant vital signs values for the measurement.  A 
separate listing will be provided that presents all of the subjects and values that meet the 
criteria.  
12.0
References
1.
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
Published:  May 28, 2009 (v4.03:  June 14, 2010).  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.