Conditions: Non-squamous Non-small Cell Lung Cancer
Keywords: veliparib carboplatin paclitaxel cisplatin pemetrexed Poly Adenosine diphosphate (ADP)-ribose Polymerase (PARP) Metastatic Non-squamous Non-small cell lung cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 595
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of veliparib plus carboplatin and paclitaxel versus the Investigator's choice of standard chemotherapy in adults with metastatic or advanced non-squamous non-small cell lung cancer.

Detailed description:

Arms:
arm 1: Participants received 120 mg veliparib twice a day (BID) on Days -2 to 5 (7 days), carboplatin at an area under the curve (AUC) of 6 mg/mL\*min on Day 1 and paclitaxel 200 mg/m² on Day 1 of each 21-day cycle for a maximum of 6 cycles.

After completion of up to 6 cycles, optional maintenance pemetrexed was administered as 500 mg/m² on Day 1 of each 21-day cycle until toxicity required cessation of therapy, or radiographic progression occurred. arm 2: Participants received Investigator's choice of standard doublet chemotherapy consisting of 1 of the following 3 options, administered on Day 1 of each 21-day cycle for a maximum of 6 cycles:

* Carboplatin AUC 6 mg/mL\*min + paclitaxel 200 mg/m²
* Cisplatin 75 mg/m² + pemetrexed 500 mg/m²
* Carboplatin AUC 6 or AUC 5 mg/mL\*min + pemetrexed 500 mg/m²

After completion of up to 6 cycles, optional maintenance pemetrexed was administered as 500 mg/m² on Day 1 of each 21-day cycle until toxicity required cessation of therapy, or radiographic progression occurred.

Interventions: intervention 1: Paclitaxel intervention 2: Carboplatin intervention 3: Cisplatin intervention 4: Veliparib intervention 5: Pemetrexed
Intervention descriptions: intervention 1: Administered by Intravenous infusion on Day 1 of each 21-day cycle intervention 2: Administered by Intravenous infusion on Day 1 of each 21-day cycle intervention 3: Administered by Intravenous infusion on Day 1 of each 21-day cycle intervention 4: Oral capsule, administered twice daily for 7 days in each 21-day cycle intervention 5: Administered by Intravenous infusion on Day 1 of each 21-day cycle

Protocol document:
Prot_000.pdf: 
NCT02264990


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
2
1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
10 July 2014
Amendment 1
20 October 2014
Amendment 2
10 December 2014
Amendment 3
17 July 2015
The primary purpose of this amendment is to revise the patient population for the primary 
endpoint with related statistical analysis changes and to provide clarifications across 
certain study-specific procedures and includes the following changes as follows:
●
The patient population for the primary endpoint of overall survival (OS) is 
being amended from current smokers to subjects who are positive for the Lung 
Subtyping Panel (LSP) signature; subjects who are LSP positive will also 
replace the current smoker population for other key efficacy analyses.  This 
change does not impact the patient management aspects of the protocol or the 
associated informed consent.  This change impacts:  Section 1.2, Synopsis; 
Section 3.0, Introduction; Section 3.5, Study Rationale; Section 4.0, Study 
Objectives; Section 5.3.3, Efficacy Variables; Section 8.1.2, Efficacy 
Endpoints; Section 8.1.3, Timing of Efficacy Analyses and Safety Evaluations; 
Section 8.1.4, Primary Analysis of Efficacy; Section 8.1.5, Secondary Analysis 
of Efficacy; Section 8.1.6, Tertiary Analyses of Efficacy; Section 8.1.7, 
Additional Exploratory Efficacy Analyses; Section 8.1.8, Statistical Analysis 
of Safety. 
Rationale:  Change is to focus the analyses on the patient population most 
likely to derive clinical benefit from veliparib, based on recent analyses of 
Phase 2 and Phase 3 studies which suggest that LSP status may be predictive 
of a possible veliparib treatment effect in combination with carboplatin and 
paclitaxel in subjects with NSCLC.  
●
Update number of subjects to be enrolled from approximately 525 to 
595 subjects.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
3
Rationale:  Change is to include accurate/updated enrollment targets.
●
Remove language in footnote "i." of Study Activities Table 2 referencing 
exclusion of the 72-hour window allowance for C1D-2 lab samples.  
Rationale:  Change is to provide clarification that C1D-2 lab samples have 
the same 72 hour window allowance as all other lab samples.
●
Include full emergency contact details for Study Designated Physician in 
Section 6.6.1 Reporting Serious Adverse Events.
Rationale:  Change is to assure full appropriate emergency contact details are 
reflected. 
●
Revise throughout to reflect updates in the latest version of the investigator's 
brochure.
Rationale:  Change is for accuracy ensuring most recent investigator's 
brochure is referenced and accompanying changes to investigator's brochure 
are reflected. 
An itemized list of all changes made to the protocol under this amendment is found in 
Appendix I.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
4
1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-359
Name of Study Drug:  Veliparib (ABT-888)
Phase of Development:  3
Name of Active Ingredient:  Not applicable
Date of Protocol Synopsis:  09 May 2018
Protocol Title:  
A Randomized, Open-Label, Multicenter, Phase 3 Trial Comparing Veliparib Plus Carboplatin and 
Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Subjects Receiving First Cytotoxic 
Chemotherapy for Metastatic or Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC) and 
Who Are Current or Former Smokers
Objectives:  
The primary objective of the study is to assess if treatment with veliparib plus carboplatin and paclitaxel 
results in improved survival compared to Investigator's choice of standard chemotherapy in Lung 
Subtype Panel (LSP) positive subjects with metastatic or advanced NSCLC.
The secondary objectives of the study are to assess if treatment with veliparib plus carboplatin and 
paclitaxel results in improved survival compared to Investigator's choice of standard chemotherapy in the 
entire study population; to compare progression-free survival (PFS) and to compare objective response 
rate (ORR) between the two treatment arms in LSP positive subjects or in entire study population.
The tertiary objectives are to compare duration of overall response (DOR), ECOG performance status 
and Quality of Life (QoL) between the two treatment arms in LSP positive subjects or in the entire study 
population.
Investigators:  Multicenter 
Study Sites:  150
Study Population:  
Subjects receiving first cytotoxic chemotherapy for Metastatic or Advanced Non-Squamous Non-Small 
Cell Lung Cancer (NSCLC) who are current or former smokers.
Chemotherapy for adjuvant or neoadjuvant treatment of NSCLC received greater than 12 months prior to 
Cycle 1 Day –2 (C1D-2) will be allowed.
Number of Subjects to be Enrolled:  595


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
5
Methodology:  
This is a Phase 3, randomized, open-label, multi-center study evaluating the efficacy, safety, and 
tolerability of veliparib plus carboplatin and paclitaxel versus Investigator's choice of standard 
chemotherapy in subjects receiving first cytotoxic chemotherapy for advanced or metastatic 
non-squamous NSCLC who are current or former smokers.  Subjects will be randomized in a 1:1 ratio to 
a maximum of 6 cycles of carboplatin/paclitaxel plus 120 mg BID of veliparib or a maximum of 6 cycles 
of Investigator's choice of platinum doublet chemotherapy (carboplatin/paclitaxel, cisplatin/pemetrexed, 
or carboplatin/pemetrexed), unless treatment is discontinued for toxicity or cancer progression.  
Investigators may elect to administer maintenance pemetrexed regardless of which therapy their subjects 
are randomized to receive.  Following completion of platinum doublet therapy, maintenance pemetrexed 
is strongly encouraged for all subjects who are suitable candidates.  Subjects LSP status (positive or 
negative) will be determined from tissue samples obtained to confirm diagnosis of NSCLC with a 
commercially developed RNA seq based LSP classifier developed in partnership with Qiagen.
Subject randomization will be stratified by smoking status (current versus former), by the Investigators' 
preferred platinum doublet therapy (carboplatin/paclitaxel versus cisplatin/pemetrexed versus 
carboplatin/pemetrexed), by gender (male versus female) and by ECOG performance status (0 versus 1).
Subjects randomized to receive veliparib will begin oral veliparib dosing 2 days prior to the start of the 
carboplatin/paclitaxel infusion on C1D-2 and will continue twice a day (BID) through C1D5 
(7 consecutive days).  
Subjects randomized to receive carboplatin/paclitaxel/veliparib will receive carboplatin (AUC 
6 mg/mL•min) and paclitaxel (200 mg/m2) IV infusion starting on Day 1 of each cycle.  Subjects will 
receive a maximum of 6 cycles of treatment, unless toxicity requires cessation of therapy, or radiographic 
progression occurs prior to completing 6 cycles.  Carboplatin/paclitaxel plus veliparib may be delayed or 
dose-modified due to toxicity.  Should a subject not receive carboplatin and paclitaxel on Day 1 of any 
cycle, the cycle will be restarted with veliparib at the newly designated Day –2 when the subject is able to 
do so.
Subjects randomized to receive Investigator's choice of platinum doublet therapy will receive therapy on 
Day 1 of each cycle.  Subjects will receive a maximum of 6 cycles of treatment, unless toxicity requires 
cessation of therapy, or radiographic progression occurs prior to completing 6 cycles.  Platinum doublet 
therapy may be delayed or dose-modified due to toxicity.  Dose delays and modification will be at the 
discretion of the Investigator per local standard practice. 
Suitable subjects in either arm will receive pemetrexed maintenance therapy after completion of platinum 
doublet chemotherapy regimen.  Maintenance pemetrexed will be administered on Day 1 of each 21-day 
cycle.  Maintenance therapy may be delayed or dose-modified due to toxicity.  Subjects will continue to 
receive maintenance therapy until toxicity requires cessation of therapy, or radiographic progression 
occurs.  Veliparib will not be administered during the maintenance phase. 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
6
Methodology (Continued):
Subjects will have physician visits q3 weeks while receiving platinum doublet and maintenance therapy.  
After cessation of therapy, physician visits and quality of life measures will be performed q9 weeks until 
1 year after beginning treatment (C1D-2) (or beyond 1 year until maintenance therapy is discontinued), 
then q12 weeks until radiographic progression.  Tumor assessments will be performed at baseline prior to 
treatment on Cycle 3 Day 1 and Cycle 5 Day 1.  After cessation of platinum doublet therapy, tumor 
assessments will be performed q9 weeks until 1 year after beginning treatment (C1D-2) (or beyond 1 year 
until maintenance therapy is discontinued), then q12 weeks until radiographic progression or death.  
Radiographic information will be collected to determine response according to the Response Evaluation 
Criteria In Solid Tumors (RECIST) version 1.1.  Toxicities will be graded at each study visit according to 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0.
The visit at which an investigator identifies disease progression or at which a subject meets other criteria 
for study discontinuation will be considered the Final Visit.  It is preferable that final visit procedures be 
conducted prior to the initiation of another anticancer therapy.
All subjects who have a Final visit ≤ 30 days after the last dose of Study drug will have a Follow-Up 
Visit approximately 30 days after the last dose of Study drug.  If a subject is discontinued from the study 
with an ongoing adverse event or an unresolved clinically significant laboratory result, the site will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory results or adverse 
event is achieved.
Subjects no longer undergoing clinical assessments will have survival information reported at 2-month 
intervals (or as requested by the sponsor to support data analysis) beginning at the last clinical assessment 
and continuing until the endpoint of death, the subject has become lost to follow-up, or AbbVie 
terminates the study.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Diagnosis:  Metastatic or advanced non-squamous Non-Small Cell Lung Cancer
Main Inclusion:  
1.
Subject must be ≥ 18 years of age.
2.
Life expectancy > 12 weeks (as per Investigator's clinical assessment).
3.
Subject must have cytologically or histologically confirmed advanced or metastatic non-squamous 
NSCLC.  Subjects with mixed histology tumors will be eligible if the tumor is predominant 
non-squamous histology and does not include tumor with small cell histology.  Subjects must have a 
pathologist's report confirming non-squamous NSCLC available for collection by the sponsor.  
Subjects with EGFR mutation (exon 19 deletion or L858R mutation in exon 21) and/or ALK gene 
rearrangement must have progressed after first line monotherapy treatment with targeted therapy.
4.
Subject must have NSCLC that is not amenable to surgical resection or radiation with curative intent 
at time of study Screening.
5.
Subjects must be current smokers (defined as having > 100 smoking events lifetime and having 
smoked within the past year) or former smokers (defined as having > 100 smoking events lifetime 
and having not smoked within the past year).


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
7
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):  
6.
Subject must have at least 1 unidimensional measurable NSCLC lesion on a CT scan as defined by 
RECIST (version 1.1).
7.
Subject must consent to provide archived tissue or cytology sample of NSCLC lesion (primary or 
metastatic) for analysis if available.  
8.
Subject must have no history of brain metastases or evidence of CNS tumors at screening 
assessment.  Subjects with signs or symptoms of CNS involvement will undergo MRI (or CT scan if 
MRI is contraindicated) to confirm absence of CNS metastases.
9.
Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 – 1.
10. Subjects with fluid retention, including ascites or pleural effusion, may be allowed at the discretion 
of the Investigator.
11. Subject must have adequate bone marrow, renal and hepatic function as follows:
!
Bone Marrow:  Absolute neutrophil count (ANC) ≥ 1,500/mm3 (1.5 × 109/L);
!
Platelets ≥ 100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.0 g/dL; 
!
Renal function:  serum calculated creatinine clearance > 50 mL/min according to the 
Cockcroft-Gault formula; confirmation of creatinine clearance/GFR may be done by a local 
direct measurement method (e.g., 24 hour urine collection or radioisotope) at the investigator's 
discretion;
!
Hepatic function:  AST and ALT ≤ 2.5 × ULN unless liver metastases are present, then AST 
and ALT < 5.0 × ULN; bilirubin ≤ 1.5 × ULN; unless Gilbert's Syndrome is present, then 
bilirubin ≥ 1.5 × ULN.
12. Female subjects of childbearing potential (i.e., those who are not postmenopausal for at least 1 year 
or surgically sterile by bilateral tubal ligation, bilateral oophorectomy or hysterectomy) and their 
male partners should practice at least one of the methods of birth control listed below during study 
and for at least 6 months after treatment with paclitaxel chemotherapy.  Male subjects and their 
female partners of childbearing potential should practice at least one of the methods of birth control 
listed below during study and for at least 6 months after treatment with chemotherapy:
!
total abstinence from sexual intercourse (if it is the subject's preferred and usual lifestyle; for 
beginning a minimum one complete menstrual cycle prior to study drug administration and to 
extend 6 months after treatment);
!
vasectomized subject or partner(s); vasectomy (males);
!
intrauterine device (females);
!
double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with 
spermicidal jellies or creams; both males and females);
!
hormonal contraceptives (oral, parenteral or transdermal) for at least 90 days prior to study drug 
administration (females).  If hormonal contraceptives are used, the subject and her partner 
should also use a single-barrier method.
13. Subject must be 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 the initiation of any screening or study-specific 
procedures.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
8
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion:  
1.
Subject has a known hypersensitivity to paclitaxel or to other drugs formulated with polyethoxylated 
castor oil (Cremophor).
2.
Subject has a known hypersensitivity to platinum compounds.
3.
Subjects with peripheral neuropathy ≥ grade 2.
4.
Subjects with squamous NSCLC, or those with an untreated EGFR mutation (exon 19 deletion or 
L858R mutation in exon 21) and/or ALK gene rearrangement.  Subjects' EGFR mutation and ALK 
gene rearrangement status must be known prior to study entry.  
5.
A history of seizure within 12 months prior to study entry.
6.
Subject has received prior cytotoxic chemotherapy or chemoradiotherapy for NSCLC, except 
adjuvant or neoadjuvant therapy > 12 months prior to C1D-2 or subject has received targeted small 
molecule monotherapy for EGFR and/or ALK-positive disease ≤ 14 days prior to C1D-2 or biologic 
therapy ≤ 21 days prior to C1D-2.
7.
Subject has received anti-cancer Chinese medicine or anti-cancer herbal remedies within 14 days 
prior to C1D-2.
8.
Subject has undergone focal External Beam Radiation Therapy (EBRT) to bone ≤ 2 weeks prior to 
C1D-2; or subject has undergone EBRT to larger fields (i.e., 100 cm2 to thorax) ≤ 4 weeks prior to 
C1D-2.
9.
Any medical condition, which in the opinion of the Investigator, places the subject at an 
unacceptably high risk for toxicities, or any subject circumstance which prohibits trial participation 
according to local law.
10. Subject is pregnant or lactating.
11. Subject has previously been treated with a PARP inhibitor.
12. The subject has a history of another cancer within the past 3 years except cervical cancer in situ, 
in situ carcinoma of the bladder, squamous or basal cell carcinoma of the skin or another in situ 
cancer that is considered cured by the Investigator (e.g., in situ prostate cancer).  
Investigational Products:
Veliparib (ABT-888)
Doses:
120 mg BID Days –2 through 5 of 21-day cycle
Mode of Administration:
Oral
Reference Therapy or 
Investigational products:
Carboplatin Day 1 of 21-day cycle
Dose:
AUC 6 mg/mL•min
Mode of Administration:
Intravenous
Reference Therapy or 
Investigational products:
Paclitaxel Day 1 of 21-day cycle
Dose:
200 mg/m2
Mode of Administration:
Intravenous


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
9
Reference Therapy:
Pemetrexed
Dose:
500 mg/m2
Mode of Administration:
Intravenous
Reference Therapy:
Cisplatin
Dose:
75 mg/m2
Mode of Administration:
Intravenous
Duration of Treatment:  
Subjects will receive veliparib in combination with carboplatin/paclitaxel for a maximum of 6 treatment 
cycles or Investigator's choice of chemotherapy for a maximum of 6 cycles unless toxicity requires 
cessation of therapy, or radiographic progression occurs prior to completing 6 cycles.  Following 
completion of platinum doublet therapy, maintenance pemetrexed is strongly encouraged for all subjects 
who are suitable candidates.
Criteria for Evaluation:
Overall survival (OS):  will be reported by the Investigator until radiographic progression or death.  
After the final visit, survival information will be collected at 2-month intervals (or as requested by 
sponsor to support data analysis).
Progression-free survival (PFS):  will be derived according to radiographic progression per RECIST 
version 1.1 or death.  Radiographic tumor assessments for response will be conducted by CT scanning 
prior to C3D1, prior to C5D1, every 9 weeks until 1 year after beginning treatment (or beyond 1 year 
until maintenance therapy is discontinued), and then every 12 weeks.
Objective response rate (ORR):  will be derived per RECIST version 1.1.  Radiographic tumor 
assessments for response will be conducted by CT scanning prior to C3D1, prior to C5D1, every 9 weeks 
until 1 year after beginning treatment (or beyond 1 year until maintenance therapy is discontinued), and 
then every 12 weeks.
Duration of overall response (DOR):  will be derived according to radiographic progression per 
RECIST version 1.1.  Radiographic tumor assessments for response will be conducted by CT scanning 
prior to C3D1, prior to C5D1, every 9 weeks until 1 year after beginning treatment (or beyond 1 year 
until maintenance therapy is discontinued), and then every 12 weeks.
ECOG performance status:  will be determined by the Investigator at each assessment.  
Quality of Life (QoL):  will be assessed at baseline prior to veliparib dosing on C1D-2, C3D1, C5D1 
and at the Final Visit, every 9 weeks until 1 year after beginning treatment (or beyond 1 year until 
maintenance therapy is discontinued), then every 12 weeks and at the Final Visit until radiographic 
progression via the NCCN-Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 
(NFLSI-17) questionnaire and the European Quality of Life-5 Dimensions (EQ-5D-5L) questionnaires.
Safety:
Adverse events, laboratory profiles, physical examinations and vital signs will be assessed throughout the 
study.
Pharmacokinetic/Pharmacogenetics:
Blood samples for pharmacokinetics of veliparib will be collected at designated timepoints throughout 
the study and will be analyzed in LSP-defined populations as well as the entire study population.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
10
Criteria for Evaluation (Continued):
LSP status: 
Available archived tumor tissue will be used to determine the subjects' tumor LSP status with a 
commercially developed RNA seq based LSP classifier developed in partnership with Qiagen.
Pharmacodynamic:
Research to find biomarkers that may serve as surrogates for clinical endpoints in future veliparib studies 
or that may be predictive of veliparib activity will be conducted.  Serum, plasma, blood and tissue 
samples will be collected at designated time points throughout the study.
Statistical Methods:
For all statistical analyses, statistical significance will be determined by a two-sided P value ≤ 0.05.  The 
date of randomization (enrollment) is defined as the date that the IRT issues a randomization number.
Sample Size:
Sample size determination for the original protocol:  Assuming the true hazard ratio of overall survival 
(OS) for current smokers in favor of the veliparib 120 mg BID + carboplatin/paclitaxel treatment group is 
0.64, a total of 210 death events among current smokers will be needed for the study to have 
approximately 90% power at one-sided α level of 0.025 to detect a statistically significant treatment 
effect for the veliparib 120 mg BID + carboplatin/paclitaxel group using the log rank test for OS.  A total 
of approximately 300 current smokers will be enrolled to obtain the 210 death events.
During the enrollment period for the approximate 300 current smokers, it is anticipated that 
approximately 225 former smokers will enroll concurrently.  Assuming the true hazard ratio of overall 
survival (OS) for all subjects (including current plus former smokers) in favor of the veliparib 120 mg 
BID + carboplatin/paclitaxel treatment group is 0.71, a total of 369 death events in all subjects will be 
needed for the study to have approximately 90% power at one-sided α level of 0.025 to detect a 
statistically significant treatment effect for the veliparib 120 mg BID + carboplatin/paclitaxel group using 
the log rank test for OS.  
Sample size consideration for OS analysis in LSP+ subgroup:
Based on 452 subjects having tissue samples (assumed 76% LSP sample availability rate, out of 
595 enrolled subjects), the below table provides the power and number of events (assuming 80% event 
rate at final analysis) for a range of likely LSP+ rates if the treatment allocation ratio is 1:1 in the LSP+ 
subgroup and true HR of OS is 0.65 in LSP+ subgroup.
Number of LSP+ 
Subjects (LSP+ rate)
Number of Events in LSP+
Power for OS in LSP+ Subgroup 
(one-sided alpha = 0.025)
271 (60%)
216
89%
226 (50%)
180
82%
180 (40%)
144
73%
  


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
11
1.3
List of Abbreviations and Definition of Terms
Abbreviations
ADP
Adenosine Diphosphate
AE
Adverse Event
ALK
Anaplastic Lymphoma Kinase
ALT
Alanine transaminase
ANC
Absolute Neutrophil Count
ANCOVA
Analysis of Covariance
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
BID
Twice a Day
BRCA
Breast Cancer Gene
BUN
Blood Urea Nitrogen
C
Cycle
CBC
Complete blood count
CFR
Code of Federal Regulations
CNS
Central Nervous System
CR
Complete Response
CRF or eCRF
Case Report Form or Electronic Case Report Form
CS
Clinically Significant
CSF
Colony-Stimulating Factor
CT
Computed Tomography
CTEP
Cancer Therapy Evaluation Program
Cmax
Maximum Drug Concentration
CYP
Cytochrome P450
D
Day
DDI
Drug-Drug Interaction
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic Acid
DOR
Duration of  Overall Response
EBRT
External Beam Radiation Treatment
ECG
Electrocardiogram


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
12
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor 
ERCC1
Excision Repair Cross-Complementary Group 1 Protein
EMA
European Medicines Agency
ESMO
European Society for Medical Oncology
FDA
US Food and Drug Administration
FFPE
Formalin fixed, paraffin embedded
GCP
Good Clinical Practice
GFR/eGFR
Glomerular Filtration Rate/estimated Glomerular Filtration Rate
hCG
Human Chorionic Gonadotropin
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IIA
Investigator Information and Agreement
IIS
Investigator initiated studies
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV, i.v.
Intravenous
LD
Longest Diameter
LDH
Lactate Dehydrogenase
LSP
Lung Subtype Panel
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliter
MRI
Magnetic Resonance Imaging
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCS
Not Clinically Significant
NCI CTCAE
National Cancer Institute Common Terminology Criteria For Adverse Events
NSCLC
Non-small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
13
PAR
Poly-(ADP-ribose)
PARP
Poly-(ADP-ribose)-Polymerase
PBMC
Peripheral Blood Mononuclear Cells
PD
Pharmacodynamic or Progressive Disease
PFS
Progression Free Survival
PG
Pharmacogenetic
PK
Pharmacokinetic
PO
Oral Route of Administration
POR
Proof of Receipt 
PR
Partial Response
QA
Quality Assurance
QC
Quality Control
QTc
QT interval corrected for heart rate
QoL
Quality of Life 
RBC
Red Blood Cell
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCLC
Small Cell Lung Cancer
SD
Stable Disease
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SmPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
TMZ
Temozolomide
TNM 
Tumor size, Nodes and Metastasis presence
ULN
Upper Limit of Normal 
US
Ultrasound or United States
VAS
Visual Analogue Scale
WBC
White Blood Cell


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
14
Definition of Terms
AUC
Area under the concentration-time curve
Cmax
Maximum observed concentration
nM
Nanomolar
Tmax
Time to maximum observed plasma concentration


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
15
2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 4
1.3
List of Abbreviations and Definition of Terms...................................... 11
2.0
Table of Contents ................................................................ 15
3.0
Introduction......................................................................... 20
3.1
NSCLC (Non-Small Cell Lung Cancer)................................................ 20
3.2
Carboplatin and Paclitaxel.................................................................... 22
3.3
PARP Inhibition for Cancer Treatment................................................. 23
3.4
Veliparib .............................................................................................. 24
3.4.1
Preclinical Studies and Toxicology....................................................... 24
3.4.2
Veliparib Pharmacokinetics/Pharmacodynamics................................... 25
3.4.3
Veliparib Clinical Studies..................................................................... 26
3.5
Study Rationale .................................................................................... 28
3.6
Differences Statement .......................................................................... 28
3.7
Benefits and Risks................................................................................ 28
4.0
Study Objectives.................................................................. 29
5.0
Investigational Plan............................................................. 30
5.1
Overall Study Design and Plan:  Description ........................................ 30
5.2
Selection of Study Population............................................................... 33
5.2.1
Inclusion Criteria.................................................................................. 33
5.2.2
Exclusion Criteria................................................................................. 36
5.2.3
Prior and Concomitant Therapy............................................................ 37
5.2.3.1
Prior Therapy ....................................................................................... 38
5.2.3.2
Concomitant Therapy for Carboplatin/Paclitaxel .................................. 38
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Pharmacogenetic, 
and Safety Assessments/Variables ........................................................ 40
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 40
5.3.1.1
Study Procedures.................................................................................. 43
5.3.1.2
Blood Samples for Pharmacogenetic Analysis (Optional) ..................... 51
5.3.1.3
Collection and Handling of Pharmacodynamic Variables ..................... 52


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
16
5.3.2
Drug Concentration Measurements....................................................... 53
5.3.2.1
Collection of Samples for Pharmacokinetic Analysis............................ 53
5.3.2.2
Measurement Methods ......................................................................... 53
5.3.3
Efficacy Variables................................................................................ 53
5.3.4
Safety Variables ................................................................................... 54
5.3.5
Pharmacokinetic Variables ................................................................... 54
5.3.6
Pharmacogenetic Variables................................................................... 54
5.3.7
Pharmacodynamic Variables ................................................................ 55
5.4
Removal of Subjects from Therapy or Assessment ............................... 55
5.4.1
Discontinuation of Individual Subjects ................................................. 56
5.4.1.1
Discontinuation of Veliparib and Carboplatin/Paclitaxel and 
Pemetrexed........................................................................................... 57
5.4.2
Discontinuation of Entire Study............................................................ 58
5.5
Treatments ........................................................................................... 59
5.5.1
Treatments Administered...................................................................... 59
5.5.1.1
Administration of Veliparib.................................................................. 59
5.5.1.2
Administration of Carboplatin/Paclitaxel with Veliparib....................... 60
5.5.2
Identity of Investigational Product........................................................ 61
5.5.2.1
Medicinal Products for Combination Treatment.................................... 61
5.5.2.2
Packaging and Labeling........................................................................ 62
5.5.2.3
Storage and Disposition of Study Drug................................................. 63
5.5.3
Preparation of Intravenous Solutions .................................................... 64
5.5.4
Method of Assigning Subjects to Treatment Groups ............................. 65
5.5.5
Selection and Timing of Dose for Each Subject.................................... 66
5.5.6
Treatment Compliance ......................................................................... 66
5.5.7
Drug Accountability............................................................................. 66
5.6
Discussion and Justification of Study Design........................................ 67
5.6.1
Discussion of Study Design and Choice of Control Groups .................. 67
5.6.2
Appropriateness of Measurements........................................................ 68
5.6.3
Suitability of Subject Population .......................................................... 69
5.6.4
Selection of Doses in the Study ............................................................ 69
5.7
Dose Reductions or Delays................................................................... 69
5.7.1
Veliparib Dose Reductions and Delays................................................. 70


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
17
5.7.2
Carboplatin/Paclitaxel Dose Reductions and Delays ............................. 71
5.7.2.1
Suggested Guidelines for Carboplatin and Paclitaxel Dose 
Reductions and Delays ......................................................................... 72
6.0
Adverse Events .................................................................... 73
6.1
Definitions ........................................................................................... 73
6.1.1
Adverse Events..................................................................................... 73
6.1.2
Serious Adverse Events........................................................................ 74
6.2
Adverse Events Expected Due to NSCLC or Progression of 
NSCLC ................................................................................................ 75
6.3
Adverse Event Severity ........................................................................ 76
6.3.1
Deaths.................................................................................................. 76
6.3.2
Lack of Efficacy or Worsening of Disease............................................ 77
6.4
Relationship to Study Drug................................................................... 77
6.5
Adverse Event Collection Period.......................................................... 78
6.6
Adverse Event Reporting...................................................................... 79
6.6.1
Reporting Serious Adverse Events........................................................ 79
6.7
Pregnancy............................................................................................. 80
6.8
Toxicity Management........................................................................... 81
7.0
Protocol Deviations ............................................................. 81
8.0
Statistical Methods and Determination of Sample 
Size ....................................................................................... 82
8.1
Statistical and Analytical Plans............................................................. 82
8.1.1.1
Demographics ...................................................................................... 82
8.1.1.2
Medical History.................................................................................... 83
8.1.2
Efficacy Endpoints ............................................................................... 83
8.1.2.1
Primary Efficacy Endpoint ................................................................... 83
8.1.2.2
Secondary Efficacy Endpoints.............................................................. 83
8.1.2.3
Tertiary Efficacy Endpoints.................................................................. 84
8.1.3
Timing of Efficacy Analyses and Safety Evaluations............................ 85
8.1.4
Primary Analysis of Efficacy................................................................ 85
8.1.5
Secondary Analysis of Efficacy............................................................ 85
8.1.5.1
Progression Free Survival in LSP + Subgroup ...................................... 85
8.1.5.2
Objective Response Rate in LSP+ Subgroup ........................................ 85


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
18
8.1.5.3
Overall Survival in All Subjects ........................................................... 86
8.1.5.4
Progression Free Survival in All Subjects............................................. 86
8.1.5.5
Objective Response Rate in All Subjects .............................................. 86
8.1.6
Tertiary Analyses of Efficacy ............................................................... 86
8.1.6.1
Duration of Overall Response............................................................... 86
8.1.6.2
General Quality of Life......................................................................... 87
8.1.6.3
Performance Status............................................................................... 87
8.1.7
Additional Exploratory Efficacy Analyses............................................ 88
8.1.8
Statistical Analysis of Safety ................................................................ 88
8.1.8.1
Duration of Study Drug ........................................................................ 89
8.1.8.2
Adverse Events..................................................................................... 89
8.1.8.3
Serious Adverse Events........................................................................ 89
8.1.8.4
Deaths .................................................................................................. 89
8.1.8.5
Longitudinal Analyses of Laboratory and Vital Signs Data................... 90
8.1.8.6
Analyses of Laboratory Data Using NCI CTCAE................................. 90
8.2
Determination of Sample Size .............................................................. 90
8.3
Randomization Methods....................................................................... 91
9.0
Ethics.................................................................................... 92
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ......................................................................................... 92
9.2
Ethical Conduct of the Study................................................................ 93
9.3
Subject Information and Consent.......................................................... 93
9.3.1
Informed Consent Form and Explanatory Material ............................... 94
9.3.2
Revision of the Consent Form and Explanatory Material ...................... 94
10.0
Source Documents and Case Report Form 
Completion ..........................................................................94
10.1
Source Documents................................................................................ 94
10.2
Case Report Forms............................................................................... 95
11.0
Data Quality Assurance ...................................................... 96
12.0
Use of Information .............................................................. 96
13.0
Completion of the Study ..................................................... 96
14.0
Investigator's Agreement.................................................... 98
15.0
Reference List...................................................................... 99


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
19
List of Tables
Table 1.
Treatment Schema for Each Cycle (Maximum of 6 Cycles).................. 33
Table 2.
Study Activities.................................................................................... 41
Table 3.
Schedule of Pharmacogenetic and Pharmacodynamic Assessments ...... 43
Table 4.
Schedule of Pharmacokinetic Assessments ........................................... 43
Table 5.
Clinical Laboratory Tests ..................................................................... 48
Table 6.
Identity of Investigational Product........................................................ 61
Table 7.
Non-Investigational Medicinal Products (Investigator's Choice 
Treatment Arm).................................................................................... 62
Table 8.
Study Drug Storage Conditions ............................................................ 63
Table 9.
Suggested Guidelines for Veliparib + Carboplatin/Paclitaxel 
Independent Dose Reductions............................................................... 70
List of Figures
Figure 1.
Study Schedule Schematic.................................................................... 32
Figure 2.
Adverse Event Collection..................................................................... 78
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................103
Appendix B.
List of Protocol Signatories .................................................................105
Appendix C.
Japan Specific Information ..................................................................106
Appendix D.
NFLSI-17............................................................................................108
Appendix E.
EQ-5D-5L Health Questionnaire .........................................................109
Appendix F.
Adverse Events Expected Due to NSCLC or Progression of 
NSCLC ...............................................................................................112
Appendix G.
Suggested Guidelines for carboplatin/paclitaxel Dose Delay or 
Reduction............................................................................................113
Appendix H.
RECIST (Version 1.1) for Tumor Response (PFS)...............................114
Appendix I.
Protocol Amendment:  List of Changes ...............................................121


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
20
3.0
Introduction
3.1
NSCLC (Non-Small Cell Lung Cancer)
Lung cancer is the leading cause of cancer-related mortality in both men and women 
throughout the world.  The prevalence of lung cancer is second only to that of prostate 
cancer in men and breast cancer in women.  Lung cancer recently surpassed heart disease 
as the leading cause of smoking-related mortality.  Most lung carcinomas are diagnosed at
an advanced stage, conferring a poor prognosis.  In 2008, an estimated 1.52 million new 
cases of lung cancer were diagnosed globally, accounting for approximately 12% of the 
global cancer burden, and an estimated 1.31 million lung cancer deaths occurred.1
The incidence of non-small cell lung cancer (NSCLC) increases with age; 60% occur in 
subjects aged 60 years and older, and 30% to 40% occur in subjects aged 70 years and 
older.  Eighty-five percent of subjects either present with or will eventually develop 
advanced or recurrent NSCLC and are considered candidates for systemic 
chemotherapy.2,3  Non-small cell lung cancer is divided further into adenocarcinoma, 
squamous cell carcinoma, and large cell carcinoma histologies.  Currently, about 40% of 
NSCLC cases are adenocarcinoma subtypes and about 40% are squamous tumors.3
National Comprehensive Cancer Network (NCCN) 2014 guidelines3 and ESMO 
guidelines4 recommend that first-line treatment with cytotoxic chemotherapy for 
metastatic non-small cell lung cancer should include a platinum combination.  Several 
randomized controlled studies have failed to show a clear superiority of 
one platinum-containing combination over another.  A landmark Eastern Cooperative 
Oncology Group (ECOG) study comparing cisplatin-gemcitabine, cisplatin-paclitaxel, 
cisplatin-docetaxel, and carboplatin-paclitaxel, suggested similar overall response rates 
(approximately 19%), and median survival (7.9 months).  1- and 2-year overall survival 
was also similar at 33% and 11%, respectively.5  Thus, significant unmet medical need 
exists to improve outcome for the majority of NSCLC subjects.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
21
A recent Phase 3 randomized trial showed that continuing pemetrexed as a single agent 
after the completion of pemetrexed-based platinum doublet therapy (continuation 
maintenance therapy) increased PFS and OS for subjects with non-squamous NSCLC 
[http://www.ncbi.nlm.nih.gov/pubmed/23835707].  A separate randomized trial showed 
PFS and OS benefit for pemetrexed maintenance therapy initiated after the completion of 
platinum doublet therapy with agents other than pemetrexed in subjects with 
non-squamous NSCLC (switch maintenance therapy) 
[ref http://www.ncbi.nlm.nih.gov/pubmed/19767093].  Even with maintenance 
chemotherapy, median survival time in these trials was 13 – 14 months.  Thus, significant 
unmet medical need exists to improve outcome for the majority of NSCLC subjects.
Large scale genomic characterization efforts including those conducted by the TCGA and 
the Lung Cancer Mutation Consortium (LCMC) have been conducted to identify 
molecular features that differ between NSCLC subtypes.  These different features may 
explain the differential therapeutic responses among different NSCLC subtypes, e.g., of 
squamous and non-squamous NSCLC.  The importance of molecular phenotyping has 
become increasingly clear as The Cancer Genome Atlas (TCGA) contributed results from 
a massive specific tumor type sequencing effort that provided a significant landmark for 
understanding the genetic mutation and gene expression profile of lung cancer in well 
characterized and distinct histologic subtypes. 
Genomic-based classification methods are more likely to capture the molecular 
characteristics of the cancer cell and therefore classify NSCLC into prognostically 
informative subgroups.  One such approach, termed LSP, is a gene expression profile 
established using a panel of 57 genes (52 classification genes plus 5 housekeeping genes) 
for the mRNA expression signature.  This panel became known as the Lung Subtype 
Panel (LSP).  Analysis in these three independent adenocarcinoma NSCLC cohorts 
demonstrated that LSP positive (LSP+) group of patients who had poor prognosis.6


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
22
3.2
Carboplatin and Paclitaxel 
NCCN and ESMO guidelines include carboplatin AUC of 6 mg/mL•min and paclitaxel 
200 mg/m2 (administered every 3 weeks) among several recommended platinum doublet 
chemotherapy combinations for the treatment of metastatic NSCLC.3,4
Carboplatin is a commonly used platinum compound that acts by binding to 
deoxyribonucleic acid (DNA) and interrupting cell division.  It is approved for the 
treatment of subjects with ovarian cancer.  It is also used for the treatment of non-small 
cell lung cancer (NSCLC), small cell lung cancer (SCLC), head and neck cancer, 
endometrial cancer, metastatic seminoma and breast cancer.  Carboplatin is eliminated by 
renal excretion, and the clearance is related to the glomerular filtration rate (GFR).  
Therefore it is dosed based on the GFR and the target area under the concentration versus 
time curve (AUC).  The main side effect of carboplatin is myelosuppression.  Other 
toxicities include nausea, vomiting, renal and neurotoxicity.7,8
Paclitaxel is an antimicrobial agent that promotes the assembly of microtubule formation 
and stabilizes them by preventing depolymerization.  It is insoluble in water and is 
therefore formulated in cremophor.  It is approved for the treatment of ovarian cancer, 
breast cancer, non-small cell lung cancer and Kaposi's sarcoma.  It is also in use for the 
treatment of several other solid tumor malignancies.  Main toxicities associated with the 
use of paclitaxel include myelosuppression, neuropathy and hypersensitivity reactions.9,10
Myelosuppression is the principal toxicity of a carboplatin/paclitaxel regimen in NSCLC, 
and peripheral neuropathy is a dose limiting toxicity of this regimen.  In the ECOG study 
of systemic treatment for advanced NSCLC, grade 3/4 granulocytopenia was reported in 
57% and 35% of subjects after the first and second cycles, but remained ≤ 22% during 
subsequent cycles.  Grade 3/4 thrombocytopenia and anemia were reported in 47% and 
33% of subjects, respectively.  Grade 3/4 peripheral neuropathy was reported in 10% of 
subjects.  Overall, 25% of the subjects discontinued therapy due to toxicities.11,12


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
23
3.3
PARP Inhibition for Cancer Treatment
Poly(ADP-ribose)-polymerase (PARP) is a nuclear enzyme that recognizes 
deoxyribonucleic acid (DNA) damage and facilitates DNA repair.13-15  Inactive PARPs 
1 and 2 bind to damaged DNA, which leads to their auto-activation.  The resulting 
activated PARP then poly(ADP-ribosyl)ates many nuclear target proteins, including those 
that facilitate DNA repair of both single-stranded or double-stranded DNA breaks.  Thus, 
inhibition of PARP results in less efficient DNA repair following a DNA damaging insult.
DNA-damaging agents, including cytotoxic chemotherapy and radiation therapy, remain a 
mainstay of treatment for advanced 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.16  Deficiencies in 
mismatch repair and homologous recombination render cells more dependent on PARP 
for DNA repair and, hence, are more prone to cytotoxicity induced by PARP inhibition.17  
In particular, tumor cells with BRCA1 or BRCA2 deficiencies are exquisitely sensitive to 
PARP inhibition, even in the absence of any other insults.18,19
Consistent with the observation that PARP activity may act as a resistance factor in some 
tumors, PARP inhibitors have been shown in preclinical models to sensitize tumors to a 
variety of DNA-damaging agents, including cross-linking chemotherapy agents such as 
carboplatin and ionizing radiation therapy.  It is unknown whether the pattern or 
prevalence of DNA damage in tumors is correlated with PARP inhibitor efficacy.  A 
direct correlation of this nature would support the use of PARP inhibitors in tumors with 
more DNA damage, such as lung tumors arising in smokers.  DNA damage is 10-fold 
more prevalent in lung tumors from smokers compared to tumors from non-smokers, and 
many DNA changes in subjects who smoke are not reversed despite smoking 
cessation.20-22


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
24
3.4
Veliparib
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology of 
veliparib can be found in the veliparib Investigator's Brochure.23  Veliparib is a potent 
PARP inhibitor that delays the repair of DNA damage induced by chemotherapeutics.  
Veliparib increases sensitivity of tumor cells to DNA-damaging agents in vitro and 
in vivo, and inhibits PARP in murine tumors in vivo, human peripheral blood 
mononuclear cells (PBMCs) ex vivo, and human tumors ex vivo.
3.4.1
Preclinical Studies and Toxicology
Veliparib is a novel small molecule that is a potent inhibitor of both PARP-1 and PARP-2 
with Ki's of 5 nM and 3 nM, respectively.  In cells under oxidative stress, veliparib 
inhibits the PARP induced formation of poly-(ADP-ribose) (PAR) with an EC50 of 
2.4 nM.  In cellular assays, veliparib increases sensitivity of tumor cells to 
DNA-damaging agents including platinum agents, irinotecan, cyclophosphamide, 
temozolomide (TMZ) and radiation.  In preclinical tumor models, veliparib enhances the 
anti-tumor efficacy of crosslinking agents (cisplatin, carboplatin), alkylating/methylating 
agents (TMZ, cyclophosphamide), topoisomerase inhibitors (irinotecan) and radiation.
Veliparib has been shown to enhance the efficacy of carboplatin or of carboplatin plus 
paclitaxel in several xenograft tumor models.  In the BRCA1 deficient MX-1 model, 
veliparib administered at doses as low as 25 mg/kg/day significantly enhanced the 
efficacy of carboplatin.  Veliparib administered at 50 and 100 mg/kg/day in combination 
with carboplatin 50 mg/kg/day intraperitoneally + paclitaxel 10 mg/kg/day IV caused 
regression of implanted MX-1 tumors, whereas veliparib alone or carboplatin + paclitaxel 
without veliparib did not.24
The toxicological profile of veliparib has been evaluated in nonclinical general toxicity 
studies that included single-dose (rats and mice), repeat-dose (duration of up to 6 months 
in rats and up to 9 months in dog), reproductive (embryofetal development in rat and 
rabbit), genetic (Ames, in vitro cytogenetics, in vivo micronucleus), phototoxicity 
(in vitro photosensitivity) and juvenile rat toxicity studies.  Primary nonclinical findings 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
25
included effects on the central nervous system (convulsions, tremors), hematopoietic 
system (bone marrow depletion), reproductive system (male germ cell depletion, female 
reproductive tract tissues degeneration), and lymphoid tissues (lymphocyte depletion), 
with lesser effects on the gastrointestinal tract (single-cell necrosis) and cardiovascular 
system (10% QTc interval prolongation).  All findings were dose-dependent and 
reversible or self-limited.  Veliparib was genotoxic (induced chromosomal aberrations in 
vitro and increased micronuclei formation in vivo) and was toxic to the developing fetus 
(increases in the incidence of fetal external/visceral/skeletal malformations/variations) in 
rats and rabbits.  Veliparib demonstrated no phototoxic potential in photosensitivity tests.
3.4.2
Veliparib Pharmacokinetics/Pharmacodynamics
Clinical pharmacokinetic (PK) data available from Phase 1 studies indicate that exposure 
of veliparib is approximately dose-proportional over 10 through 500 mg BID dose range.  
The absorption of veliparib after oral dosing is rapid, and veliparib plasma concentrations 
peak at approximately 1 to 2 hours after dosing across dose levels.  The terminal half-life 
of veliparib is about 6 hours, with minimal accumulation following multiple BID dosing.  
Food does not have a significant effect on veliparib bioavailability.  On average, 73% and 
86% of the orally administered veliparib dose were recovered in urine as the parent drug 
alone and as the parent drug plus an M8 metabolite, which indicates that veliparib is 
highly absorbed after oral dosing and the renal excretion is the major pathway in veliparib 
elimination.
Veliparib is not a potent inhibitor, nor an inducer, of the major human cytochrome P450s 
(CYPs), suggesting a minimal potential for DDIs at the anticipated therapeutic 
concentrations.  Potential drug-drug interactions (DDI) of veliparib have been or are being 
evaluated in veliparib combination studies.  There was no significant PK interaction 
between veliparib and TMZ, and preliminary results indicate the absence of a DDI 
between veliparib and carboplatin/gemcitabine, between veliparib and FOLFIRI, between 
veliparib and carboplatin/paclitaxel, or between veliparib and capecitabine/5-FU.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
26
In Phase 0 Study A10-161, substantial inhibition of PARP activity was observed in tumor 
biopsies collected 3 to 6 hours after dosing in all 3 subjects who received a single-dose of 
25 mg veliparib (92%, 95%, and 100%).  For subjects receiving  50 mg, PARP activity 
inhibition in tumor biopsies averaged 75% at 3 to 6 hours after dosing (N = 3) and 
averaged 74% at 24 hours after dosing (N = 3).  Therefore, both 25 mg and 50 mg 
veliparib doses were biologically active.
3.4.3
Veliparib Clinical Studies
Veliparib is investigated in AbbVie-sponsored studies, in Investigator initiated studies 
(IIS), and in CTEP-sponsored studies.  In these studies, veliparib is administered as 
monotherapy, combined with a variety of chemotherapeutic agents, or combined with 
radiation therapy.
Summary preliminary or final efficacy data from AbbVie sponsored studies show that 
veliparib has activity in combination with TMZ, with radiotherapy, and with 
carboplatin + paclitaxel.21  Data from non-AbbVie sponsored studies show veliparib has 
activity as monotherapy for treatment of ovarian cancer25 and activity in combination with 
carboplatin + paclitaxel for treatment of early breast cancer.26  Veliparib is currently in 
Phase 2 clinical development in combination with several DNA-damaging agents across a 
variety of cancer indications and Phase 3 clinical development in combination with 
carboplatin and paclitaxel for early breast cancer and squamous NSCLC.
Phase 1 data from subjects treated with veliparib, carboplatin, and paclitaxel for advanced 
NSCLC are available from CTEP Study 7967.27  Subjects had advanced solid tumors, 
received ≤ 3 prior chemotherapy regimens for advanced disease, and had ECOG 
performance status 0 to 2.  Veliparib was given PO BID on Days 1 to 7 of each 21-day 
cycle, and paclitaxel and carboplatin were administered on Day 3.  Dose escalation was 
started at veliparib 20 mg BID, paclitaxel 150 mg/m2, and carboplatin AUC 5.  Backbone 
therapy was escalated to paclitaxel 200 mg/m2 and carboplatin AUC 6 in later cohorts.  
Among 68 initial subjects, partial responses were seen in 11 subjects and complete 
response in 2 subjects.  Among 11 subjects with NSCLC (8 evaluable), 4 subjects had 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
27
responses and 3 additional subjects had stable disease at first tumor evaluation.  
Two DLTs (febrile neutropenia and hyponatremia) were observed in 2 of 7 evaluable 
subjects treated at the maximum tolerated dose of veliparib 120 mg BID, paclitaxel 
200 mg/m2, and carboplatin AUC 6.  The most common AEs reported in this study were 
neutropenia and fatigue (reported in > 50% of subjects); nausea, thrombocytopenia, and 
peripheral sensory neuropathy (> 40% of subjects); and anemia, constipation, alopecia, 
diarrhea, decreased appetite, lymphopenia, and myalgia (> 20% of subjects).
A double-blind, randomized Phase 2 study of carboplatin and paclitaxel with veliparib or 
placebo for subjects with advanced NSCLC is ongoing.  Therapy is delivered for up to 
6 cycles with carboplatin AUC 6 (IV) and paclitaxel 200 mg/m2 (IV) every 3 weeks plus 
veliparib/placebo 120 mg BID (PO) on 7 days around chemotherapy administration.  All 
subjects have completed therapy.  Data showed an improvement in median 
progression-free survival of 1.3 months (HR 0.38, 95% CI:  0.21 – 0.67) and an 
improvement in overall survival of 7.1 months (HR 0.43, 95% CI:  0.26 – 0.70) in 
95 current smokers with NSCLC.28  Similar effect on PFS and OS was observed in 
non-squamous NSCLC current smokers (data on file with AbbVie).
Leukopenia was increased in frequency by < 15% for veliparib versus placebo-treated 
subjects, and neutropenia was increased in frequency by < 10% for veliparib versus 
placebo-treated subjects. No other AE was increased by > 5%.  AEs led to reduction or 
discontinuation of backbone therapies at similar rates (± 3%) with or without veliparib.
At present, AbbVie's safety database for veliparib is based on the exposure of 
approximately 3,700 cancer subjects to veliparib in clinical studies.  Veliparib's known 
and potential safety risks were identified based on clinical safety analyses, as well as 
evaluation of pharmacological mechanism, preclinical studies, and literature.  Identified 
risks associated with veliparib administration are hematological cytopenias when veliparib 
is added to backbone chemotherapy regimens.  Most observed toxicities in subjects 
exposed to veliparib have been as expected with DNA-damaging agents and are 
manageable with routine oncology supportive care.  Potential risks of veliparib 
administration, identified mostly in preclinical studies or based on pharmacological 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
28
mechanism, but not confirmed in clinical studies, are seizures, changes in testes/ovaries, 
and toxicity to the developing fetus.  A potential risk of secondary malignancies is 
theoretical based on veliparib's mechanism of action.
3.5
Study Rationale
Most NSCLC subjects are diagnosed at an advanced stage, conferring a poor prognosis.  
Current standard therapy for NSCLC provides time-to-progression of 4 to 6 months and 
overall survival of 10 to 12 months.29  Phase 1 data and Phase 2 data described above 
suggest the addition of veliparib to carboplatin and paclitaxel may improve outcome of 
LSP+ subjects and/or current-smokers with advanced or metastatic NSCLC.  Current 
smokers and former smokers will be enrolled into the trial, based on the findings from 
other research showing that DNA damage is 10-fold more prevalent in lung tumors from 
smokers compared to tumors from non-smokers, and that many DNA changes in smokers 
are not reversed despite smoking cessation.20-22  All enrolled subjects with available tumor 
tissue will be evaluated for the LSP gene expression signature status.  This study will 
investigate carboplatin and paclitaxel with veliparib with or without maintenance therapy 
compared to different platinum doublet chemotherapies for non-squamous NSCLC.
3.6
Differences Statement
The current study is the first randomized, open-label, multicenter, Phase 3 trial comparing 
veliparib plus carboplatin and paclitaxel versus Investigator's choice of standard 
chemotherapy in previously untreated subjects with metastatic or advanced non-squamous 
non-small cell lung cancer (NSCLC), now as defined by LSP status.
3.7
Benefits and Risks
This study proposes to establish improved clinical outcomes for subjects with advanced 
NSCLC through the addition of veliparib to standard therapy with carboplatin and 
paclitaxel.  Preclinical data demonstrate that veliparib potentiates the anti-tumor activity 
of platinums, and data from early-phase studies (completed or preliminary) is consistent 
with these observations.  As described above, non-squamous NSCLC study subjects 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
29
receiving veliparib with carboplatin and paclitaxel have shown favorable results for the 
current smokers group (as presented above) and the LSP+ group for the endpoints of 
overall survival.  Overall survival is a clinically meaningful endpoint for NSCLC, as 
shown in several studies that have influenced treatment for the disease over the last 
15 years.31-34
Risks in this study include toxicity from the addition of veliparib to standard therapy.  
Safety data from a blinded, randomized Phase 2 study of the proposed combination 
therapy in subjects with advanced NSCLC suggest low rates of additional toxicities and 
no compromise to the delivery of carboplatin and paclitaxel.  Standard clinical practices to 
manage the toxicity of carboplatin + paclitaxel are well established.  Other potential risks 
of veliparib administration, identified in preclinical studies or based on pharmacological 
mechanism, but not confirmed in clinical studies must also be considered.  These risks 
include seizures, changes in testes/ovaries, toxicity to the developing fetus and secondary 
malignancies.
4.0
Study Objectives
The primary objective of the study is to assess if treatment with veliparib plus carboplatin 
and paclitaxel results in improved survival compared to Investigator's choice of standard 
chemotherapy in LSP positive subjects with metastatic or advanced NSCLC.
The secondary objectives of the study are to assess if treatment with veliparib plus 
carboplatin and paclitaxel results in improved survival compared to Investigator's choice 
of standard chemotherapy in the entire study population with metastatic or advanced 
NSCLC; to compare progression-free survival (PFS) and to compare objective response 
rate (ORR) between the two treatment arms in LSP positive subjects or in the entire study 
population.
The tertiary objectives are to compare duration of overall response (DOR), ECOG 
performance status and Quality of Life (QoL) between the two treatment arms in LSP 
positive subjects or in the entire study population.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
30
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3, randomized, open-label, multi-center study evaluating the efficacy, 
safety, and tolerability of veliparib plus carboplatin and paclitaxel versus Investigator's 
choice of standard chemotherapy in subjects receiving first cytotoxic chemotherapy for 
advanced or metastatic non-squamous NSCLC who are current or former smokers.  
Subjects will be randomized in a 1:1 ratio to a maximum of 6 cycles of 
carboplatin/paclitaxel plus 120 mg BID of veliparib or a maximum of 6 cycles of 
Investigator's choice of platinum doublet chemotherapy (carboplatin/paclitaxel, 
cisplatin/pemetrexed, or carboplatin/pemetrexed).  Following completion of platinum 
doublet therapy, maintenance pemetrexed is strongly encouraged for all subjects who are 
suitable candidates.  Subject randomization will be stratified by smoking status (current 
versus former), by the Investigators' preferred platinum therapy (carboplatin/paclitaxel 
versus cisplatin/pemetrexed versus carboplatin/pemetrexed), by gender (male versus 
female) and by ECOG performance status (0 versus 1).
Subjects randomized to receive veliparib will begin oral veliparib dosing 2 days prior to 
the start of the carboplatin/paclitaxel infusion on C1D-2 and will continue twice a day 
BID through C1D5 (7 consecutive days).  Subjects randomized to receive 
carboplatin/paclitaxel/veliparib will receive carboplatin (AUC 6 mg/mL•min) and 
paclitaxel (200 mg/m2) IV infusion starting on Day 1 of each cycle.  Subjects will receive 
a maximum of 6 cycles of treatment, unless toxicity requires cessation of therapy, or 
radiographic progression occurs prior to completing 6 cycles.  Carboplatin/paclitaxel plus 
veliparib may be delayed or dose-modified due to toxicity.  Should a subject not receive 
carboplatin and paclitaxel on Day 1 of any cycle, the cycle will be restarted with veliparib 
at the newly designated Day –2 when the subject is able to do so.
Subjects randomized to receive Investigator's choice of platinum doublet therapy will 
receive therapy on Day 1 of each cycle.  Subjects will receive a maximum of 6 cycles of 
treatment, unless toxicity requires cessation of therapy, or radiographic progression occurs 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
31
prior to completing 6 cycles.  Platinum doublet therapy may be delayed or dose-modified 
due to toxicity.  Dose delays and modification will be at the discretion of the Investigator 
per local standard practice.
Suitable subjects in either arm will receive pemetrexed maintenance therapy after 
completion of platinum doublet chemotherapy regimen.  Maintenance pemetrexed will be 
administered on Day 1 of each 21-day cycle.  Maintenance therapy may be delayed or 
dose-modified due to toxicity.  Subjects will continue to receive maintenance therapy until 
toxicity requires cessation of therapy, or radiographic progression occurs.
Subjects will have physician visits q3 weeks while receiving platinum doublet and 
maintenance therapy.  After cessation of therapy, physician visits and quality of life 
measures will be performed q9 weeks until one year after randomization (or beyond 
1 year until maintenance therapy is discontinued), then q12 weeks until radiographic 
progression or death.  Tumor assessments will be performed at baseline, prior to treatment 
on Cycle 3 Day 1 and Cycle 5 Day 1.  After cessation of platinum doublet therapy, tumor 
assessments will be performed q9 weeks until 1 year after C1D-2 (or beyond 1 year until 
maintenance therapy is discontinued), then q12 weeks until radiographic progression or 
death.  Radiographic information will be collected to determine response according to the 
Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1.38  Toxicities will be 
graded at each study visit according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0.36
The visit at which an investigator identifies disease progression or at which a subject 
meets other criteria for study discontinuation will be considered the Final Visit.
All subjects who have a Final Visit ≤30 days after the last dose of study drug will have a 
Follow-Up Visit approximately 30 days after the last dose of study drug.  If a subject is 
discontinued from the study with an ongoing adverse event or an unresolved clinically 
significant laboratory result, the site will attempt to provide follow-up until a satisfactory 
clinical resolution of the laboratory results or adverse event is achieved.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
32
Subjects no longer undergoing clinical assessments will have survival information 
reported via the eCRF at two month intervals (or as requested by sponsor to support data 
analysis) beginning at the last clinical assessment and continuing until the endpoint of 
death, the subject has become lost to follow-up, or AbbVie terminates the study.  In 
addition, all post treatment therapy, if applicable and available, will be collected in the 
survival follow-up period.  
Figure 1.
Study Schedule Schematic


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
33
Table 1.
Treatment Schema for Each Cycle (Maximum of 6 Cycles)
Days
–2
–1
1
2
3
4
5
6 – 19
veliparib
Twice 
a day
Twice 
a day
Twice 
a day
Twice 
a day
Twice 
a day
Twice 
a day
Twice 
a day
paclitaxel
Once
carboplatin
Once
Investigator's choice of Standard 
Doublet Chemotherapy
Once
5.2
Selection of Study Population
The study population will consist of adult subjects who are current or former smokers 
with cytologically or histologically confirmed locally advanced or metastatic 
non-squamous NSCLC that is not amenable to surgical resection or radiation with 
curative intent, and who have not received prior cytotoxic chemotherapy or 
chemoradiotherapy for their NSCLC.  Chemotherapy or chemoradiotherapy received 
previously for adjuvant or neoadjuvant treatment will be allowed if last treatment was 
greater than 12 months prior to C1D-2.  Subjects must meet all inclusion criteria and none 
of the exclusion criteria within 28 days of randomization.  Subjects should be assessed for 
eligibility based on the most recent data collected prior to randomization.
5.2.1
Inclusion Criteria
1.
Subject must be ≥ 18 years of age.
2.
Life expectancy > 12 weeks (as per Investigator's clinical assessment).
3.
Subject must have cytologically or histologically confirmed advanced or metastatic 
non-squamous NSCLC.  Subjects with mixed histology tumors will be eligible if 
the tumor is predominant non-squamous histology and does not include tumor with 
small cell histology.  Subjects must have a pathologist's report confirming 
non-squamous NSCLC available for collection by the sponsor.  Subjects with 
EGFR mutation (exon 19 deletion or L858R mutation in exon 21) and/or ALK 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
34
gene rearrangement must have progressed after first line monotherapy treatment 
with targeted therapy.
4.
Subject must have NSCLC that is not amenable to surgical resection or radiation 
with curative intent at time of study Screening.
5.
Subjects must be current smokers (defined as having > 100 smoking events lifetime 
and having smoked within the past year) or former smokers (defined as having 
> 100 smoking events lifetime and having not smoked within the past year).
6.
Subject must have at least 1 unidimensional measurable NSCLC lesion on a 
CT scan as defined by RECIST (version 1.1).
7.
Subject must consent to provide archived tissue or cytology sample of NSCLC 
lesion (primary or metastatic) for analysis if available.
8.
Subject must have no history of brain metastases or evidence of CNS tumors at 
screening assessment.  Subjects with signs or symptoms of CNS involvement will 
undergo MRI (or CT scan if MRI is contraindicated) to confirm absence of CNS 
metastases.
9.
Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance 
Score of 0 – 1.
10.
Subjects with fluid retention, including ascites or pleural effusion, may be allowed 
at the discretion of the Investigator.
11.
Subject must have adequate bone marrow, renal and hepatic function as follows:
●
Bone Marrow:  Absolute neutrophil count (ANC) ≥ 1,500/mm3 (1.5 × 109/L); 
Platelets ≥ 100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.0 g/dL; 
●
Renal function:  Serum calculated creatinine clearance > 50 mL/min according 
to the Cockcroft-Gault formula; confirmation of creatinine clearance/GFR may 
be done by a local direct measurement method (e.g., 24 hour urine collection 
or radioisotope) at the investigator's discretion;


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
35
●
Hepatic function:  AST and ALT ≤ 2.5 × ULN unless liver metastases are 
present, then AST and ALT < 5.0 × ULN; bilirubin ≤ 1.5 × ULN unless 
Gilbert's Syndrome is present, then bilirubin ≥ 1.5 × ULN.
12.
Female subjects of childbearing potential (i.e., those who are not postmenopausal 
for at least 1 year or surgically sterile by bilateral tubal ligation, bilateral 
oophorectomy or hysterectomy) and their male partners should practice at least one 
of the methods of birth control listed below during study and for at least 6 months 
after treatment with paclitaxel chemotherapy.  Male subjects and their female 
partners of childbearing potential should practice at least one of the methods of 
birth control listed below during study and for at least 6 months after treatment 
with chemotherapy.
●
total abstinence from sexual intercourse (if it is the subject's preferred and 
usual lifestyle; for beginning a minimum one complete menstrual cycle prior 
to study drug administration and to extend 6 months after treatment);
●
vasectomized subject or partner(s); vasectomy (males);
●
intrauterine device (females);
●
double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal 
ring with spermicidal jellies or creams; both males and females);
●
hormonal contraceptives (oral, parenteral or transdermal) for at least 90 days 
prior to study drug administration (females).  If hormonal contraceptives are 
used, the subject and her partner should also use a single-barrier method.
13.
Subject must be 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 
the initiation of any screening or study-specific procedures.
Rationale for Inclusion Criteria
(1 – 10)  These criteria were selected to ensure the appropriate subject population with 
sufficient disease severity for evaluation.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
36
(11)  This is standard criteria to ensure general good health and safety of the subjects.
(12)  The impact of veliparib/carboplatin/paclitaxel on the unborn fetus is unknown, 
therefore, this criteria ensures that adequate precautions are taken to avoid pregnancy.
(13)  This is standard criteria in accordance with harmonized Good Clinical Practice.
5.2.2
Exclusion Criteria
1.
Subject has a known hypersensitivity to paclitaxel or to other drugs formulated 
with polyethoxylated castor oil (Cremophor).
2.
Subject has a known hypersensitivity to platinum compounds.
3.
Subjects with peripheral neuropathy ≥ grade 2.
4.
Subjects with squamous NSCLC, or those with an untreated EGFR mutation (exon 
19 deletion or L858R mutation in exon 21) and/or ALK gene rearrangement.  
Subjects' EGFR mutation and ALK gene rearrangement status must be known prior 
to study entry.
5.
A history of seizure within 12 months prior to study entry.
6.
Subject has received prior cytotoxic chemotherapy or chemoradiotherapy for 
NSCLC, except adjuvant or neoadjuvant therapy > 12 months prior to C1D-2, or 
subject has received targeted small molecule monotherapy for EGFR and/or 
ALK-positive disease ≤ 14 days prior to C1D-2 or biologic therapy ≤ 21 days prior 
to C1D-2.
7.
Subject has received anti-cancer Chinese medicine or anti-cancer herbal remedies 
within 14 days prior to C1D-2.
8.
Subject has undergone focal External Beam Radiation Therapy (EBRT) to bone 
≤2 weeks prior to C1D-2; or subject has undergone EBRT to larger fields 
(i.e., 100 cm2 to thorax) ≤ 4 weeks prior to C1D-2. 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
37
9.
Any medical condition, which in the opinion of the Investigator, places the subject 
at an unacceptably high risk for toxicities, or any subject circumstance which 
prohibits trial participation according to local law.
10.
Subject is pregnant or lactating.
11.
Subject has previously been treated with a PARP inhibitor.
12.
The subject has a history of another cancer within the past 3 years except cervical 
cancer in situ, in situ carcinoma of the bladder, squamous or basal cell carcinoma 
of the skin or another in situ cancer that is considered cured by the Investigator 
(e.g., in situ prostate cancer).
Rationale for Exclusion Criteria
(1 – 8, 11, 12)  These criteria were selected to ensure the appropriate subject population 
with sufficient disease severity for evaluation.
(9)  This is standard criteria to ensure general good health and safety of the subjects.
(10)  The impact of veliparib/carboplatin/paclitaxel on the unborn fetus is unknown, 
therefore, this criteria ensures exclusion of pregnant subjects.
5.2.3
Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) that the subject is receiving at 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.
For purposes of this protocol, anti-tumor treatment may be defined as, but is not limited 
to, anti-cancer agents (cytotoxic chemotherapy, immunotherapy, biologic and targeted 
therapy), radiotherapy and investigational agents.  An investigational agent is any drug or 
therapy not currently approved for use in humans.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
38
The AbbVie study designated physician (identified in Section 6.6.1) should be contacted 
if there are any questions regarding concomitant or prior therapies.
5.2.3.1
Prior Therapy
Subjects who have not received prior cytotoxic chemotherapy or chemoradiotherapy after 
diagnosis of non-squamous NSCLC are considered eligible for the study, except previous 
adjuvant/or neoadjuvant chemotherapy (with or without radiotherapy) for NSCLC will be 
allowed if completed greater than 12 months prior to C1D-2.  Prior targeted small 
molecule monotherapy for EGFR and/or ALK-positive disease will be allowed if received 
> 14 days prior to C1D-2 and prior biologic treatment if received > 21 days prior to 
C1D-2.
Previous focal EBRT to a metastatic lesion will be allowed if completed greater than 
2 weeks prior to C1D-2, or if greater than 4 weeks prior to C1D-2 if delivered to a larger 
field (i.e., 100 cm2).  Radiated lesions may not be considered target lesions.
5.2.3.2
Concomitant Therapy for Carboplatin/Paclitaxel
The locally approved product label or applicable Summary of Product Characteristics 
(SmPC) for carboplatin/paclitaxel and pemetrexed should be referenced for any 
concomitant therapy guidelines.
Premedication:
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 SmPC (i.e., premedication with corticosteroids, 
diphenhydramine, and H2 antagonists).
Anti-cancer 
agents:
No anti-cancer agents or investigational agents may be taken 
throughout the study until after the Final Visit.  The locally 
approved carboplatin and paclitaxel product labels or SmPCs 
should be referenced to determine if there are any 
contraindications associated with concomitant medications 
(e.g., yellow fever vaccine, phenytoin, etc.).  Hormonal 
contraceptives, hormonal replacement therapy, etc. are allowed.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
39
Supportive care:
Best supportive care and treatment will be given as appropriate 
to each subject (antiemetics, antibiotics, transfusions, nutritional 
support, palliative treatment for pain, etc.) according to 
institutional guidelines, NCCN guidelines or ASCO guidelines.  
For anti-emetic therapy, ASCO guidelines recommend a 
two drug combination of palonosetron and dexamethasone.  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
Aprepitant is not recommended, though clinicians may consider 
its use.  If clinicians opt to use aprepitant, dosing guidelines are 
as follows:
Aprepitant:  125 mg Day 1, 80 mg Days 2 and 3
5-HT3 receptor antagonist dosing
Dexamethasone:  12 mg on Day 1 only35
The use of bisphosphonates or denosumab for bone metastases is 
permitted, but it is strongly encouraged that first time 
administration of a bisphosphonate or denosumab should be 
delayed until after cycle 1 so as to not introduce both the 
veliparib and bisphosphonate/denosumab together for the 
first time.  
Growth factors:
Biologic response modifiers administered for erythropoiesis 
(e.g., erythropoietin, darbepoetin alpha) may be administered 
during dosing of veliparib and carboplatin/paclitaxel.  
Granulocyte growth factors (e.g., G CSF, GM-CSF, etc.) are to 
be administered according to the Investigator's standard practice 
and/or ASCO guidelines.  After C1D1, growth factors may be 
given with the intent to prevent dose reductions or delays after 
C1D1.
Radiation:
Radiation therapy is not allowed during the study, except for 
palliative radiation to a non-target lesion.  Sites to be radiated 
should be assessed for radiographic progression, prior to 
beginning radiotherapy.  If the subject requires radiotherapy 
during the study, the AbbVie medical monitor must be 
contacted.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
40
Surgery:
If the subject requires surgery during the study, the AbbVie 
medical monitor must be contacted.
Alternate therapy:
No herbal remedies or non-prescription anti-cancer supplements 
may be taken for cancer treatment concurrently with veliparib (a 
14-day washout period from C1D-2 must be documented).
Therapies to take 
caution with when 
administered with 
paclitaxel or 
carboplatin
Carboplatin:  Ototoxic and nephrotoxic drugs such as
aminoglycosides, vancomycin, capreomycin and diuretics, may 
increase or exacerbate toxicity due to carboplatin induced 
changes in renal function.
Paclitaxel:  Caution should also be taken when administering 
paclitaxel concomitantly with known substrates 
(e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, 
repaglinide, rosiglitazone, sildenafil, simvastatin, and triazolam), 
inhibitors (e.g., atazanavir, clarithromycin, erythromycin, 
fluoxetine, gemfibrozil, indinavir, itraconazole, ketoconazole,
nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), 
and inducers (e.g., rifampin, carbamazepine, phenytoin, 
phenobarbital, efavirenz, and nevirapine) of CYP3A4 or 
CYP2C8.
Recommendations per the local label should be observed.
The locally approved product label or applicable Summary of Product Characteristics 
(SmPC) for cisplatin and pemetrexed (if randomized to Investigator's choice of standard 
chemotherapy) should be referenced for any concomitant therapy guidelines.
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, 
Pharmacogenetic, and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
A schedule of study activities is presented in Table 2.  Pharmacodynamic (PD) and 
Pharmacogenetic (PG) assessments will be performed as summarized in Table 3.  
Pharmacokinetic (PK) assessments will be performed as summarized in Table 4.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
41
Table 2.
Study Activities
Activity
SCRa
Cycle 1 Day –2
Cycle 1 Day 1
Cycle 1 Day 15
Cycle 2 – 6 Day 1*
Final Visitb
30-day FU Visitc
Maintenance 
Therapyd
Post-Treatment 
Visitsp
Survival Period
Informed Consente
X
Medical and Cancer History
X
Physical Exam (including weight)
Xf
Xf
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
Performance Status (ECOG)
Xq
Xg
X
X
X
X
X
Documentation of Non-Childbearing 
Status or Pregnancy Testh
X
X
X
Chemistry/Hematologyi
X
X
X
X
X
X
X
Urinalysisi
X
X
aPTT, INRi
X
Tumor Assessments
Xj
Xj
Xk
X
Xj,k
MRI of the Brainl
X
QoL Questionnairesm
X
X
X
X
X
Adverse Event and Concomitant 
Medication Assessment
X
X
X
X
X
X
X
X
Xr
Randomizationg
Xg
Dispense veliparibn
X
X
X
Administer premedication
X
X
X
Administer platinum doublet 
chemotherapyo
X
X
Administer maintenance pemetrexed
X
Survivalr
X
SCR = Screening
*
Subjects who complete up to 6 treatment cycles or who discontinue treatment prior to reaching an event of disease 
progression are to continue visits and radiographic assessments until progression.
a.
The Screening Visit must be performed within 28 days of randomization.
b.
When an Investigator has determined that a subject should discontinue the study, a Final Visit will be conducted.
c.
A Follow-Up visit is required if the Final Visit is < 30 days from the last administration of drug.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
42
Table 2.
Study Activities (Continued)
d.
Following completion of platinum doublet therapy, maintenance pemetrexed 500 mg q3 weeks is strongly 
encouraged for all subjects who are suitable candidates.  For those subjects in maintenance therapy, tumor 
assessments will be completed q9 weeks until radiographic progression.  
e.
Must be performed prior to initiation of any screening or study-specific procedures.  Informed Consent may be 
obtained before 28 day screening window.
f.
Physical exam not required, if performed within 7 days prior to randomization.  Height is only measured at 
Screening. 
g.
May occur up to 4 calendar days before C1D-2 to facilitate dispensing and morning administration of Study Drug.
h.
Serum pregnancy test will be done at Screening.  Urine pregnancy test will be done prior to dosing at C1D-2 unless 
the serum pregnancy test was collected within 7 days of C1D-2.  Local urine pregnancy testing should also be 
performed at each subsequent Cycle Day 1 visit.  The test results must be reviewed and determined to be negative 
prior to dosing.  A positive urine pregnancy test will be confirmed with a serum pregnancy test.  Pregnancy tests 
may also be repeated per the discretion of the Investigator at any time during the study.
i.
Study samples for central laboratory analysis may be performed within 72 hours of the scheduled day.  A qualified 
(e.g., certification or accreditation) local laboratory may be used to perform laboratory analyses for treatment 
decisions but this cannot replace the central laboratory analysis on a protocol defined visit.
j.
Baseline tumor assessments must be conducted within 28 days (inclusive) of randomization.  Post-baseline tumor 
assessment will be conducted within 7 days prior to chemotherapy on C3D1 and C5D1, every 9 weeks ± 7 days 
from the last scan after treatment discontinuation until 1 year on study (or beyond 1 year until maintenance therapy 
is discontinued), and then every 12 weeks ± 7 days.  If desired, tumor assessments during protocol therapy may be 
coordinated to occur on treatment initiation Days C3D1 and C5D1.
k.
An unscheduled tumor assessment should be performed if the subject discontinues from the study for a reason 
other than radiographic progression, and no scan has been performed within the last 4 weeks.
l.
Baseline MRI of the brain only for subjects with suspected metastases due to neurologic signs or symptoms.  A CT 
scan may be performed if an MRI is contraindicated.
m.
Questionnaires for the assessment of quality of life will be collected prior to dosing on C1D-2, C3D1, C5D1 and at 
the Final Visit, every 9 weeks until 1 year after beginning therapy (C1D-2) ± 7 days (or beyond 1 year until 
maintenance therapy is discontinued), then every 12 weeks ± 7 days and at the Final Visit.
n.
Sufficient medication will be dispensed to cover the entire cycle.  The site is advised to contact the subject on the 
morning of Day –2 to reiterate the dosing instructions of pre--chemotherapy-veliparib.  It is recommended the site 
contact the subject on Day 5 to instruct about ceasing dosing.
o.
Carboplatin and paclitaxel are to be given only after veliparib dosing on cycle Day –2 and Day –1 are confirmed.
p.
Following treatment discontinuation, subjects will have post-treatment visits q9 weeks until one year after 
randomization, then q12 weeks until radiographic progression or death.
q.
Screening ECOG may be used to stratify during a randomization call if randomization is performed prior to C1D-2.
r.
All systemic post treatment anti-cancer therapy, if applicable and available, will be collected in the survival follow-
up period.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
43
Table 3.
Schedule of Pharmacogenetic and Pharmacodynamic Assessments
Activity
Visit 
Schedule
Before Drug 
Administration
Sampling Plan
Specimen Matrix
Optional with Consent 
PG Blood Sampling*
Genetic (DNA)
C1D-2
Independent of 
dose
Whole Blood
Frozen (as per the study specific 
laboratory manual)
PD Blood Sampling
Plasma Markersa
C1D-2, C3D1
Pre-dose
Blood →Plasma
Frozen (as per the study specific 
laboratory manual)
Final Visit
At the time of the 
clinic visit
Serum Markers
C1D-2, C3D1
Pre-dose
Blood →Serum
Frozen (as per the study specific 
laboratory manual)
Final Visit
At the time of the 
clinic visit
Tissue Sample 
Collection
Screening or 
C1D-2
Archived FFPE tissue blocks (as per 
the study specific laboratory manual)
*
(Optional) only to be collected after additional informed consent is obtained.  If sample is not collected at C1D-2, it 
may be collected at any time throughout the study.
a.
At C1D-2 and the Final Visit, 12 mL of blood for plasma markers will be collected.  At C3D1, it will be 6 mL of 
blood.
Table 4.
Schedule of Pharmacokinetic Assessments
Procedure
Visit 
Schedule
Before Drug 
Administration
After 
Veliparib 
AM Dose
Sampling Plan
Specimen Matrix
Veliparib PK Sampling
C1D-2
--
1, 2, 3 h
Blood →Plasma
Frozen (as per the study 
specific laboratory manual)
Veliparib PK Samplinga
C2D1, 
C3D1, 
C4D1.
0 ha
--
Blood →Plasma
Frozen (as per the study 
specific laboratory manual)
a.
Before the administration of the morning dose of veliparib.
5.3.1.1
Study Procedures
The study procedures outlined in Table 2 are discussed in detail in this section, with the 
exception of the monitoring of treatment compliance and adverse event information 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
44
(discussed in Section 5.5.6).  All study data will be recorded on eCRFs with supporting 
source documentation.
Screening procedures will occur within 28 days prior to randomization.  Radiographic 
assessments will occur within 28 days prior to randomization.  For procedures performed 
at Screening and repeated prior to dosing on C1D-2, the later procedure performed prior 
to dosing will serve as baseline for clinical assessment.  Subsequent study procedures 
should be performed within 4 days surrounding the scheduled study visit date during the 
post treatment phase a 7 day allowance is permitted.  Clinical laboratory tests can be 
performed up to 72 hours prior to dosing.
Informed Consent
Signed informed consent will be obtained from the subject before any study procedures 
are undertaken or before any prohibited medications are withheld from the subject in 
order to participate in this study.  A separate optional informed consent will be required 
for pharmacogenetic testing.  Details about how informed consent will be obtained and
documented are provided in Section 9.3.
Subjects will be considered screen failures if the informed consent has been signed and a 
study-specific procedure has been performed (e.g., central laboratories drawn), but subject 
does not randomize into the study.  The reason for screen failure will be documented in 
the source and will be captured in the eCRF.
Medical History
The medical history includes complete medical history, including documentation of any 
clinically significant medical condition; history of tobacco and alcohol use; presence and 
severity of any symptoms/conditions associated with NSCLC; and detailed NSCLC 
oncology history (histology, TNM staging, date of diagnosis, tumor burden, metastatic 
sites, and prior treatment).


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
45
On C1D-2 any changes observed from the screening assessments, prior to dosing, will be 
recorded in the subject's medical history.  At each subsequent visit, the subject's medical 
history will be reviewed and any clinically significant changes from baseline will be 
recorded in the source documents and on the adverse event eCRF.
Physical Examination
A physical examination, including body weight, will be performed per Table 2.  If the 
Screening physical examination is performed within 7 days of randomization, it is not 
required to repeat the exam on C1D-2 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 Screening Visit only.  For height and weight assessments, 
the subject should not wear shoes.
Physical exam will include neurological (sensory, motor, cranial nerves), head and neck, 
lymphatic, cardiac, pulmonary, hepatobiliary, gastrointestinal, genitourinary, and skin 
evaluation per local standard of care and in line with local label requirements.
Vital Signs
Vital signs will be performed per 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.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed per Table 2.  A qualified physician will 
determine whether any findings outside of normal physiological variation are clinically 
significant (in consultation with a cardiologist if necessary).  The physician will document
whether findings are clinically significant (CS) or not clinically significant (NCS) on the 
tracing and sign and date the tracing.  The original annotated ECG tracing along with a 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
46
photocopy of the tracing containing the physician's assessment will be retained in the 
subject's records at the study site.
ECOG Performance Status
The ECOG performance status will be assessed per Table 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.
Documentation of Non-Childbearing Status or Pregnancy Test
For each female subject, the Investigator will document non-childbearing status 
(surgically sterile or post-menopausal for at least 1 year) or potential childbearing status.  
Subjects with non-childbearing status do not require pregnancy tests.  For subjects of 
childbearing potential, a serum pregnancy test will be performed at Screening and the 
results must be available prior to the administration of the first dose of study drug on 
C1D-2.  A urine pregnancy test should also be performed prior to dosing on C1D-2 if 
> 7 days since obtaining Screening serum test results.  Local urine pregnancy testing 
should also be performed at each subsequent Cycle Day 1 visit.  The test results must be 
reviewed and determined to be negative prior to dosing.  A positive urine pregnancy test 
will be confirmed with a serum pregnancy test.  Pregnancy tests may also be repeated per 
the discretion of the Investigator at any time during the study.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
47
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).
Clinical Laboratory Tests
Samples for chemistry, hematology and urinalysis will be collected per Table 2.  Specific 
laboratory assessments are outlined in Table 5.
All laboratory samples will be assessed using a certified central laboratory and these data 
will be used for all data analysis.  The central laboratory will provide instructions 
regarding the collection, processing and shipping of samples.  All laboratory samples will 
be shipped to the central laboratory.  A qualified (e.g., certification or accreditation) local 
laboratory may be used to perform laboratory analyses for treatment decisions as per 
standard of care.  Qualified medical staff at the site will review, initial and date all local 
and central laboratory results.  Any laboratory value outside the reference range that is 
considered clinically significant by the Investigator will be followed as appropriate.  
Clinically significant laboratory values will be recorded as adverse events if they meet the 
criteria as specified in Section 6.1.1.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
48
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
Calcium
Inorganic phosphorus
Uric acid
Total protein
Glucose
Albumin
Lactate dehydrogenase (LDH)
Magnesium
Chloride
Bicarbonate
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Serum Pregnancy Test
Human Chorionic 
Gonadotropin (hCG)***
Coagulation
Activated Partial 
Thromboplastin Time (aPTT)*
International Normalized Ratio
(INR)*
*
Collected at Screening only.
**
A renal function assessment will be done on all subjects at screening to assess eligibility.
*** At Screening and at any time point in which pregnancy is suspected or following a positive urine pregnancy test.
Tumor Assessments (Radiologic)
A CT scan of the full chest and abdomen (with image of liver and adrenal glands) will be 
used in the evaluation of tumor responses, as per Table 2 (the estimated amount of 
radiation per CT scan would be 1700 mrem [17mSv] {700mrem [7mSv] for chest + 
1000 mrem [10mSv] for abdomen and pelvis} as per 
http://www.ans.org/pi/resources/dosechart/).  If the subject is unable to undergo a CT scan 
with IV contrast due to allergy or renal insufficiency, a non-contrast CT may be 
performed.  Magnetic resonance imaging (MRI) can be conducted in cases where local 
laws/requirements mandate, but should have Sponsor approval prior to performing the 
MRI.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
49
A baseline MRI (or CT if MRI is contraindicated) of the brain is to be performed on any 
subject with signs or symptoms suggesting CNS involvement by tumor.
Tumor assessment is to be performed at the Final Visit for subjects who discontinue the 
study for reasons other than radiographic progression and if no assessment has been 
performed within the last 4 weeks.  An unscheduled assessment should be obtained in 
such subjects if a Final Visit will not be conducted.  Subjects are to continue monitoring 
by the same methods unless evidence of tumor metastasis warrants otherwise or a medical 
contraindication is noted.
Randomization and Subject Number Assignment
An Interactive Response Technology system (IRT) will be utilized to register subjects.
Subjects who complete all Screening procedures and meet the eligibility criteria will 
proceed to randomization.  The site will access the system within 4 calendar days prior to 
or on the subject's C1D-2 visit and a unique randomization number will be provided.  A 
bottle number randomization schedule and a subject randomization schedule will be 
generated by the Clinical Statistics Department at AbbVie prior to the start of the study.  
A copy of all randomization schedules will be kept by the Clinical Statistics Department 
at AbbVie and a copy will be forwarded to the IRT vendor.
Dispensing Study Drug
Randomized subjects will receive sufficient quantities of veliparib for Cycle 1 Days –2 
and –1.  Beginning with C1D1, subjects will receive veliparib for Days 1 – 5 of the 
current cycle and a separate bottle for Days –2, –1 of the following cycle.  This dispensing 
schedule will allow subjects to begin veliparib dosing prior to Cycle 2 through Cycle 6 
carboplatin and paclitaxel administration without requiring a return to the investigative 
site on Day –2.  The IRT will assign every bottle of study drug to be dispensed to a 
subject.  Prior to each scheduled drug dispensation visit (per Table 2), site personnel must 
contact IRT for the next bottle number assignment.  Study medication cannot be 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
50
dispensed without contacting the IRT.  AbbVie or designee will provide specific 
instructions on the use of IRT.
Trained site personnel will administer the carboplatin/paclitaxel intravenously on Day 1 of 
each 21-day cycle.  Subjects will be supervised at the time of the infusion.
Quality of Life Assessment
Advanced lung cancer, is often symptomatic; thus the goals of treatment include 
maintenance of function and palliation of symptoms.  Symptom management requires 
validated systematic symptom assessment by subjects.  To assess the subject's 
health-related quality of life and symptoms, two questionnaires will be administered:  the 
NCCN-Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 
(NFLSI-17) questionnaire and the European Quality of Life-5 Dimensions (EQ-5D-5L).  
To minimize response bias, the questionnaires will be administered before drug 
administration and before subjects are informed of their tumor assessment.  Subjects in 
both arms must complete this questionnaire on paper forms, which is then entered into 
EDC by the Investigator or designee.  The Investigator or a designee will need to check 
the form returned by the subject for completeness before the subject leaves the clinic.
The NFLSI-17 is a validated scale developed as a brief version of the longer validated 
FACT-L questionnaire to overcome concerns about subject burden, interruption of clinic 
flow, and interpretability associated with longer questionnaires.  The NFLSI-17 is a 
validated scale which has 17 items broken into the following:  a 10-item disease-related 
symptoms-physical subscale (DRS-P), and a 3-item treatment side effect subscale, plus 
4 additional items of importance to subjects regarding emotional health and quality of life.  
The NFLSI-17 was developed and validated along the steps that are consistent with the 
PRO guidance from the FDA, based on additional input from both advanced lung cancer 
subjects and clinical experts.
The EuroQol 5 Dimensions 5 Level (EQ-5D-5L) is a generic preference instrument that 
has been validated in numerous populations.  The EQ-5D-5L is composed of 5 questions 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
51
that can be converted into a utility score for use in an economic evaluation to adjust 
life- years gained by the subject's health-related quality of life.  The EQ-5D-5L also 
contains a visual analog scale (VAS) to assess the subject's overall health.
Survival Information
Subjects no longer undergoing clinical assessments will have survival information 
reported at 2-month intervals (or as requested by sponsor to support data analysis) 
beginning at the last clinical assessment and continuing until the endpoint of death, the 
subject has become lost to follow-up, or AbbVie terminates the study.  If the subject 
withdraws from study follow-up, the study staff may use a public information source 
(such as county records) to obtain information about survival status only, as appropriate 
per local regulations.  Post-study anti-cancer therapy information (including type of agent, 
initiation date, end date, and clinical response), if known, will also be collected in the 
survival follow-up period.
5.3.1.2
Blood Samples for Pharmacogenetic Analysis (Optional)
One 4 mL whole blood sample for DNA isolation will be collected on C1D-2 from each 
subject who consents to provide a sample for pharmacogenetic analysis.  The procedure 
for obtaining and documenting informed consent is discussed in Section 9.3.  If the 
sample is not collected on C1D-2, it may be collected at any time throughout the study.
Samples will be shipped frozen to AbbVie or a designated laboratory for DNA extraction 
and long-term storage.  Instructions for the preparation and shipment of pharmacogenetic 
samples will be provided in the lab manual.
AbbVie will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.  The samples will be retained while research on ABT-888 (or 
drugs of this class) continues but no longer than 20 years.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
52
5.3.1.3
Collection and Handling of Pharmacodynamic Variables
Pharmacodynamic correlative studies are exploratory in nature.  Serum, plasma and tissue 
specimens may be utilized to evaluate known and novel markers (nucleic acids, 
peptides/proteins and/or metabolites) of disease status.  PD variables will be further 
discussed in Section 5.3.7.
Blood Collection for Plasma Markers
Approximately 12 mL (Baseline and Final Visit) or 6 mL (all other timepoints) of blood 
will be collected pre-dose by venipuncture at timepoints outlined in Table 3 in 
conjunction with PK samples, if possible.  The collection, processing and storage should 
be performed as described in the study specific laboratory manual.  The complete process 
of centrifugation, transfer to cryovial and freezing should be accomplished in less than 
1 hour from the time of blood draw.
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 90 minutes from the time of blood draw.
Tissue Collection
Subjects must consent to provide available archival tumor (biopsy preferred, or cytology) 
for analysis.  It is recognized that samples suitable for analysis will not be available from 
all consenting subjects.  Tissue biopsies (10 – 15 slides with quality controls) or cytology 
slides (if no tissue specimen was obtained) may be provided to AbbVie as detailed in the 
study specific laboratory manual.  Study-specific biopsies are not required for subject 
participation.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
53
Shipment of Pharmacodynamic Samples
All pharmacodynamics samples should be labeled and shipped as outlined in the study 
specific laboratory manual.  Also, pathology reports showing histologic confirmation of 
NSCLC should be labeled and shipped as outlined in the study specific laboratory manual.  
An inventory of the samples being shipped will accompany the package.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Pharmacokinetic 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 timepoints as 
specified per Table 4.  The date/time of collection of each blood sample will be recorded.  
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing and shipment.
5.3.2.2
Measurement Methods
Plasma concentrations of veliparib will be determined using validated methods under the 
supervision of 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 overall survival (OS) in LSP+ subgroup.  The secondary 
efficacy endpoints are:  progression free survival (PFS) in LSP+ subgroup, objective 
response rate (ORR) in LSP+ subgroup, OS in all subjects, PFS in all subjects, and ORR 
in all subjects.  The tertiary efficacy endpoints are duration of response, ECOG 
performance status and Quality of Life (QoL) in LSP+ subgroup and in all subjects.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
54
5.3.4
Safety Variables
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 NCI CTCAE version 4.0.
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 including apparent oral clearance (CL/F) and 
volume of distribution (V/F).  Additional parameters may be calculated if useful in the 
interpretation of the data.
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
Pharmacogenetic Variables
DNA samples may be sequenced and data analyzed for genetic factors contributing to the 
disease or to the subject's response to veliparib, other study treatment, in terms of 
pharmacokinetics, efficacy, tolerability, and safety.  Such genetic factors may include 
genes for drug metabolizing enzymes, drug transport proteins, genes within the target 
pathway, other genes believed to be related to the disease or to drug response.  Some 
genes currently insufficiently characterized or unknown may be understood to be 
important at the time of analysis.  The samples may be analyzed as part of a multi-study 
assessment of genetic factors involved in the response to veliparib, drugs of this class, or 
the disease state.  The samples may also be used for the development of diagnostic tests 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
55
related to veliparib, drugs of this class, or the disease state.  The results of 
pharmacogenetic analyses may not be reported with the study summary.
5.3.7
Pharmacodynamic Variables
Several putative biomarkers of efficacy and response may be evaluated in this protocol 
with the goal of exploring the relationship between tumor response and/or disease status.
Biospecimens collected may be evaluated for genetic lesions whether they occur by 
amplification, chromosomal loss and/or mutational/methylation with the intent of 
identifying potential associations with subject outcome or to better characterize the 
disease.  These characterizations may be included, but are not limited, characterization of 
gene methylation/mutational status or copy number changes of genes, particularly those 
involved in DNA repair pathways.  Additional analysis aimed at identifying underlying 
defects in the homologous recombination pathway, regardless of etiology, may be 
performed and associated with response.
Biospecimens may be evaluated for levels of biomarkers including nucleic acids, 
proteins/peptides and metabolites.  For example protein analysis of relevant proteins, 
including but not limited to, DNA repair proteins, such as ERCC1 and XPF, may be 
performed on tumor tissue obtained from each consented subject.
Samples collected during the course of this study may be used to investigate new 
scientific questions related to this study.  Additionally, the samples may be anonymized 
and used for diagnostic test development.  AbbVie (or a designated laboratory) will store 
the samples in a secure storage space with adequate measures to protect confidentiality.  
The samples will be retained while research on veliparib (or drugs of this class) continues 
for up to but no longer than 20 years.
5.4
Removal of Subjects from Therapy or Assessment
Each subject has the right to withdraw from study treatment at any time.  In addition, the 
Investigator may discontinue a subject from the study treatment at any time for any reason 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
56
if the Investigator considers it necessary, including the occurrence of an adverse event or 
noncompliance with the protocol.  Each subject will be withdrawn from the study or study 
treatment (as applicable) per Section 5.4.1 if any of the following occur:
●
The subject has radiographic progression according to RECIST version 1.1.
●
The subject requires cancer-directed radiotherapy or surgery related to clinical 
disease progression, or alternate anti-cancer agents during the study period.  
Palliative radiation to a symptomatic bone lesion is permitted during study if 
no radiographic progression is visible on radiographic assessments.
●
The subject experiences treatment toxicity which, in the Investigator's opinion, 
prohibits further therapy or the Investigator believes it is otherwise in the best 
interest of the subject.
●
Subject is suspected to be pregnant; pregnancy is confirmed or begins 
breastfeeding during the treatment portion of the study.
●
The subject decides to withdraw consent for any reason.
●
Any other medical reason that AbbVie or the study Investigator deems 
appropriate.
Discontinued subjects will not be replaced.
5.4.1
Discontinuation of Individual Subjects
Subjects who complete therapy or who discontinue treatment prior to reaching an event of 
disease progression are to continue assessments until disease progression.  Refer to 
Section 5.3.1 for more details.
When subject discontinuation from the study (without reaching a protocol-defined 
endpoint) is planned, the Investigator is to notify the AbbVie medical monitor or the 
clinical team representative (Section 7.0) via telephone as soon as possible (provided, in 
each case, subject care and safety are not compromised).  If not notified prior to 
discontinuation, the AbbVie medical monitor may contact the site to discuss the reason 
for withdrawal from the study.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
57
The visit at which an investigator identifies disease progression or at which a subject 
meets other criteria for study discontinuation will be considered the Final Visit.  The 
reason(s) for the discontinuation from the study will be recorded and assessments will be 
performed per Table 2.  It is preferable that Final Visit procedures be conducted prior to 
the initiation of another anticancer therapy.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
Investigator feels are necessary to treat the subject's condition.
Subjects who have a Final Visit within 30 days of therapy will have one Follow-Up Visit 
approximately 30 days after the last dose of study drug.  This Follow-Up Visit does not 
need to be performed for subjects who have had a Final Visit conducted ≥ 30 days after 
last dose of study drug.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
clinically significant laboratory result, the site will attempt to provide follow-up until a 
satisfactory clinical resolution of the laboratory results or adverse event is achieved.
Subjects no longer undergoing clinical assessments will have survival information 
reported at 2-month intervals (or as requested by sponsor to support data analysis) 
beginning at the last clinical assessment and continuing until the endpoint of death, the 
subject has become lost to follow-up, or AbbVie terminates the study.
In the event that a positive result is obtained on a pregnancy test for a subject during the 
study, the administration of study drug to that subject must be discontinued immediately.  
The site must report the positive pregnancy test result by telephone within 24 hours to 
one of the AbbVie representatives listed in Section 7.0.
5.4.1.1
Discontinuation of Veliparib and Carboplatin/Paclitaxel and 
Pemetrexed
Subjects will receive veliparib, carboplatin and paclitaxel up to a maximum of 6 cycles or 
until reaching a protocol defined event of disease progression or experiencing 
unmanageable toxicity.  Dose reductions of carboplatin and paclitaxel will occur on the 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
58
basis of the toxicity observed and may result in discontinuation of either agent 
(e.g., discontinuation of paclitaxel for neurotoxicity).  The subject may continue on 
therapy with the remaining agent in combination with veliparib.  If toxicities have resulted 
in discontinuation of both carboplatin and paclitaxel, veliparib will also be discontinued.  
At the Investigator's discretion, carboplatin and/or paclitaxel administration may continue 
after veliparib has been discontinued.  Suitable subjects will receive pemetrexed 
maintenance therapy until reaching a protocol defined event of disease progression or 
experiencing unmanageable toxicity.
5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/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.
The following procedures for discontinuation will be followed:
●
If the Sponsor has decided to prematurely discontinue the study, the Sponsor 
will promptly notify in writing each Investigator as well as regulatory 
authorities of the decision and give detailed reasons for the discontinuation.
●
Each Investigator must promptly notify the IRB/IEC and give detailed reasons 
for the discontinuation.
●
Each Investigator must promptly notify the enrolled subjects of the premature 
discontinuation and administer appropriate treatments such as replacement of 
protocol therapy, if applicable, by other appropriate regimens.
If AbbVie terminates the study for safety reasons, AbbVie will immediately notify the 
Investigator by telephone and subsequently provide written instructions for study 
termination.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
59
5.5
Treatments
5.5.1
Treatments Administered
Subjects will receive the following:
●
Veliparib 120 mg BID Days –2 through 5; carboplatin AUC 6 mg/mL•min
administered on Day 1; and paclitaxel 200 mg/m2 administered on Day 1 of 
each 21-day cycle;
●
Investigator's choice of standard doublet chemotherapy (one of the following 
three options, to be administered on Day 1 of each 21-day cycle):
o
Carboplatin AUC 6 mg/mL•min + paclitaxel 200 mg/m2
o
Cisplatin 75 mg/m2 + pemetrexed 500 mg/m2
○
Carboplatin AUC 6 or AUC 5 mg/mL•min + pemetrexed 500 mg/m2
●
Maintenance therapy after completion of up to 6 cycles of either 
veliparib/carboplatin/paclitaxel or Investigator's choice of chemotherapy. 
Maintenance therapy consists of pemetrexed or no maintenance therapy 
(observational). Maintenance pemetrexed will be administered as 500 mg/m2
on Day 1 of each 21-day cycle.  Following completion of platinum doublet 
therapy, maintenance pemetrexed is strongly encouraged for all subjects who 
are suitable candidates.
5.5.1.1
Administration of Veliparib
Subjects will self-administer the morning dose of veliparib and the evening doses of 
veliparib approximately 12 hours after the morning dose with or without food in the same 
calendar day.
It is recommended that if a subject misses a scheduled dose of veliparib and less than
6 hours have passed since the scheduled dosing time, the dose should be immediately 
taken.  It is recommended that if more than 6 hours have passed since the scheduled 
dosing time, the subject should not take the missed dose but should wait for the next 
regularly scheduled dose.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
60
If the subject vomits within 15 minutes of taking veliparib, another dose is to be taken.  
The dose may only be repeated once.  If more than 15 minutes has passed from the time of 
oral dosing then no additional doses will be taken.  The subject is to contact the 
Investigator if additional veliparib is needed to complete BID dosing through Day 5 of the 
cycle.
Subjects will be provided self-administration instructions and subject dosing cards to 
record the date and time the veliparib was administered.  Subjects will be instructed to 
store veliparib according to specific directions included in Section 5.5.2.3.  Subjects 
should return bottles of veliparib (empty, partially filled or full) to the study site prior to 
each cycle and at the Final Visit.
5.5.1.2
Administration of Carboplatin/Paclitaxel with Veliparib
Carboplatin and paclitaxel will be administered intravenously on Day 1 of every 21-day 
cycle.  Carboplatin and paclitaxel are to be given only after veliparib dosing on cycle 
Day –2 and Day –1 are confirmed.  If veliparib was not taken by the subject on Day –2 
and Day –1, a new supply of veliparib is to be dispensed, and Day –2 and Day –1 are to 
be repeated for that cycle.  Paclitaxel will be infused prior to carboplatin.  Investigators 
should evaluate subjects for carboplatin and paclitaxel treatment per the locally approved 
product label, local practice, or applicable SmPC.  Paclitaxel will be administered 
intravenously over 3 hours at a dose of 200 mg/m2.  Carboplatin will be administered 
intravenously over approximately 15 to 30 minutes at (AUC 6 mg/mL•min) immediately 
following paclitaxel infusion.
Calculation of Carboplatin Dose
Per the FDA Guidelines, the maximum dose of carboplatin (this dose should not be 
exceeded) may be calculated using the following formulas:37
Total carboplatin dose (mg) = target AUC × (GFR + 25) [Calvert formula]
Maximum carboplatin Dose (mg) = target AUC (mg/mL•min) × (150 mL/min)


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
61
●
For a target AUC = 6, the maximum dose is 6 × 150 = 900 mg
●
For a target AUC = 5, the maximum dose is 5 × 150 = 750 mg*
●
For a target AUC = 4, the maximum dose is 4 × 150 = 600 mg*
*
Only for subjects who have had dose modifications.
5.5.2
Identity of Investigational Product
Information regarding the veliparib formulation to be used in this study is presented in 
Table 6.
Table 6.
Identity of Investigational Product
Study Drug
Dosage 
Form
Strength
Route of 
Administration
Manufacturer
Veliparib (ABT-888)
Capsule
40 mg active
Oral
AbbVie
Carboplatin*
Vials**
150 mg and/or 450 mg
Intravenous (IV)
various***
Paclitaxel*
Vials**
100 mg
Intravenous (IV)
various***
*
Carboplatin and paclitaxel will be supplied as investigational medicinal products in required countries for the 
veliparib treatment arm only.
**
Carboplatin and paclitaxel dosage forms could vary based on the supplier as a powder for solution for injection, a 
concentrate for solution for infusion, or a solution for infusion/injection.
*** Carboplatin and paclitaxel will be sourced from approved marketed products from various commercial 
manufacturers depending on availability.
5.5.2.1
Medicinal Products for Combination Treatment 
The non-investigational medicinal products available for use within the Investigator's 
choice of standard chemotherapy treatment arm are listed in Table 7.  Unless directed 
otherwise by AbbVie, sites are responsible for obtaining the non-investigational products 
listed below as needed to conduct this study at their site.  For operational or logistical 
purposes, AbbVie may supply non-investigational products depending on need.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
62
Table 7.
Non-Investigational Medicinal Products (Investigator's Choice 
Treatment Arm)
Study Treatment
Dosage Form
Route of Administration
Carboplatin 
(commercially available)*
Vial**
Intravenous (IV)
Paclitaxel
(commercially available)*
Vial**
Intravenous (IV)
Cisplatin 
(commercially available)*
Vial**
Intravenous (IV)
Pemetrexed 
(commercially available)*
Vial**
Intravenous (IV)
*
Carboplatin, paclitaxel, cisplatin and pemetrexed formulations may vary based on regional source.  Carboplatin, 
paclitaxel, cisplatin and pemetrexed supplied by AbbVie will be sourced from approved marketed products from 
various commercial manufacturers depending on availability.
**
Carboplatin, paclitaxel, cisplatin, pemetrexed dosage forms could vary based on the supplier as a powder for 
solution for injection, a concentrate for solution for infusion, or a solution for infusion/injection.
5.5.2.2
Packaging and Labeling
Veliparib will be packaged in bottles containing 15 or 33 of the 40 mg strength capsules.  
This will allow for the 2 or 5 days of administration with one additional dose to cover 
loss, spillage or replacement due to vomiting within 15 minutes.  Each bottle label will 
include all information as required by local regulations and must remain affixed to the 
bottle.  All blank spaces on the label will be completed by site staff prior to dispensing to 
the subject.
Carboplatin, paclitaxel, cisplatin and pemetrexed supplied by AbbVie will be provided in 
commercial primary packaging with a study label affixed to the primary container and/or 
secondary packaging.
Instructions for the handling of study supplies to the study site are available in the 
veliparib IB, study Dosing Cards and from participants at the Site Initiation Visit.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
63
5.5.2.3
Storage and Disposition of Study Drug
Veliparib
Table 8.
Study Drug Storage Conditions
Study Drug
Country
Storage Conditions
Veliparib 
All countries, except 
Australia/New Zealand/Japan
Store at 15° to 25°C (59° to 77°F)
Veliparib
Australia/New Zealand
Store below 25°C
Veliparib
Japan
Store at 15° to 30°C
All clinical supplies must be stored in a secure place until they are dispensed for subject 
use, are destroyed at the site or are returned to AbbVie.
Investigational products are for investigational use only, and are to be used only within 
the context of this study.  The clinical supplies for this study must be maintained under 
adequate security and stored under conditions specified on the label.
Storage and Disposition of Carboplatin, Paclitaxel, Cisplatin and Pemetrexed
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.
Pemetrexed
Vials must be stored between 15° to 25°C (59° to 77°F) (or per locally approved label or 
SmPC).
Cisplatin
Vials must be stored between 15° to 25°C (59° to 77°F) and protected from light or as 
directed per locally approved label or SmPC).


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
64
Carboplatin
Vials must be stored between 15° to 25°C (59° to 77°F) and protected from light or as 
directed per locally approved label or SmPC.
5.5.3
Preparation of Intravenous Solutions
All chemotherapy agents administered as part of this protocol should be prepared for 
administration by clinicians experienced in the preparation and handling of parenteral 
cancer chemotherapeutic agents.  For complete product information, site personnel should 
consult their locally approved commercial product labeling or current Summary of 
Product Characteristics (SmPC) if applicable.
1. Carboplatin 
Carboplatin is commercially available as both premixed aqueous solutions and 
lyophilized powders containing 50 mg, 150 mg, or 450 mg of carboplatin per vial.  All 
forms of carboplatin are intended for administration by intravenous infusion after 
further dilution in a suitable parenteral solution such as 5% Dextrose in Water (D5W) 
or 0.9% Sodium Chloride Injection.  
2. Paclitaxel
Paclitaxel is commercially available as a nonaqueous solution containing 30 mg, 
100 mg or 300 mg paclitaxel per vial.  All forms of paclitaxel are intended for 
administration by intravenous infusion after further dilution in a suitable parenteral 
solution such as 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection.  
3. Cisplatin
Cisplatin is commercially available as both premixed aqueous solutions and 
lyophilized powders containing 50 mg, 100 mg, or 200 mg cisplatin per vial.  
Cisplatin is intended for administration by slow intravenous infusion after further 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
65
dilution in a suitable parenteral solution such as 5% Dextrose in Water (D5W) or 
0.9% Sodium Chloride Injection.  
4. Pemetrexed
Pemetrexed (ALIMTA) is commercially supplied as a white to either light yellow or 
green-yellow lyophilized powder in a vial containing 100 mg or 500 mg pemetrexed.  
Both forms of pemetrexed are intended for administration by intravenous infusion 
after further dilution in a suitable parenteral solution such as 5% Dextrose in Water 
(D5W) or 0.9% Sodium Chloride Injection.  
5.5.4
Method of Assigning Subjects to Treatment Groups
All subjects in the study will be randomized using an IRT system.  Before the study is 
initiated, directions for the IRT will be provided to each site.  The site will contact the IRT 
system to obtain a Screening (subject) number once the subject has signed the informed 
consent and a study-specific procedure has been performed (i.e., central 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 on or prior to (within 
4 calendar days) the subject's C1D-2 and a unique randomization number will be 
provided.
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.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
66
5.5.5
Selection and Timing of Dose for Each Subject
All subjects randomized to the experimental arm will receive 120 mg of veliparib orally 
for BID dosing for 7 of 21 days in each treatment cycle (maximum 6 cycles) as described 
above.  No other doses or schedules of veliparib are being investigated in this study.
5.5.6
Treatment Compliance
The Investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol. The study drug must not be used for reasons other than that described in the 
protocol.  Veliparib should be taken as directed by the Investigator.  Carboplatin, 
paclitaxel, cisplatin and pemetrexed will be administered intravenously by trained site 
personnel.
Subjects will be instructed to return all veliparib bottles (empty, partially filled or full) to 
the study site personnel prior to each cycle, their first post-treatment visit and/or at the 
Final Visit.  The site staff will document the bottles returned and the number of capsules 
per bottle on the appropriate form.
Unless otherwise directed by the Investigator, a subject will be considered compliant with 
study drug, veliparib, 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, paclitaxel, cisplatin and pemetrexed given to 
each subject in the source documents and on the eCRF.  If the Investigator will obtain 
carboplatin, paclitaxel, cisplatin and pemetrexed commercially, site inventory and 
accountability of carboplatin, paclitaxel, cisplatin and pemetrexed will not be performed, 
and drug accountability forms will not be provided.  If the investigative site has received 
carboplatin, paclitaxel, cisplatin and pemetrexed centrally sourced by AbbVie, site 
inventory and accountability of these drugs will be performed in the IRT system and drug 
accountability forms will be provided. 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
67
Upon receipt of a shipment of veliparib and if applicable carboplatin, paclitaxel, cisplatin 
and pemetrexed, the representative at each site will; 1) open and inspect the shipment; 
2) verify that the veliparib 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 Proof of Receipt (POR) or similar 
document or via direct recording in the IRT.
An overall accountability of the study drug supplied by AbbVie 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 and if applicable carboplatin, paclitaxel, cisplatin 
and pemetrexed will be maintained utilizing the IRT drug accountability module and, if 
required, according to your institutional policy and will include the lot number, POR 
number(s), the bottle/kit numbers, and the date study drug was dispensed for each subject.
Upon completion or termination of the study, all original bottles/cartons containing 
unused veliparib and if applicable carboplatin, paclitaxel, cisplatin and pemetrexed 
(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/cartons 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
Phase 1 data and preliminary Phase 2 data described in Section 3.4.2 and Section 3.4.3
suggest the addition of veliparib to carboplatin and paclitaxel may improve outcome of 
non-squamous NSCLC subjects who are current or former smokers.  This randomized, 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
68
open-label study will evaluate the effect of veliparib added to carboplatin and paclitaxel 
for treatment of advanced or metastatic non-squamous NSCLC in subjects who are 
current or former smokers.
ESMO4 and National Comprehensive Cancer Network (NCCN) guidelines3 recommend 
first-line cytotoxic chemotherapy treatment for metastatic non-small cell lung cancer with 
a platinum doublet combination.  Commonly used platinum doublets for advanced 
NSCLC are cisplatin-gemcitabine, cisplatin-paclitaxel, cisplatin-docetaxel, 
carboplatin-paclitaxel, and cisplatin-pemetrexed (non-squamous NSCLC only).  Several 
randomized controlled studies have failed to show a clear superiority of 
one platinum-containing combination over another for squamous NSCLC.  Furthermore, 
Phase 3 randomized trials showed that continuing pemetrexed as a single agent after the 
completion of platinum doublet therapy increased PFS and OS for subjects with 
non-squamous NSCLC [http://www.ncbi.nlm.nih.gov/pubmed/23835707].  Thus, 
platinum doublet chemotherapy followed by pemetrexed maintenance therapy is a suitable 
treatment for the control subjects in this study.
5.6.2
Appropriateness of Measurements
Standard pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized 
in this study.
The efficacy measurements in this study are standard and validated.  Overall survival is a 
widely accepted endpoint of clinical importance for the evaluation of subjects with 
previously untreated advanced or metastatic NSCLC.  Multiple prior studies have led to 
changes in standard practice after demonstrating a survival advantage in such subjects.30-34  
The secondary endpoints of progression-free survival and overall response rate may add 
supporting evidence to a finding of improved overall survival with veliparib combination 
therapy.  Additionally, RECIST 1.1 is a validated guideline for the measurement of 
responses in subjects with advanced or metastatic solid tumors.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
69
5.6.3
Suitability of Subject Population
Subjects who are either current or former smokers with pathologically documented and 
previously untreated advanced or metastatic non-squamous NSCLC will be selected to 
participate in this study.  The proposed inclusion and exclusion criteria are anticipated to 
result in a study subjects population representative of advanced or metastatic 
non-squamous NSCLC subjects who are current or former smokers and who receive 
cytotoxic therapy according to current practice guidelines.3,4  The poor prognosis of 
subjects with advanced or metastatic NSCLC suggests that potential late adverse events, 
such as the theoretical risk of secondary malignancies due to inhibition of DNA repair by 
PARP inhibitors, are unlikely to be encountered in this study.  Of note, the risk of 
secondary malignancies after veliparib combined with carboplatin and paclitaxel will be 
assessed in a large randomized study of subjects with early breast cancer.
5.6.4
Selection of Doses in the Study
The doses of standard therapy (carboplatin, paclitaxel, cisplatin, pemetrexed) are 
guideline-recommended for advanced NSCLC.3,4  Doses of standard therapy (carboplatin 
and paclitaxel) and the dose of investigational agent (veliparib) in this study are identical 
to those used in a randomized, double-blind placebo-controlled Phase 2 study of 
carboplatin and paclitaxel ± veliparib for advanced NSCLC.  As described in Section 3.0, 
preliminary data from this study show the combination is well-tolerated, showed delivery 
of carboplatin and paclitaxel were not substantially compromised, and showed an 
improvement in overall survival of 8.0 months in current smokers with non-squamous 
NSCLC.
The maximum dose of veliparib for any subject in this study is 120 mg BID for 7 of 
21 days per cycle.
5.7
Dose Reductions or Delays
All dose modifications (including dose delay, reduction, resumption, and discontinuation) 
are to be performed at the discretion of the Investigator.  Guidelines suggesting dose 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
70
modifications based on prior studies with veliparib, carboplatin, and paclitaxel appear in 
Table 9 and Appendix G.  Study drug interruptions for events that are clearly not related 
to the study drug treatment, (e.g., underlying cancer, planned surgical procedures or acute 
viral illnesses), should not necessitate a dose reduction.  The AbbVie medical monitor is 
to be contacted for subjects who require more than a 2-week delay in the re-initiation of 
the next cycle.
All dose reductions are considered permanent.  Re-escalation of chemotherapy treatments 
or veliparib doses is not allowed.
If a subject experiences an adverse event that results in a delay in starting chemotherapy 
or requires that study regimen is delayed or interrupted during a cycle, Day 1 of a 
treatment cycle may follow the prior cycle Day 1 by greater than 21 days.  In this case, 
study activities should be aligned with newly designated cycle Day 1 as per Section 5.3.1.  
For modification of agents that are not administered with veliparib (i.e., Investigator's 
choice platinum doublet chemotherapy, maintenance pemetrexed), the Investigator should 
follow procedures as defined in the locally approved product label or applicable Summary 
of Product Characteristics (SmPC).
Table 9.
Suggested Guidelines for Veliparib + Carboplatin/Paclitaxel 
Independent Dose Reductions
Dose Level
carboplatin
paclitaxel
veliparib
Starting Dose Level
AUC 6
200 mg/m2
120 mg BID
Dose Level –1
AUC 5
175 mg/m2
80 mg BID
Dose Level –2
AUC 4
150 mg/m2
40 mg BID
5.7.1
Veliparib Dose Reductions and Delays
The following are guidelines for dose reduction, delay and discontinuation of veliparib:
1.
Veliparib is to be discontinued if both carboplatin and paclitaxel are discontinued.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
71
2.
For any subject who experiences grade 3/4 toxicity which is not attributable to 
carboplatin/paclitaxel or the underlying disease, the veliparib dose is to be held 
until the toxicity resolves to grade 1 or lower or to baseline if grade 2 is present at 
the time of study entry.  Upon resuming veliparib treatment, the dose is to be 
reduced one dose level.  Any dose reduction beyond 40 mg BID is to result in 
veliparib discontinuation.
3.
If a subject begins veliparib on Cycle Day –2 but subsequently experiences an 
event requiring delay of the carboplatin/paclitaxel dosing on Day 1, the subject is 
to stop veliparib dosing immediately.  Upon resolution of the event, the subject 
may restart the current cycle by repeating Day –2 and Day –1.  For such delays, a 
new veliparib supply will be dispensed to restart the cycle at Day –2.
4.
For any ≥ grade 2 event of seizure attributed to veliparib, veliparib is to be 
discontinued and the event should be discussed with the AbbVie medical monitor.
5.7.2
Carboplatin/Paclitaxel Dose Reductions and Delays
For carboplatin and/or paclitaxel dose modifications, the Investigator should follow 
procedures as defined in the locally approved product label or applicable Summary of 
Product Characteristics (SmPC).  Suggested dose reductions for carboplatin/paclitaxel if 
above information is not available are summarized in Appendix G.  If the Investigator 
considers an event attributable to carboplatin and/or paclitaxel, the Investigator may 
consider reducing the dose of both agents.
All toxicities are to be resolved to grade 1 or less prior to initiation of a new cycle of 
therapy, with the exception of anemia, alopecia, neuropathy, and non-treatment related 
clinically insignificant laboratory abnormalities.
If chemotherapy must be withheld due to hematologic toxicity, CBC and platelet counts 
should be obtained weekly until the counts reach the lower limits for treatment as 
outlined.  The treatment schedule will then proceed in the usual sequence.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
72
Carboplatin and paclitaxel are to be delayed if veliparib was not taken by the subject on 
Day –2 and Day –1.  In such a case, a new supply of veliparib is to be dispensed, and 
Day –2 and Day –1 are to be repeated for that cycle.
5.7.2.1
Suggested Guidelines for Carboplatin and Paclitaxel Dose 
Reductions and Delays
Hematologic Toxicity
For absolute neutrophil count (ANC) < 1,500/mm3 or platelet count < 100,000/mm3 on 
Day 1 of each cycle, treatment is to be delayed until recovery of ANC and platelet count 
above these values.  For febrile neutropenia or for grade 4 thrombocytopenia, carboplatin 
and paclitaxel doses are to be reduced by one dose level.
If the subject experiences fever with neutropenia, then neutrophil growth factors are to be 
given based on local standard of care guidelines or ASCO guidelines.
Non-Hematological Toxicity
Gastrointestinal Toxicity
For grade 3 or 4 nausea/vomiting despite maximal anti-emetic therapy or for grade 3 or 4 
stomatitis, the dose of carboplatin and paclitaxel are to be reduced by 1 dose level.  
Nausea, vomiting, and stomatitis are to have resolved to grade 1 before initiation of a new 
cycle of therapy.
If the stomatitis has not resolved to grade 1 or less within 3 weeks, the subject's study 
treatment is to be discontinued.
Hepatic Toxicity
For bilirubin > 1.5 × ULN with increased ALT above ULN that is attributed to protocol 
therapy, paclitaxel is to be held until bilirubin is ≤ 1.5 × ULN, and the dose is to be 
reduced by one level when treatment is resumed.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
73
For ALT > 5 × ULN with bilirubin < 1.5 × ULN that is attributed to protocol therapy, 
paclitaxel dose is to be reduced by one level.
Neurologic Toxicity
For grade 2 neuropathy, paclitaxel dose is to be reduced to Dose Level –1.  For grade 3/4 
neuropathy, paclitaxel dose is to be held until neuropathy is grade 2, and the dose is to be 
reduced to Dose Level –2 when treatment is resumed.  The dose of carboplatin will not be
reduced for neurologic toxicity.
6.0
Adverse Events
The Investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study.  The Investigator will assess and record 
any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken.  For serious adverse events 
considered as having "no reasonable possibility" of being associated with study drug, the 
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 Events
An adverse event (AE) is defined as any untoward medical occurrence in a subject 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), 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
74
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, 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.
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.
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.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
75
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.
6.2
Adverse Events Expected Due to NSCLC or Progression of 
NSCLC
Adverse events that may be expected from primary NSCLC lesions, compression of 
adjacent thoracic structures or distant metastases are presented in Appendix F of the 
protocol.
These adverse events may occur alone or in various combinations and are considered 
expected adverse events in NSCLC subjects.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
76
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.
For adverse events not captured by the NCI CTCAE version 4.0, the Investigator will use 
the following definitions to rate the severity of each adverse event:
Mild (Grade 1)
The adverse event is transient and easily tolerated by the 
subject.
Moderate (Grade 2)
The adverse event causes the subject discomfort and 
interrupts the subject's usual activities.
Severe (Grade 3 or 4)
The adverse event causes considerable interference with the 
subject's usual activities and may be incapacitating or 
life-threatening.
Death (Grade 5)
Death.
If a reported adverse event increases in severity, the initial adverse event should be given 
an outcome date and a new adverse event should be reported to reflect the change in 
severity.
For all reported serious adverse events that increase in severity, the supplemental CRFs 
also need to be updated and need to include the new AE serial number.
6.3.1
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol 
specified adverse event reporting period (Section 6.6.1) that are more likely related to 
disease progression will therefore be an expected adverse event and will not be an 
expedited report.
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 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
77
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.
6.3.2
Lack of Efficacy or Worsening of Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease are also considered an expected outcome for this study and will be 
captured as adverse events, but will not be subject to expedited reporting unless locally 
required.
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 drug (for the purpose of this section, study drug is considered 
veliparib, carboplatin, paclitaxel, cisplatin or pemetrexed):
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, to cisplatin, to pemetrexed, and to NSCLC.  Most events will be 
reasonably related to one treatment or to the underlying NSCLC, though some events may 
be reasonably related to more than one or to none.  For causality assessments, events 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
78
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 
veliparib will be considered "not associated."  In addition, when the Investigator has not 
reported a causality or deemed it not assessable, AbbVie will consider the event 
associated.
If an Investigator's opinion of no reasonable possibility of being related to study drug or 
NSCLC 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 adverse events will be collected from the signing of the study specific 
informed consent until 30 days following discontinuation of study drug administration 
have elapsed.  All adverse events (regardless of whether they are protocol-related) will be 
collected from the time of study drug administration until 30 days following 
discontinuation of study drug administration have elapsed.  Adverse events are to be 
collected whether solicited or spontaneously reported by the subject.
Adverse event information will be collected as shown in Figure 2.
Figure 2.
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
*
Only if considered by the Investigator to be causally related to study-required procedures.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
79
6.6
Adverse Event Reporting 
6.6.1
Reporting Serious Adverse Events
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify the Clinical Pharmacovigilance within 24 hours of the site being 
made aware of the serious adverse event by entering the serious adverse event data into 
the electronic data capture (EDC) system.  Serious adverse events that occur when the 
EDC system is not operable should be faxed or emailed to the Clinical Pharmacovigilance 
within 24 hours of being made aware of the serious adverse event.
Serious adverse events which are considered expected due to the underlying disease of 
NSCLC as described in Section 6.2 or Appendix F would not be expedited as individual 
safety case reports to regulatory authorities unless locally required.
FAX to:  
Email to:
For safety related concerns, contact the Oncology Safety Management Team at:
Oncology Group Safety Management
AbbVie
1 North Waukegan Road, IL  60064
Office:
Fax:
Email:
Or the physician through the operator at:
Phone:  




Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
81
Male subjects should be informed that contraceptive measures should be taken by their 
female partners.  If the subject's partner should become pregnant during the study, this 
should also be reported and data may be collected.  In the event of pregnancy occurring in 
the partner of an enrolled subject, written informed consent for release of medical 
information from the partner must be obtained prior to the collection of any 
pregnancy-specific information and the pregnancy will be followed to outcome.
Pregnancy in a study subject or female partner is not considered an adverse event.  
However, the medical outcome of an elective or spontaneous abortion, stillbirth or 
congenital anomaly is considered a serious adverse event and must be reported to AbbVie 
within 24 hours of the site becoming aware of the event.
6.8
Toxicity Management
Management of toxicity should be performed by Investigators according to standard 
medical practice and according to local label for toxicity due to chemotherapy treatment.  
See Section 5.7 for dose delay and modification guidelines to adjust study treatment 
medication for any observed toxicity.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol.  The 
principal Investigator is responsible for complying with all protocol requirements, and 
applicable global and local laws regarding protocol deviations.  If a protocol deviation 
occurs (or is identified) after a subject has been enrolled, the principal Investigator is 
responsible for notifying Independent Ethics Committee (IEC)/Independent Review 
Board (IRB) regulatory authorities (as applicable), and the following AbbVie Clinical 
Monitor(s):




Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
83
otherwise stated, baseline for a given variable will be defined as the last value for that 
variable obtained prior to the first dose of study drug.
8.1.1.2
Medical History
Frequencies and percentages will be computed for each medical history parameter.
8.1.2
Efficacy Endpoints
8.1.2.1
Primary Efficacy Endpoint
The primary efficacy analysis will be a comparison of OS distributions between the 
120 mg of veliparib BID + carboplatin/paclitaxel and Investigators' choice of platinum 
therapy groups in LSP + subgroup.
Time to death for a given subject will be defined as the number of days from the date that 
the subject was randomized to the date of the subject's death.  All events of death will be 
included, regardless of whether the event occurred while the subjects was still taking
study drug, or after the subject discontinued study drug.  If a subject has not died, then the 
data will be censored at the date when the subject was last known to be alive.
8.1.2.2
Secondary Efficacy Endpoints
Fixed sequence testing procedure will be used for analyses of the primary and secondary 
efficacy endpoints to control for the family-wise error rate (FWER).  If veliparib 
treatment group is not statistically significantly better than the Investigator's choice of 
platinum therapy group for the primary efficacy endpoint of OS in LSP + subgroup, then 
statistical significance will not be declared for any of the secondary efficacy endpoints, 
regardless of the observed P values.
P values for the secondary efficacy analyses will be subject to multiple comparison 
adjustments using the fixed sequence test method, with the analyses performed in the 
following order:  progression-free survival (PFS) in LSP+ subgroup, objective response 
rate (ORR) in LSP+ subgroup, OS in all subjects, PFS in all subjects, ORR in all subjects.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
84
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 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 
assessments, then this subject's data will be censored at the last disease progression 
assessment prior to the missing disease assessments.  All events of death will be included 
for subjects who had not experienced disease progression provided the death occurred 
within 18 weeks of the last tumor assessment.  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.
ORR is defined as the proportion of subjects with complete or partial response using 
measurements according to RECIST (version 1.1).  For the measurement of ORR, only 
confirmed responses will be considered.
8.1.2.3
Tertiary Efficacy Endpoints
In addition to the primary and secondary efficacy analyses, the tertiary objectives are to 
compare DOR, ECOG performance status and Quality of Life (QoL) via the 
NCCN-Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 
(NFLSI-17) questionnaire and the European Quality of Life-5 Dimensions (EQ-5D-5L) in 
LSP+ subjects and in the entire study population between the two treatment groups.
The duration of overall response for a given subject will be defined as the number of days 
from the day the criteria are met for CR or PR (whichever is recorded first) to the date that 
PD is objectively documented or subject's death.  If a subject is still responding then the 
subject's data will be censored at date of the last available disease progression assessment.  
For subjects who never experienced CR or PR, the subject's data will not be included in 
the DOR analysis.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
85
8.1.3
Timing of Efficacy Analyses and Safety Evaluations
When LSP status is determined by the Qiagen assay for all submitted tissue samples, there 
will be a final review of the eCRF data.  When the data collection is completed and 
reviewed for completeness and all data management quality assurance (QA) and quality 
control (QC) procedures are performed, the clinical database data will be extracted for 
documentation and statistical analyses of the efficacy and safety data.  The exact data 
cutoff date for the analyses of primary and secondary efficacy endpoints will be specified 
in the statistical analysis plan (SAP) prior to database lock.
8.1.4
Primary Analysis of Efficacy
For the LSP+ subgroup, the distribution of OS will be estimated for each treatment group 
using Kaplan-Meier methodology and compared between the two treatment groups (HR 
and 95%CI) using Cox proportional hazard model with treatment group, important 
prognostic factors (e.g., ECOG, Investigator's choice of platinum therapy, and smoking 
status) as the covariates.
8.1.5
Secondary Analysis of Efficacy
8.1.5.1
Progression Free Survival in LSP + Subgroup
For the LSP+ subgroup, the distribution of PFS will be estimated for each treatment group 
using Kaplan-Meier methodology and compared between the two treatment groups (HR 
and 95% CI) using Cox proportional hazard model with treatment group, important 
prognostic factors (e.g., ECOG, Investigator's choice of platinum therapy and smoking 
status) as covariates.
8.1.5.2
Objective Response Rate in LSP+ Subgroup
For the LSP+ subgroup, the ORR (proportion of subjects with a complete or partial 
response based on RECIST (version 1.1) will be estimated and compared between the 
two treatment groups using Fisher's exact test.  In addition, 95% confidence interval will 
be constructed for the estimated proportion.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
86
8.1.5.3
Overall Survival in All Subjects
For all subjects, the distribution of OS will be estimated for each treatment group using 
Kaplan-Meier methodology and compared between the two treatment groups (HR and 
95% CI) using the Cox Proportional hazard model with treatment group, important 
prognostic factors (e.g., ECOG, smoking history (current versus former smokers), and 
Investigator's choice of  platinum therapy) as the covariates.
8.1.5.4
Progression Free Survival in All Subjects
For all subjects, the distribution of PFS will be estimated for each treatment group using 
Kaplan-Meier methodology and compared between the two treatment groups (HR and 
95%CI) using Cox proportional hazard model with treatment group, important prognostic 
factors (e.g., ECOG, and Investigator's choice of platinum therapy, smoking status) as the 
covariates. 
8.1.5.5
Objective Response Rate in All Subjects
For all subjects, the ORR will be estimated and compared between the two treatment 
groups using Cochran-Mantel-Haenszel (CMH) test; stratified by ECOG, smoking history 
(current versus former smokers), and Investigator's preferred platinum therapy.  In 
addition, 95% confidence interval will be constructed for the estimated proportion.
8.1.6
Tertiary Analyses of Efficacy
8.1.6.1
Duration of Overall Response
The distribution of duration of overall response (DOR) will be estimated for each 
treatment group using Kaplan-Meier methodology for LSP+ as well as for all subjects.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
87
8.1.6.2
General Quality of Life
European Quality of Life-5 Dimensions (EQ-5D-5L)
Descriptive statistics will be calculated for individual 5 items and the utility score, and the 
EQ-5D-5L VAS score including mean change from baseline to each scheduled 
post-baseline visit.
EQ-5D-5L will be evaluated for subjects with a baseline assessment and at least 
one post-baseline EQ-5D-5L assessment that generate a score.  Scores at baseline and 
change from baseline scores for each time point will be quantified using descriptive 
statistics.  The EQ-5D-5L data may be used for additional health economic analyses 
whose results may be reported separately from the Clinical Study Report.
Subject Reported Symptoms and QOL (NFLSI-17)
The objective is to compare subject reported symptoms and QOL following treatment 
with the veliparib treated arm and the comparator arm for both the LSP+ subgroup and the 
whole population using the NFLSI-17 questionnaire.  Summary statistics of the NFLSI-17 
questionnaire including the individual questions and the 4 subscales and their changes 
from baseline will be calculated at each assessment time point for both study arms.  
Appropriate multivariate repeated measures models will be used to compare changes from 
baseline between the arms.  Specific hypotheses, statistical methods and analysis plan 
details of these subject-reported outcomes will be provided in the Statistical Analysis 
Plan.  For the development of the hypotheses, the DRS-P subscale score will be the 
primary PRO variable to estimate the differences in disease-related symptoms between the 
treatment arms.
8.1.6.3
Performance Status
Changes from baseline in ECOG performance status will be summarized using descriptive 
statistics for each scheduled post-baseline visit and for LSP+ as well as all subjects.  
Subjects that do not have a baseline measurement or do not have any post-baseline 
measurements will not be included.  Changes from baseline to each scheduled post-


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
88
baseline visit in ECOG performance status will be compared between the two treatment 
groups, using an analysis of covariance (ANCOVA) model with treatment group as the 
factor and baseline value as a covariate.
8.1.7
Additional Exploratory Efficacy Analyses
In addition to the covariate-adjusted Cox PH analyses for the primary and secondary 
efficacy endpoints, the unstratified log-rank test and unstratified and unadjusted Cox 
proportional hazards model may be used for the comparison of OS and PFS between the 
two treatment groups.
For those subjects who take other chemotherapies during the study or after they withdraw 
from the study, the primary efficacy OS and secondary efficacy endpoint of PFS will be 
censored at the date of subject's initiation of other chemotherapies.  These modified 
primary and secondary efficacy endpoints will be analyzed using the same methodology 
as detailed in previous sections.
For OS and PFS, additional analyses may also be performed, such as 1) including only 
data and events occurring on treatment or within 30 days of the last dose of study drug, 
2) using a Cox proportional hazard model to explore the effect of baseline factors 
including (but not limited to) the following:  LSP subgroup, LSP status unknown, tumor 
stage (locally advanced versus metastatic), smoking history (current smoker versus former 
smoker), gender, ECOG performance status (0 versus 1), Investigator's preferred platinum 
doublet therapy, and others, 3) subgroup analysis by LSP subgroup, LSP status unknown, 
smoking history (current smoker versus former smoker), gender, ECOG performance 
status (0 versus 1), Investigator's preferred platinum doublet therapy, post-study anti-
cancer therapy (e.g., anti-PD-1, IO etc.) and others.  Alternative statistical analyses may 
be performed if deemed as necessary and helpful in understanding the drug effect.
8.1.8
Statistical Analysis of Safety
Statistical analyses of safety data described below will be performed for three study 
population separately:  LSP+ subgroup, LSP– subgroup, entire study population.  The 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
89
safety of veliparib BID + carboplatin/paclitaxel 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 will not be included in the analyses of safety.
8.1.8.1
Duration of Study Drug
A summarization of the number of days and/or cycles subjects were exposed to study drug 
will be provided.
8.1.8.2
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.  Analyses will not include 
those that have an onset greater than 30 days after the last dose of study drug.  
Treatment-emergent adverse events will be summarized by preferred terms within a 
System and Organ Class according to the most current MedDRA dictionary.  In addition, 
the percentage of subjects experiencing an adverse event at a NCI CTCAE version 4.0 
toxicity grade, and relationship to study drug will be provided.  The percentages of 
subjects experiencing an adverse event will be presented by treatment group.
8.1.8.3
Serious Adverse Events
Serious adverse events will be summarized using the same methods as Adverse Events 
described above.
8.1.8.4
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.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
90
8.1.8.5
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline will be analyzed for each scheduled post-baseline visit and for the 
final visit for blood chemistry and hematology parameters, as well as 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.  
8.1.8.6
Analyses of Laboratory Data Using NCI CTCAE
Where applicable, blood chemistry and hematology determinations will be categorized 
according to NCI CTCAE version 4.0 grades, and shifts from baseline NCI CTCAE 
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 between 
veliparib BID + carboplatin/paclitaxel and Investigators' preferred platinum therapy will 
be presented.  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.
8.2
Determination of Sample Size
Sample size calculation for the original protocol:
Assuming the true hazard ratio of overall survival (OS) for current smokers in favor of the 
veliparib 120 mg BID + carboplatin/paclitaxel treatment group is 0.64, a total of 
210 death events in the current smokers will be needed for the study to have 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
91
approximately 90% power at one-sided α level of 0.025 to detect a statistically significant 
treatment effect for the veliparib 120 mg BID + carboplatin/paclitaxel group using the 
log-rank test for OS.  A total of approximately 300 current smokers will be enrolled to 
acquire the 210 death events.
During the enrollment period for approximately 300 current smokers, it is anticipated that 
approximately 225 former smokers will enroll concurrently.  Assuming the true hazard 
ratio of OS for current plus former smokers in favor of the veliparib 120 mg BID + 
carboplatin/paclitaxel treatment group is 0.71, a total of 369 death events in current plus 
former smokers will be needed for the study to have approximately 90% power at 
one-sided α level of 0.025 to detect a statistically significant treatment effect for the 
veliparib 120 mg BID + carboplatin/paclitaxel group using the log-rank test for OS.
Sample size consideration for OS analysis in LSP+ subgroup
Based on 452 subjects having LSP tissue samples (assumed 76% LSP sample availability 
rate), the below table provides the power and number of events with different assumed 
LSP+ rate if the treatment allocation ratio is 1:1 in the LSP+ subgroup and true HR of OS 
is 0.65 in LSP+ subgroup.
Number of LSP+ Subjects 
(LSP+ rate)
Number of Events in 
LSP+
Power for OS in LSP+ Subgroup 
(one-sided alpha = 0.025)
271 (60%)
216
89%
226 (50%)
180
82%
180 (40%)
144
73%
8.3
Randomization Methods
The randomization numbers of the study will assign subjects in a 1:1 ratio to either the 
120 mg of veliparib BID + carboplatin/paclitaxel treatment group or the Investigators' 
preferred platinum therapy treatment group.  Subject randomization will be stratified by 
smoking status (current versus former), Investigators' preferred platinum therapy 
(carboplatin/paclitaxel versus cisplatin/pemetrexed versus carboplatin/pemetrexed), 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
92
ECOG (0 versus 1) and gender (male versus female).  Current smokers are defined as 
subjects having > 100 smoking events lifetime and having smoked within the past year 
while former smokers are defined as subjects having > 100 smoking events lifetime and 
having not smoked within the past year.
A set of subject randomization schedules 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.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information related to the study (e.g., advertisements used to recruit subjects) and 
any other necessary documents be reviewed by an IEC/IRB.  The IEC/IRB will review the 
ethical, scientific and medical appropriateness of the study before it is conducted.  
IEC/IRB approval of the protocol, informed consent and subject information and/or 
advertising, as relevant, will be obtained prior to the authorization of drug shipment to a 
study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The Investigator will be required to submit, 
maintain and archive study essential documents according to ICH GCP.
Any serious adverse events that meet the reporting criteria, as dictated by local 
regulations, will be reported to both responsible Ethics Committees and Regulatory 
Agencies, as required by local regulations.  During the conduct of the study, the 
Investigator should promptly provide written reports (e.g., ICH Expedited Reports, and 
any additional reports required by local regulations) to the IEC/IRB of any changes that 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
93
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.  On-site monitoring will be performed before, during and after the trial to assure 
appropriate conduct of the trial in accordance with ICH GCP.  Responsibilities of the 
clinical Investigator are specified in Appendix A.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Pharmacogenetic analysis will only be performed if the subject has voluntarily signed and 
dated a separate pharmacogenetic informed consent, approved by an IRB/IEC, after the 
nature of the testing has been explained and the subject has had an opportunity to ask 
questions.  The separate pharmacogenetic informed consent must be signed before the 
pharmacogenetic testing is performed.  If the subject does not consent to the 
pharmacogenetic testing, it will not impact the subject's participation in the study.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
94
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.
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.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
95
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (eCRFs) will comply with Title 21 CFR 
Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study-specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
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 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
96
Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
Any pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature and the results will not be suitable for clinical decision making 
or subject management.  Hence, neither the Investigator, the subject, nor the subject's 
physician (if different from the Investigator) will be informed of individual subject 
pharmacogenetic results, should analyses be performed, nor will anyone not directly 
involved in this research.  Correspondingly, genetic researchers will have no access to 
subject identifiers.  Individual results will not be reported to anyone not directly involved 
in this research other than for regulatory purposes.  Aggregate pharmacogenetic 
information from this study may be used in scientific publications or presented at medical 
conventions.  Pharmacogenetic information will be published or presented only in a way 
that does not identify any individual subject.
13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator (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 
conclusion of the study, and will forward a copy of this report to AbbVie or their 
representative.  In the study site in Japan, the Investigator will provide a final report to the 
Director of the Site following conclusion of the study.  Upon providing the report, the 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
97
Director of the Site will notify AbbVie or their representative and IEC/IRB of the 
conclusion of the study in Japan.
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 Medicines Agency (EMA) Guidance on Investigator's 
Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.  The sponsor may 
also end the study upon confirmation that the primary endpoint was statistically met.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
98
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 Randomized, Open-Label, Multicenter, Phase 3 Trial Comparing 
Veliparib Plus Carboplatin and Paclitaxel Versus Investigator's 
Choice of Standard Chemotherapy in Subjects Receiving First 
Cytotoxic Chemotherapy for Metastatic or Advanced Non-Squamous 
Non-Small Cell Lung Cancer (NSCLC) and Who Are Current or 
Former Smokers
Protocol Date:
09 May 2018
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
99
15.0
Reference List
1.
World Health Organization, International Agency for Research on Cancer.  World 
cancer report:  2008.
2.
Weir HK, Thun MJ, Hankey BF, et al.  Annual report to the nation on the status of 
cancer, 1975-2000, featuring the uses of surveillance data for cancer prevention 
and control.  J Natl Cancer Inst.  2003;95(17):1276-99.
3.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).  Non-Small 
Cell Lung Cancer, version 4.  2014.  Available from:  
http://www.nccn.org/index.asp.
4.
Peters S, Adjei AA, Gridelli C, et al.  Metastatic non-small-cell lung cancer 
(NSCLC):  ESMO Clinical Practice Guidelines for diagnosis, treatment and 
follow-up.  Ann Oncol.  2012 Oct;23 (Suppl 7):vii56-64.
5.
Schiller JH, Harrington, D, Belani CP, et al.  Comparison of Four Chemotherapy 
Regimens for Advanced Non-Small Cell Lung Cancer.  New Engl J Med.  
2002;346(2):92-8.
6.
Mayhew G, Hayes N, Perou C, et al.  Survival differences of adenocarcinoma lung 
tumors with squamous cell carcinoma or neuroendocrine profiles by gene 
expression subtyping.  Abstract #384.  Presented at the 16th World Conference on 
Lung Cancer, September 06-09, 2015; Denver, CO.
7.
Carboplatin [package insert].  Irvine, CA; Teva Parenteral Medicines, Inc., 2010.
8.
National Cancer Institute [updated 2011 May 5] Available from:  
http://www.cancer.gov/cancertopics/druginfo/carboplatin.
9.
Paclitaxel [package insert].  Bedford, OH; Ben Venue Laboratories, Inc., 2010.
10.
National Cancer Institute [updated 2010 July 2] Available from:  
http://www.cancer.gov/cancertopics/druginfo/paclitaxel.
11.
Langer CJ, Leighton JC, Comis RL, et al.  Paclitaxel and carboplatin in 
combination in the treatment of advanced non-small-cell lung cancer:  a phase II 
toxicity, response and survival analysis.  J Clin Onc.  1995;13(8):1860-70.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
100
12.
Rosell R, Gatzemeier U, Betticher DC, et al.  Phase III randomised trial comparing 
paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced 
non-small-cell lung cancer: a cooperative multinational trial.  Ann Oncol.  
2002;13(10):1539-49.
13.
Chiarugi A.  Poly (ADP-ribose) polymerase:  killer or conspirator?  The 'suicide 
hypothesis' revisited.  Trends Pharmacol Sci.  2002;23(3):122-9.
14.
Virag L, Szabo C.  The therapeutic potential of poly(ADP-Ribose) polymerase 
inhibitors.  Pharmacol Rev.  2002;54(3):375-429.
15.
Schreiber V, Amé JC, Dollé P, et al.  Poly(ADP ribose) polymerase-2 (PARP-2) is 
required for efficient base excision DNA repair in association with PARP-1 and 
XRCC1.  J Biol Chem.  2002;277(25):23028-36.
16.
Sharpless NE, DePinho RA.  Telomeres, stem cells, senescence, and cancer.  J Clin 
Invest.  2004;113(2):160-8.
17.
Curtin NJ, Wang LZ, Yiakouvaki A, et al.  Novel poly(ADP-ribose) polymerase-1 
inhibitor, AG14361, restores sensitivity to temozolomide in mismatch 
repair-deficient cells.  Clin Cancer Res.  2004;10(3):881-9.
18.
Bryant HE, Schultz N, Thomas HD, et al.  Specific killing of BRCA2-deficient 
tumours with inhibitors of poly(ADP-ribose) polymerase.  Nature.  
2005;434(7035):913-7.
19.
Farmer H, McCabe N, Lord CJ, et al.  Targeting the DNA repair defect in BRCA 
mutant cells as a therapeutic strategy.  Nature.  2005;434(7035):917-21.
20.
Govindan R, Ding L, Griffith M, et al.  Genomic landscape of non-small cell lung 
cancer in smokers and never-smokers.  Cell.  2012,150(6):1121-34.
21.
Mao L, Lee JS, Kurie JM, et al.  Clonal genetic alterations in the lungs of current 
and former smokers.  J Natl Cancer Inst.  1997;89(12):857-62.
22.
Beane J, Sebastiani P, Liu G, et al.  Reversible and permanent effects of tobacco 
smoke exposure on airway epithelial gene expression.  Genome Biol.  
2007;8(9):R201.
23.
AbbVie.  Veliparib (ABT-888) Investigator Brochure, Edition 11.  22 June 2017.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
101
24.
AbbVie.  R&D/10/098.  Effects of veliparib (ABT-888) in syngeneic and xenograft 
tumors series 1. 2010.
25.
Coleman RL, Sill M, Aghajanian CA, et al.  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 – a gynecologic oncology group study.  
SGO 2013 Annual Meeting on Women's Cancer; March 2013; Los Angeles, CA.
26.
Rugo HS, Olopade O, DiMichele A, et al.  veliparib/carboplatin plus standard 
neoadjuvant therapy for high-risk breast cancer:  First efficacy results from the 
I-SPY 2 TRIAL.  In:  Proceedings of the 2013 San Antonio Breast Cancer 
Symposium; 13 December, 2013; San Antonio, TX.  Abstract S5-02.
27.
Ramalingam S.  A phase I study of veliparib (ABT-888) in combination with 
carboplatin and paclitaxel in advanced solid malignancies.  J Clin Oncol 30, 2012 
(suppl; abstr 3049).
28.
Ramalingam SS, Blais N, Mazières J, et al.  Smoking status to predict sensitivity to 
PARP inhibitor, veliparib, in patients with advanced NSCLC.  
2015;33 (15 Suppl):8038.
29.
Non-Small Cell Lung Cancer Treatment.  National Cancer Institute.  Available 
from:  http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-
lung/healthprofessional/page11.
30.
Wozniak AJ, Crowley JJ, Balcerzak SP, et al.  Randomized trial comparing 
cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small-cell 
lung cancer:  a Southwest Oncology Group study.  J Clin Oncol.  
1998;16(7):2459-65.
31.
Sandler AB, Nemunaitis J, Denham C, et al.  Phase III trial of gemcitabine plus 
cisplatin versus cisplatin alone in patients with locally advanced or metastatic 
non-small-cell lung cancer.  J Clin Oncol.  2000;18(1):122-30.
32.
Shepherd FA, Rodrigues P, Ciuleanu T, et al.  Erlotinib in previously treated 
non-small-cell lung cancer.  N Engl J Med.  2005;353(2):123-32.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
102
33.
Sandler A, Gray R, Perry MC, et al.  Paclitaxel-carboplatin alone or with 
bevacizumab for non-small-cell lung cancer.  N Engl J Med.  
2006;355(24):2542-50. 
34.
Scagliotti GV, Parikh P, von Pawel J, et al.  Phase III study comparing cisplatin 
plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients 
with advanced-stage non-small-cell lung cancer.  J Clin Oncol.  
2008;26(21):3543-51.
35.
Basch E, Prestrud AA, Hesketh PJ, et al.  Antiemetics:  American Society of 
Clinical Oncology clinical practice guideline update.  J Clin Oncol.  
2011;29(31):4189-98.
36.
Common Terminology Criteria for Adverse Events, Version 4.0, DCTD, NCI, 
NIH, DHHS.  28 May 2009.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.p
df.  Accessed on:  29 July 2009.
37.
FDA Carboplatin Dosing Notification, 2010.  Available from:  
http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm.
38.
Eisenhauer EA, Therasse P, Bogaerts B, et al.  New response evaluation criteria in 
solid tumors:  Revised RECIST guideline (version 1.1).  Eur J Cancer.  
2009;45(2):228-47.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
103
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.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
104
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.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
105
Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Clinical Program Development
Oncology Development
Oncology Development
Statistics
Pharmacokinetics


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
106
Appendix C.
Japan Specific Information
1.0
Clinical Expense and Compensation
1.1
Expenditure of the Clinical Expense
The sponsor will pay the expenses related to this study to the investigative site in 
accordance with "Special Healthcare Expenditure."  The expenses of screening test, etc. 
will be paid based on the contract concluded with each investigative site.  To lighten the 
burden imposed on the subject with participation to the study, transportation expenses, 
etc. will be paid to the subjects via participating investigative site in accordance with the 
rules of the investigative site.
1.2
Compensation for Health Impairment and Insurance
1.
If a subject suffers some sort of health impairment due to this study, the 
investigative site will provide treatment and take other necessary measures.  
Among the expenses required for the treatment, the amount not covered by health 
insurance that the patient must pay directly will be borne by the sponsor only when 
the event is associated with the use of the study drug.
2.
When a subject suffers health impairment during this study and a dispute occurs or 
might occur between the investigative site and the subject, the investigative site 
will report it to the sponsor immediately, and resolve it.  The sponsor will 
cooperate with the investigative site in resolving the problem.
3.
When the investigative site must compensate to the subject's health impairment 
caused by this study, the compensation paid by the investigative site and the 
expenses related to any dispute will be borne in full by the sponsor, except in cases 
where the responsibility for the problem is attributed to the investigative site.  This 
shall not apply to cases where the health impairment occurred because the 
investigative site performed the study with marked deviation from the GCP or the 
protocol or because of a deliberate action or a major error by investigative site.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
107
4.
When a subject suffers health impairment during this study and liability for 
compensation arises, the sponsor will compensate in accordance with the SOP 
regarding the compensation prepared in advance.
5.
The sponsor will obtain clinical study insurance and will take other necessary 
measures to cover the claims and compensation required in such cases.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
108
Appendix D.
NFLSI-17
Below is a list of statements that other people with your illness have said are important.  
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
109
Appendix E.
EQ-5D-5L Health Questionnaire
EQ-5D-5L
Health Questionnaire
(English version for the US)
© EuroQoL Group 2009


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
110
Under each heading, please check the ONE box that best describes your health TODAY
Mobility
I have no problems walking
I have slight problems walking
I have moderate problems walking
I have severe problems walking
I am unable to walk
Self-Care
I have no problems washing or dressing myself
I have slight problems washing or dressing myself
I have moderate problems washing or dressing myself
I have severe problems washing or dressing myself
I am unable to wash or dress myself
Usual Activities (e.g., work, study, housework, family or leisure activities)
I have no problems doing my usual activities
I have slight problems doing my usual activities
I have moderate problems doing my usual activities
I have severe problems doing my usual activities
I am unable to do my usual activities
Pain/Discomfort
I have no pain or discomfort
I have slight pain or discomfort
I have moderate pain or discomfort
I have severe pain or discomfort
I have extreme pain or discomfort
Anxiety/Depression
I am not anxious or depressed
I am slightly anxious or depressed
I am moderately anxious or depressed
I am severely anxious or depressed
I am extremely anxious or depressed


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
111
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The worst health       
you can imagine
The best health     
you can imagine
YOUR HEALTH TODAY =
• We would like to know how good or bad your health is
TODAY.
• This scale is numbered from 0 to 100.
• 100 means the best health you can imagine.
0 means the worst health you can imagine.
• Mark an X on the scale to indicate how your health is
TODAY.  
• Now, please write the number you marked on the
scale in the box below.
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The worst health       
you can imagine
The best health     
you can imagine
YOUR HEALTH TODAY =
• We would like to know how good or bad your health is
TODAY.
• This scale is numbered from 0 to 100.
• 100 means the best health you can imagine.
0 means the worst health you can imagine.
• Mark an X on the scale to indicate how your health is
TODAY.  
• Now, please write the number you marked on the
scale in the box below.
The best health     
you can imagine
YOUR HEALTH TODAY =
• We would like to know how good or bad your health is
TODAY.
• This scale is numbered from 0 to 100.
• 100 means the best health you can imagine.
0 means the worst health you can imagine.
• Mark an X on the scale to indicate how your health is
TODAY.  
• Now, please write the number you marked on the
scale in the box below.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
112
Appendix F.
Adverse Events Expected Due to NSCLC or Progression of NSCLC
Preferred Term (MedDRA Version 13.1)
Pleural effusion
Malignant pleural effusion
Metastases to pleura
Dyspnoea
Cough
Non-cardiac chest pain
Haemoptysis
Oesophageal obstruction
Pneumonia
Vocal cord paralysis
Dysphonia
Dysphagia
Superior vena cava syndrome
Horner's syndrome
Metastases to bone
Metastases to lymph nodes
Metastases to liver
Metastases to spine
Metastases to the mediastinum
Metastases to pleura
Metastases to adrenals
Metastases to meninges
Metastases to central nervous system
Metastatic pain
Cancer pain
Tumour pain
Fatigue
Asthenia
Pulmonary embolism


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
113
Appendix G.
Suggested Guidelines for carboplatin/paclitaxel Dose Delay or 
Reduction
Adverse Event
Carboplatin Dose
Paclitaxel Dose
Grade 3/4 Neutropenia without 
fever
Wait until ANC ≥ 1,500/mm3.
Wait until ANC ≥ 1,500/mm3.
Grade 3/4 Febrile Neutropenia
Reduce to Dose Level –1 for 1st
episode and Dose Level –2 for 
2nd episode.  Any further 
reduction after consultation with 
AbbVie medical monitor.  
Consider Prophylactic G-CSF 
after 1st episode
Reduce to Dose Level –1 for 
1st episode and Dose Level –2 
for 2nd episode.  Any further 
reduction requires consultation 
with AbbVie medical monitor.  
Consider Prophylactic G-CSF 
after 1st episode. 
Grade 3/4 nausea, vomiting 
despite standard supportive care, 
or grade 3/4 Stomatitis 
Dose Level –1 for 1st episode 
and Dose Level –2 for 
2nd episode. Any further 
reduction after consultation with 
AbbVie medical monitor.
Dose Level –1 for 1st episode 
and Dose Level –2 for 
2nd episode.  Any further 
reduction requires consultation 
with AbbVie medical monitor.
Grade 4 Thrombocytopenia
Dose Level –1 for 1st episode 
and Dose Level –2 for 
2nd episode.  Any further 
reduction after consultation with 
AbbVie medical monitor.
Dose Level –1 for 1st episode 
and Dose Level –2 for 
2nd episode.  Any further 
reduction requires consultation 
with AbbVie medical monitor.
Bilirubin  > 1.5 × ULN with 
increased ALT above ULN
No Change
Hold until recovery, then reduce 
to Dose Level –1 for 1st episode 
and Dose Level –2 for 
2nd episode.  Any further 
reduction requires consultation 
with AbbVie medical monitor.
ALT > 5 × ULN with Bilirubin 
< 1.5 × ULN
No Change
Reduce to Dose Level –1 for 1st
episode and Dose Level –2 for 
2nd episode.  Any further 
reduction requires consultation 
with AbbVie medical monitor.
Grade 2 Neuropathy 
No Change
Reduce to Dose Level –1.
Grade 3/4 Neuropathy 
No Change
Hold until recovery to Grade 2.  
Reduce to Dose Level –2.
Any other Grade 3/4 toxicity
Discuss with AbbVie medical 
monitor
Discuss with AbbVie medical 
monitor.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
114
Appendix H.
RECIST (Version 1.1) for Tumor Response (PFS)
Response criteria will be assessed using RECIST (version 1.1).  Changes in the 
measurable lesions over the course of therapy must be evaluated using the criteria listed 
below.
Eligibility
Subjects with measurable disease at baseline can have objective tumor response evaluated 
by RECIST (version 1.1).  Measurable disease is defined by the presence of at least 
one measurable lesion.  If the measurable disease is restricted to a solitary lesion, its 
neoplastic nature should be confirmed by cytology/histology if possible.
Measurability
Measurable Lesions
Lesions accurately measured in at least one dimension with a 
minimum size of: 
●
Longest diameter ≥ 10 mm (CT scan slice thickness no 
greater than 5 mm)
●
10 mm caliper measurement by clinical exam
Non-Measurable 
Lesions
All other lesions, including small lesions (longest diameter 
< 10 mm) as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include:  leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung and 
also abdominal masses that are not confirmed and followed 
by imaging techniques.
Measurable 
Malignant Lymph 
Nodes
To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in short axis when assessed by 
CT scan (CT scan slice thickness recommended to be no 
greater than 5 mm).  At baseline and in follow-up, only the 
short axis will be measured and followed.
Non-Measurable 
Malignant Lymph 
Nodes
Pathological lymph nodes with ≥ 10 to < 15 mm short axis.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
115
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.
All measurements should be taken and recorded in metric notation, using calipers if 
clinically assessed.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and not more than 28 days before the beginning of the 
treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers.  For 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
116
the case of skin lesions, documentation by color photography including a ruler to estimate 
the size of the lesion is recommended.
Methods of Measurement
Conventional CT should be performed with cuts of 5 mm or less in slice thickness 
contiguously.  This applies to tumors of the chest and abdomen.  A scale should be 
incorporated into all radiographic measurements.  MRI can be performed if required by 
local law, but should have sponsor approval.
If prior to enrollment, it is known a subject is not able to undergo CT scans with IV 
contrast due to allergy or renal insufficiency, the decision as to whether a non-contrast CT 
or MRI should be used to evaluate the subject at baseline and follow-up should be guided 
by the tumor type under investigation and the anatomic location of the disease.  For 
subjects who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI should be made based upon discussion 
with the AbbVie medical monitor.
For accurate objective response evaluation, ultrasound (US) should not be used to 
measure tumor lesions.
The utilization of endoscopy and laparoscopy for objective tumor evaluation is not 
advised.  However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained.
Cytology and histology can be used to differentiate between partial response (PR) and 
complete response (CR) in rare cases.
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 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
117
addition should be those that lend themselves to reproducible repeated measurements.  
Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion.
Lymph nodes merit special mention since they are normal anatomical structures which 
may be visible by imaging even if not involved by tumor.  Pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a 
short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes will contribute to 
the baseline sum.  The short axis of the node is the diameter normally used by radiologists 
to judge if a node is involved by solid tumor.  Nodal size is normally reported as 
two dimensions in the plane in which the image is obtained (for CT scan this is almost 
always the axial plane).  The smaller of these measures is the short axis.  For example, an 
abdominal node which is reported as being 20 mm × 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis 
≥10 mm but < 15 mm) should be considered non-target lesions.  Nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or followed.
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD.  If lymph nodes are to be included in the sum, then as noted above, 
only the short axis is added into the sum.  The baseline sum LD will be used as reference 
by which to characterize the objective tumor response.
All other lesions (or sites of disease) including pathological lymph nodes should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements of 
these lesions are not required, but the presence (stable, increasing or decreasing) or 
absence of each should be noted throughout follow-up.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
118
Evaluation of Target Lesions
Complete Response (CR):
The disappearance of all target lesions.  Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of the LD of target lesions, taking as reference the 
smallest sum LD recorded since the treatment started (baseline or after) or the appearance 
of one or more new lesions.  In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum LD since the treatment started (baseline or after).
Assessment of Target Lesions:
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study.  This means that when 
lymph nodes are included as target lesions, the 'sum' of lesions may not be zero even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm.  For PR, SD and PD, the actual short axis measurement of the nodes is 
to be included in the sum of target lesions.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
119
All lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (< 5 mm).  
However, sometimes target lesions or lymph nodes become too small to measure.  If it is 
in the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present, but too small to 
measure, a default value of 5 mm should be assigned (as derived from the 5 mm CT slice 
thickness).  The measurement of these lesions is potentially non-reproducible; therefore 
providing this default value will prevent false responses or progression based upon 
measurement error.
Evaluation of Non-Target Lesions
Complete Response (CR):
The disappearance of all non-target lesions and normalization of tumor marker level.  All 
lymph nodes must be non-pathological in size (< 10 mm short axis).
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits.
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.
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.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
120
New Lesions
The appearance of new malignant lesions denotes disease progression.  While there are no 
specific criteria for the identification of new radiographic lesions, the findings of a new 
lesion should be unequivocal; i.e., not attributable to differences in scanning technique, 
timing of scanning, phase of contrast administration, change in imaging modality or 
finding thought to represent something other than tumor (e.g., some 'new' bone lesions 
may be simply healing or flare of pre-existing lesions).  A lesion identified on a follow-up 
study in an anatomical location that was not scanned at baseline is considered a new 
lesion and will indicate disease progression.  An example of this is the subject who has 
visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases.  The subject's brain metastases are considered evidence of progressive 
disease even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal (e.g., too small to measure), continued therapy and follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is a 
new lesion, then progression should be declared using the date of the initial scan.




Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
122
Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M14-359
Name of Study Drug:  Veliparib (ABT-888)
Phase of Development:  3
Name of Active Ingredient:  Not applicable
Date of Protocol Synopsis:  17 July 2015
Protocol Title:  
A Randomized, Open-Label, Multicenter, Phase 3 Trial Comparing Veliparib Plus Carboplatin and 
Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Subjects Receiving First Cytotoxic 
Chemotherapy for Metastatic or Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC) and 
Who Are Current or Former Smokers
Objectives:  
The primary objective of the study is to assess if treatment with veliparib plus carboplatin and paclitaxel 
results in improved survival compared to Investigator's choice of standard chemotherapy in current 
smokers with metastatic or advanced NSCLC.
The secondary objectives of the study are to assess if treatment with veliparib plus carboplatin and 
paclitaxel results in improved survival compared to Investigator's choice of standard chemotherapy in 
current plus former smokers with metastatic or advanced NSCLC; to compare progression-free survival 
(PFS) and to compare objective response rate (ORR) between the two treatment arms in current smokers 
or in current plus former smokers.
The tertiary objectives are to compare duration of overall response (DOR), ECOG performance status 
and Quality of Life (QoL) between the two treatment arms in current smokers or in current plus former 
smokers.
Investigators:  Multicenter 
Study Sites:  150
Study Population:  
Subjects receiving first cytotoxic chemotherapy for Metastatic or Advanced Non-Squamous Non-Small 
Cell Lung Cancer (NSCLC) who are current or former smokers.
Chemotherapy for adjuvant or neoadjuvant treatment of NSCLC received greater than 12 months prior to 
Cycle 1 Day –2 (C1D-2) will be allowed.
Number of Subjects to be Enrolled:  Approximately 525


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
123
Methodology:  
This is a Phase 3, randomized, open-label, multi-center study evaluating the efficacy, safety, and 
tolerability of veliparib plus carboplatin and paclitaxel versus Investigator's choice of standard 
chemotherapy in subjects receiving first cytotoxic chemotherapy for advanced or metastatic 
non-squamous NSCLC who are current or former smokers.  Subjects will be randomized in a 1:1 ratio to 
a maximum of 6 cycles of carboplatin/paclitaxel plus 120 mg BID of veliparib or a maximum of 6 cycles 
of Investigator's choice of platinum doublet chemotherapy (carboplatin/paclitaxel, cisplatin/pemetrexed, 
or carboplatin/pemetrexed), unless treatment is discontinued for toxicity or cancer progression.  
Investigators may elect to administer maintenance pemetrexed regardless of which therapy their subjects 
are randomized to receive.  Following completion of platinum doublet therapy, maintenance pemetrexed 
is strongly encouraged for all subjects who are suitable candidates.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
124
Methodology (Continued):
Subject randomization will be stratified by smoking status (current versus former), by the Investigators' 
preferred platinum doublet therapy (carboplatin/paclitaxel versus cisplatin/pemetrexed versus 
carboplatin/pemetrexed), by gender (male versus female) and by ECOG performance status (0 versus 1).
Subjects randomized to receive veliparib will begin oral veliparib dosing 2 days prior to the start of the 
carboplatin/paclitaxel infusion on C1D-2 and will continue twice a day (BID) through C1D5 
(7 consecutive days).  
Subjects randomized to receive carboplatin/paclitaxel/veliparib will receive carboplatin (AUC 
6 mg/mL•min) and paclitaxel (200 mg/m2) IV infusion starting on Day 1 of each cycle.  Subjects will 
receive a maximum of 6 cycles of treatment, unless toxicity requires cessation of therapy, or radiographic 
progression occurs prior to completing 6 cycles.  Carboplatin/paclitaxel plus veliparib may be delayed or 
dose-modified due to toxicity.  Should a subject not receive carboplatin and paclitaxel on Day 1 of any 
cycle, the cycle will be restarted with veliparib at the newly designated Day –2 when the subject is able to 
do so.
Subjects randomized to receive Investigator's choice of platinum doublet therapy will receive therapy on 
Day 1 of each cycle.  Subjects will receive a maximum of 6 cycles of treatment, unless toxicity requires 
cessation of therapy, or radiographic progression occurs prior to completing 6 cycles.  Platinum doublet 
therapy may be delayed or dose-modified due to toxicity.  Dose delays and modification will be at the 
discretion of the Investigator per local standard practice. 
Suitable subjects in either arm will receive pemetrexed maintenance therapy after completion of platinum 
doublet chemotherapy regimen.  Maintenance pemetrexed will be administered on Day 1 of each 21-day 
cycle.  Maintenance therapy may be delayed or dose-modified due to toxicity.  Subjects will continue to 
receive maintenance therapy until toxicity requires cessation of therapy, or radiographic progression 
occurs.  Veliparib will not be administered during the maintenance phase. 
Subjects will have physician visits q3 weeks while receiving platinum doublet and maintenance therapy.  
After cessation of therapy, physician visits and quality of life measures will be performed q9 weeks until 
1 year after beginning treatment (C1D-2) (or beyond 1 year until maintenance therapy is discontinued), 
then q12 weeks until radiographic progression.  Tumor assessments will be performed at baseline prior to 
treatment on Cycle 3 Day 1 and Cycle 5 Day 1.  After cessation of platinum doublet therapy, tumor 
assessments will be performed q9 weeks until 1 year after beginning treatment (C1D-2) (or beyond 1 year 
until maintenance therapy is discontinued), then q12 weeks until radiographic progression or death.  
Radiographic information will be collected to determine response according to the Response Evaluation 
Criteria In Solid Tumors (RECIST) version 1.1.  Toxicities will be graded at each study visit according to 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0.
The visit at which an investigator identifies disease progression or at which a subject meets other criteria 
for study discontinuation will be considered the Final Visit.  It is preferable that final visit procedures be 
conducted prior to the initiation of another anticancer therapy.
All subjects who have a Final visit ≤ 30 days after the last dose of Study drug will have a Follow-Up 
Visit approximately 30 days after the last dose of Study drug.  If a subject is discontinued from the study 
with an ongoing adverse event or an unresolved clinically significant laboratory result, the site will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory results or adverse 
event is achieved.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
125
Methodology (Continued):
Subjects no longer undergoing clinical assessments will have survival information reported at 2-month 
intervals (or as requested by the sponsor to support data analysis) beginning at the last clinical assessment 
and continuing until the endpoint of death, the subject has become lost to follow-up, or AbbVie 
terminates the study.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Diagnosis:  Metastatic or advanced non-squamous Non-Small Cell Lung Cancer
Main Inclusion:  
1.
Subject must be ≥ 18 years of age.
2.
Life expectancy > 12 weeks (as per Investigator's clinical assessment).
3.
Subject must have cytologically or histologically confirmed advanced or metastatic non-squamous 
NSCLC.  Subjects with mixed histology tumors will be eligible if the tumor is predominant 
non-squamous histology and does not include tumor with small cell histology.  Subjects must have a 
pathologist's report confirming non-squamous NSCLC available for collection by the sponsor.  
Subjects with EGFR mutation (exon 19 deletion or L858R mutation in exon 21) and/or ALK gene 
rearrangement must have progressed after first line monotherapy treatment with targeted therapy.
4.
Subject must have NSCLC that is not amenable to surgical resection or radiation with curative intent 
at time of study Screening.
5.
Subjects must be current smokers (defined as having > 100 smoking events lifetime and having 
smoked within the past year) or former smokers (defined as having > 100 smoking events lifetime 
and having not smoked within the past year).
6.
Subject must have at least 1 unidimensional measurable NSCLC lesion on a CT scan as defined by 
RECIST (version 1.1).
7.
Subject must consent to provide archived tissue or cytology sample of NSCLC lesion (primary or 
metastatic) for analysis if available.  
8.
Subject must have no history of brain metastases or evidence of CNS tumors at screening 
assessment. Subjects with signs or symptoms of CNS involvement will undergo MRI (or CT scan if 
MRI is contraindicated) to confirm absence of CNS metastases.
9.
Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 – 1.
10. Subjects with fluid retention, including ascites or pleural effusion, may be allowed at the discretion 
of the Investigator.
11. Subject must have adequate bone marrow, renal and hepatic function as follows:
!
Bone Marrow:  Absolute neutrophil count (ANC) ≥ 1,500/mm3 (1.5 × 109/L);
!
Platelets ≥ 100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.0 g/dL; 
!
Renal function:  serum calculated creatinine clearance > 50 mL/min according to the 
Cockroft-Gault formula; confirmation of creatinine clearance/GFR may be done by a local 
direct measurement method (e.g., 24 hour urine collection or radioisotope) at the investigator's 
discretion;
!
Hepatic function:  AST and ALT ≤ 2.5 × ULN unless liver metastases are present, then AST 
and ALT < 5.0 × ULN; bilirubin ≤ 1.5 × ULN; unless Gilbert's Syndrome is present, then 
bilirubin ≥ 1.5 × ULN.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
126
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):  
12. Female subjects of childbearing potential (i.e., those who are not postmenopausal for at least 1 year 
or surgically sterile by bilateral tubal ligation, bilateral oophorectomy or hysterectomy) and their 
male partners should practice at least one of the methods of birth control listed below during study 
and for at least 6 months after treatment with paclitaxel chemotherapy.  Male subjects and their 
female partners of childbearing potential should practice at least one of the methods of birth control 
listed below during study and for at least 6 months after treatment with chemotherapy:
!
total abstinence from sexual intercourse (if it is the subject's preferred and usual lifestyle; for 
beginning a minimum one complete menstrual cycle prior to study drug administration and to 
extend 6 months after treatment);
!
vasectomized subject or partner(s); vasectomy (males);
!
intrauterine device (females);
!
double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with 
spermicidal jellies or creams; both males and females);
!
hormonal contraceptives (oral, parenteral or transdermal) for at least 90 days prior to study drug 
administration (females).  If hormonal contraceptives are used, the subject and her partner 
should also use a single-barrier method.
13. Subject must be 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 the initiation of any screening or study-specific 
procedures.
Main Exclusion:  
1.
Subject has a known hypersensitivity to paclitaxel or to other drugs formulated with polyethoxylated 
castor oil (Cremophor).
2.
Subject has a known hypersensitivity to platinum compounds.
3.
Subjects with peripheral neuropathy ≥ grade 2.
4.
Subjects with squamous NSCLC, or those with an untreated EGFR mutation (exon 19 deletion or 
L858R mutation in exon 21) and/or ALK gene rearrangement.  Subjects' EGFR mutation and ALK 
gene rearrangement status must be known prior to study entry.  
5.
A history of seizure within 12 months prior to study entry.
6.
Subject has received prior cytotoxic chemotherapy or chemoradiotherapy for NSCLC, except 
adjuvant or neoadjuvant therapy > 12 months prior to C1D-2 or subject has received targeted small 
molecule monotherapy for EGFR and/or ALK-positive disease ≤ 14 days prior to C1D-2 or biologic 
therapy ≤ 21 days prior to C1D-2.
7.
Subject has received anti-cancer Chinese medicine or anti-cancer herbal remedies within 14 days 
prior to C1D-2.
8.
Subject has undergone focal External Beam Radiation Therapy (EBRT) to bone ≤ 2 weeks prior to 
C1D-2; or subject has undergone EBRT to larger fields (i.e., 100 cm2 to thorax) ≤ 4 weeks prior to 
C1D-2.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
127
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion (Continued):  
9.
Any medical condition, which in the opinion of the Investigator, places the subject at an 
unacceptably high risk for toxicities, or any subject circumstance which prohibits trial participation 
according to local law.
10. Subject is pregnant or lactating.
11. Subject has previously been treated with a PARP inhibitor.
12. The subject has a history of another cancer within the past 3 years except cervical cancer in situ, 
in situ carcinoma of the bladder, squamous or basal cell carcinoma of the skin or another in situ 
cancer that is considered cured by the Investigator (e.g., in situ prostate cancer).  
Investigational Products:
Veliparib (ABT-888)
Doses:
120 mg BID Days –2 through 5 of 21-day cycle
Mode of Administration:
Oral
Reference Therapy or 
Investigational products:
Carboplatin Day 1 of 21-day cycle
Dose:
AUC 6 mg/mL•min
Mode of Administration:
Intravenous
Reference Therapy or 
Investigational products:
Paclitaxel Day 1 of 21-day cycle
Dose:
200 mg/m2
Mode of Administration:
Intravenous
Reference Therapy:
Pemetrexed
Dose:
500 mg/m2
Mode of Administration:
Intravenous
Reference Therapy:
Cisplatin
Dose:
75 mg/m2
Mode of Administration:
Intravenous
Duration of Treatment:  
Subjects will receive veliparib in combination with carboplatin/paclitaxel for a maximum of 6 treatment 
cycles or Investigator's choice of chemotherapy for a maximum of 6 cycles unless toxicity requires 
cessation of therapy, or radiographic progression occurs prior to completing 6 cycles.  Following 
completion of platinum doublet therapy, maintenance pemetrexed is strongly encouraged for all subjects 
who are suitable candidates.
Criteria for Evaluation:
Overall survival (OS):  will be reported by the Investigator until radiographic progression or death.  
After the final visit, survival information will be collected at 2-month intervals (or as requested by 
sponsor to support data analysis).


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
128
Criteria for Evaluation (Continued):
Progression-free survival (PFS):  will be derived according to radiographic progression per RECIST 
version 1.1 or death.  Radiographic tumor assessments for response will be conducted by CT scanning 
prior to C3D1, prior to C5D1, every 9 weeks until 1 year after beginning treatment (or beyond 1 year 
until maintenance therapy is discontinued), and then every 12 weeks.
Objective response rate (ORR):  will be derived per RECIST version 1.1.  Radiographic tumor 
assessments for response will be conducted by CT scanning prior to C3D1, prior to C5D1, every 9 weeks 
until 1 year after beginning treatment (or beyond 1 year until maintenance therapy is discontinued), and 
then every 12 weeks.
Duration of overall response (DOR):  will be derived according to radiographic progression per 
RECIST version 1.1.  Radiographic tumor assessments for response will be conducted by CT scanning 
prior to C3D1, prior to C5D1, every 9 weeks until 1 year after beginning treatment (or beyond 1 year 
until maintenance therapy is discontinued), and then every 12 weeks.
ECOG performance status:  will be determined by the Investigator at each assessment.  
Quality of Life (QoL):  will be assessed at baseline prior to veliparib dosing on C1D-2, C3D1, C5D1 
and at the Final Visit, every 9 weeks until 1 year after beginning treatment (or beyond 1 year until 
maintenance therapy is discontinued), then every 12 weeks and at the Final Visit until radiographic 
progression via the NCCN-Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 
(NFLSI-17) questionnaire and the European Quality of Life-5 Dimensions (EQ-5D-5L) questionnaires.
Safety:
Adverse events, laboratory profiles, physical examinations and vital signs will be assessed throughout the 
study.
Pharmacokinetic/Pharmacogenetics:
Blood samples for pharmacokinetics of veliparib will be collected at designated timepoints throughout 
the study.
Pharmacodynamic:
Research to find biomarkers that may serve as surrogates for clinical endpoints in future veliparib studies 
or that may be predictive of veliparib activity will be conducted.  Serum, plasma, blood and tissue 
samples will be collected at designated time points throughout the study.
Statistical Methods:
For all statistical analyses, statistical significance will be determined by a two-sided P value ≤ 0.05.  The 
date of randomization (enrollment) is defined as the date that the IRT issues a randomization number.
Sample Size:
Assuming the true hazard ratio of overall survival (OS) for current smokers in favor of the veliparib 
120 mg BID + carboplatin/paclitaxel treatment group is 0.64, a total of 210 death events among current 
smokers will be needed for the study to have approximately 90% power at one-sided α level of 0.025 to 
detect a statistically significant treatment effect for the veliparib 120 mg BID + carboplatin/paclitaxel 
group using the log rank test for OS.  A total of approximately 300 current smokers will be enrolled to 
obtain the 210 death events.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
129
Statistical Methods (Continued):
Sample Size (Continued):
During the enrollment period for the approximate 300 current smokers, it is anticipated that 
approximately 225 former smokers will enroll concurrently.  Assuming the true hazard ratio of overall 
survival (OS) for all subjects (including current plus former smokers) in favor of the veliparib 120 mg 
BID + carboplatin/paclitaxel treatment group is 0.71, a total of 369 death events in all subjects will be 
needed for the study to have approximately 90% power at one-sided α level of 0.025 to detect a 
statistically significant treatment effect for the veliparib 120 mg BID + carboplatin/paclitaxel group using 
the log rank test for OS.  


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
130
Has been changed to read:
AbbVie Inc.
Protocol Number:  M14-359
Name of Study Drug:  Veliparib (ABT-888)
Phase of Development:  3
Name of Active Ingredient:  Not applicable
Date of Protocol Synopsis:  09 May 2018
Protocol Title:  
A Randomized, Open-Label, Multicenter, Phase 3 Trial Comparing Veliparib Plus Carboplatin and 
Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Subjects Receiving First Cytotoxic 
Chemotherapy for Metastatic or Advanced Non-Squamous Non-Small Cell Lung Cancer (NSCLC) and 
Who Are Current or Former Smokers
Objectives:  
The primary objective of the study is to assess if treatment with veliparib plus carboplatin and paclitaxel 
results in improved survival compared to Investigator's choice of standard chemotherapy in Lung 
Subtype Panel (LSP) positive subjects with metastatic or advanced NSCLC.
The secondary objectives of the study are to assess if treatment with veliparib plus carboplatin and 
paclitaxel results in improved survival compared to Investigator's choice of standard chemotherapy in the 
entire study population; to compare progression-free survival (PFS) and to compare objective response 
rate (ORR) between the two treatment arms in LSP positive subjects or in entire study population.
The tertiary objectives are to compare duration of overall response (DOR), ECOG performance status 
and Quality of Life (QoL) between the two treatment arms in LSP positive subjects or in the entire study 
population.
Investigators:  Multicenter 
Study Sites:  150
Study Population:  
Subjects receiving first cytotoxic chemotherapy for Metastatic or Advanced Non-Squamous Non-Small 
Cell Lung Cancer (NSCLC) who are current or former smokers.
Chemotherapy for adjuvant or neoadjuvant treatment of NSCLC received greater than 12 months prior to 
Cycle 1 Day –2 (C1D-2) will be allowed.
Number of Subjects to be Enrolled:  595


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
131
Methodology:  
This is a Phase 3, randomized, open-label, multi-center study evaluating the efficacy, safety, and 
tolerability of veliparib plus carboplatin and paclitaxel versus Investigator's choice of standard 
chemotherapy in subjects receiving first cytotoxic chemotherapy for advanced or metastatic 
non-squamous NSCLC who are current or former smokers.  Subjects will be randomized in a 1:1 ratio to 
a maximum of 6 cycles of carboplatin/paclitaxel plus 120 mg BID of veliparib or a maximum of 6 cycles 
of Investigator's choice of platinum doublet chemotherapy (carboplatin/paclitaxel, cisplatin/pemetrexed, 
or carboplatin/pemetrexed), unless treatment is discontinued for toxicity or cancer progression.  
Investigators may elect to administer maintenance pemetrexed regardless of which therapy their subjects 
are randomized to receive.  Following completion of platinum doublet therapy, maintenance pemetrexed 
is strongly encouraged for all subjects who are suitable candidates.  Subjects LSP status (positive or 
negative) will be determined from tissue samples obtained to confirm diagnosis of NSCLC with a 
commercially developed RNA seq based LSP classifier developed in partnership with Qiagen.
Subject randomization will be stratified by smoking status (current versus former), by the Investigators' 
preferred platinum doublet therapy (carboplatin/paclitaxel versus cisplatin/pemetrexed versus 
carboplatin/pemetrexed), by gender (male versus female) and by ECOG performance status (0 versus 1).
Subjects randomized to receive veliparib will begin oral veliparib dosing 2 days prior to the start of the 
carboplatin/paclitaxel infusion on C1D-2 and will continue twice a day (BID) through C1D5 
(7 consecutive days).  
Subjects randomized to receive carboplatin/paclitaxel/veliparib will receive carboplatin (AUC 
6 mg/mL•min) and paclitaxel (200 mg/m2) IV infusion starting on Day 1 of each cycle.  Subjects will 
receive a maximum of 6 cycles of treatment, unless toxicity requires cessation of therapy, or radiographic 
progression occurs prior to completing 6 cycles.  Carboplatin/paclitaxel plus veliparib may be delayed or 
dose-modified due to toxicity.  Should a subject not receive carboplatin and paclitaxel on Day 1 of any 
cycle, the cycle will be restarted with veliparib at the newly designated Day –2 when the subject is able to 
do so.
Subjects randomized to receive Investigator's choice of platinum doublet therapy will receive therapy on 
Day 1 of each cycle.  Subjects will receive a maximum of 6 cycles of treatment, unless toxicity requires 
cessation of therapy, or radiographic progression occurs prior to completing 6 cycles.  Platinum doublet 
therapy may be delayed or dose-modified due to toxicity.  Dose delays and modification will be at the 
discretion of the Investigator per local standard practice. 
Suitable subjects in either arm will receive pemetrexed maintenance therapy after completion of platinum 
doublet chemotherapy regimen.  Maintenance pemetrexed will be administered on Day 1 of each 21-day 
cycle.  Maintenance therapy may be delayed or dose-modified due to toxicity.  Subjects will continue to 
receive maintenance therapy until toxicity requires cessation of therapy, or radiographic progression 
occurs.  Veliparib will not be administered during the maintenance phase. 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
132
Methodology (Continued):
Subjects will have physician visits q3 weeks while receiving platinum doublet and maintenance therapy.  
After cessation of therapy, physician visits and quality of life measures will be performed q9 weeks until 
1 year after beginning treatment (C1D-2) (or beyond 1 year until maintenance therapy is discontinued), 
then q12 weeks until radiographic progression.  Tumor assessments will be performed at baseline prior to 
treatment on Cycle 3 Day 1 and Cycle 5 Day 1.  After cessation of platinum doublet therapy, tumor 
assessments will be performed q9 weeks until 1 year after beginning treatment (C1D-2) (or beyond 1 year 
until maintenance therapy is discontinued), then q12 weeks until radiographic progression or death.  
Radiographic information will be collected to determine response according to the Response Evaluation 
Criteria In Solid Tumors (RECIST) version 1.1.  Toxicities will be graded at each study visit according to 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0.
The visit at which an investigator identifies disease progression or at which a subject meets other criteria 
for study discontinuation will be considered the Final Visit.  It is preferable that final visit procedures be 
conducted prior to the initiation of another anticancer therapy.
All subjects who have a Final visit ≤ 30 days after the last dose of Study drug will have a Follow-Up 
Visit approximately 30 days after the last dose of Study drug.  If a subject is discontinued from the study 
with an ongoing adverse event or an unresolved clinically significant laboratory result, the site will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory results or adverse 
event is achieved.
Subjects no longer undergoing clinical assessments will have survival information reported at 2-month 
intervals (or as requested by the sponsor to support data analysis) beginning at the last clinical assessment 
and continuing until the endpoint of death, the subject has become lost to follow-up, or AbbVie 
terminates the study.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Diagnosis:  Metastatic or advanced non-squamous Non-Small Cell Lung Cancer
Main Inclusion:  
1.
Subject must be ≥ 18 years of age.
2.
Life expectancy > 12 weeks (as per Investigator's clinical assessment).
3.
Subject must have cytologically or histologically confirmed advanced or metastatic non-squamous 
NSCLC.  Subjects with mixed histology tumors will be eligible if the tumor is predominant 
non-squamous histology and does not include tumor with small cell histology.  Subjects must have a 
pathologist's report confirming non-squamous NSCLC available for collection by the sponsor.  
Subjects with EGFR mutation (exon 19 deletion or L858R mutation in exon 21) and/or ALK gene 
rearrangement must have progressed after first line monotherapy treatment with targeted therapy.
4.
Subject must have NSCLC that is not amenable to surgical resection or radiation with curative intent 
at time of study Screening.
5.
Subjects must be current smokers (defined as having > 100 smoking events lifetime and having 
smoked within the past year) or former smokers (defined as having > 100 smoking events lifetime 
and having not smoked within the past year).


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
133
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion (Continued):  
6.
Subject must have at least 1 unidimensional measurable NSCLC lesion on a CT scan as defined by 
RECIST (version 1.1).
7.
Subject must consent to provide archived tissue or cytology sample of NSCLC lesion (primary or 
metastatic) for analysis if available.  
8.
Subject must have no history of brain metastases or evidence of CNS tumors at screening 
assessment.  Subjects with signs or symptoms of CNS involvement will undergo MRI (or CT scan if 
MRI is contraindicated) to confirm absence of CNS metastases.
9.
Subject must have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 – 1.
10. Subjects with fluid retention, including ascites or pleural effusion, may be allowed at the discretion 
of the Investigator.
11. Subject must have adequate bone marrow, renal and hepatic function as follows:
!
Bone Marrow:  Absolute neutrophil count (ANC) ≥ 1,500/mm3 (1.5 × 109/L);
!
Platelets ≥ 100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.0 g/dL; 
!
Renal function:  serum calculated creatinine clearance > 50 mL/min according to the 
Cockcroft-Gault formula; confirmation of creatinine clearance/GFR may be done by a local 
direct measurement method (e.g., 24 hour urine collection or radioisotope) at the investigator's 
discretion;
!
Hepatic function:  AST and ALT ≤ 2.5 × ULN unless liver metastases are present, then AST 
and ALT < 5.0 × ULN; bilirubin ≤ 1.5 × ULN; unless Gilbert's Syndrome is present, then 
bilirubin ≥ 1.5 × ULN.
12. Female subjects of childbearing potential (i.e., those who are not postmenopausal for at least 1 year 
or surgically sterile by bilateral tubal ligation, bilateral oophorectomy or hysterectomy) and their 
male partners should practice at least one of the methods of birth control listed below during study 
and for at least 6 months after treatment with paclitaxel chemotherapy.  Male subjects and their 
female partners of childbearing potential should practice at least one of the methods of birth control 
listed below during study and for at least 6 months after treatment with chemotherapy:
!
total abstinence from sexual intercourse (if it is the subject's preferred and usual lifestyle; for 
beginning a minimum one complete menstrual cycle prior to study drug administration and to 
extend 6 months after treatment);
!
vasectomized subject or partner(s); vasectomy (males);
!
intrauterine device (females);
!
double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with 
spermicidal jellies or creams; both males and females);
!
hormonal contraceptives (oral, parenteral or transdermal) for at least 90 days prior to study drug 
administration (females).  If hormonal contraceptives are used, the subject and her partner 
should also use a single-barrier method.
13. Subject must be 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 the initiation of any screening or study-specific 
procedures.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
134
Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Exclusion:  
1.
Subject has a known hypersensitivity to paclitaxel or to other drugs formulated with polyethoxylated 
castor oil (Cremophor).
2.
Subject has a known hypersensitivity to platinum compounds.
3.
Subjects with peripheral neuropathy ≥ grade 2.
4.
Subjects with squamous NSCLC, or those with an untreated EGFR mutation (exon 19 deletion or 
L858R mutation in exon 21) and/or ALK gene rearrangement.  Subjects' EGFR mutation and ALK 
gene rearrangement status must be known prior to study entry.  
5.
A history of seizure within 12 months prior to study entry.
6.
Subject has received prior cytotoxic chemotherapy or chemoradiotherapy for NSCLC, except 
adjuvant or neoadjuvant therapy > 12 months prior to C1D-2 or subject has received targeted small 
molecule monotherapy for EGFR and/or ALK-positive disease ≤ 14 days prior to C1D-2 or biologic 
therapy ≤ 21 days prior to C1D-2.
7.
Subject has received anti-cancer Chinese medicine or anti-cancer herbal remedies within 14 days 
prior to C1D-2.
8.
Subject has undergone focal External Beam Radiation Therapy (EBRT) to bone ≤ 2 weeks prior to 
C1D-2; or subject has undergone EBRT to larger fields (i.e., 100 cm2 to thorax) ≤ 4 weeks prior to 
C1D-2.
9.
Any medical condition, which in the opinion of the Investigator, places the subject at an 
unacceptably high risk for toxicities, or any subject circumstance which prohibits trial participation 
according to local law.
10. Subject is pregnant or lactating.
11. Subject has previously been treated with a PARP inhibitor.
12. The subject has a history of another cancer within the past 3 years except cervical cancer in situ, 
in situ carcinoma of the bladder, squamous or basal cell carcinoma of the skin or another in situ 
cancer that is considered cured by the Investigator (e.g., in situ prostate cancer).  
Investigational Products:
Veliparib (ABT-888)
Doses:
120 mg BID Days –2 through 5 of 21-day cycle
Mode of Administration:
Oral
Reference Therapy or 
Investigational products:
Carboplatin Day 1 of 21-day cycle
Dose:
AUC 6 mg/mL•min
Mode of Administration:
Intravenous
Reference Therapy or 
Investigational products:
Paclitaxel Day 1 of 21-day cycle
Dose:
200 mg/m2
Mode of Administration:
Intravenous


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
135
Reference Therapy:
Pemetrexed
Dose:
500 mg/m2
Mode of Administration:
Intravenous
Reference Therapy:
Cisplatin
Dose:
75 mg/m2
Mode of Administration:
Intravenous
Duration of Treatment:  
Subjects will receive veliparib in combination with carboplatin/paclitaxel for a maximum of 6 treatment 
cycles or Investigator's choice of chemotherapy for a maximum of 6 cycles unless toxicity requires 
cessation of therapy, or radiographic progression occurs prior to completing 6 cycles.  Following 
completion of platinum doublet therapy, maintenance pemetrexed is strongly encouraged for all subjects 
who are suitable candidates.
Criteria for Evaluation:
Overall survival (OS):  will be reported by the Investigator until radiographic progression or death.  
After the final visit, survival information will be collected at 2-month intervals (or as requested by 
sponsor to support data analysis).
Progression-free survival (PFS):  will be derived according to radiographic progression per RECIST 
version 1.1 or death.  Radiographic tumor assessments for response will be conducted by CT scanning 
prior to C3D1, prior to C5D1, every 9 weeks until 1 year after beginning treatment (or beyond 1 year 
until maintenance therapy is discontinued), and then every 12 weeks.
Objective response rate (ORR):  will be derived per RECIST version 1.1.  Radiographic tumor 
assessments for response will be conducted by CT scanning prior to C3D1, prior to C5D1, every 9 weeks 
until 1 year after beginning treatment (or beyond 1 year until maintenance therapy is discontinued), and 
then every 12 weeks.
Duration of overall response (DOR):  will be derived according to radiographic progression per 
RECIST version 1.1.  Radiographic tumor assessments for response will be conducted by CT scanning 
prior to C3D1, prior to C5D1, every 9 weeks until 1 year after beginning treatment (or beyond 1 year 
until maintenance therapy is discontinued), and then every 12 weeks.
ECOG performance status:  will be determined by the Investigator at each assessment.  
Quality of Life (QoL):  will be assessed at baseline prior to veliparib dosing on C1D-2, C3D1, C5D1 
and at the Final Visit, every 9 weeks until 1 year after beginning treatment (or beyond 1 year until 
maintenance therapy is discontinued), then every 12 weeks and at the Final Visit until radiographic 
progression via the NCCN-Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 
(NFLSI-17) questionnaire and the European Quality of Life-5 Dimensions (EQ-5D-5L) questionnaires.
Safety:
Adverse events, laboratory profiles, physical examinations and vital signs will be assessed throughout the 
study.
Pharmacokinetic/Pharmacogenetics:
Blood samples for pharmacokinetics of veliparib will be collected at designated timepoints throughout 
the study and will be analyzed in LSP-defined populations as well as the entire study population.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
136
Criteria for Evaluation (Continued):
LSP status: 
Available archived tumor tissue will be used to determine the subjects' tumor LSP status with a 
commercially developed RNA seq based LSP classifier developed in partnership with Qiagen.
Pharmacodynamic:
Research to find biomarkers that may serve as surrogates for clinical endpoints in future veliparib studies 
or that may be predictive of veliparib activity will be conducted.  Serum, plasma, blood and tissue 
samples will be collected at designated time points throughout the study.
Statistical Methods:
For all statistical analyses, statistical significance will be determined by a two-sided P value ≤ 0.05.  The 
date of randomization (enrollment) is defined as the date that the IRT issues a randomization number.
Sample Size:
Sample size determination for the original protocol:  Assuming the true hazard ratio of overall survival 
(OS) for current smokers in favor of the veliparib 120 mg BID + carboplatin/paclitaxel treatment group is 
0.64, a total of 210 death events among current smokers will be needed for the study to have 
approximately 90% power at one-sided α level of 0.025 to detect a statistically significant treatment 
effect for the veliparib 120 mg BID + carboplatin/paclitaxel group using the log rank test for OS.  A total 
of approximately 300 current smokers will be enrolled to obtain the 210 death events.
During the enrollment period for the approximate 300 current smokers, it is anticipated that 
approximately 225 former smokers will enroll concurrently.  Assuming the true hazard ratio of overall 
survival (OS) for all subjects (including current plus former smokers) in favor of the veliparib 120 mg 
BID + carboplatin/paclitaxel treatment group is 0.71, a total of 369 death events in all subjects will be 
needed for the study to have approximately 90% power at one-sided α level of 0.025 to detect a 
statistically significant treatment effect for the veliparib 120 mg BID + carboplatin/paclitaxel group using 
the log rank test for OS.  
Sample size consideration for OS analysis in LSP+ subgroup:
Based on 452 subjects having tissue samples (assumed 76% LSP sample availability rate, out of 
595 enrolled subjects), the below table provides the power and number of events (assuming 80% event 
rate at final analysis) for a range of likely LSP+ rates if the treatment allocation ratio is 1:1 in the LSP+ 
subgroup and true HR of OS is 0.65 in LSP+ subgroup.
Number of LSP+ 
Subjects (LSP+ rate)
Number of Events in LSP+
Power for OS in LSP+ Subgroup 
(one-sided alpha = 0.025)
271 (60%)
216
89%
226 (50%)
180
82%
180 (40%)
144
73%
  


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
137
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:
LSP
Lung Subtype Panel
Section 3.1  NSCLC (Non-Small Cell Lung Cancer)
Add:  new fifth and sixth paragraph
Large scale genomic characterization efforts including those conducted by the TCGA and 
the Lung Cancer Mutation Consortium (LCMC) have been conducted to identify 
molecular features that differ between NSCLC subtypes.  These different features may 
explain the differential therapeutic responses among different NSCLC subtypes, e.g., of 
squamous and non-squamous NSCLC.  The importance of molecular phenotyping has 
become increasingly clear as The Cancer Genome Atlas (TCGA) contributed results from 
a massive specific tumor type sequencing effort that provided a significant landmark for 
understanding the genetic mutation and gene expression profile of lung cancer in well 
characterized and distinct histologic subtypes. 
Genomic-based classification methods are more likely to capture the molecular 
characteristics of the cancer cell and therefore classify NSCLC into prognostically 
informative subgroups.  One such approach, termed LSP, is a gene expression profile 
established using a panel of 57 genes (52 classification genes plus 5 housekeeping genes) 
for the mRNA expression signature.  This panel became known as the Lung Subtype 
Panel (LSP).  Analysis in these three independent adenocarcinoma NSCLC cohorts 
demonstrated that LSP positive (LSP+) group of patients who had poor prognosis.6
Section 3.5  Study Rationale
Third sentence previously read:
Phase 1 data and Phase 2 data described above suggest the addition of veliparib to 
carboplatin and paclitaxel may improve outcome of current-smokers with advanced or 
metastatic NSCLC.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
138
Has been changed to read:
Phase 1 data and Phase 2 data described above suggest the addition of veliparib to 
carboplatin and paclitaxel may improve outcome of LSP+ subjects and/or current-smokers 
with advanced or metastatic NSCLC.
Section 3.5  Study Rationale
Add:  new fifth sentence 
All enrolled subjects with available tumor tissue will be evaluated for the LSP gene 
expression signature status.
Section 3.6  Differences Statement
Previously read:
The current study is the first randomized, open-label, multicenter, Phase 3 trial comparing 
veliparib plus carboplatin and paclitaxel versus Investigator's choice of standard 
chemotherapy in previously untreated subjects with metastatic or advanced non-squamous 
non-small cell lung cancer (NSCLC) who are current or former smokers.
Has been changed to read:
The current study is the first randomized, open-label, multicenter, Phase 3 trial comparing 
veliparib plus carboplatin and paclitaxel versus Investigator's choice of standard 
chemotherapy in previously untreated subjects with metastatic or advanced non-squamous 
non-small cell lung cancer (NSCLC), now as defined by LSP status.
Section 3.7  Benefits and Risks
First paragraph, third sentence previously read:
As described above, non-squamous NSCLC study subjects receiving veliparib with 
carboplatin and paclitaxel have shown favorable results for the current smokers group (as 
presented above) for the endpoints of overall survival.  


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
139
Has been changed to read:
As described above, non-squamous NSCLC study subjects receiving veliparib with 
carboplatin and paclitaxel have shown favorable results for the current smokers group (as 
presented above) and the LSP+ group for the endpoints of overall survival.  
Section 4.0  Study Objectives
Previously read:
The primary objective of the study is to assess if treatment with veliparib plus carboplatin 
and paclitaxel results in improved survival compared to Investigator's choice of standard 
chemotherapy in current smokers with metastatic or advanced NSCLC.
The secondary objectives of the study are to assess if treatment with veliparib plus 
carboplatin and paclitaxel results in improved survival compared to Investigator's choice 
of standard chemotherapy in current plus former smokers with metastatic or advanced 
NSCLC; to compare progression-free survival (PFS) and to compare objective response 
rate (ORR) between the two treatment arms in current smokers or in current plus former 
smokers.
The tertiary objectives are to compare duration of overall response (DOR), ECOG 
performance status and Quality of Life (QoL) between the two treatment arms in current 
smokers or in current plus former smokers.
Has been changed to read:
The primary objective of the study is to assess if treatment with veliparib plus carboplatin 
and paclitaxel results in improved survival compared to Investigator's choice of standard 
chemotherapy in LSP positive subjects with metastatic or advanced NSCLC.
The secondary objectives of the study are to assess if treatment with veliparib plus 
carboplatin and paclitaxel results in improved survival compared to Investigator's choice 
of standard chemotherapy in the entire study population with metastatic or advanced 
NSCLC; to compare progression-free survival (PFS) and to compare objective response 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
140
rate (ORR) between the two treatment arms in LSP positive subjects or in the entire study 
population.
The tertiary objectives are to compare duration of overall response (DOR), ECOG 
performance status and Quality of Life (QoL) between the two treatment arms in LSP 
positive subjects or in the entire study population.
Section 5.1  Overall Study Design and Plan:  Description
Last paragraph
Add:  new last sentence
In addition, all post treatment therapy, if applicable and available, will be collected in the 
survival follow-up period.  
Table 2.  Study Activities 
Activity "Adverse Event and Concomitant Medication Assessment" and "Survival"
previously read:
Activity
SCRa
Cycle 1 Day –2
Cycle 1 Day 1
Cycle 1 Day 15
Cycle 2 – 6 Day 1*
Final Visitb
30-day FU Visitc
Maintenance 
Therapyd
Post-Treatment 
Visitsp
Survival Period
Adverse Event and Concomitant 
Medication Assessment
X
X
X
X
X
X
X
X
Survival
X


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
141
Has been changed to read:
Activity
SCRa
Cycle 1 Day –2
Cycle 1 Day 1
Cycle 1 Day 15
Cycle 2 – 6 Day 1*
Final Visitb
30-day FU Visitc
Maintenance 
Therapyd
Post-Treatment 
Visitsp
Survival Period
Adverse Event and Concomitant 
Medication Assessment
X
X
X
X
X
X
X
X
Xr
Survivalr
X
Table 2.  Study Activities 
Table note "i." 
Delete:  second sentence
This does not include C1D-2 as any sample prior to randomization is still considered to be 
screening.   
Table 2.  Study Activities 
Add:  new table note "r."
All systemic post treatment anti-cancer therapy, if applicable and available, will be 
collected in the survival follow-up period.
Section 5.3.1.1  Study Procedures
Subsection Survival Information
Add:  new last sentence
Post-study anti-cancer therapy information (including type of agent, initiation date, end 
date, and clinical response), if known, will also be collected in the survival follow-up 
period.
Section 5.3.3  Efficacy Variables
Previously read:
The primary efficacy endpoint is overall survival (OS) in current smokers.  The secondary 
efficacy endpoints are OS in all subjects (current and former smokers), progression-free 






Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
144
Has been changed to read:
The primary efficacy analysis will be a comparison of OS distributions between the 
120 mg of veliparib BID + carboplatin/paclitaxel and Investigators' choice of platinum 
therapy groups in LSP + subgroup.
Section 8.1.2.2  Secondary Efficacy Endpoints
First paragraph, last sentence previously read:
If veliparib treatment group is not statistically significantly better than the Investigator's 
preferred platinum therapy group for the primary efficacy endpoint of OS in current 
smokers, then statistical significance will not be declared for any of the secondary 
efficacy endpoints, regardless of the observed P values.
Has been changed to read:
If veliparib treatment group is not statistically significantly better than the Investigator's 
choice of platinum therapy group for the primary efficacy endpoint of OS in LSP + 
subgroup, then statistical significance will not be declared for any of the secondary 
efficacy endpoints, regardless of the observed P values.
Section 8.1.2.2  Secondary Efficacy Endpoints
Second paragraph previously read:
P values for the secondary efficacy analyses will be subject to multiple comparison 
adjustments using the fixed sequence test method, with the analyses performed in the 
following order:  OS in current plus former smokers, progression-free survival (PFS) in 
current smokers, PFS in current plus former smokers, objective response rate (ORR) in 
current smokers, ORR in current plus former smokers.
Has been changed to read:
P values for the secondary efficacy analyses will be subject to multiple comparison 
adjustments using the fixed sequence test method, with the analyses performed in the 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
145
following order:  progression-free survival (PFS) in LSP+ subgroup, objective response 
rate (ORR) in LSP+ subgroup, OS in all subjects, PFS in all subjects, ORR in all subjects.
Section 8.1.2.3  Tertiary Efficacy Endpoints
First paragraph previously read:
In addition to the primary and secondary efficacy analyses, the tertiary objectives are to 
compare DOR, ECOG performance status and Quality of Life (QoL) via the 
NCCN-Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 
(NFLSI-17) questionnaire and the European Quality of Life-5 Dimensions (EQ-5D-5L) in 
current smokers and in current plus former smokers between the two treatment arms and 
ECOG performance status will be performed.
Has been changed to read:
In addition to the primary and secondary efficacy analyses, the tertiary objectives are to 
compare DOR, ECOG performance status and Quality of Life (QoL) via the 
NCCN-Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 
(NFLSI-17) questionnaire and the European Quality of Life-5 Dimensions (EQ-5D-5L) in 
LSP+ subjects and in the entire study population between the two treatment groups.
Section 8.1.2.3  Tertiary Efficacy Endpoints
Last paragraph, first sentence previously read:
The duration of overall response for a given subject will be defined as the number of days 
from the day the criteria are met for CR or PR (whichever is recorded first) to the date that 
PD is objectively documented.  
Has been changed to read:
The duration of overall response for a given subject will be defined as the number of days 
from the day the criteria are met for CR or PR (whichever is recorded first) to the date that 
PD is objectively documented or subject's death.   


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
146
Section 8.1.3  Timing of Efficacy Analyses and Safety Evaluations
First sentence previously read:
When both the 210th death event in the current smokers and the 369th death event in 
current plus former smokers occur, there will be a final review of the eCRF data.  
Has been changed to read:
When LSP status is determined by the Qiagen assay for all submitted tissue samples, there 
will be a final review of the eCRF data.  
Section 8.1.4  Primary Analysis of Efficacy
Previously read:
For the current smokers, the distribution of OS will be estimated for each treatment group 
using Kaplan-Meier methodology and compared between the two treatment groups using 
the log-rank test, stratified by ECOG and Investigator's preferred platinum therapy.
Has been changed to read:
For the LSP+ subgroup, the distribution of OS will be estimated for each treatment group 
using Kaplan-Meier methodology and compared between the two treatment groups (HR 
and 95%CI) using Cox proportional hazard model with treatment group, important 
prognostic factors (e.g., ECOG, Investigator's choice of platinum therapy, and smoking 
status) as the covariates.
Section 8.1.5  Secondary Analysis of Efficacy
Previously read:
8.1.5
Secondary Analysis of Efficacy
8.1.5.1
Overall Survival in Current Plus Former Smokers
For current plus former smokers, the distribution of OS will be estimated for each 
treatment group using Kaplan-Meier methodology and compared between the 
two treatment groups using the log-rank test, stratified by ECOG, smoking history 
(current versus former smokers), and Investigator's preferred platinum therapy.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
147
8.1.5.2
Progression Free Survival in Current Smokers
For the current smokers, the distribution of PFS will be estimated for each treatment 
group using Kaplan-Meier methodology and compared between the two treatment groups
using the log-rank test, stratified by ECOG and Investigator's preferred platinum therapy.
8.1.5.3
Progression Free Survival in Current Plus Former Smokers
For current plus former smokers, the distribution of PFS will be estimated for each 
treatment group using Kaplan-Meier methodology and compared between the 
two treatment groups using the log-rank test, stratified by ECOG, smoking history 
(current versus former smokers), and Investigator's preferred platinum therapy.
8.1.5.4
Objective Response Rate in Current Smokers
For the current smokers, the ORR (proportion of subjects with a complete or partial 
response based on RECIST (version 1.1) will be estimated and compared between the 
two treatment groups using Cochran-Mantel-Haenszel (CMH) test; stratified by ECOG 
and Investigator's preferred platinum therapy.  In addition, 95% confidence interval will 
be constructed for the estimated proportion.
8.1.5.5
Objective Response Rate in Current Plus Former Smokers
For current smokers plus former smokers, the ORR will be estimated and compared 
between the two treatment groups using Cochran-Mantel-Haenszel (CMH) test; stratified 
by ECOG, smoking history (current versus former smokers), and Investigator's preferred 
platinum therapy.  In addition, 95% confidence interval will be constructed for the 
estimated proportion.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
148
Has been changed to read:
8.1.5
Secondary Analysis of Efficacy
8.1.5.1
Progression Free Survival in LSP + Subgroup
For the LSP+ subgroup, the distribution of PFS will be estimated for each treatment group 
using Kaplan-Meier methodology and compared between the two treatment groups (HR 
and 95% CI) using Cox proportional hazard model with treatment group, important 
prognostic factors (e.g., ECOG, Investigator's choice of platinum therapy and smoking 
status) as covariates.
8.1.5.2
Objective Response Rate in LSP+ Subgroup
For the LSP+ subgroup, the ORR (proportion of subjects with a complete or partial 
response based on RECIST (version 1.1) will be estimated and compared between the 
two treatment groups using Fisher's exact test.  In addition, 95% confidence interval will 
be constructed for the estimated proportion.
8.1.5.3
Overall Survival in All Subjects
For all subjects, the distribution of OS will be estimated for each treatment group using 
Kaplan-Meier methodology and compared between the two treatment groups (HR and 
95% CI) using the Cox Proportional hazard model with treatment group, important 
prognostic factors (e.g., ECOG, smoking history (current versus former smokers), and 
Investigator's choice of  platinum therapy) as the covariates.
8.1.5.4
Progression Free Survival in All Subjects
For all subjects, the distribution of PFS will be estimated for each treatment group using 
Kaplan-Meier methodology and compared between the two treatment groups (HR and 
95%CI) using Cox proportional hazard model with treatment group, important prognostic 
factors (e.g., ECOG, and Investigator's choice of platinum therapy, smoking status) as the 
covariates. 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
149
8.1.5.5
Objective Response Rate in All Subjects
For all subjects, the ORR will be estimated and compared between the two treatment 
groups using Cochran-Mantel-Haenszel (CMH) test; stratified by ECOG, smoking history 
(current versus former smokers), and Investigator's preferred platinum therapy.  In 
addition, 95% confidence interval will be constructed for the estimated proportion.
Section 8.1.6.1  Duration of Overall Response
Previously read:
For the current smoker subgroup, the distribution of duration of overall response (DOR) 
will be estimated for each treatment group using Kaplan-Meier methodology and 
compared between the two treatment groups using the log-rank test, stratified by ECOG 
and Investigator's preferred platinum therapy.
For the whole population (including both current smokers and former smokers), the 
distribution of (DOR) will be estimated for each treatment group using Kaplan-Meier 
methodology and compared between the two treatment groups using the log-rank test, 
stratified by ECOG, smoking history (current versus former smokers), and Investigator's 
preferred platinum therapy.
Has been changed to read:
The distribution of duration of overall response (DOR) will be estimated for each 
treatment group using Kaplan-Meier methodology for LSP+ as well as for all subjects.
Section 8.1.6.2  General Quality of Life
Subsection Subject Reported Symptoms and QOL (NFLSI-17)
First sentence previously read:
The objective is to compare subject reported symptoms and QOL following treatment 
with the veliparib treated arm and the comparator arm for both the smoker subgroup and 
the whole population using the NFLSI-17 questionnaire.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
150
Has been changed to read:
The objective is to compare subject reported symptoms and QOL following treatment 
with the veliparib treated arm and the comparator arm for both the LSP+ subgroup and the 
whole population using the NFLSI-17 questionnaire.
Section 8.1.6.3  Performance Status
First sentence previously read:
Changes from baseline in ECOG performance status will be summarized using descriptive 
statistics for each scheduled post-baseline visit.
Has been changed to read:
Changes from baseline in ECOG performance status will be summarized using descriptive 
statistics for each scheduled post-baseline visit and for LSP+ as well as all subjects.
Section 8.1.7  Additional Exploratory Efficacy Analyses
First paragraph previously read:
In addition to the stratified log-rank test for the primary and secondary efficacy endpoints, 
the unstratified log-rank test, Wilcoxon test, and the Cox proportional hazards model may 
be used for the comparison of OS and PFS between the two treatment groups.
Has been changed to read:
In addition to the covariate-adjusted Cox PH analyses for the primary and secondary 
efficacy endpoints, the unstratified log-rank test and unstratified and unadjusted Cox 
proportional hazards model may be used for the comparison of OS and PFS between the 
two treatment groups.
Section 8.1.7  Additional Exploratory Efficacy Analyses
Last paragraph, first sentence previously read:
For OS and PFS, additional analyses may also be performed, such as 1) including only 
data and events occurring on treatment or within 30 days of the last dose of study drug, 


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
151
2) using a Cox proportional hazard model to explore the effect of baseline factors 
including (but not limited to) the following:  tumor stage (locally advanced versus 
metastatic), smoking history (current smoker versus former smoker), gender, ECOG 
performance status (0 versus 1), Investigator's preferred platinum doublet therapy, and 
others, 3) subgroup analysis by smoking history (current smoker versus former smoker), 
gender, ECOG performance status (0 versus 1), Investigator's preferred platinum doublet 
therapy and others.
Has been changed to read:
For OS and PFS, additional analyses may also be performed, such as 1) including only 
data and events occurring on treatment or within 30 days of the last dose of study drug, 
2) using a Cox proportional hazard model to explore the effect of baseline factors 
including (but not limited to) the following:  LSP subgroup, LSP status unknown, tumor 
stage (locally advanced versus metastatic), smoking history (current smoker versus former 
smoker), gender, ECOG performance status (0 versus 1), Investigator's preferred platinum 
doublet therapy, and others, 3) subgroup analysis by LSP subgroup, LSP status unknown, 
smoking history (current smoker versus former smoker), gender, ECOG performance 
status (0 versus 1), Investigator's preferred platinum doublet therapy, post-study anti-
cancer therapy (e.g., anti-PD-1, IO etc.) and others.
Section 8.1.8  Statistical Analysis of Safety
Add:  new first sentence
Statistical analyses of safety data described below will be performed for three study 
population separately:  LSP+ subgroup, LSP– subgroup, entire study population.
Section 8.1.8.2  Adverse Events
Last sentence previously read:
The percentages of subjects experiencing an adverse event will be compared between 
veliparib BID + carboplatin/paclitaxel and Investigators' preferred platinum therapy using 
Fisher's exact test.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
152
Has been changed to read:
The percentages of subjects experiencing an adverse event will be presented by treatment 
group.
Section 8.1.8.5  Longitudinal Analyses of Laboratory and Vital Signs Data
First sentence previously read:
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.  
Has been changed to read:
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 vital sign 
parameters.  
Section 8.1.8.5  Longitudinal Analyses of Laboratory and Vital Signs Data
Delete:  last sentence 
Comparisons of the differences in mean changes from baseline between veliparib BID + 
carboplatin/paclitaxel and Investigators' preferred platinum therapy will be made using 
ANOVA with treatment group as the factor.
Section 8.1.8.6  Analyses of Laboratory Data Using NCI CTCAE
Third sentence previously read:
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 between veliparib BID + carboplatin/paclitaxel and 
Investigators' preferred platinum therapy will be compared using Fisher's exact test.  


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
153
Has been changed to read:
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 between veliparib BID + carboplatin/paclitaxel and 
Investigators' preferred platinum therapy will be presented.  
Section 8.2  Determination of Sample Size
Add:  new first paragraph
Sample size calculation for the original protocol:
Section 8.2  Determination of Sample Size
Add:  new third and fourth paragraph
Sample size consideration for OS analysis in LSP+ subgroup
Based on 452 subjects having LSP tissue samples (assumed 76% LSP sample availability 
rate), the below table provides the power and number of events with different assumed 
LSP+ rate if the treatment allocation ratio is 1:1 in the LSP+ subgroup and true HR of OS 
is 0.65 in LSP+ subgroup.
Number of LSP+ Subjects 
(LSP+ rate)
Number of Events in 
LSP+
Power for OS in LSP+ Subgroup 
(one-sided alpha = 0.025)
271 (60%)
216
89%
226 (50%)
180
82%
180 (40%)
144
73%
Section 15.0  Reference List
Add:  new Reference 6
Mayhew G, Hayes N, Perou C, et al.  Survival differences of adenocarcinoma lung tumors 
with squamous cell carcinoma or neuroendocrine profiles by gene expression subtyping.  
Abstract #384.  Presented at the 16th World Conference on Lung Cancer, September 06-
09, 2015; Denver, CO.


Veliparib
M14-359 Protocol Amendment 4
EudraCT 2014-002565-30
154
Section 15.0  Reference List
Reference 22 previously read:
AbbVie.  Veliparib (ABT-888) Investigator Brochure, Edition 9.  12 June 2015.
Has been changed to read:
AbbVie.  Veliparib (ABT-888) Investigator Brochure, Edition 11.  22 June 2017.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Clinical Operations
GDSM
Clinical
Clinical
Statistics
Pharmacokinetics
Has been changed to read:
Name
Title
Functional Area
Clinical Program Development
Oncology Development
Oncology Development
Statistics
Pharmacokinetics

SAP_001.pdf: 
Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
1
1.0
Title Page
Statistical Analysis Plan
Study M14-359
A Randomized, Open-Label, Multicenter, Phase 3 
Trial Comparing Veliparib Plus Carboplatin and
Paclitaxel Versus Investigator's Choice of Standard 
Chemotherapy in Subjects Receiving First Cytotoxic 
Chemotherapy for Metastatic or Advanced 
Non-Squamous Non-Small-Cell Lung Cancer (NSCLC) 
and Who Are Current or Former Smokers
Date:  06 Nov 2019
Version 4.0
NCT02264990


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
2
2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
2.1
Summary of Versions ................................................................................5
2.2
List of Abbreviations and Definition of terms...........................................6
3.0
Introduction .............................................................................8
4.0
Study Objectives, Design and Procedures.............................9
4.1
Objectives ..................................................................................................9
4.2
Design Diagram .........................................................................................9
4.3
Sample Size..............................................................................................11
5.0
Analysis Populations .............................................................13
5.1
Definition for Analysis Populations.........................................................13
5.2
Variables Used for Stratification of Randomization................................13
6.0
Analysis Conventions ............................................................14
7.0
Demographics, Baseline Characteristics, Medical 
History, Prior/Concomitant Medications, Prior 
Oncology Therapies and Post-Treatment Medication.......18
7.1
Demographic and Baseline Characteristics .............................................18
7.2
Medical History .......................................................................................19
7.3
Prior/Concomitant Medications, Prior Oncology Therapies and 
Post-Treatment Medications ....................................................................20
8.0
Subject Disposition................................................................20
9.0
Study Drug and Maintenance Drug Exposure ...................21
9.1
Exposure to study drug during platinum doublet therapy period ............21
9.2
Exposure to maintenance pemetrexed......................................................23
10.0
Efficacy Analyses...................................................................23
10.1
General Considerations............................................................................23
10.2
Primary Efficacy Analysis .......................................................................24
10.3
Secondary Efficacy Analyses...................................................................25
10.3.1
Progression-Free Survival in LSP+ subjects............................................25
10.3.2
Objective Response Rate in LSP+ Subjects.............................................26
10.3.3
Overall Survival in All Subjects ..............................................................27


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
3
10.3.4
Progression-Free Survival in All Subjects...............................................28
10.3.5
Objective Response Rate in All Subjects.................................................28
10.4
Tertiary Efficacy Analyses.......................................................................29
10.4.1
Duration of Overall Response..................................................................29
10.4.2
Quality of Life..........................................................................................29
10.4.3
Performance Status ..................................................................................34
10.5
Additional Efficacy Analyses ..................................................................34
11.0
Safety Analyses ......................................................................36
11.1
General Considerations............................................................................36
11.2
Analyses of Adverse Events ....................................................................36
11.2.1
Analysis of Adverse Events of Special Interest.......................................37
11.3
Analyses of Deaths ..................................................................................39
11.4
Analyses of Laboratory and Vital Signs Data..........................................39
11.4.1
Longitudinal Analyses of Laboratory and Vital Signs Data....................39
11.4.2
Analyses of Laboratory Data Using NCI CTCAE v4.0...........................39
11.4.3
Drug-Induced Liver Injury.......................................................................42
11.5
Analyses of Safety by Subgroup (All population)...................................43
11.5.1
Adverse Events Subgroup Analyses ........................................................43
11.5.2
Laboratory Variables Subgroup Analyses ...............................................43
12.0
Summary of Changes ............................................................44
12.1
Summary of Major Changes from the Last Version of the SAP .............44
13.0
References...............................................................................44
List of Tables
Table 1.
Treatment Schema for Each Cycle for Veliparib and 
Carboplatin/Paclitaxel Treatment Group .................................................10
Table 2.
Treatment Schema for Each Cycle for Investigators' Choice of 
Platinum Doublet Chemotherapy.............................................................10
Table 3.
Summary of Estimated Number of Events and Power in LSP+ 
Subjects....................................................................................................12
Table 4.
Time Windows for Visit-Wise Analysis (Laboratory, and Vital 
Signs) .......................................................................................................16


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
4
Table 5.
Time Windows for Visit-Wise Analysis (EQ-5D-5L, NFLSI-17, 
ECOG) .....................................................................................................17
Table 6.
Dose Intensity for platinum doublet of chemotherapy.............................23
Table 7.
NCCN-FACT Lung Symptom Index (NFLSI-17)...................................32
Table 8.
Adverse Event of Special Interest in Veliparib Program.........................38
Table 9.
Definitions of Toxicity Grades 1, 2, 3, and 4 for Laboratory 
Values ......................................................................................................41


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
5
2.1
Summary of Versions
Version
Date of Completion
Summary
1.0
29 July 2016
First finalized version
2.0
31 July 2018
Second finalized version submitting to FDA for 
review at pre-NDA meeting
3.0
24 May 2019
Third finalized version incorporating FDA's feedback
4.0
06 Nov 2019
!
Clarified the LSP subgroup definitions
!
Added assumed median OS for sample size 
calculation to address FDA's comment
!
Added summary for tissue sample disposition and
LSP assay results in the patient disposition 
section


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
6
2.2
List of Abbreviations and Definition of terms
Abbreviation
Term
AE
Adverse Event
AESI
Adverse Event of Special Interest
ANCOVA
Analysis of Covariance
AST
As Treated
BID
Twice a Day
C
Cycle
CI
Confidence Interval
CR
Complete Response
CRF or eCRF
Case Report Form or Electronic Case Report Form
D
Day
DNA
Deoxyribonucleic Acid
DOR
Duration of overall response
ECOG
Eastern Cooperative Oncology Group
EQ-5D-5L
European Quality of Life-5 Dimensions 
FACT
Functional Assessment of Cancer Therapy 
HR
Hazard ratio
IRT
Interactive Response Technology
ITT
Intent-To-Treat 
LSP
Lung Subtype Panel 
LSP+
Lung Subtype Panel positive
LSP-
Lung Subtype Panel negative
NSCLC
Non-small cell lung cancer
NCI CTCAE
National Cancer Institute Common Terminology Criteria For Adverse Events
NFLSI-17
NCCN-Functional Assessment of Cancer Therapy (FACT) Lung Symptom Index-17 
ORR
Objective response rate
OS
Overall survival
PARP
Poly-(ADP-ribose)-Polymerase
PD
Pharmacodynamic or Progressive Disease
PR
Partial response
PT
Preferred term
QoL
Quality of Life
SAE
Serious adverse event


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
7
SAP
Statistics analysis plan
SOC
System organ class
TEAE
Treatment emergent adverse event
VAS
Visual analog scale


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
8
3.0
Introduction
Veliparib is a potent Poly-(ADP-ribose)-Polymerase (PARP) inhibitor that inhibits the 
repair of Deoxyribonucleic Acid (DNA) damage induced by chemotherapeutics.  
Veliparib increases sensitivity of tumor cells to DNA-damaging agents in vitro and in 
vivo.  It has been shown to inhibit PARP in murine tumors experimental models in vivo.  
In addition, in clinical trials, veliparib has been shown to inhibit PARP in tumors in 
humans.
Phase 1 and preliminary Phase 2 study data suggest the addition of veliparib to 
carboplatin and paclitaxel may improve progression free survival (PFS) and overall 
survival (OS) in patients with advanced or metastatic non-squamous non-small cell lung 
cancer (NSCLC).  Therefore, this study (Study M14-359) is being conducted to assess 
efficacy and toxicity of veliparib in combination with carboplatin and paclitaxel versus 
investigator's choice of standard chemotherapy in subjects with metastatic or advanced 
non-squamous NSCLC receiving first cytotoxic chemotherapy and who are current or 
former smokers.  In addition, exploratory biomarker analysis from Phase 2 
Study M10-898 and Phase 3 Study M11-089 showed OS benefit from veliparib treatment 
in Lung Subtype Panel (LSP) positive (LSP+) subjects, based on research assay
conducted at Washington University. Therefore, this study will assess efficacy and safety 
in LSP+ subjects. 
This statistical analysis plan (SAP) provides details to further elaborate statistical methods 
as outlined in Clinical Study Protocol M14-359 incorporating Amendments 1, 2, 3, and 4 
and describes analysis conventions to guide the statistical programming.  LSP status will 
be based on results of LSP assay developed in partnership with Qiagen (may also be 
referred to as LSA or LP52).  LSP status (LSP positive, LSP negative and LSP unknown) 
will be defined based on all analytically valid results from up to two repeat assay runs 
(maximum of 3 runs including initial testing).  However, please note that SAP should not 
be impacted regardless of which LSP assay method applied. Analyses will be performed 
using SAS® Version 9.3 (SAS Institute, Inc., Cary, NC) or later under the UNIX operating 
system.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
9
4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective of the study is to assess if the addition of oral veliparib to 
carboplatin and paclitaxel in subjects who are metastatic or advanced NSCLC and have 
LSP+ biomarker will improve OS versus investigator's choice of platinum doublet 
standard chemotherapy.
The secondary objectives of the study are to assess PFS in LSP+ subjects, objective 
response rate (ORR) in LSP+ subjects, OS in all subjects, PFS in all subjects, and ORR in 
all subjects.  The tertiary objectives are to assess duration of overall response (DOR), 
Quality of Life (QoL), and ECOG performance status in LSP+ subjects and all subjects.
4.2
Design Diagram
This is a Phase 3, randomized, open-label multicenter study to assess efficacy, safety and 
tolerability of veliparib plus carboplatin and paclitaxel versus investigator's choice of 
platinum doublet standard chemotherapy in subjects receiving first cytotoxic 
chemotherapy for documented metastatic or advanced non-squamous NSCLC and who 
are current or former smokers.  The study is designed to enroll approximately 525 subjects 
at approximately 150 sites.  The enrollment is completed with 595 subjects randomized in 
this study.
Subjects will be randomized in a 1:1 ratio using Interactive Response Technology (IRT)
into one of the two treatment arms:
Arm A:  veliparib 120 mg BID and carboplatin (AUC 6 mg/mL/min)/paclitaxel 
(200 mg/m2)
Arm B:  investigators' choice of platinum doublet chemotherapy (carboplatin/paclitaxel, 
cisplatin/pemetrexed, or carboplatin/pemetrexed)


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
10
Subject randomization will be stratified by investigators' preferred platinum doublet 
chemotherapy (carboplatin/paclitaxel versus cisplatin/pemetrexed versus 
carboplatin/pemetrexed), smoking status (current smoker versus former smoker), ECOG 
performance status (0 versus 1) and gender (male versus female).  
The dose schedules for both groups of the study are detailed below in Table 1 and 
Table 2.
Table 1.
Treatment Schema for Each Cycle for Veliparib and 
Carboplatin/Paclitaxel Treatment Group
Days*
1
2
3
4
5
6
7
8 – 21
Veliparib
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Paclitaxel
Once
Carboplatin
Once
Note:
Day 1 and Day 2 of veliparib is labeled as Day –2 and Day –1 (pre-dose) in the protocol.  Day 3, the start of 
Paclitaxel and Carboplatin, is labeled as Day 1 in the protocol.  Day 1 for each cycle is calculated from start of 
veliparib in the analyses.
Table 2.
Treatment Schema for Each Cycle for Investigators' Choice of 
Platinum Doublet Chemotherapy
Days
1
2
3
4
5
6
7
8 – 21
Carboplatin/Paclitaxel
Once
Cisplatin/Pemetrexed
Once
Carboplatin/Pemetrexed
Once
Subjects will receive veliparib 120 mg BID in combination with carboplatin/paclitaxel or 
investigators' choice of platinum doublet chemotherapy for up to a maximum 6 cycles of 
treatment.  This interval is defined as the platinum-based treatment period.  After 6 cycles 
of platinum doublet chemotherapy, investigators may elect to administer maintenance 
pemetrexed in the post first line setting regardless of which therapy their subjects are 
randomized to receive.  This interval is defined as maintenance period.  All subjects will 
remain on study until reaching a protocol-defined event of disease progression.  


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
11
Study visits and assessments (except for tumor assessment) will be performed on the day 
of chemotherapy administration in each cycle until the subject reaches a radiographic
progression or prematurely discontinue.  Tumor assessment will be performed at baseline, 
Cycle 3 Day 1 and Cycle 5 Day 1.  After cessation of first line platinum doublet therapy, 
tumor assessments will be performed every 9 (q9) weeks until 1 year after the 1st dose of 
veliparib (or beyond 1 year until maintenance therapy is discontinued), then q12 weeks 
until radiographic progression or death.  After the determination of first radiographic 
progression, subjects no longer undergoing clinical assessments will have survival 
information reported via the Electronic Case Report Form (eCRF) at two-month intervals 
(or as requested by sponsor to support data analysis) beginning at the last clinical 
assessment and continuing until the endpoint of death, the subject has become lost to 
follow-up, or AbbVie terminates the study.
The detail of study schedule can be found in Figure 1 of the protocol (Study Schedule 
Schematic).
4.3
Sample Size
Sample size calculation for the original protocol:
Assuming the true hazard ratio of OS in favor of the veliparib 120 mg BID + 
carboplatin/paclitaxel treatment group is 0.64 in current smokers, a total of 210 OS events 
will be needed for the study to have at least 90% power at one-sided α level of 0.025 to 
detect a statistically significant treatment effect in current smokers for the veliparib 
120 mg BID + carboplatin/paclitaxel group using the log rank test for OS.  A total of 
approximately 300 current smokers will be enrolled to acquire the 210 death events. 
During the enrollment period for approximately 300 current smokers, it is anticipated that 
approximately 225 former smokers will be enrolled concurrently.  Assuming the true 
hazard ratio (HR) of OS in favor of the veliparib 120 mg BID + carboplatin/paclitaxel 
treatment group is 0.71 in the whole population (current plus former smokers), a total of 
369 OS events will be needed for the study to have approximately 90% power at 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
12
one-sided α level of 0.025 to detect a statistically significant treatment effect in the whole 
population for the veliparib 120 mg BID + carboplatin/paclitaxel group using the log rank 
test for OS.
Sample size consideration for OS analysis in LSP+ subgroup:
Among subjects classified as LSP+ (based on research assay) in Study M10-898, it was 
noted that there was an improvement in overall survival in the veliparib in combination 
with carboplatin and paclitaxel group compared to the carboplatin and paclitaxel alone.  
This finding was later confirmed by a subset of the sampled population from the Phase 3 
NSCLC squamous Study M11-089.  Based on the meaningful clinical benefit of veliparib 
treatment observed retrospectively in the LSP+ (based on research assay) subset of 
subjects from Study M10-898 and Study M11-089 collectively, the primary analysis
population in Study M14-359 has been changed from OS in the current smoker population 
to OS in the biomarker defined LSP+ (based on Qiagen assay) population. 
Based on 452 subjects having tissue samples (assumed 76% LSP sample availability rate, 
out of 595 enrolled subjects), Table 3 below provides the power and number of events 
(assuming 80% event rate at final analysis) for a range of likely LSP+ (based on Qiagen 
assay) rates if the treatment ratio is 1:1 in the LSP+ group and true HR of OS is 0.65 in 
LSP+ subgroup.
Table 3.
Summary of Estimated Number of Events and Power in LSP+ 
Subjects
Number of LSP+ Subjects 
(LSP+ rate)
Number of Events in LSP+
Power in LSP+ Subgroup 
(one-sided alpha = 0.025)
271 (60%)
216
89%
226 (50%)
180
82%
180 (40%)
144
73%
Median OS of 11.3 – 13.9 months have been reported in the literature for the control 
treatment in populations similar to the ITT population.1-3 An expected median OS in 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
13
LSP+ patients in a similar patient population is not available due to very limited clinical 
outcomes data in this patient population from Study M10-898 and external sources.
5.0
Analysis Populations
5.1
Definition for Analysis Populations
Study populations that will be involved in analyses are defined as follows:
●
Intent-To-Treat (ITT) population - all subjects who are randomized by IRT.  
The data from ITT population will be analyzed by the treatment group 
assignment given at the time of randomization, even if the subject takes the 
incorrect drugs that do not match the assigned treatment, or does not receive 
any treatment, or does not follow the protocol until completion.
●
As Treated (AST) population – all subjects who are randomized by IRT and 
take at least 1 dose of study drug (veliparib/investigators' choice of standard 
chemotherapy) as assigned treatment given at time of randomization.
●
LSP subgroup - ITT and AST population definition are also applied to LSP+, 
LSP-, unknown LSP. Note that unknown LSP status pools two subgroups:
○
subjects without available samples and 
○
subjects with samples, which either did not run based on quality or 
quantity of assay input material, or which ran but did not render a positive 
or negative analytically valid result based on up to 2 repeat runs.
5.2
Variables Used for Stratification of Randomization
Subject randomization is stratified by investigators' preferred platinum therapy 
(carboplatin/paclitaxel, cisplatin/pemetrexed, and carboplatin/pemetrexed), smoking 
status (current smoker, former smoker), ECOG performance status (0, 1) and gender 
(male, female).
Smoking status was a stratification factor at randomization for overall population per 
protocol. However, based on the evidence provided by Study M11-089 and 
Study M10-898, smoking status is not a significant prognostic factor in this patient 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
14
population. Therefore, smoking status is excluded from stratified efficacy analysis even 
though it was a stratification factor at randomization.
6.0
Analysis Conventions
General Considerations
Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a two-sided P value ≤ 0.05.  The date of randomization is defined as the 
date that the IRT issues a randomization number.
Definition of Platinum-doublet Study Drug
Unless otherwise specified, the platinum-based study drug in this document refers to 
veliparib plus carboplatin and paclitaxel or investigators' choice of standard chemotherapy 
for up to 6 cycles.  
Definition of Post-Platinum-doublet Study Drug
Unless otherwise specified, the post-platinum-based study drug in this document refers to 
pemetrexed maintenance after veliparib plus carboplatin/paclitaxel or investigator's choice 
of standard chemotherapy (carboplatin/paclitaxel, cisplatin/pemetrexed, and 
carboplatin/pemetrexed) for up to 6 cycles.
Definition of Post-Treatment Therapy (new anti-cancer therapy)
Unless otherwise specified, the post-treatment therapy (excluding surgical and radiation 
therapy) in this document refers to the therapy after veliparib plus carboplatin/paclitaxel 
or investigator's choice of standard chemotherapy (carboplatin/paclitaxel, 
cisplatin/pemetrexed, and carboplatin/pemetrexed) or after pemetrexed maintenance.
Pemetrexed maintenance is not considered as post-treatment therapy.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
15
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 in 
the shift analyses of laboratory parameters; the worst symptom value will be selected as 
the value for that day in the mean change from baseline in quality of Life (European 
Quality of Life-5 Dimensions (EQ-5D-5L), NCCN-Functional Assessment of Cancer 
Therapy (FACT) Lung Symptom Index-17 (NFLSI-17)) and mean change from baseline 
in performance status (ECOG).  In the analyses of change from baseline in laboratory and 
vital signs parameters, the arithmetic average will be calculated and used as the value for 
the day which multiple values are collected on the same day. 
Definition of Baseline
Unless otherwise specified, the baseline is defined as the last non-missing observation 
collected on or prior to the date of the first dose of study drug (veliparib plus carboplatin 
and paclitaxel or investigators' choice of standard chemotherapy) for treated subjects (or 
the date of randomization for non-treated subjects).
Definition of Final Observation (Platinum-doublet Study Drug)
For laboratory and vital signs variables, Final Observation is defined as the last non-
missing observation collected within 30 days following the last dose of platinum-based 
study drug (veliparib plus carboplatin and paclitaxel or investigators' choice of standard 
chemotherapy).  
Definition of Cycle Rx Days in Each Cycle
Cycle Rx Days for each cycle are calculated for each time point relative to first dose of 
veliparib or investigators' choice of standard chemotherapy/carboplatin/paclitaxel in each 
cycle.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
16
Definition of Analysis Windows
All time points and corresponding time windows are defined for each cycle based on 
Cycle Rx Day 1 to obtain number of days relative to the Cycle Rx Day 1 of each cycle.
For visit-wise longitudinal analyses such as change from baseline to all post-baseline 
assessments in EQ-5D-5L, NFLSI-17, ECOG, laboratory, and vital signs values, the time 
windows specified in Table 4 and Table 5 describe how the data will be assigned to the 
protocol specified visits.  Analysis time windows are constructed using the following 
algorithm:
●
Determine the nominal Cycle Rx Day for each scheduled visit.
●
Determine the window around a specific nominal Cycle Rx Day as in Table 4
and Table 5.
●
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.
Table 4.
Time Windows for Visit-Wise Analysis (Laboratory, and Vital 
Signs)
Scheduled Visit
Nominal Cycle Rx Day/
Time Window
Cycle 1 Day 1
BASELINE
As baseline definition
Cycle 1 Day 15(1)
17
(14, 20)
Cycle X Day 1
1
(–7, 7)
(1)
For Chemistry and Hematology only.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
17
Table 5.
Time Windows for Visit-Wise Analysis (EQ-5D-5L, NFLSI-17, 
ECOG)
Scheduled Visit
Nominal Cycle Rx Day
Time Window
Cycle 1 Day 1
BASELINE
As baseline definition
Cycle 1 Day 15 
17
(14, 20)
Cycle X Day 1
1
(–7, 7)
Post Platinum Doublet Visit X(1)
1
(–10, 10)
Pemetrexed Maintenance therapy Visit X(2)
1
(–10, 10)
Post Pemetrexed Maintenance therapy Visit X(3)
1
(–10, 10)
(1)
For EQ-5D-5L, NFLSI-17, and ECOG, nominal Cycle Rx Day 1 for Post Platinum Doublet Visit will be generated 
as 21 days from the study drug end date before Pemetrexed maintenance therapy if subjects receive Pemetrexed 
maintenance therapy or 21 days from study drug end date if subjects don't receive Pemetrexed maintenance 
therapy.
(2)
During maintenance therapy, nominal Maintenance Visit X will be generated as 60 days from Day 1 of the 
first maintenance therapy for EQ-5D-5L, NFLSI-17, and ECOG.
(3)
Post Maintenance Visit X will be generated as 60 days from the last date of maintenance therapy for EQ-5D-5L, 
NFLSI-17, and ECOG.
Chemistry Laboratory Platform Change
ICON Inc is the central laboratory used in this study.  The chemistry platform will be 
transitioned from the Roche Diagnostics Hitachi Modular System (old) to the Abbott 
Architecture (new) in December 2015 while the study is expected to be still on-going.  
The chemistry data obtained from the old chemistry platform will be converted to the new 
chemistry platform and the converted data will be combined with the data obtained from 
the new system for all statistical analysis and the normal ranges associated with the new 
chemistry platform will be applied.  The analysis of mean changes from baseline shifts 
above and below the normal ranges, the flagging of potentially clinically significant (PCS) 
laboratory data, and the Common Terminology Criteria for Adverse Events (CTCAE) 
grading of chemistry labs will be performed as if all the chemistry data were generated by 
one platform – the new chemistry platform.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
18
7.0
Demographics, Baseline Characteristics, Medical 
History, Prior/Concomitant Medications, Prior 
Oncology Therapies and Post-Treatment 
Medication
ITT population will be used in the analyses of demographic, baseline characteristics, 
medical history, and prior/concomitant medication, prior oncology therapy for adjuvant, 
neo-adjuvant, metastatic, surgical, or radiation therapies and post-treatment medication.
There are 5 treatment groups to be displayed for all analyses: veliparib 120 mg BID + 
carboplatin + paclitaxel, each of investigator's choice of platinum doublet therapy group 
(carboplatin + paclitaxel, cisplatin + pemetrexed, carboplatin + pemetrexed), and overall 
investigator's choice of platinum doublet therapy group.
The data will be summarized for LSP+ subjects, LSP- subjects, LSP unknown status, and 
all subjects by each treatment group unless otherwise specified.  
7.1
Demographic and Baseline Characteristics
Categorical demographic and baseline characteristic variables will be summarized with 
the number and percentage of subjects.  The number of subjects with missing information 
will also be summarized.  Continuous variables will be summarized with mean, standard 
deviation, median, minimum and maximum.  There will be no statistical comparison for 
the demographic and baseline characteristics.
Continuous demographic variables include age, baseline height and weight.  Categorical 
demographic variables include gender, age category (< 65 versus ≥ 65 years), race (White, 
Black, Asian, Other), and region 1 (Japan, US and western EU and Australia and Canada, 
Eastern EU/Russia, Other Asia).
US and western EU and Australia and Canada Region include Australia, Austria, 
Argentina, Brazil, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Mexico, 
Netherlands, New Zealand, Norway, Portugal, Puerto Rico, South Africa, Spain, Sweden, 
Switzerland, United Kingdom, United States, and Canada. 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
19
Eastern Europe/Russia includes Belarus, Croatia, Czech Republic, Egypt, Estonia, 
Hungary, Israel, Latvia, Lithuania, Poland, Russia, Serbia, Slovakia, Turkey, and Ukraine.
Continuous baseline characteristics include average pack years smoking exposure, 
baseline tumor burden (based on the sum of baseline target lesion sizes (mm)), time from 
diagnosis to first dose of study drug, time from tissue obtained for LSP (if available) 
and/or histology (if available) to first dose of study drug.
Categorical baseline characteristics include:
●
Smoking status (current smoker versus former smoker)
●
Investigators' preferred platinum doublet therapy (carboplatin/paclitaxel versus 
cisplatin/pemetrexed versus carboplatin/pemetrexed) 
●
ECOG (0 versus 1)
●
Number of Involved Organ Sites from baseline Tumor Assessment (1 –
2 versus > 2) and type of organ (e.g., lung, liver etc)
●
Site of biopsy (if data is available)
●
Reported differentiation status (if data is available)
Smoking status definition can be found in Protocol Section 8.3.
In addition, demographic and baseline characteristics will also be summarized by 
stratification variables under which subjects are randomized in IRT.
7.2
Medical History
Medical history data will be summarized and presented using System Organ Class (SOC 
and Preferred Terms (PT) according to the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary.  The SOCs will be presented in alphabetical order and the PTs will 
be presented in alphabetical order within each body system. The number and percentage 
of subjects with a particular PT will be summarized for LSP+ subjects and all subjects by 
each treatment group. Subjects reporting more than one PT within a SOC will be counted 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
20
only once for that SOC. The data will be summarized for LSP+ subjects and all subjects 
by each treatment group.  There will be no statistical comparison for the medical history.
7.3
Prior/Concomitant Medications, Prior Oncology Therapies 
and Post-Treatment Medications
A prior medication is defined as any medication taken prior to the date of the first dose of 
study drug (Veliparib or investigators' preferred platinum therapy).  A concomitant 
medication is defined as any medication that started prior to the date of the first dose of 
study drug and continued to be taken on or after the first dose of study drug or any 
medication that started on or after the date of the first dose of study drug, but not after the 
date of the last dose of study drug.  A post-treatment medication for the treatment of 
oncology is defined as any medication taken after veliparib plus carboplatin/paclitaxel or 
investigator's choice of standard chemotherapy (carboplatin/paclitaxel, 
cisplatin/pemetrexed, or carboplatin/pemetrexed) or after pemetrexed maintenance and 
entered as "Post Treatment Therapy" on the eCRF excluding surgical and radiation 
therapy.  Pemetrexed maintenance is not considered as post-treatment medication.
The number and percentage of subjects taking prior medications, concomitant 
medications, and post-treatment medications will be summarized by the generic name 
coded by WHO dictionary.  The number and percentage of subjects who have prior 
oncology therapies will be summarized by regimen names and treatment setting (adjuvant, 
neoadjuvant, metastatic).  In addition, the best response of any therapies prior to study 
drug (or randomization for non-treated subjects) will be summarized.  The data will be 
summarized for LSP+ subjects and all subjects by each treatment group. There will be no 
statistical comparison for the prior medications, prior oncology therapies, concomitant 
medications, and post-treatment medications.
8.0
Subject Disposition
Analyses for the subject disposition will be performed on ITT population.  The data will 
be summarized for LSP+ subjects, LSP- subjects, LSP unknown status, and all subjects, 
by each treatment group.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
21
The screen failure reasons will be summarized for the screen failure subjects.  The number 
of randomized subjects, the number of treated subjects, and the number of subjects in the 
maintenance pemetrexed will be summarized by country and investigator. 
The number and percentage of subjects who discontinue study and study drug will be 
summarized.  All reasons and the primary reason for discontinuation will be included in 
the summary.  There will be no formal statistical comparison for the subject disposition.
In addition, summary of LSP status would be provided with the following information:
●
Number of subjects with no sample for LSP status evaluation
●
Number of subjects with sample available for LSP status evaluation
○
Number of subjects for whom sample did not run
○
Number of subjects for which sample ran but with no positive or negative
result (QC fail)
○
Number of subjects for whom sample ran but with positive or negative
result (QC pass)
●
Number subjects with LSP positive status
●
Number of subjects with LSP negative status
9.0
Study Drug and Maintenance Drug Exposure
Analyses for the study drug and maintenance drug exposure will be performed on AST 
population. The summary will include two parts: the exposure to study drug during 
platinum doublet therapy period and the exposure to pemetrexed during the maintenance 
treatment period. The data will be summarized for LSP+ subjects, LSP- subjects, LSP 
unknown status, and all subjects, by each treatment group.
9.1
Exposure to study drug during platinum doublet therapy 
period
Duration of veliparib exposure is defined as total number of days a subject received 
veliparib.  Average dosed days per cycle of veliparib is defined as total number of days a 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
22
subject received veliparib divided by the number of cycles that subject were exposed to 
veliparib.  Descriptive statistics (mean, standard deviation, median, and range) will be 
used to summarize study drug exposure.  In addition, the number and percentage of 
subjects exposed to veliparib will be summarized for each of the following 7-day duration 
intervals.
●
1 to 7 days
●
8 to 14 days
●
15 to 21 days
●
22 to 28 days
●
29 to 35 days
●
36 to 42 days
●
> 42 days
The average number of cycles that subjects were exposed to veliparib, carboplatin, 
paclitaxel, cisplatin and pemetrexed will be summarized.  
The numbers and percentages of subjects having dose reduction of veliparib, carboplatin, 
paclitaxel, cisplatin, and pemetrexed will be summarized.  If a subject has any dose 
reduction from the previous dose, this subject will be considered as having experienced 
dose reduction.  All AST subjects will be included in the summary.
The numbers and percentages of subjects having dose delay of carboplatin, paclitaxel, 
cisplatin, and pemetrexed will be summarized.  If the elapsed time between 
two consecutive doses of platinum doublet therapy (carboplatin, paclitaxel, cisplatin, and 
pemetrexed) is more than 27 days, the subject will be considered as having experienced a 
dose delay of platinum doublet therapy.  Subjects who take only one cycle of platinum 
doublet therapy will not be included in this summary.
Dose Intensity of veliparib is defined as the ratio of actual total veliparib dose and the 
planned total veliparib dose.  Each planned cycle length for veliparib is 21 days.  The 
planned cycles for veliparib include the cycles before veliparib is discontinued.  


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
23
Dose Intensity of veliparib for each subject = actual total veliparib dose in all 
cycles/(240 mg *7 days *number of planned cycles for veliparib)
Dose intensity will also be calculated for carboplatin, cisplatin, paclitaxel and pemetrexed 
as defined in Table 6. 
Table 6.
Dose Intensity for platinum doublet of chemotherapy
Actual total Dose
Planned total Dose
Dose Intensity (%)
Carboplatin
Actual total dose AUC 
(mg/mL/min)
AUC 6 (mg/mL/min) * total 
number cycles of carboplatin
100*actual total 
dose/Planned total dose
Paclitaxel
Actual total dose (mg/m2)
200 mg/m2 * total number of 
cycles of paclitaxel
100*actual total 
dose/Planned total dose
Cisplatin
Actual total dose (mg/m2)
75 mg/m2 * total number of 
cycles of cisplatin
100*actual total 
dose/Planned total dose
Pemetrexed 
Actual total dose (mg/m2)
500 mg/m2 *total number of 
cycles of pemetrexed
100*actual total 
dose/Planned total dose
9.2
Exposure to maintenance pemetrexed
The number and percentage of subjects exposed to maintenance pemetrexed treatment 
will be summarized.  
10.0
Efficacy Analyses
10.1
General Considerations
Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a two-sided P value ≤ 0.05 (when rounded to three decimal places).
When LSP status is obtained by the Qiagen assay for all submitted tissue samples (LSP 
positive, LSP negative, LSP unknown), the date of EDC data cutoff will be determined 
and there will be a final LSP data transferred and database will be locked.  For overall 
survival (OS) and response/progression related efficacy endpoints (PFS, ORR, DOR, best 
response rate (BRR), depth of response (DpR), QoL), the same cutoff date will be used as 
the primary endpoint (OS in LSP+ subjects).


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
24
All efficacy endpoints will be analyzed for LSP+, LSP-, LSP unknown and all subjects 
unless otherwise specified.  The date of randomization is defined as the date when the 
randomization number is issued by IRT.  Pemetrexed maintenance period is included in 
efficacy analyses.
There will be 5 treatment groups presented in efficacy analyses:  veliparib 120 mg BID + 
carboplatin + paclitaxel, each of investigator's choice of platinum doublet therapy group 
(carboplatin + paclitaxel, cisplatin + pemetrexed, carboplatin + pemetrexed), and overall 
investigator's choice of platinum doublet therapy group.  Statistical comparison will be 
between the two randomized treatment groups (veliparib 120 mg BID + carboplatin + 
paclitaxel versus overall investigator's choice of platinum doublet therapy). 
If a subject starts Post-Treatment Therapy as described in Section 6.0, then all data except 
death for this subject measured on or after the start date of Post-Treatment Therapy 
(excluding surgical and radiation therapy) will not be used for PFS, ORR, BRR, DOR, 
DpR, ECOG, and QoL analyses, unless otherwise specified.
10.2
Primary Efficacy Analysis
The primary efficacy analysis will be a comparison of overall survival (OS) distributions 
between the two randomized treatment groups in LSP+ subjects, using the log-rank test, 
stratified by ECOG performance status, investigators' preferred platinum therapy, and 
gender. The balance of treatment groups in each stratum will be checked before 
conducting the stratified analysis.  The hazard ratio and corresponding 95% CI between
the two randomized treatment groups in LSP+ subjects will also be obtained using the 
covariate adjusted Cox Proportional Hazard Model with covariates being ECOG 
performance status, investigators' preferred platinum therapy, and gender. In addition, the 
median survival time with the corresponding 95% CI as well as the survival rates at 
Month 12, 18 and 24 will be provided from Kaplan-Meier estimation.
OS for a given subject will be defined as the number of days from the date that the subject 
is randomized to the date of the subject's death.  All events of death on or prior to the 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
25
"Cutoff" date will be included, regardless of whether the event occurred while the subject 
was still taking study drug, or after the subject discontinued study drug.  If a subject has 
not died on or before the "Cutoff" date, and there is any data (survival follow-up, study 
visit, death date, etc.) confirming that the subject is still alive or dies after the "Cutoff" 
date, the data will be censored at the "Cutoff" date; otherwise the data will be censored at 
the date when the subject was last known to be alive.
10.3
Secondary Efficacy Analyses
Fixed sequence testing procedure4 is used for analyses of the primary and secondary 
efficacy endpoints to control for the familywise error rate (FWER).  If veliparib plus 
carboplatin/paclitaxel treatment group is not statistically significantly better than the 
investigators' choice of standard therapy group for the primary efficacy endpoint of OS in 
LSP+ subjects, then statistical significance will not be declared for any of the secondary 
efficacy endpoints, regardless of the observed P values.  P values for the secondary 
efficacy analyses will be subject to multiple comparison adjustments using the fixed 
sequence testing method, with the analyses performed in the following order:  PFS in 
LSP+ subjects, ORR in LSP+ subjects, OS in all subjects, PFS in all subjects, and ORR in 
all subjects.
10.3.1
Progression-Free Survival in LSP+ subjects
PFS for a given subject 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 or to the date of death (all causes of mortality) if disease progression is not 
reached.  All events of disease progression occurring on or before the "Cutoff" date will 
be included, regardless of whether the event occurred while the subject was still taking 
study drug or had discontinued study drug.  However, if a disease progression event 
occurred immediately after that subject missed more than one scheduled consecutive 
disease progression assessments (e.g., the disease progression event occurred more than 
182 days (24 weeks + 14 days) after the last disease progression assessment), this subject 
will be censored at the last disease progression assessment prior to the disease progression 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
26
event.  All events of death occurring on or before the "Cutoff" date will be included for 
subjects who had not experienced disease progression provided the death occurred within 
84 days (12 weeks) of the last disease progression assessment.  If the subject does not 
have an event of disease progression nor has the subject died on or before the "Cutoff" 
date, the subject's data will be censored at the date of the subject's last disease progression 
assessment on or before the "Cutoff" date.  The two thresholds here, 182 days and 
84 days, were evaluated based on the time schedule for tumor assessment. If the 
randomized subject did not have any post-baseline disease progression assessment, the 
subject's data will be censored on the date of randomization.  If the result of disease 
progression assessment is 'unevaluable', this disease progression assessment is not 
included in the analyses.
The median PFS time with the corresponding 95% CI will be provided from Kaplan-
Meier estimation for each treatment group in LSP+ subjects and compared between 
two randomized treatment groups using the log-rank test, stratified by ECOG performance 
status, investigators' preferred platinum therapy, and gender.  The hazard ratio and 
corresponding 95% CI between the two randomized treatment groups will also be 
obtained using the covariate adjusted Cox Proportional Hazard Model with covariates 
being ECOG performance status, investigators' preferred platinum therapy, and gender.  
In addition, progression free rates at Month 6, 12, and 18 will be provided from Kaplan-
Meier estimation.
10.3.2
Objective Response Rate in LSP+ Subjects
ORR is defined as the proportion of subjects with complete response (CR) or partial 
response (PR) per RECIST (version 1.1).  Confirmation is required to determine objective 
response.  Confirmation rules are as follows:
Confirmed CR:  After the first tumor assessment showing CR, the CR will be considered 
as confirmed if the very next tumor assessment also shows CR (with no other responses in 
between), and if the duration between the two CRs is greater than or equal to 28 days.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
27
Confirmed PR:  After the first tumor assessment showing PR, the PR will be considered 
as confirmed if a subsequent tumor assessment also shows CR/PR (irrespective of tumor 
assessment in between that shows stable disease) and if the duration of the first PR and 
the next CR/PR is greater than or equal to 28 days.
Data after the first appearance of progressive disease (PD) will not be included since 
responses after PD may be due to other non-study drug influences (e.g., post-treatment 
therapy).
The ORR will be estimated and compared between the two randomized treatment groups 
using covariate adjusted logistic regression with the covariates being ECOG performance 
status, investigators' preferred platinum therapy, and gender.  In addition, 95% confidence 
interval will be constructed for the estimated proportion and the odds ratio of ORR and 
corresponding 95% CI between two randomized treatment groups will be estimated. 
BRR (best response rate) in LSP+ subjects will also be summarized for each treatment 
group, with BRR defined as the best response in all post-baseline disease assessments in 
the following order:  complete response, partial response, stable disease, progressive 
disease, and unevaluable response.  No confirmation is required for CR or PR.
All LSP+ subjects who were randomized regardless of whether they have any post-
baseline disease progression assessment will be included in the analysis.
10.3.3
Overall Survival in All Subjects
For all subjects, the distribution of OS including median survival time with the 
corresponding 95% CI will be estimated for each treatment group using Kaplan-Meier 
methodology and compared between the two randomized treatment groups using the log-
rank test, stratified by LSP status (LSP+ versus LSP- versus unknown LSP), ECOG 
performance status, investigators' preferred platinum therapy, and gender.  The hazard 
ratio and corresponding 95% CI between the two randomized treatment groups in all 
subjects will also be obtained using the covariate adjusted Cox Proportional Hazard 
Model with covariates being LSP status (LSP+ versus LSP- versus unknown LSP), ECOG 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
28
performance status, investigators' preferred platinum therapy, and gender.  In addition, 
survival rates at Month 12, 18, and 24 will be provided from Kaplan-Meier estimation.
10.3.4
Progression-Free Survival in All Subjects
For all subjects, the distribution of PFS including median PFS time with the 
corresponding 95% CI will be estimated using Kaplan-Meier methodology and compared 
between the two randomized treatment groups using the log-rank test, stratified by LSP 
status (LSP+ versus LSP- versus unknown LSP), ECOG performance status, investigators' 
preferred platinum therapy, and gender.  The hazard ratio and corresponding 95% CI 
between the two randomized treatment groups will also be obtained using the covariate 
adjusted Cox Proportional Hazard Model.  Covariates to be adjusted are LSP status (LSP+ 
versus LSP- versus unknown LSP), ECOG performance status, investigators' preferred 
platinum therapy, and gender. In addition, progression free rates at Month 6, 12, and 18 
will be provided from Kaplan-Meier estimation.
10.3.5
Objective Response Rate in All Subjects
The ORR will be estimated and compared between the two randomized treatment groups 
using covariate adjusted logistic regression with the covariates being by LSP status (LSP+ 
versus LSP- versus unknown LSP), ECOG performance status, investigators' preferred 
platinum therapy, and gender.  In addition, 95% confidence interval will be constructed 
for the estimated proportion.  All subjects who were randomized regardless of whether 
they have any post-baseline disease progression assessment will be included in the 
analysis.
BRR (best response rate) in all subjects will also be summarized for each treatment group, 
with BRR defined as the best response in all post-treatment disease assessments in the 
order specified in Section 10.3.2.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
29
10.4
Tertiary Efficacy Analyses
10.4.1
Duration of Overall Response
The duration of overall response (DOR) for a given subject will be defined as the number 
of days from the day the criteria are met for confirmed CR or PR (whichever is recorded 
first) to the date that PD is objectively documented by investigators or death, whichever is 
early.  If a subject is still responding on or before the "Cutoff" date, then the subject's data 
will be censored at date of the last evaluable disease progression assessment on or before 
the "Cutoff."  All events of death occurring on or before the "Cutoff" date will be included 
for subjects who had not experienced disease progression provided the death occurred 
within 84 days (12 weeks) of the last disease progression assessment.  However, if a 
disease progression event occurred immediately after that subject missed more than 
one scheduled consecutive disease progression assessments (e.g., the disease progression 
event occurred more than 182 days (24 weeks + 14 days) after the last disease progression 
assessment), this subject will be censored at the last disease progression assessment prior 
to the disease progression event.  For subjects who never experienced CR or PR, the 
subject's data will not be included.
If the number of subjects with confirmed CR or PR are at least 20% for both randomized 
treatment groups combined, the distribution of the DOR will be estimated for each 
treatment group using Kaplan-Meier methodology.  Median DOR with the corresponding 
95% CI will be provided from Kaplan-Meier estimation.  DOR will be summarized for 
LSP+, LSP-, LSP unknown and all subjects.
10.4.2
Quality of Life
All subjects who do not have baseline measurement or any post-baseline measurements 
on ITT population will not be included in QoL analyses.  Post-baseline measurements will 
be obtained according to the visit window as in Table 4.  
Descriptive statistics will be presented for baseline and each scheduled post-baseline visit 
(as defined in Table 4) of both overall and domain specific scores of EQ-5D-5L5 and 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
30
NFLSI-17.  Mean change (95% CI) from baseline to each scheduled post-baseline visit 
within treatment group and the mean difference of change (95% CI) from baseline to each 
scheduled post baseline visit between the two randomized treatment groups will be 
obtained from the ANCOVA model with treatment group as the factor and baseline value 
as a covariate.  
The mean change from baseline for overall score and domain specific scores at each 
assessment time point may also be compared between the two randomized treatment 
groups using a longitudinal repeated measures model. This analysis will include all 
available data, from baseline to 2 years or disease progression, or initiation of post-
treatment therapy, or discontinuation, whichever is latest.  
The data will be analyzed at visits with at least 5 subjects for each randomized treatment 
group.  QoL endpoints will be summarized for LSP+, LSP-, LSP unknown and all 
subjects.
EQ-5D-5L
EQ-5D-5L consists of 5 items:  mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression and a self-rated health visual analogue scale (EQ VAS).
An EQ-5D-5L utility score will be calculated based on country specific preference-
weighted index score method.  If a country is not included in list of preference weighted 
index scores, the US preference-weighted index score will be used.  If any of the 5 items 
are missing, the utility score is set to missing.  Ambiguous values (e.g., 2 responses are 
given for a question) is set to missing.
Mean change in utility score (and 95% CI) from baseline to each scheduled post-baseline 
visit within each treatment group and between the two randomized treatment groups will 
be obtained from the ANCOVA model with treatment group as the factor and baseline 
value as a covariate. 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
31
Item 6 of EQ-5D-5L, a visual analog scale (VAS) will be analyzed using the same 
methodology as detailed for the utility score.
NFLSI-17
The overall and domain specific scores will be calculated from the 17 items of NFLSI-17 
questioners for each subject based on NFLSI-17 instruction.  The items and scales 
including calculation formula are shown as follows.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
32
Table 7.
NCCN-FACT Lung Symptom Index (NFLSI-17)
Scale
Reverse item?
Item Score
NFLSI-17 Total
I have a lack of energy
GP1
Yes
4 - Item Response
I have pain
GP4
Yes
4 - Item Response
I am losing weight
C2
Yes
4 - Item Response
I have been short of breath
B1
Yes
4 - Item Response
I feel fatigued
H17
Yes
4 - Item Response
I have been coughing
L2
Yes
4 - Item Response
I have bone pain
BP1
Yes
4 - Item Response
Breathing is easy for me
L4
No
Item Response
I have a good appetite
C6
No
Item Response
I am sleeping well
GF5
No
Item Response
I worry that my condition will get worse
GE6
Yes
4 - Item Response
I have nausea
GP2
Yes
4 - Item Response
I am bothered by hair loss
B5
Yes
4 - Item Response
I am bothered by side effects of treatment
GP5
Yes
4 - Item Response
My thinking is clear
L1
No
Item Response
I am able to enjoy life
GF3
No
Item Response
I am content with the quality of my life right now
GF7
No
Item Response
Subscale
I have a lack of energy
GP1
Yes
4 - Item Response
I have pain
GP4
Yes
4 - Item Response
I am losing weight
C2
Yes
4 - Item Response
I have been short of breath
B1
Yes
4 - Item Response
I feel fatigued
H17
Yes
4 - Item Response
I have been coughing
L2
Yes
4 - Item Response
I have bone pain
BP1
Yes
4 - Item Response
Breathing is easy for me
L4
No
Item Response
I have a good appetite
C6
No
Item Response
I am sleeping well
GF5
No
Item Response
Disease Related Symptoms-Emotional
I worry that my condition will get worse
GE6
Yes
4 - Item Response


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
33
Table 7.
NCCN-FACT Lung Symptom Index (NFLSI-17) (Continued)
Scale
Reverse item?
Item Score
Subscale (continued)
Treatment Side Effects
I have nausea
GP2
Yes
4 - Item Response
I am bothered by hair loss
B5
Yes
4 - Item Response
I am bothered by side effects of treatment
GP5
Yes
4 - Item Response
Function/Well-Being
My thinking is clear
L1
No
Item Response
I am able to enjoy life
GF3
No
Item Response
I am content with the quality of my life right now
GF7
No
Item Response
NFLSI-17 total score = (Sum individual items sore) × 17/(number of items answered)
NFLSI-Disease Related Symptom-Physical score = (Sum individual items sore for 
Disease Related Symptom-Physical) × 10/(number of items answered)
NFLSI-Disease Related Symptom-Emotional = Disease Related Symptom Emotional 
Score
NFLSI-Treatment Side effects score = (Sum individual items sore for Treatment Side 
Effects) × 3/(number of items answered)
NFLSI-Function/Well-Being score = (Sum individual items sore for function/well-being) 
× 3/(number of items answered)
If a subject responds 50% or more of the items in a scale (e.g., NFLSI-17 total score), then 
the raw score of that subject will contribute to the scale.  Otherwise, a subject's data will 
be excluded from the calculation of the summary statistics of that item.  
Mean change of each subscale and total scale from baseline to each scheduled post-
baseline visit within treatment group and between two randomized treatment groups will 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
34
be obtained from the ANCOVA model with treatment group as the factor and baseline 
value as a covariate.
10.4.3
Performance Status
All subjects who do not have baseline measurement or any post-baseline measurement 
will not be included in ECOG analyses. ECOG at the scheduled post-baseline visits will 
be obtained according to the visit window as in Table 4.
Descriptive statistics will be presented for baseline and each scheduled post-baseline visit 
(as defined in Table 4) of ECOG.  Mean change (95% CI) from baseline to each 
scheduled post-baseline visit within treatment group and the mean difference in change 
(95% CI) from baseline to each scheduled post-baseline visit between the two randomized 
treatment groups will be obtained from the ANCOVA model with treatment group as the 
factor and baseline ECOG as a covariate.  The data will be analyzed at visits with at least 
5 subjects for each randomized treatment group.  ECOG will be summarized for LSP+, 
LSP-, LSP unknown and all subjects.
10.5
Additional Efficacy Analyses
The following analyses might be performed for the comparison of treatments in LSP-
subjects and unknown LSP status subjects, provided there are enough data points in each 
LSP subgroup.
●
For OS and PFS, the log-rank test, stratified by ECOG performance status, 
investigators' preferred platinum therapy, and gender, will be used to compare 
the two randomized treatment groups. 
●
For ORR, the covariate adjusted logistic regression with the covariates being 
ECOG performance status, investigators' preferred platinum therapy, and 
gender, will be used to compare between the two randomized treatment 
groups. 
●
BRR will also be summarized for each treatment group, with BRR defined as 
the best response in all post-treatment disease assessments in the order 
specified in Section 10.3.2.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
35
The following sensitivity analyses for OS will be performed in LSP+, LSP-, LSP 
unknown and all subjects.  The same statistical methods as for the primary and secondary 
endpoints will be used to compare the two randomized treatment groups.
●
Modified OS using all data available in the extracted database without cutoff 
date.
The following sensitivity analyses for PFS will be performed in LSP+, LSP-, LSP 
unknown subjects and all subjects.
●
Modified PFS using all data available in the extracted database without cutoff 
date.
●
Modified PFS endpoint to consider initiation of post-treatment therapy as an 
event.
Subgroup analyses for OS defined in Section 10.2, PFS endpoints defined in 
Section 10.3.1, and ORR defined in Section 10.3.2 will be performed for LSP+, LSP-, 
LSP unknown and all subjects.  The subgroups are
●
Gender (male/female)
●
Age categories (< 65 years, ≥ 65 years)
●
ECOG (0 versus 1)
●
Region 1 (Japan, US and western EU and Australia and Canada, Eastern 
EU/Russia, Other Asia)
Due to the small number of subjects as Black, Asian and others enrolled into this study, 
no subgroup analysis will be conducted by Race.
The odd ratio of ORR and corresponding 95% CI between two randomized treatment 
groups by logistic regression model will be estimated for the above subgroups and will be 
displayed in forest plots.  The hazard ratio and 95% CI for OS and PFS will be estimated 
by the Cox proportional hazards model for the above subgroups and will be displayed in 
forest plots.  


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
36
In addition, the following analyses might be performed.
●
Depth of response (DpR) (as defined as the number/percentage of subjects
achieving 50% of reduction in the best percentage change from baseline in
sum of target lesion sizes among confirmed PR for LSP+ and all subjects.
●
Analysis of best percentage of change in tumor shrinkage (assessed by largest 
decrease or smallest increase if no decrease in sum of target lesion sizes from 
baseline) for LSP+ subjects and all subjects. All post-baseline responses from 
evaluable tumor assessment will be included (do not need to be confirmed) and 
will be displayed in waterfall plot.
●
The median OS time with the corresponding 95% CI as well as the survival 
rates at Month 12, 18 and 24 will be provided from Kaplan-Meier estimation 
for LSP profiled (LSP+ and LSP-), LSP unprofiled (sample provided with 
indeterminate results or sample not provided) and all subjects.
11.0
Safety Analyses 
11.1
General Considerations
Safety analyses will be performed on AST population.  Pemetrexed maintenance is NOT 
considered as study drug.  For the visit wise safety analyses, the analysis visit widow as 
described in Table 4 will be used to align the data.  
There will be 5 treatment groups presented in all safety summaries:  veliparib 120 mg BID 
+ carboplatin + paclitaxel, each of investigator's choice of platinum doublet therapy group 
(carboplatin + paclitaxel, cisplatin + pemetrexed, carboplatin + pemetrexed), and overall 
investigator's choice of platinum doublet therapy group.  There will be no statistical 
comparisons in any of the safety analyses.  All safety analysis will be conducted by 
treatment group for LSP+, LSP-, LSP unknown and all subjects.  
11.2
Analyses of Adverse Events
AEs will be coded using the MedDRA coding dictionary.  The actual version of the 
MedDRA coding dictionary will be noted in the CSR.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
37
Analyses of AEs will include only "treatment-emergent" events.  "Treatment-emergent 
adverse events" (TEAEs) are defined as any AEs that first occur on or after the date of 
first dosing and with an onset date no more than 30 days after the last dose of study drug 
(veliparib or investigators' choice of standard chemotherapy).  TEAEs will be summarized 
by preferred terms (PT) within a system organ class (SOC).  The SOCs will be presented 
in alphabetical order, and the PTs will be presented in alphabetical order within each 
SOC.  Subjects reporting more than one AE for a given PT will be counted only once for 
that term (most severe/highest grade incident for the severity tables and most related 
incident for the relationship tables).  Subjects reporting more than one AE within a SOC 
will be counted only once for that SOC.  Subjects reporting more than one AE will be 
counted only once in the overall total.
The numbers and percentages of subjects experiencing an AE at NCI CTCAE version 4.0 
terminology grade,6 and relationship to veliparib, carboplatin, cisplatin, pemetrexed, or 
paclitaxel will be provided.  SAEs, AEs leading to veliparib, carboplatin, cisplatin, 
pemetrexed, or paclitaxel discontinuation due to disease progression or not due to disease 
progression, AEs leading to veliparib dose interruption, cisplatin, pemetrexed, 
carboplatin, or paclitaxel dose delay, veliparib, carboplatin, cisplatin, pemetrexed, or 
paclitaxel dose reduction will be summarized by treatment group for LSP+, LSP-, LSP 
unknown and all subjects.
11.2.1
Analysis of Adverse Events of Special Interest
Analyses of adverse events of special interest will be supported through the summary of
MedDRA preferred terms identified using standard MedDRA queries (SMQ-s) and 
company MedDRA queries (CMQ-s).  The incidence rates of these events will be 
summarized by PT in descending order of veliparib.  The same overview summary as for 
TEAE and listing of subjects' data will be provided for each AESI.  All AESI analysis will 
be conducted by treatment group for LSP+, LSP-, LSP unknown and all subjects unless 
otherwise specified. 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
38
Table 8.
Adverse Event of Special Interest in Veliparib Program
Adverse Event of 
Special Interest
Search Criteria
Event Definition/Medical Concept
Nausea and 
vomiting 
Nausea and vomiting MedDRA 
preferred terms (PT code 
10028813, 10047700)
Treatment-emergent adverse events coded 
to MedDRA preferred terms.
Seizures
Convulsions SMQ 20000079 
(query for convulsions)
Treatment-emergent adverse events coded 
to MedDRA terms on the broad search list.
Anemia
Haematopoietic erythropenia 
SMQ 20000029
Treatment-emergent adverse events coded 
to MedDRA terms on the broad search list.
Thrombocytopenia
Haematopoietic thrombocytopenia 
SMQ 20000031
Treatment-emergent adverse events coded 
to MedDRA terms on the broad search list.
Neutropenia
Hematological Toxicity-
Neutropenia CMQ 80000154
Treatment-emergent adverse events coded 
to MedDRA terms.
Infection events 
within 14 days 
after neutropenia 
events
Infections CMQ 80000018 and 
hematological toxicity-neutropenia 
CMQ 80000154 
Treatment-emergent adverse events from 
the MedDRA terms on the broad search list.
Haemorrhage 
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.
Myelodysplastic 
Syndromes (MDS)
Myelodysplastic syndrome SMQ 
(Narrow) 20000217
Treatment-emergent adverse events from 
the MedDRA terms on the search list.
Acute Myeloid 
Leukemia (AML)
Acute myeloid leukaemia PT 
(10000880)
Treatment-emergent adverse events from 
the MedDRA preferred terms on the search 
list.
Changes in 
reproductive organ 
function
SMQ 20000210 (fertility 
disorders)
Treatment-emergent adverse events from 
the MedDRA terms on the search list.
Teratogenicity
Pregnancies and outcomes will be analyzed 
individually as they occur.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
39
11.3
Analyses of 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.  
11.4
Analyses of Laboratory and Vital Signs Data
11.4.1
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline to each scheduled post-baseline visit and Final Visit are analyzed 
for hematology variables, chemistry variables, urinalysis variables (if collected), and vital 
signs variables including diastolic/systolic blood pressure, heart rate, and body 
temperature.  Post-baseline visits more than 30 days after the last dose of study drug 
(veliparib or investigators' choice of standard chemotherapy) will not be included.  
Subjects who do not have a baseline visit or do not have any post-baseline visits will not 
be included.  
Descriptive statistics will be presented for baseline, each scheduled post-baseline 
including final visit, and change from baseline.
11.4.2
Analyses of Laboratory Data Using NCI CTCAE v4.0
Following categorization of hematology variables and chemistry variables by NCI 
CTCAE version 4.0 grades, shift tables from baseline to maximum post-baseline and 
Final Visit terminology grade will be presented.  Post-baseline visits more than 30 days 
after the last dose of study drug will not be included.
The tables will contain a cross-tabulation of number and percentage of categorized 
baseline grades versus maximum post-baseline/Final Visit grades.  The categories in the 
cross-tabulation include terminology grades 0 to 4 and missing value.  The Grade 0 is 
defined as the value within the normal range or any value that is outside the normal range 
but in the opposite direction of toxicity criteria.  The maximum post-baseline grade for 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
40
each subject is based on the graded values (0 to 4).  For each parameter, post-baseline 
laboratory abnormalities will be summarized by the number and percentage of subjects 
that have a grade 0 or unknown baseline and also have a grade 1 - 4 post-baseline or 
worsened from an abnormal baseline value by at least one grade post-baseline. Grade 3 
and 4 post-baseline laboratory abnormalities will also be summarized by number and 
percentage of subjects shifting from grade 0 or unknown to grade 2 at baseline to grade 3 
or 4 post-baseline and from grade 3 baseline to grade 4 post-baseline at both the 
maximum and final observation grade.
Listings of the applicable NCI CTCAE criteria and detailed listings of data for subjects 
with measurements (regardless of the number of days after the last dose of study drug) 
meeting the NCI CTCAE grade 3 to grade 4 criteria will be presented.
The definitions of toxicity grades for laboratory parameters are presented in Table 9.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
41
Table 9.
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 –
2.5 mg/DL
< 2.5 –
2.0 mg/DL
< 2.0 –
1.0 mg/DL
< 1.0 mg/DL
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


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
42
Table 9.
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
11.4.3
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 
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 criteria3)
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 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
43
will be used in the plot.  A listing of lab data for subjects meeting potential Hy's law 
criteria will be provided.
11.5
Analyses of Safety by Subgroup (All population)
11.5.1
Adverse Events Subgroup Analyses
Subgroup analyses may be performed on treatment-emergent G3/4 AEs for imbalance 
safety observation between randomized treatment groups.  The subgroups to be evaluated 
include:
●
Gender (male/female)
●
Age categories (< 65 years, ≥ 65 years)
●
Region 2 (Japan, US, EU/Canada)
Due to the small number of subjects as Black, Asian and others enrolled into this study, 
no subgroup analysis will be conducted by Race.
11.5.2
Laboratory Variables Subgroup Analyses
Subgroup analyses for all subjects will be performed for the shifts from baseline 0 - 2 to 
maximum grade of 3 and 4 the hematology variables and chemistry variables for the 
following subgroups:
●
Gender (male/female)
●
Age categories (< 65 years, ≥ 65 years)
●
Region 2 (Japan, US, EU/Canada)
Due to the small number of subjects as Black, Asian and others enrolled into this study, 
no subgroup analysis will be conducted by Race.


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
44
12.0
Summary of Changes
12.1
Summary of Major Changes from the Last Version of the 
SAP
1.
Clarified the definition of LSP subgroups including the LSP+ primary population.
Rational: Patients with analytically valid LSP results can be included in the LSP+ 
subgroups (primary analysis set) regardless of RNA mass (including those below 
the 35 ng RNA threshold described in the assay protocol) or re-test status. 
●
Although the likelihood of QC failure increases with the decreased RNA mass, 
the LSP subgroup determination (positive or negative) remains reliable among 
QC-pass samples. 
●
The LSA testing protocol allows re-testing to resolve trouble-shooting (QC 
failure or qPCR failure) with no upper limit to the number of repeat runs.
●
The assay data transfer specifications have been revised to include 
subcategories that will capture data related to multiple runs
2.
Added reference for median OS for sample size calculation to address FDA's 
comment
Rational: To address FDA comment received on Jan 2019: "In the SAP, please 
provide the assumed medians for the final OS analyses in the LSP-positive and ITT 
populations."
3.
Added summary for LSP results in the patient disposition section
13.0
References
1.
Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus 
chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med.
2018;378(22):2078-92.
2.
Paz-Ares LG, de Marinis F, Dediu M, et al.  PARAMOUNT:  Final overall 
survival results of the phase III study of maintenance pemetrexed versus placebo 


Veliparib
M14-359 – Statistical Analysis Plan
Version 4.0 – 06 Nov 2019
45
immediately after induction treatment with pemetrexed plus cisplatin for advanced 
nonsquamous non-small-cell lung cancer.  J Clin Oncol. 2013;31(23):2895-902.
3.
Ciuleanu T, Brodowicz T, Zielinski C, et al.  Maintenance pemetrexed plus best 
supportive care versus placebo plus best supportive care for non-small-cell lung 
cancer: a randomised, double-blind, phase 3 study.  The Lancet.  
2009;374(9699):1432-40.
4.
Glimm E, Maurer W, Bretz F.  Hierarchical testing of multiple endpoints in group-
sequential trials.  Stat Med.  2010;29(2):219-28.
5.
Mandy van Reenen and Bas Janssen.  EQ-5D-5L User Guide:  Basic Information 
on How to Use the EQ-5D-5L Instrument, Version 2.1.  April 2015.
6.
Common Terminology Criteria for Adverse Events, Version 4.0, DCTD, NCI, 
NIH, DHHS.  28 May 2009 [cited 29 July 2009].  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev4.p
df.