Conditions: Small Cell Lung Cancer
Keywords: Extensive Stage Smal Cell Lung Cancer ABT-888 Veliparib PARP - Poly (ADP) ribose polymerase
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 221
Healthy volunteers: no

Brief summary:
The study seeks to assess the efficacy of veliparib (ABT-888) in combination with carboplatin and etoposide in participants with extensive disease small cell lung cancer (ED SCLC).

Detailed description:
This is a Phase 1, open-label, dose-escalation/Phase 2 randomized double-blind study of veliparib in combination with carboplatin and etoposide and maintenance veliparib monotherapy.

Participants in Phase 1 will be sequentially assigned to ascending dose levels of veliparib in combination with standard carboplatin/etoposide regimen for up to four 21-day cycles based on the observed toxicities. The study design for Phase 1 will follow a traditional "3 + 3" dose-escalation protocol.

Once the veliparib recommended Phase 2 dose (RPTD) and schedule is determined, enrollment into Phase 2 will begin. Participants from the Phase 1 dose-escalation portion of the study are not eligible for enrollment into the Phase 2 portion. Participants in Phase 2 will be randomized in a 1:1:1 ratio to carboplatin, etoposide, placebo followed by placebo maintenance (Arm C), or carboplatin, etoposide, veliparib followed by either veliparib (Arm A) or placebo (Arm B) maintenance. Randomization for Phase 2 will be stratified by baseline lactate dehydrogenase (LDH) level (\> upper limit of normal \[ULN\] vs. ≤ ULN), and gender.

Arms:
arm 1: Participants in Phase 1 will be sequentially assigned to ascending dose levels of veliparib in combination with carboplatin/etoposide for up to four 21-day cycles.

Participants without evidence of disease progression will continue on veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. arm 2: Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by veliparib monotherapy at 400 mg BID continuous dosing (21-day cycles) until disease progression or unacceptable toxicity. arm 3: Participants will receive veliparib 240 mg in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs. arm 4: Participants will receive placebo in combination with carboplatin/etoposide for four to six 21-day cycles followed by placebo monotherapy continuous dosing (21-day cycles) until disease progression or unacceptable toxicity occurs.

Interventions: intervention 1: Veliparib intervention 2: Carboplatin intervention 3: Etoposide intervention 4: Placebo
Intervention descriptions: intervention 1: Capsules administered orally twice a day according to the dosing schedule. intervention 2: Administered by intravenous infusion on Day 1 of each 21-day cycle over approximately 30 minutes at a target area under the curve (AUC) 5 mg/mL\*minute. intervention 3: Administered by intravenous infusion on Days 1 to 3 of every 21-day cycle over approximately 60 minutes at 100 mg/m². intervention 4: Placebo to veliparib administered orally twice a day according to the dosing schedule.

Protocol document:
Prot_000.pdf: 
Veliparib
M14-361 Protocol Amendment 5
EudraCT 2014-001764-35
1
1.0
Title Page
Clinical Study Protocol M14-361
A Phase 1 Dose Escalation and Phase 2 Randomized 
Double-Blind Study of Veliparib in Combination with 
Carboplatin and Etoposide as a Therapy of
Treatment-Naïve Extensive Stage Disease Small Cell 
Lung Cancer
Incorporating Administrative Changes 1 and 2, and 
Amendments 1, 2, 3, 4 and 5
AbbVie Investigational
  Product:
Veliparib
Date:
22 November 2016
Development Phase:
1/2
Study Design:
This is a Phase 1 3 + 3 dose-escalation/Phase 2 randomized 
double-blind study of veliparib in combination with carboplatin 
and etoposide and followed by maintenance veliparib 
monotherapy.  Subjects in Phase 2 will be randomized in a 
1:1:1 ratio to carboplatin, etoposide, placebo followed by placebo 
maintenance or carboplatin, etoposide, veliparib followed by 
either veliparib or placebo maintenance.
EudraCT Number:
2014-001764-35
Investigator:
Multicenter Trial:  Investigator information is on file at AbbVie
Sponsor:
AbbVie Inc.* (AbbVie)
NCT02289690


Veliparib
M14-361 Protocol Amendment 5
EudraCT 2014-001764-35
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Sponsor/Emergency 
  Contact:
Medical Director
Oncology
 
AbbVie FNC
200 Sidney Street
Cambridge, MA  02139
Phone:
Fax:
Email:  
*  The specific contract details of the AbbVie legal/regulatory entity (person) within the relevant country 
and provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


Veliparib
M14-361 Protocol Amendment 5
EudraCT 2014-001764-35
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions 
Protocol 
Date 
Original
23 June 2014
Amendment 1
04 May 2015
Administrative Change 1
17 June 2015
Amendment 2
30 July 2015
Amendment 3
18 December 2015
Amendment 4
14 June 2016
Administrative Change 2
28 June 2016
●
Added veliparib/placebo Recommended Phase 2 Dose (RPTD) of 240 mg BID 
in a 14-day schedule as the veliparib/placebo dose and schedule for Phase 2 
combination therapy.
Rationale:  To define the veliparib RPTD and schedule per Phase 1 study 
data.
●
Added Post-Treatment Follow-Up in Table 8, Study Activities in Phase 2, and 
clarified Post-Treatment Follow-Up vs. Survival Follow-Up periods 
throughout.
Rationale:  To clarify tumor assessment data collection after Phase 2 study 
drug discontinuation.
●
Modified tumor assessment procedure timing to Q6W for the first 30 weeks in 
Phase 2.
Rationale:  To improve resolution of progression free endpoint analysis.
●
Added Section 5.2.4, Contraception Recommendations.
Rationale:  To include the current protocol template contraception language.
●
Updated Inclusion Criterion 9 to reference new Section 5.2.4, Contraception 
Recommendations.
Rationale:  To simplify the Inclusion criteria.
●
Included HBsAg, HCV RNA and Urinalysis to Table 7, Study Activities 
Phase 1 Dose Escalation, and Table 8, Study Activities in Phase 2.


Veliparib
M14-361 Protocol Amendment 5
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Rationale:  To clarify collection requirements for each.
●
Clarified that Vital Signs collection on Cycle Day 2 and Cycle Day 3 are for 
C1 only.
Rationale:  To simplify the study procedures.
●
Clarified the 30-Day Follow-Up visit timing.
Rationale:  To ensure safety follow up after drug discontinuation.
●
Clarified anatomy to be scanned during CT scan performance.
Rationale:  To ensure proper and consistent imaging across the study sites.
●
Updated Physical Examination procedure to include a hearing assessment if 
recommended per local label for carboplatin.
Rationale:  To address comments from ethics committee.
●
Updated Section 5.4.1, Discontinuation of Individual Subjects, with the 
requirement to notify AbbVie of lost progression free survival endpoints.
Rationale:  To ensure resolution of progression free endpoint analysis.
●
Updated Table 13, Identity of Investigational Products, with a footnote.
Rationale:  To clarify that 20 mg veliparib capsules will be used in Phase 1 
only.
●
Updated Table 16, Guidelines for Veliparib, Carboplatin, and Etoposide Dose 
Reduction Levels During Combination Therapy, with a footnote.
Rationale:  To clarify that etoposide drug reduction guidelines due to bilirubin 
values prevail.
●
Updated survival data collection requirements.
Rationale:  To clarify that all deaths are to be reported in eCRF, regardless of 
causality.
●
Updated safety wording.
Rationale:  To include the current protocol template safety language.
●
Updated Primary Contact for protocol deviations.
Rationale:  To reflect current team.
●
Updated Section 8.1.1.1, Demographics
Rationale:  To provide smoking history definitions.


Veliparib
M14-361 Protocol Amendment 5
EudraCT 2014-001764-35
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●
Added a paragraph to define the process for transition from Phase 1 to Phase 2.
Rationale:  To clarify actions after RPTD is determined.
●
Updated requirement to collect HBsAg and HCV RNA laboratory tests at 
Screening for subjects with unknown history of HBsAg and HCV RNA for 
Phase 2.
Rationale:  To ensure subjects positive to hepatitis B and hepatitis C are not 
enrolled.
●
Replaced "medical monitor" with "Therapeutic Area Medical Director" 
throughout the document.
Rationale:  To align the content with the company role name.
●
Replaced "Interactive Voice/Web Response Technology (IVRS)" with 
"Interactive Response Technology (IRT)" throughout the document.
Rationale:  To align the content with the company system name.
●
Added new wording to radiation in Concomitant Therapy section.
Rationale:  To clarify radiation to non-target lesions during the study.
●
Removed coagulation sample collection at odd numbered cycles in Table 8,
Study Activities in Phase 2.
Rationale:  To simplify the laboratory sample collections.
●
Clarified collection window for clinical laboratory tests is 48 hours.
Rationale: To allow for flexibility in the laboratory sample collection.
●
Added the requirement for sites to electronically transfer copies of all CT or 
MRI scans used for radiographic tumor assessments in Phase 2 at the request 
of AbbVie.
Rationale:  To facilitate the collection of scans for central review, if 
necessary.
●
Removed the requirement of survival data collection for up to 2 years in 
Phase 2.
Rationale:  To improve resolution of overall survival analysis.
●
Clarified disease progression definition per protocol is radiographic 
progression.


Veliparib
M14-361 Protocol Amendment 5
EudraCT 2014-001764-35
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Rationale: To clearly define disease progression per protocol to minimize the 
amount of lost endpoints.
●
Include the language in the Administrative Change 2.
Rationale:  Include the administrative change language.
●
Other changes to the protocol are minor administrative changes throughout the 
document for clarification, typographical and grammatical error corrections 
and overall flow of the document.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix G.


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M14-361 Protocol Amendment 5
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-361
Name of Study Drug:  Veliparib
Phase of Development:  1 – 2
Name of Active Ingredient:  Veliparib
Date of Protocol Synopsis:  22 November 2016
Protocol Title:  
A Phase 1 Dose Escalation and Phase 2 Randomized Double-Blind Study of Veliparib in Combination 
with Carboplatin and Etoposide as a Therapy of Treatment-Naïve Extensive Stage Disease Small Cell 
Lung Cancer
Objectives:
Phase 1 Dose Escalation:
Primary Objectives:
●
To establish the Maximum Tolerated Dose (MTD) and to establish the Recommended Phase 2 
Dose (RPTD) and schedule for veliparib in combination with carboplatin and etoposide.
●
To evaluate the pharmacokinetic interaction between veliparib and etoposide.
Secondary Objective:
●
To evaluate the safety of maintenance veliparib monotherapy at 400 mg twice daily (BID) in 
subjects completing 4 cycles of carboplatin, etoposide and veliparib without evidence of disease 
progression.
Phase 2 Randomized Double-Blind:
Primary Objective:
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by veliparib 
maintenance monotherapy results in improved progression free survival (PFS) versus placebo in 
combination with carboplatin and etoposide followed by placebo monotherapy in subjects with 
treatment-naïve ED SCLC.
Secondary Objectives:
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by placebo
monotherapy results in improved progression free survival (PFS) versus placebo in combination 
with carboplatin and etoposide followed by placebo monotherapy in subjects with 
treatment-naïve ED SCLC.
●
To evaluate if veliparib in combination with carboplatin and etoposide results in improved 
objective response rate (ORR) versus placebo in combination with carboplatin and etoposide at 
the time of completion of combination therapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by veliparib 
maintenance monotherapy results in improved overall survival (OS) versus placebo in 
combination with carboplatin and etoposide followed by placebo monotherapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by placebo 
monotherapy results in improved overall survival (OS) versus placebo in combination with 
carboplatin and etoposide followed by placebo monotherapy.
●
To further evaluate the safety of veliparib in combination with carboplatin and etoposide 
followed by veliparib maintenance monotherapy.


Veliparib
M14-361 Protocol Amendment 5
EudraCT 2014-001764-35
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Objectives (Continued):
Tertiary Objectives:
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by veliparib 
maintenance monotherapy results in improved duration of overall response (DOR) versus
placebo in combination with carboplatin and etoposide followed by placebo monotherapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by placebo 
monotherapy results in improved duration of overall response (DOR) versus placebo in 
combination with carboplatin and etoposide followed by placebo monotherapy. 
●
To compare PFS and OS of subjects treated with veliparib in combination with carboplatin and 
etoposide followed by veliparib maintenance to PFS and OS of subjects treated with veliparib 
in combination with carboplatin and etoposide followed by placebo maintenance.
●
To evaluate performance status.
Investigators:  
Multicenter
Study Sites:  
Approximately 65 globally
Study Population:  
Phase 1:  Histologically or cytologically confirmed extensive stage disease SCLC or any other 
advanced/metastatic solid tumor for which carboplatin/etoposide treatment is considered appropriate.
Phase 2:  Histologically or cytologically confirmed treatment-naïve extensive stage disease SCLC.
Number of Subjects to be Enrolled:  
Phase 1 Dose Escalation portion:  Approximately:  35
Phase 2 Randomized Double-Blind portion:  Approximately:  180
Methodology:
This is a Phase 1 dose escalation and Phase 2 randomized double-blind study.
Screening Procedures:
Screening procedures should be performed within 28 days of Cycle 1 Day –2.  If the screening visit is 
performed greater than 7 days prior to Cycle 1 Day –2, the physical exam, laboratory tests, and 
pregnancy test (for female subjects of childbearing potential) must be repeated on Cycle 1 Day –2.  Vital 
signs and performance status assessments will be performed on Cycle 1 Day –2 for all subjects.  
Baseline radiographic tumor assessments per computed tomography (CT) with IV contrast/magnetic 
resonance imaging (MRI) of the chest, abdomen, and pelvis will be conducted within 21 days prior to 
Cycle 1 Day –2.  If CNS metastases are suspected, a head CT must also be performed at screening.  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.
Phase 1 Dose Escalation:
For subjects in the dose escalation portion of the study, each subject will participate in only 1 dose group 
and there is no provision for intra-subject dose-escalation.  Study procedures will be provided in the 
Schedule of Assessments and Pharmacokinetic and Pharmacodynamic tables.


Veliparib
M14-361 Protocol Amendment 5
EudraCT 2014-001764-35
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Methodology (Continued):
Phase 1 Dose Escalation (Continued):
The Phase 1 portion of this study will evaluate the safety, tolerability, dose limiting toxicities (DLTs), 
RPTD, pharmacokinetics (PK), and pharmacodynamics (PD), of veliparib/carboplatin/etoposide 
combination in subjects diagnosed with Extensive Stage Disease Small Cell Lung Cancer or, other 
advanced/metastatic solid tumor for which carboplatin/etoposide treatment is considered appropriate.  
Veliparib will be administered on Days –2 to 5 (7-day schedule), and, if the MTD of the 7-day schedule 
is not reached at ≤ 200 mg BID veliparib dose level, may be administered on Days –2 to 12 (14-day 
schedule) and/or Days –2 to 19 (continuous schedule) orally BID, in combination with carboplatin area 
under the curve 5 mg/mL*min administered on Day 1 and etoposide 100 mg/m2 administered on Days 1 
to 3 via intravenous (IV) infusion in 21-day cycles.  An exception would be for the Phase 1 Cycle 2:  In 
the 7-day schedule, veliparib in Cycle 2 will be administered on Days 2 to 5 and for the 14-day schedule, 
Days 2 to 12 (veliparib dose on Cycle 2 Days –2 and –1 and Cycle 2 Day 1 will be omitted to allow for 
the evaluation of drug-drug interaction of veliparib with etoposide).
Upon completion of 4 cycles of combination therapy, subjects without evidence of disease progression 
will continue on veliparib 400 mg BID until disease progression or unacceptable toxicity.  Subjects who 
will be receiving prophylactic cranial irradiation (PCI) will have maintenance veliparib interrupted for 
the duration of radiotherapy.
All subjects will be monitored for DLTs during the DLT observation period (Cycle 1 Day –2 to pre-dose 
Cycle 2 Day 1), and treatment-related adverse events (AEs) will be evaluated throughout the course of 
the study for evidence of acute, delayed, or cumulative toxicities.
The dose levels of veliparib to be evaluated in the dose-escalation portion of this study were determined 
based on the outcome of prior clinical studies of veliparib as well as on pre-clinical toxicology, 
toxicokinetic, and nonclinical anti-tumor efficacy studies.  The following dose levels may be evaluated 
in the dose-escalation portion of the study:  80, 120, 160, 200, and 240 mg BID.  Reduced dose levels 
may be evaluated based upon review of subject safety and PK data.  Intermediate dose levels may be 
evaluated based upon review of subject safety including, but not limited to, Grade 2 study-drug related 
AEs.  If the MTD is not reached at veliparib 200 mg BID dose level, higher dose levels (with no more 
than 25% veliparib dose increments, and not exceeding single agent veliparib RPTD of 400 mg BID) 
may be evaluated at the discretion of the sponsor.  The alternative dosing schedules can include dosing 
veliparib Day –2 to 12 (14-day schedule) and/or Day –2 to 19 (continuous schedule) of 21 day Cycle.  
The initial dose for these schedules will be 200 mg BID or the maximum administered dose (MAD), not 
exceeding the MTD, in the 7-day schedule.  The 14-day schedule will be explored prior to continuous 
dosing schedule.  Reduced or interim dose levels may be evaluated based on review of the safety and 
PK.
A "3 + 3" escalation rule will be used for the dose-escalation portion of this study, with a condition 
applied for the Dose Level 1, which will allow 3 additional subjects to be entered in Dose Level 1 if 2 of 
6 initial subjects experience DLTs.  Enrollment of the 3 additional subjects at all dose levels will depend 
on a review of the specific DLTs observed and discussion with the Investigators.
Dose-Escalation Criteria:
AEs, clinical laboratory results, and vital signs will be assessed throughout the study in each 
dose-escalation cohort.


Veliparib
M14-361 Protocol Amendment 5
EudraCT 2014-001764-35
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Methodology (Continued):
Dose-Escalation Criteria (Continued):
DLTs will be assessed in each dose-escalation cohort during the DLT observation period
(Cycle 1 Day –2 to pre-dose on Cycle 2 Day 1).  Based on the safety and tolerability of study drugs after 
the first cycle of treatment has been completed in at least 3 subjects, escalation to a subsequent dose 
level or expansion of the current dose level will occur based upon the following criteria:
Number of Subjects with 
DLT in the First Cycle
Escalation Decision Rule
0 out of 3
Enter 3 subjects at the next dose level.
1 out of 3
Add 3 more subjects at current dose level.  If AbbVie or the investigator 
considers the DLT(s) clinically significant, AbbVie will determine if it 
is appropriate to add more patients at this dose level.
!
If < 2 of 6 subjects (or < 33% of subjects) experience DLT, dose 
escalation will proceed to the next dose level.
!
If ≥ 2 of total 6 subjects (or ≥ 33% of subjects) experience DLTs, 
then dose escalation will be stopped.*
≥ 2 out of 3 or 6
Dose escalation will be stopped.  *Additional subjects will be enrolled 
at the previous lower dose level as needed.  The following exceptions 
apply to Dose Level 1:
!
If 2 of 6 initial subjects at Dose Level 1 experience DLTs, 
3 additional subjects may be entered and the cohort will be 
expanded up to 9 subjects for further DLT assessment.  
o
Enrollment of the 3 additional subjects will depend on a review 
of the specific DLTs observed and discussion with the 
Investigators.  
!
If 2 of 9 subjects at Dose Level 1 experience DLTs, then escalation 
to the next dose level may proceed.
!
If > 2 of 9 subjects in Dose Level 1 experience drug-related DLTs, 
dose-escalation will stop.
*
If 2 out of 6 subjects experience different DLTs, for example nausea and neutropenia, the data will be reviewed 
by the investigator and AbbVie to determine if 3 additional subjects should be added at that dose level.  If 
3 subjects will be added and none experience DLTs, this dose level will be declared the MTD.
An MTD and/or maximum administered dose (MAD), and RPTD, will be determined.  The MTD is 
defined as the maximum dose at which < 2 of 6 or ≤ 2 of 9 subjects experience a DLT during the DLT 
observation period.  The MAD is defined as the highest dose tested.  Both MAD and MTD may be 
determined independently for each tested dosing schedule of veliparib.  The RPTD and schedule will be 
determined based on the assessment of the observed toxicities, the MTD or MAD, and the overall safety 
profile of the study drug.  The RPTD cannot exceed the lower of MTD or MAD.  At the RPTD and 
schedule, additional subjects will be added as needed so that a total of at least 9 subjects will be treated 
at the RPTD during the dose escalation part of the study.


Veliparib
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Methodology (Continued):
DLT Definition:
DLT is defined as any of the following drug-related toxicities occurring during the DLT observation 
period in any of the dose-escalation cohorts, with grading according to the National Cancer Institute 
(NCI) Common Toxicity Criteria for Adverse Events (CTCAE), Version 4.0:
1.
Cycle 1 events associated with treatment delay > 14 days in initiating Cycle 2:
a.
Grade 4 thrombocytopenia (platelets < 25.0 × 109/L)
b.
Grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5 × 109/L)
c.
Grade 3 febrile neutropenia with fever lasting for > 7 days
d.
Grade 4 febrile neutropenia of any duration
NOTE:  Delay of more than 14 days in initiating Cycle 2 due to factors not directly related to 
treatment-emergent toxicity will not be considered a DLT.
2.
Grade ≥ 3 non-hematologic toxicity that represents at least 2 grade increase from baseline and is 
attributed to veliparib treatment:
a.
Exclusion:  nausea and vomiting lasting ≤ 48 hours or inadequately treated
b.
Exclusion:  electrolyte abnormalities resolving within ≤ 24 hours
c.
Exclusion:  hypersensitivity reactions
d.
Exclusion:  alopecia
3.
Grade 2 non-hematologic toxicity that represents at least 2 grade increase from baseline, is 
attributed to veliparib treatment and requires a treatment delay of > 14 days in initiation of Cycle 2
4.
Any toxicity that represents at least 2 grade increase from baseline, is attributed to veliparib 
treatment and requires at least one of:
a.
Dose modification within Cycle 1
b.
Omission of carboplatin, > 1 daily etoposide dose, or > 30% veliparib doses in Cycle 1
Subjects experiencing DLT(s) during DLT observation period (Cycle 1 Day –2 to pre-dose Cycle 2 
Day 1) will require an interruption and possible discontinuation from further participation in the study.  
Veliparib may be reintroduced at a reduced dose, if the toxicity returns to ≤ Grade 1 or to baseline if 
Grade 2 at study entry.  All decisions regarding continued dosing for individual subjects who experience 
a DLT will be medically managed by the investigator in conjunction with the AbbVie TA MD.
Pharmacokinetics:
Pharmacokinetics of veliparib and etoposide will be assessed to determine the drug-drug interactions.  
Further pharmacokinetics of carboplatin will be assessed on Day 1 of Cycle 1.
Phase 2 Randomized Double-Blind
The veliparib dose and schedule for the Phase 2 was determined to be 240 mg BID on a 14 day schedule 
based on the analysis of Phase 1 data.
Approximately 180 total subjects with treatment-naïve ED SCLC will be enrolled at the 240 mg BID 
veliparib/placebo dose and 14 day schedule in the Phase 2 double-blinded portion of the study.  They 
will be randomized in a 1:1:1 ratio to one of three treatment arms: 
●
Arm A:  veliparib in combination with carboplatin/etoposide followed by veliparib 
monotherapy
●
Arm B:  veliparib in combination with carboplatin/etoposide followed by placebo monotherapy


Veliparib
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Methodology (Continued):
Phase 2 Randomized Double-Blind (Continued)
!
Arm C:  placebo in combination with carboplatin/etoposide followed by placebo monotherapy
Subjects in all Phase 2 study arms will receive a minimum of 4 cycles of combination therapy unless 
disease progression or unacceptable toxicity warrants earlier discontinuation from the treatment.  
Additional 2 cycles of combination therapy (e.g., up to a total of 6 cycles) may be administered at the 
investigators discretion if subject status at the completion of initial 4 cycles warrants continued 
combination treatment and/or if local SOC guidelines require 6 cycles of platinum-based therapy.  In the 
combination cycles of Arms A and B, subjects will receive veliparib at 240 mg BID on a 14-day 
schedule, Arm C will receive matching placebo.  After completion of the chemotherapy combination 
cycles (at least 4), subjects without evidence of disease progression will receive veliparib at 400 mg BID 
continuous dosing (21-day cycles) (Arms A), or matching placebo (Arms B and C) as per treatment arm 
assignment, until disease progression or unacceptable toxicity occurs.  
Subjects who will be receiving prophylactic cranial irradiation (PCI) will have maintenance veliparib 
interrupted for the duration of radiotherapy.
Subject randomization for Phase 2 will be stratified by baseline LDH level (> ULN versus ≤ ULN), and 
gender.
Pharmacodynamics (Phase 1 Dose Escalation and Phase 2 Randomized Double-Blind):
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.
Tumor Assessments and Safety Follow-Up
Tumor assessments will be performed until radiographic disease progression.  Tumor assessment and 
assessment of response will occur every 6 weeks (± 1 week) from C1D-2 for the first 24 weeks (Phase 1) 
or 30 weeks (Phase 2), then every 9 weeks (± 1 week) thereafter.  Tumor response will be determined 
according to the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1.  Subjects will 
continue on study until they meet defined discontinuation criteria.  When the investigator has determined 
that a subject should discontinue the study, a Final Visit will be conducted.  Subjects will have a 30-Day 
Follow-Up Visit following the last dose of study drugs or placebo (Phase 2, dependent on treatment 
arm).  If the subject begins another treatment regimen directly following protocol treatment and if a 
30-Day Follow-Up Visit is not possible, all adverse events ongoing as of the end of study must be 
followed to a satisfactory conclusion.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Inclusion:
1.
Subject has histologically or cytologically confirmed ED SCLC which is newly diagnosed and 
chemotherapy naïve.
2.
Phase 1 ONLY:  histologically or cytologically confirmed advanced/metastatic solid tumors for 
which carboplatin/etoposide treatment is considered appropriate.
3.
Subject in Phase 2 ONLY:  must have measureable disease per RECIST 1.1.
4.
Subjects with ED SCLC must consent to provide available archived formalin fixed paraffin 
embedded (FFPE) tissue sample of SCLC lesion (primary or metastatic) for central review and 
biomarker analysis.  NOTE:  If sufficient tissue is unavailable for analysis, subjects will still be 
allowed to enroll.


Veliparib
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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Inclusion (Continued):
5.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
6.
Subject must be ≥ 18 years of age.
7.
Subject must have adequate hematologic, renal and hepatic function as follows:
●
Bone Marrow:  Absolute neutrophil count ANC ≥ 1,500/mm3 (1.5 × 109/L); White blood cells 
≥ 3,000/mm3 (3 × 109/L); Platelets ≥ 100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9 g/dL 
(5.58 mmol/L)
●
Renal function:  creatinine ≤ ULN or if creatinine > ULN calculated creatinine clearance via 
the Cockroft Gault formula of ≥ 50 mL/min
●
Hepatic function:
o
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper 
limits of normal (ULN).  For subjects with liver metastases, AST and ALT ≤ 5 × ULN;
o
Bilirubin:  ≤ 1.5 × ULN; for subjects with Gilbert's syndrome bilirubin > 1.5 × ULN is 
allowed if no symptoms of compromised liver function are present.
8.
Subject must be able to swallow pills.
9.
Female and male patients of fertile age, and/or their partners should use contraception.  If male, 
subject and subject's female partner(s) of childbearing potential must follow the contraception 
recommendations as described in Section 5.2.4.  If female, subject must be either postmenopausal 
for at least 1 year, surgically sterile (bilateral tubal ligation, bilateral oophorectomy or 
hysterectomy), or the subject and the subject's male partner(s) must follow the contraception 
recommendations as described in Section 5.2.4.
Female subjects must have negative results for pregnancy tests performed:
!
Screening on a serum specimen obtained within 7 days prior to initial study drug 
administration, and 
!
prior to dosing on a urine sample obtained C1D-2 unless the serum pregnancy test was collected 
within 7 days of C1D-2.
10. Must voluntarily sign and date each informed consent, approved by an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study 
specific procedures.
Exclusion:
1.
Phase 1 ONLY:  Subject has had any prior anti-cancer therapy other than:
●
Hormonal, non-myelosuppressive, biologic, targeted, or immune therapy (must be completed 
≥4 weeks prior to Cycle 1 Day –2).
●
One line of cytotoxic chemotherapy (must be completed ≥ 4 weeks prior to Cycle 1 Day –2).
●
Adjuvant/neoaduvant radiotherapy (must be completed ≥ 12 months prior to Cycle 1 Day –2, 
with field not involving > 10% of bone marrow reserve).
●
Tumor lesion irradiation with intent of symptom palliation ≥ 4 weeks prior Cycle 1 Day –2.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Exclusion (Continued):
2.
Phase 2 ONLY:  Subject has had any prior chemotherapy, radiotherapy, investigational anti-cancer 
agents or biologic therapy for the disease under study.  Single non-target lesion irradiation with 
intent of symptom palliation is allowed if ≥ 2 weeks prior Cycle 1 Day –2.
3.
Subject has known hypersensitivity to etoposide, platinum compounds or veliparib.
4.
Phase 1 ONLY:  Subject has received prior myelopoietic growth factors.
5.
Subject has current central nervous system (CNS) or leptomeningeal metastases or history of CNS 
or leptomeningeal metastases.  If CNS metastasis is suspected, a head CT should be performed at 
screening.
6.
Subject has a history of seizures within 12 months of Cycle 1 Day –2 or diagnosed neurological 
condition placing subject at the increased risk of seizures.
7.
Subject has received traditional herbal anti-cancer medicine (e.g., Chinese, Asian etc.) within 
14 days prior to Cycle 1 Day –2.
8.
Subject has had major surgery within 6 weeks prior to Cycle 1 Day –2 (subjects must have 
completely recovered from any previous surgery prior to Cycle 1 Day –2).
9.
Subject has clinically significant and uncontrolled major medical condition(s) including but not 
limited to:
●
Uncontrolled nausea/vomiting/diarrhea;
●
Active uncontrolled infection;
●
History of hepatitis B (HBV) with surface antigen (HBsAg) positivity within 3 months prior to 
the date of informed consent for this study (if HBsAg status is unknown it must be tested at 
screening);
●
History of hepatitis C (HCV) with HCV RNA positivity within 3 months prior to the date of 
informed consent for this study (if HCV RNA status is unknown it must be tested at screening);
●
Symptomatic congestive heart failure (New York Heart Association [NYHA] class ≥ II);
●
Unstable angina pectoris or cardiac arrhythmia;
●
Psychiatric illness/social situation that would limit compliance with study requirements;
●
Any other medical condition, which in the opinion of the Investigator, places the subject at an 
unacceptably high risk for toxicities.
10. Subject is pregnant or lactating.
11. The subject has a history of another active 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, breast ductal 
carcinoma in situ [DCIS]).
Questions regarding the eligibility of individual subjects should be directed to the AbbVie TA MD.


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Investigational Products:
Veliparib
Doses:
Phase 1 Dose Escalation cohorts:  80, 120, 160, 200 and 240 mg BID 
(higher doses up to 400 mg BID may be tested)
Phase 2 Randomized Double-Blind arms:  240 mg BID
Continuous monotherapy maintenance:  400 mg BID
Mode of Administration:
Oral
Investigational Products:
Placebo – BID Phase 2 ONLY
Doses:
Combination therapy:  matching capsules for 240 mg BID
Continuous monotherapy maintenance:  matching capsules for 400 mg 
BID
Mode of Administration:
Oral
Reference Therapy:
Carboplatin
Doses:
AUC 5 mg/mL*min
Mode of Administration:
Intravenous infusion
Reference Therapy:
Etoposide
Doses:
100 mg/m2
Mode of Administration:
Intravenous infusion
Duration of Treatment:
Subject will remain on study drug until disease progression or unacceptable toxicity. 
Criteria for Evaluation:
Efficacy:
Progression-free survival (PFS) will be derived according to disease progression (radiographic 
progression per RECIST version 1.1) or death.  Radiographic tumor assessments for response will be 
conducted by CT scanning at baseline, every 6 weeks from C1D-2 for the first 24 weeks (Phase 1) or 
30 weeks (Phase 2), then every 9 weeks until disease progression.
Objective response rate (ORR) will be derived per RECIST version 1.1.  Radiographic tumor 
assessments for response will be conducted by CT scanning at baseline, every 6 weeks from C1D-2 for 
the first 24 weeks (Phase 1) or 30 weeks (Phase 2), then every 9 weeks until disease progression.
Duration of overall response (DOR) will be derived according to disease progression (radiographic 
progression per RECIST version 1.1). 
Overall survival will be determined by the Investigator at assessments throughout therapy.  After the 
final visit, survival information will be collected via electronic data capture (EDC) at 2 month intervals 
(or as requested by sponsor to support data analysis).
ECOG performance status will be determined by the Investigator at each assessment.  
Pharmacokinetic:
Blood samples for pharmacokinetics of veliparib, carboplatin (Phase 1 Dose Escalation only) and 
etoposide (Phase 1 Dose Escalation only) will be collected at designated time points throughout the 
study.  Pharmacokinetics of veliparib and etoposide will be assessed to determine the drug-drug 
interactions.  In addition, pharmacokinetics of carboplatin will be determined.


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Criteria for Evaluation (Continued):
Pharmacodynamic:
Research to find biomarkers that may be predictive of veliparib activity will be conducted.  Serum, 
plasma, blood and archived tissue samples will be collected at designated time points throughout the 
study.
Pharmacogenetic:
DNA samples may be analyzed for genetic factors contributing to the subject's response to veliparib, or 
other study treatment, in terms of pharmacokinetics, efficacy, tolerability and safety.
Safety:
Adverse events, laboratory profiles, physical examinations, vital signs and neurological assessments will 
be evaluated and recorded throughout the study.
Statistical Methods:
Efficacy:
The following end point will be analyzed using data obtained from subjects in Phase 1 and Phase 2 
separately:
Objective Response Rate
The proportion of subjects with objective response (CR or PR) as assessed by the investigator using 
RECIST 1.1 will be calculated for all dosed subjects.
The following end point will be analyzed using data obtained from subjects in Phase 2:
Progression-Free Survival
Progression-Free Survival will be defined as the number of days from the date of randomization to the 
date of earliest radiographic disease progression or death.  All disease progression will be included 
regardless whether the event occurred while the subject was taking study drug or had previously 
discontinued study drug.  If the subject does not experience disease progression or death, then the data 
will be censored at the date of the last radiographic disease assessment.
Overall Survival
Overall survival will be defined as the number of days from the date of randomization to the date of 
death.  For subjects who did not die, their data will be censored at the date of last study visit or the last 
known date to be alive, whichever is later.  
Duration of Overall Response
Duration of overall response will be defined as the number of days from the date of first response (CR or 
PR) to the earliest documentation of radiographic progressive disease.  If a subject is still responding, 
then the subject's data will be censored at the date of the subject's last available radiographic disease 
assessment.  For subjects who never experience response, the subject's data will not be included in the 
analysis.
Performance Status
Changes and/or percent changes from baseline will be summarized using descriptive statistics for each 
scheduled post-baseline visit and for the Final Visit for ECOG performance status.  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.


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Statistical Methods (Continued):
Pharmacokinetic:
Plasma concentrations of veliparib, etoposide, and carboplatin and pharmacokinetic parameter values 
will be tabulated for each subject and each dose level, and summary statistics will be computed for each 
sampling time and each parameter.
The effects of co-administration of veliparib on etoposide pharmacokinetics will be addressed by 
analyzing the Cycle 1 Day 1 (veliparib with carboplatin and etoposide) and Cycle 2 Day 1 (carboplatin 
and etoposide alone) etoposide pharmacokinetic variables, including Tmax, dose normalized Cmax and 
dose normalized AUC.
Pharmacodynamic:
Biomarker results will be tabulated for each subject and each regimen, and summary statistics will be 
computed for each sampling time and each parameter.  The relationship between biomarker status and 
clinical outcome or drug exposure may be examined.
Safety:
●
The safety of veliparib in combination with carboplatin/etoposide will be assessed by 
evaluating the study drugs exposure, adverse events, serious adverse events, all deaths, as well 
as changes in laboratory determinations and vital sign parameters.  Safety will be summarized 
per dose level using descriptive statistics for the dose escalation cohorts and per treatment arm 
in Phase 2.
●
RPTD was determined based on the rate of DLTs and overall tolerability of the combination of 
veliparib, carboplatin and etoposide with at least 9 subjects treated at the RPTD in Phase 1 and 
will be further evaluated in Phase 2.


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1.3
List of Abbreviations and Definition of Terms
Abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AUC
Area Under the Plasma Concentration-time Curve
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
aPTT
Activated Partial Thromboplastin Time
BID
Twice Daily
BRCA
Breast Cancer Gene (susceptibility)
BUN
Blood Urea Nitrogen
CS
Clinically Significant
CTEP
Cancer Therapy Evaluation Program
CNS
Central Nervous System
CR
Complete Response
CRF or eCRF
Case Report Form or Electronic Case Report Form
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
DCIS
Ductal Carcinoma in situ
DICOM
Digital Imaging and Communications in Medicine
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of Overall Response
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group 
ED
Extensive Disease
EDC
Electronic Data Capture
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
ESMO
European Society For  Medical Oncology
FDA
US Food and Drug Administration


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FFPE
Formalin Fixed Paraffin Embedded 
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GFR
Glomerular Filtration Rate
GM-CSF
Granulocyte Macrophage-Colony Stimulating Factor
GOG
Gynecologic Oncology Group
HBsAg
Hepatitis B surface antigen
HCV 
Hepatitis C Virus
Hgb
Hemoglobin
HIV
Human Immunodeficiency Virus
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IIS
Investigator initiated studies 
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
LD
Limited Disease
MAD
Maximum Administered Dose
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NCS
Not Clinically Significant
NSCLC
Non-small Cell Lung Cancer
NYHA
New York Heart Association
ORR
Objective Response Rate
OS
Overall Survival
PARP
Poly(ADP-ribose)-polymerase
Pd
Pharmacodynamics
PD
Progressive Disease


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PFS
Progression Free Survival
PK
Pharmacokinetics
PLTs
Platelets
PoR
Proof of Receipt
PR
Partial Response
PT
Prothrombin Time
QA
Quality Assurance
QC
Quality Control
QTc
QT interval corrected for heart rate
RBC
Red Blood Cells
RECIST
Response Evaluation Criteria in Solid Tumors
RNA 
Ribonucleic acid
RPTD
Recommended Phase Two Dose
SCLC
Small Cell Lung Cancer
SAE
Serious Adverse Event
SD
Stable Disease
SGOT
Serum Glutamic-oxaloacetic Transaminase
SGPT
Serum Glutamic-pyruvic Transaminase
SmPC
Summary of Product Characterizations
SOC
Standard of Care
SOD
Sum of Diameter
SUSAR
Suspected Unexpected Serious Adverse Reactions 
TA MD
Therapeutic Area Medical Director
TMZ
Temozolomide
TTP
Time to Progression
ULN
Upper Limit of Normal
US
Ultrasound
WOCBP
Women of Childbearing Potential
WBC
White Blood Cell 


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................7
1.3
List of Abbreviations and Definition of Terms........................................18
2.0
Table of Contents...................................................................21
3.0
Introduction ...........................................................................27
3.1
Small Cell Lung Cancer (SCLC) .............................................................27
3.2
Poly (ADP) Ribose Polymerase (PARP) .................................................27
3.3
Veliparib ..................................................................................................28
3.3.1
Preclinical Studies and Toxicology .........................................................29
3.3.2
Veliparib Pharmacokinetics/Pharmacodynamics.....................................30
3.3.3
Veliparib Clinical Studies........................................................................31
3.4
Carboplatin and Etoposide.......................................................................33
3.5
Study Rationale........................................................................................34
3.6
Differences Statement..............................................................................35
3.7
Benefits and Risks....................................................................................35
4.0
Study Objectives....................................................................36
5.0
Investigational Plan...............................................................38
5.1
Overall Study Design and Plan:  Description ..........................................38
5.2
Selection of Study Population..................................................................48
5.2.1
Inclusion Criteria .....................................................................................48
5.2.2
Exclusion Criteria ....................................................................................50
5.2.3
Prior and Concomitant Therapy...............................................................52
5.2.3.1
Prior Therapy ...........................................................................................53
5.2.3.2
Concomitant Therapy...............................................................................54
5.2.4
Contraception Recommendations ............................................................55
5.3
Efficacy, Pharmacokinetic, Pharmacodynamic, Pharmacogenetic 
and Safety Assessments/Variables...........................................................57
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ................57
5.3.1.1
Study Procedures .....................................................................................68
5.3.1.2
Confinement.............................................................................................76


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5.3.1.3
Meals and Dietary Requirements.............................................................76
5.3.1.4
Blood Samples for Pharmacogenetic Analysis ........................................76
5.3.1.5
Collection and Handling of Pharmacodynamic Variables.......................77
5.3.1.6
Shipment of Pharmacodynamic Samples.................................................78
5.3.2
Drug Concentration Measurements .........................................................78
5.3.2.1
Collection of Samples for Analysis .........................................................78
5.3.2.2
Handling/Processing of Samples .............................................................80
5.3.2.3
Disposition of Samples ............................................................................80
5.3.2.4
Measurement Methods.............................................................................80
5.3.3
Efficacy Variables....................................................................................80
5.3.3.1
RECIST 1.1 for Tumor Response............................................................81
5.3.3.2
Definition of Disease Progression............................................................81
5.3.4
Safety Variables.......................................................................................82
5.3.5
Pharmacokinetic Variables ......................................................................82
5.3.6
Pharmacogenetic Variables......................................................................82
5.3.7
Pharmacodynamic Variables....................................................................83
5.4
Removal of Subjects from Therapy or Assessment.................................84
5.4.1
Discontinuation of Individual Subjects....................................................84
5.4.1.1
Discontinuation of Combination and Maintenance Therapies in 
Phase 2 .....................................................................................................86
5.4.2
Discontinuation of Entire Study...............................................................86
5.5
Treatments................................................................................................86
5.5.1
Treatments Administered.........................................................................86
5.5.1.1
Administration of Veliparib/Placebo .......................................................88
5.5.1.2
Administration of Carboplatin and Etoposide .........................................88
5.5.2
Identity of Investigational Products.........................................................89
5.5.2.1
Standard of Care Medicinal Products for Study Treatment.....................90
5.5.2.2
Packaging and Labeling...........................................................................90
5.5.2.3
Storage and Disposition of Study Drug ...................................................91
5.5.3
Method of Assigning Subjects to Treatment Groups (Phase 1 
Dose Escalation) ......................................................................................92
5.5.4
Method of Assigning Subjects to Treatment Groups (Phase 2 
Randomized Double-Blind).....................................................................92


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5.5.5
Selection and Timing of Dose for Each Subject......................................93
5.5.6
Blinding....................................................................................................94
5.5.7
Treatment Compliance.............................................................................95
5.5.8
Drug Accountability.................................................................................96
5.6
Discussion and Justification of Study Design..........................................97
5.6.1
Discussion of Study Design and Choice of Control Groups....................97
5.6.2
Appropriateness of Measurements...........................................................97
5.6.3
Suitability of Subject Population .............................................................98
5.6.4
Selection of Doses in the Study ...............................................................98
5.7
Dose Reductions or Delays......................................................................99
5.7.1
Veliparib/Placebo Dose Reductions and Interruptions............................99
5.7.2
Carboplatin/Etoposide Dose Reductions and Delays.............................101
5.7.2.1
Guidelines for Carboplatin and Etoposide Dose Reductions and 
Delays ....................................................................................................102
5.7.2.1.1
Hematologic Toxicity ............................................................................103
5.7.2.1.2
Non-Hematological Toxicity .................................................................104
5.7.2.1.3
Other Grade 3/4 Non-Hematologic Toxicity .........................................105
6.0
Adverse Events.....................................................................106
6.1
Definitions..............................................................................................107
6.1.1
Adverse Event........................................................................................107
6.1.2
Deaths ....................................................................................................108
6.1.3
Lack of Efficacy or Worsening of Disease Under Study.......................108
6.1.4
Serious Adverse Events .........................................................................109
6.2
Adverse Events Expected Due to SCLC or Progression of SCLC ........110
6.3
Adverse Event Severity..........................................................................110
6.4
Relationship to Study Drug....................................................................111
6.5
Adverse Event Collection Period...........................................................112
6.6
Adverse Event Reporting.......................................................................113
6.7
Pregnancy...............................................................................................115
6.8
Dose Limiting Toxicities .......................................................................116
6.8.1
Determination of the MTD ....................................................................116
6.8.2
Determination of the RPTD...................................................................117
7.0
Protocol Deviations..............................................................117


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8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................118
8.1
Statistical and Analysis Plans ................................................................118
8.1.1
Baseline Characteristics.........................................................................119
8.1.1.1
Demographics ........................................................................................119
8.1.1.2
Medical History .....................................................................................119
8.1.2
Efficacy Endpoints.................................................................................119
8.1.2.1
Primary Efficacy Endpoint ....................................................................119
8.1.2.2
Secondary Efficacy Endpoints...............................................................120
8.1.2.3
Tertiary Efficacy Endpoints...................................................................120
8.1.3
Primary Analysis of Efficacy.................................................................121
8.1.4
Secondary Analysis of Efficacy.............................................................121
8.1.4.1
Progression-Free Survival (Arm B Versus Arm C)...............................121
8.1.4.2
Objective Response Rate .......................................................................121
8.1.4.3
Overall Survival.....................................................................................122
8.1.5
Tertiary Analysis of Efficacy.................................................................122
8.1.5.1
Duration of Overall Response................................................................122
8.1.5.2
Progression-Free Survival (Arm A Versus Arm B)...............................122
8.1.5.3
Overall Survival (Arm A Versus Arm B)..............................................122
8.1.5.4
ECOG Performance Status ....................................................................123
8.1.6
Pharmacokinetics ...................................................................................123
8.1.6.1
Tabulations and Summary Statistics......................................................123
8.1.6.2
Model and Tests.....................................................................................123
8.1.6.3
Missing Values and Model Violations...................................................125
8.1.7
Safety .....................................................................................................125
8.1.7.1
Duration of Study Drug .........................................................................125
8.1.7.2
Adverse Events ......................................................................................126
8.1.7.3
Serious Adverse Events .........................................................................126
8.1.7.4
Deaths ....................................................................................................126
8.1.7.5
Longitudinal Analyses of Laboratory and Vital Signs Data..................126
8.1.7.6
Analyses of Laboratory Data Using NCI CTCAE.................................127
8.1.7.7
Analyses of Vital Signs Using Criteria for Potentially Clinically 
Significant Vital Sign Values.................................................................128


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8.1.8
Timing of Efficacy Analyses and Safety Evaluations ...........................128
8.1.9
Data Monitoring Committee (DMC) .....................................................128
8.2
Determination of Sample Size ...............................................................129
8.3
Randomization Methods ........................................................................129
9.0
Ethics.....................................................................................130
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................130
9.2
Ethical Conduct of the Study .................................................................131
9.3
Subject Information and Consent...........................................................131
10.0
Source Documents and Case Report Form 
Completion ...........................................................................132
10.1
Source Documents .................................................................................132
10.2
Case Report Forms.................................................................................132
11.0
Data Quality Assurance ......................................................133
12.0
Use of Information...............................................................134
13.0
Completion of the Study .....................................................135
14.0
Investigator's Agreement....................................................136
15.0
Reference List ......................................................................137
List of Tables
Table 1.
Treatment Schema for Combination Therapy Cycles 1, 3, 4 in 
Phase 1 Dose Escalation (Non-Continuous Veliparib Dosing 
Schedules)................................................................................................39
Table 2.
Treatment Schema for Combination Therapy Cycle 2 in Phase 1 
Dose Escalation (Non-Continuous Veliparib Dosing Schedules) ...........40
Table 3.
Treatment Schema for Combination Therapy Cycles in Phase 1 
Dose Escalation (Continuous Veliparib Dosing Schedule) .....................40
Table 4.
Phase 1 Dose Escalation ..........................................................................42
Table 5.
Dose Escalation Guidelines .....................................................................43
Table 6.
Treatment Schematic for Combination Cycles in Phase 2.......................47
Table 7.
Study Activities Phase 1 Dose Escalation ...............................................58
Table 8.
Study Activities in Phase 2 ......................................................................62


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Table 9.
Schedule of Pharmacogenetic and Pharmacodynamic Assessments 
for Phase 1 Dose Escalation and Phase 2.................................................66
Table 10.
Schedule of Pharmacokinetic Assessments for Phase 1 Dose 
Escalation.................................................................................................67
Table 11.
Schedule of Pharmacokinetic Assessments in Phase 2............................67
Table 12.
Clinical Laboratory Tests.........................................................................73
Table 13.
Identity of Investigational Products.........................................................89
Table 14.
Standard of Care Medicinal Products for Study Treatment.....................90
Table 15.
Study Drug Storage Conditions ...............................................................91
Table 16.
Guidelines for Veliparib, Carboplatin, and Etoposide Dose 
Reduction Levels During Combination Therapy.....................................99
Table 17.
Dose Interruption or Reduction Due to Toxicity Attributable to 
Veliparib in the Combination Therapy Cycles ......................................101
Table 18.
Veliparib Dose Interruption or Reduction Due to Toxicity 
Attributable to Veliparib in the Maintenance Therapy Cycles ..............101
Table 19.
Suggested Guidelines for Carboplatin/Etoposide Dose Delay or 
Reduction ...............................................................................................106
List of Figures
Figure 1.
BRCA Deficient MX-1 Model.................................................................29
Figure 2.
Phase 2 Treatment and Randomization Schematics ................................47
Figure 3.
Sequence of Administration*...................................................................87
Figure 4.
Adverse Event Collection ......................................................................113
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator..........................................140
Appendix B.
List of Protocol Signatories....................................................................142
Appendix C.
RECIST (Version 1.1) for Tumor Response (PFS) ...............................143
Appendix D.
NYHA Functional Classification...........................................................150
Appendix E.
Calculation of Carboplatin Dose............................................................151
Appendix F.
Adverse Events Expected Due to SCLC or Progression of SCLC ........154
Appendix G.
Protocol Amendment:  List of Changes.................................................156


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3.0
Introduction
3.1
Small Cell Lung Cancer (SCLC)
Small cell lung cancer (SCLC) is a neuroendocrine carcinoma that exhibits aggressive 
behavior, rapid growth, and early spread to distant sites.  It constitutes approximately 15% 
of lung carcinomas.  SCLC is staged as limited or extensive stage disease (LD and ED 
SCLC, respectively).  LD SCLC is defined herein as a disease confined to the hemithorax 
of origin, with or without the involvement of regional lymph nodes, including ipsilateral 
and contralateral hilar, ipsilateral and contralateral mediastinal, and ipsilateral 
supraclavicular nodes.  ED SCLC is defined as all other SCLC.  At presentation, 60% to 
70% of SCLC cases in the United States are diagnosed as extensive-stage disease, for 
which at present there is no curative treatment.  There has been no significant 
improvement in the clinical outcome for subjects with ED SCLC in the last 2 decades, and 
it remains one of the most fatal cancers.  The National Comprehensive Cancer Network 
(NCCN) recommended management approach for ED SCLC is platinum-based doublet 
systemic chemotherapy, and platinum-etoposide is the most common regimen in the 
North America and Europe.  This regimen achieves a response rate of 50% to 70%, 
median survival of 9 – 11 months and median 5-year survival of less than 5%.1-3  While 
SCLC is very sensitive to frontline platinum based doublet chemotherapy, most patients 
relapse and die of their disease.  Previous strategy to improve the outcome of the disease 
was the use of high intensity chemotherapy which led to an improvement in the response 
rate; however this did not translate into survival benefit due to heightened toxicities.4-6  
The incorporation of novel targeted agents with excellent safety profile and limited 
additive toxicity in combination with standard chemotherapy agents as a strategy for 
improved efficacy has a great potential for improved clinical outcome in this disease.
3.2
Poly (ADP) Ribose Polymerase (PARP)
Poly (ADP) ribose polymerases (PARPs) are a family of enzymes that catalyze the 
addition of ADP-ribose to a variety of cellular molecules.  Several members of PARP 
family are involved in DNA damage repair, primarily through base excision repair 


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mechanism.7-9  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.  Veliparib potently inhibits PARP-1 
and -2 enzymes at clinically relevant concentrations.
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.8  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.10  
In particular, tumor cells with BRCA1 or BRCA2 deficiencies are exquisitely sensitive to 
PARP inhibition, even in the absence of any other insults.11-14
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.
3.3
Veliparib
Veliparib is a potent oral PARP inhibitor that delays the repair of DNA damage induced 
by chemotherapeutic agents, including alkylating agents, platinums, and topoisomerase 
inhibitors, and radiation.  Nonclinical efficacy with veliparib in combination with these 
agents has been demonstrated across an array of tumor types, including melanoma, 
glioma, prostate, breast, and colon.
A detailed discussion of the preclinical toxicology, metabolism, and pharmacology can be 
found in the Investigator's Brochure.15


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3.3.1
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 in several xenograft 
tumor models.  
 


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The toxicological profile of veliparib has been evaluated in nonclinical general toxicity 
studies that included single-dose (rats and mice), repeat-dose (duration of up to 6 months 
in rats and up to 9 months in dog), reproductive (embryofetal development in rat and 
rabbit), genetic (Ames, in vitro cytogenetics, in vivo micronucleus), phototoxicity (in 
vitro photosensitivity) and juvenile rat toxicity studies.  Primary nonclinical findings 
included effects on the central nervous system (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.
3.3.2
Veliparib Pharmacokinetics/Pharmacodynamics
In humans, at least 90% of the dose is absorbed after oral administration of veliparib.  
Veliparib is primarily cleared in the urine as intact parent drug (73% of administered 
dose), with a small fraction of clearance from metabolism.  Preliminary clinical 
pharmacokinetic (PK) data available from 6 studies indicate that exposure of veliparib is 
approximately dose proportional over 10 through 500 mg BID dose range.  The 
absorption of veliparib after oral dosing is 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.  
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.  In study subjects, there was no significant pharmacokinetic interaction 
between veliparib and TMZ, and preliminary results indicate the absence of DDI between 


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veliparib and carboplatin/gemcitabine, between veliparib and FOLFIRI, between veliparib 
and carboplatin/paclitaxel, or between veliparib and capecitabine/5-FU.
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.
3.3.3
Veliparib Clinical Studies
Veliparib is being 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 temozolomide (TMZ), with radiotherapy, and 
with carboplatin + paclitaxel.17 Data from non-AbbVie sponsored studies show veliparib 
has activity as monotherapy for treatment of ovarian cancer18 and activity in combination 
with carboplatin + paclitaxel for treatment of early breast cancer.19   Veliparib is currently 
in Phase 2 and Phase 3 clinical development in combination with several DNA-damaging 
agents across a variety of cancer indications.
Several clinical studies explored combinations of veliparib with carboplatin-based 
combination chemotherapies and one study is evaluating cisplatin/etoposide/veliparib 
combination.
Phase 1 data from subjects treated with veliparib, carboplatin, and paclitaxel for advanced 
non-small cell lung cancer (NSCLC) are available from Cancer Therapy Evaluation 
Program (CTEP) Study 7967.20  Veliparib was given orally BID on Days 1 to 7 of each 
21-day cycle, and paclitaxel and carboplatin were administered on Day 3.  Two DLTs 


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(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 (Study M10-898) of carboplatin and paclitaxel 
with veliparib or placebo for subjects with advanced NSCLC is complete.  Therapy was 
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.  Seventy-six squamous NSCLC subjects were treated with veliparib 
combination.  All subjects have completed therapy.  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.  The efficacy data are 
summarized in Investigator Brochure, version 9.
An ongoing ECOG study E2511 is a Phase 1 and randomized Phase 2 double-blind 
clinical study of cisplatin and etoposide in combination with veliparib or placebo as 
frontline therapy for ED SCLC.21 In the Phase 1 part of the study the maximum 
administered dose of veliparib in combination with 75 mg/m2 cisplatin and 100 mg/m2
etoposide was 100 mg BID.  This dose was selected as the recommended Phase 2 dose for 
the randomized part of the study, which is currently ongoing.  The Phase 1 part of the 
study enrolled 9 patients with ED SCLC.  Veliparib was well tolerated at the 60 mg dose 
(0 of 3 patients with DLT).  DLT was seen in 1 of 6 patients treated at the 100 mg dose 
(grade 5 cardiac failure; Takotsubo cardiomyopathy).  The same subject experienced G4 
respiratory failure prior to G5 cardiac failure.  The maximum administered dose of 
veliparib of 100 mg BID on D1-7 in combination with standard doses of cisplatin and 
etoposide was defined as the RPTD.  Other Grades 3 – 4 adverse events irrespective of 


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attribution included:  neutropenia (6), leukopenia (5), nausea (3), thrombocytopenia (2), 
fatigue (2), hyponatremia (2), dehydration (1), febrile neutropenia (1), and diarrhea (1).  
Unconfirmed investigator-assessed efficacy outcome in 7 evaluable patients were stable 
disease in 2/7 (28.6%), partial response in 4/7 (57.1%) and complete response in 
1/7 (14.3%) patients.21
Overall, approximately 3,700 cancer patients have been exposed to veliparib in AbbVie 
and CTEP clinical trials with veliparib administered as monotherapy and as combination 
therapy to study subjects with various solid and hematological tumors.  Based upon 
mechanism of action, nonclinical, and clinical data, hematological cytopenias 
(thrombocytopenia, anemia, neutropenia, and lymphopenia) are toxicities that may result 
from veliparib therapy.  When veliparib is administered as single-agent therapy, these 
toxicities are predominantly Grade 1 or Grade 2 toxicities.  In combination with cytotoxic 
chemotherapy, Grade 3 or Grade 4 cytopenias may be observed.  These toxicities are 
commonly associated with cancer therapies, and standard clinical practices to manage 
these toxicities are well-established.
Nausea and vomiting have been commonly observed in clinical trials with veliparib, 
including in subjects receiving single-agent therapy with veliparib.  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 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.15
3.4
Carboplatin and Etoposide
Carboplatin is a commonly used platinum compound that acts by binding to 
Deoxyribonucleic Acid (DNA) and interrupting cell division.  It is approved by the Food 
and Drug Administration (FDA) for the treatment of patients with ovarian cancer.  It is 
also used for the treatment of non-small cell lung cancer (NSCLC), small cell lung cancer 


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(SCLC), head and neck cancer, endometrial cancer, metastatic seminoma and more 
recently in breast cancer.  Carboplatin is eliminated by renal excretion.  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.22,23
Etoposide, commonly known as VP-16, is a semi-synthetic derivative of podophyllotoxin.  
Etoposide in combination with other approved chemotherapeutic agents is FDA approved 
as first-line treatment in subjects with small cell lung cancer.  The predominant 
macromolecular effect of etoposide appears to be the induction of DNA strand breaks by 
an interaction with DNA-topoisomerase II or the formation of free radicals.  Its main 
effect appears to be at the G2 portion of the cell cycle in mammalian cells.  Hematologic 
toxicity (myelosuppression) is the most frequently observed toxicity of etoposide.  Other 
frequent toxicities include nausea and vomiting, anorexia and alopecia.24
Carboplatin in combination with etoposide (both IV and oral formulations) has been 
extensively tested in randomized clinical trials in SCLC as well as in other tumor 
types.24-27  Most frequently reported adverse events in subjects treated with carboplatin 
and etoposide combination were myelosuppression (leukopenia and thrombocytopenia), 
nausea, vomiting and alopecia.
The recommended dose of carboplatin for this combination is AUC of 5 – 6 mg/mL*min 
on Day 1 and the dose for etoposide 100 mg/m2 on Days 1 – 3 of 21-day cycles per 
NCCN 2014 guidelines for the treatment of ED SCLC.
3.5
Study Rationale
The proposed study has the potential to advance the management of SCLC if it results in 
improved clinical outcome as anticipated, based on preclinical evaluation.
DNA damaging agents constitute the mainstay of therapy for SCLC.  The combination of 
DNA damaging cytotoxic chemotherapy (e.g., cisplatin and etoposide) and a 


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pharmacologic inhibitor of DNA damage repair enzyme, poly (ADP) Ribose polymerase 
(PARP), may result in greater cytotoxicity and antitumor efficacy of the cytotoxic agents.  
It is postulated that enhanced efficacy may translate into improved disease progression 
without concomitant increased toxicity in subjects with extensive stage SCLC.
The in vitro and in vivo studies of veliparib and standard cytotoxic agents for SCLC 
including cisplatin, carboplatin and etoposide, discussed in the preceding sections provide 
specific supporting evidence for the clinical evaluation of veliparib as an agent that can 
further potentiate currently available therapies for the treatment of SCLC.  Similar 
strategies are currently in clinical translation for various types of cancer including 
melanoma, breast and ovarian cancers.4-6  This clinical protocol represents the 
first attempt to translate the same concept into the treatment of SCLC where DNA 
damage-inducing agents form the cornerstone of therapy.  If successful, the proposed trial 
is able to provide additional clinical proof for the biologic principle that DNA damage 
repair enzyme inhibition through pharmacological agents will enhance the efficacy of 
classic cytotoxic agents that act by inducing DNA damage.
A positive outcome in this Phase 2 evaluation, in conjunction with such outcome from 
ECOG E2511 study, will provide a strong rationale to conduct a large definitive 
registration study of veliparib in combination with platinums and etoposide in ED SCLC.
3.6
Differences Statement
This study is designed to evaluate the safety and tolerability of veliparib in combination 
with carboplatin and etoposide in subjects with small cell lung cancer or 
advanced/metastatic solid tumors.  This is the first study being conducted with this 
combination of treatment.  Previous early phase studies have been designed to test the 
safety and tolerability of veliparib as monotherapy or in combination with chemotherapy.
3.7
Benefits and Risks
The Phase 1 Dose Escalation portion of this study proposed to establish the recommended 
Phase 2 dose and veliparib schedule.  These were determined to be veliparib 240 mg BID 


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on Days –2 – 12 (14-Day schedule) in combination with carboplatin AUC 5 mg/ml*hr on 
Day 1 and etoposide 100 mg/m2 on Days 1 – 3 of 21-Day cycle.  The Phase 2 portion of 
this study proposes to evaluate clinical outcomes for subjects with ED SCLC treated with 
veliparib added to standard therapy with carboplatin and etoposide.  Preclinical data 
demonstrate that veliparib potentiates the anti-tumor activity of platinums, and that 
platinum sensitivity often correlates with the sensitivity to PARP inhibitors.  The current 
study, Study M14-361, is the first to test veliparib in combination with carboplatin and 
etoposide in human subjects.
Risks in this study include toxicity from the addition of veliparib to standard therapy.  
Preliminary safety data from several Phase 1 and Phase 2 studies indicate that veliparib is 
tolerated in combination with carboplatin and paclitaxel at doses of up to 120 – 200 mg 
BID, and with cisplatin and etoposide at the maximum tested dose of 100 mg BID.  
Standard clinical practices to manage the toxicity of carboplatin + etoposide are well 
established.  Toxicity will be closely monitored at all study visits.  Toxicities of veliparib 
expected to overlap with the toxicity of carboplatin + etoposide regimen include 
nausea/vomiting and myelosuppression.  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.  
Addition of veliparib resulted in no compromise to the delivery of carboplatin.  Drug-drug 
interaction with etoposide is not anticipated, but will be monitored.
4.0
Study Objectives
The objectives of the Phase 1 dose escalation are:
Primary Objectives:
●
To establish the Maximum Tolerated Dose (MTD) and to establish the 
Recommended Phase 2 Dose (RPTD) and schedule for veliparib in 
combination with carboplatin and etoposide.
●
To evaluate the pharmacokinetic interaction between veliparib and etoposide.


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Secondary Objective:
●
To evaluate the safety of maintenance veliparib monotherapy at 400 mg BID 
in subjects completing 4 cycles of carboplatin, etoposide and veliparib without 
evidence of disease progression.
The objectives of Phase 2 are:
Primary Objective:
●
To evaluate if veliparib in combination with carboplatin and etoposide 
followed by veliparib maintenance monotherapy results in improved 
progression free survival (PFS) versus placebo in combination with 
carboplatin and etoposide followed by placebo monotherapy in subjects with 
treatment-naïve ED SCLC.
Secondary Objectives:
●
To evaluate if veliparib in combination with carboplatin and etoposide 
followed by placebo monotherapy results in improved progression free 
survival (PFS) versus placebo in combination with carboplatin and etoposide 
followed by placebo monotherapy in subjects with treatment-naïve ED SCLC.
●
To evaluate if veliparib in combination with carboplatin and etoposide results 
in improved objective response rate (ORR) versus placebo in combination with 
carboplatin and etoposide, at the time of completion of combination therapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide 
followed by veliparib maintenance monotherapy results in improved overall 
survival (OS) versus placebo in combination with carboplatin and etoposide 
followed by placebo monotherapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide 
followed by placebo monotherapy results in improved overall survival (OS) 
versus placebo in combination with carboplatin and etoposide followed by 
placebo monotherapy.


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●
To further evaluate the safety of veliparib in combination with carboplatin and 
etoposide followed by veliparib maintenance monotherapy.
Tertiary Objectives are:
●
To evaluate if veliparib in combination with carboplatin and etoposide 
followed by veliparib maintenance monotherapy results in improved duration 
of overall response (DOR) versus placebo in combination with carboplatin and 
etoposide followed by placebo monotherapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide 
followed by placebo monotherapy results in improved duration of overall
response (DOR) versus placebo in combination with carboplatin and etoposide 
followed by placebo monotherapy.
●
To compare PFS and OS of subjects treated with veliparib in combination with 
carboplatin and etoposide followed by veliparib maintenance to PFS and OS of 
subjects treated with veliparib in combination with carboplatin and etoposide 
followed by placebo maintenance.
●
To evaluate performance status.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 1, open-label, dose escalation/Phase 2 randomized double-blind study of 
veliparib in combination with carboplatin and etoposide and maintenance veliparib 
monotherapy.  Subjects in Phase 1 will be group sequentially assigned to the ascending 
dose levels of veliparib in combination with standard carboplatin/etoposide regimen based 
on the observed toxicities.  Subjects in Phase 2 will be randomized in a 1:1:1 ratio to 
carboplatin, etoposide, placebo followed by placebo maintenance, or carboplatin, 
etoposide, veliparib followed by either veliparib or placebo maintenance.  Approximately 
215 adult male or female subjects diagnosed with extensive stage disease SCLC or other 
advanced/metastatic solid tumors will be selected to participate in the study according to 
the inclusion/exclusion criteria.


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The study was designed to enroll approximately 35 subjects in Phase 1 and approximately 
180 subjects in Phase 2 to meet scientific and regulatory objectives without enrolling an 
undue number of subjects in alignment with ethical considerations.  Possible dose levels
to be evaluated are as shown in Table 4.
Phase 1 Dose Escalation
The Phase 1 portion of this study will evaluate the safety, tolerability, dose limiting 
toxicities (DLTs), RPTD, pharmacokinetics (PK), and pharmacodynamics (PD) of 
veliparib in combination with carboplatin and etoposide in 21-day cycles in subjects with 
small cell lung cancer or advanced/metastatic solid tumors with possible schedules 
outlined in Table 1, Table 2 and Table 3.  For the Phase 1 subjects receiving 
non-continuous dosing, veliparib in Cycle 2 will be administered on Days 2 – 5 or Days 2 
– 12 dependent on the dosing schedule to allow for evaluation of drug-drug interaction of 
veliparib with etoposide (Table 2).  Details on drug administration and cycle schedules are 
described in Section 5.5.1.2.  
Table 1.
Treatment Schema for Combination Therapy Cycles 1, 3, 4 in 
Phase 1 Dose Escalation (Non-Continuous Veliparib Dosing 
Schedules)
Days
–2
–1
1
2
3
4 – 5 or 
4 – 12
6 – 19 or 
13 – 19
Veliparib
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Twice a 
day
Carboplatin 
Once
Etoposide
Once
Once
Once
Note: 
Starting at Cycle 5 Day 1 veliparib dosed at 400 mg BID monotherapy continuous dosing for 21 days per 
cycle.


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Table 2.
Treatment Schema for Combination Therapy Cycle 2 in Phase 1 
Dose Escalation (Non-Continuous Veliparib Dosing Schedules)
Days
–2
–1
1
2
3
4 – 5 or 
4 – 12
6 – 19 or 
13 – 19
Veliparib
Twice a 
day
Twice a 
day
Twice a 
day
Carboplatin 
Once
Etoposide
Once
Once
Once
Table 3.
Treatment Schema for Combination Therapy Cycles in Phase 1 
Dose Escalation (Continuous Veliparib Dosing Schedule)
Days
–2
–1
1
2
3
4 – 19
Veliparib
Twice a day
Twice a day
Twice a day
Twice a day
Twice a day
Twice a day
Carboplatin 
Once
Etoposide
Once
Once
Once
Note: 
Starting at Cycle 5 Day 1 veliparib dosed at 400 mg BID monotherapy continuous dosing for 21 days per 
cycle.
Upon completion of 4 cycles of combination therapy, subjects without evidence of disease 
progression will continue on maintenance monotherapy veliparib 400 mg BID until 
disease progression or unacceptable toxicity.  Subjects who will be receiving prophylactic 
cranial irradiation (PCI) will have maintenance veliparib interrupted for the duration of 
radiotherapy as described in Section 5.2.3.2.
For subjects in the Phase 1 dose escalation portion of the study, each subject will 
participate in only 1 dose group and there is no provision for intra-subject dose-escalation. 
Study procedures are provided in the Schedule of Assessments and Pharmacokinetic and 
Pharmacodynamic tables (Section 5.3.1).
All subjects will be monitored for DLTs during DLT observation period (Cycle 1 Day –2 
to pre-dose on Cycle 2 Day 1), and treatment-related adverse events (AEs) will be 
evaluated throughout the course of the study for evidence of acute, delayed, or cumulative 
toxicities.


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Subjects who do not complete the DLT observation period for reasons other than DLT 
(e.g., withdraw consent, non-compliance, etc.) will be replaced to ensure appropriate 
number of subjects are evaluated.
The dose levels of veliparib to be evaluated in the dose-escalation portion of this study 
were determined based on the outcome of prior clinical studies of veliparib as well as on 
pre-clinical toxicology, toxicokinetic, and nonclinical anti-tumor efficacy studies.  The 
following dose levels may be evaluated in the dose-escalation portion of the study:  80, 
120, 160, 200 and 240 mg BID (Table 4).  Reduced dose levels may be evaluated based 
upon review of subject safety and PK data.  Intermediate dose levels may be evaluated 
based upon review of subject safety including, but not limited to, Grade 2 study-drug 
related AEs.  If the MTD is not reached at veliparib 200 mg BID dose level, higher dose 
levels (with no more than 25% veliparib dose increments, and not exceeding single agent 
veliparib RPTD of 400 mg BID (Table 4, Levels V – VIII) or alternative veliparib dosing 
schedules may be evaluated at the discretion of the sponsor.  The alternative dosing 
schedules can include dosing veliparib for Day –2 to Day 12 (14-day schedule) and/or 
Day –2 to Day 19 (continuous schedule) of the 21 day cycle (Table 1, Table 2 and 
Table 3).  The initial dose for these schedules will be 200 mg BID or the maximum 
administered dose (MAD), not exceeding the MTD in the 7 day schedule.  The 14-day 
schedule will be explored prior to continuous dosing schedule.  Reduced or interim dose 
levels may be evaluated based on review of the safety and PK.


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Table 4.
Phase 1 Dose Escalation 
Dose Level
Number of Subjects
Doses
Veliparib
mg
Carboplatin AUC, 
mg/mL*min
Etoposide
mg/m2
I
3 – 9
80
5
100
II
3 – 6
120
5
100
III
3 – 6
160
5
100
IV
3 – 6
200
5
100
V
3 – 6
240
5
100
VI
3 – 6
300
5
100
VII
3 – 6
340
5
100
VIII
3 – 6
400
5
100
A "3 + 3" escalation rule will be used for the dose-escalation portion of this study, with a 
condition applied for the Dose Level 1, which will allow 3 additional subjects to be 
entered in Dose Level 1 if 2 of 6 initial subjects experience DLTs.  Enrollment of the 
3 additional subjects at all dose levels will depend on a review of the specific DLTs 
observed and discussion with the Investigators.
A minimum of 3 evaluable subjects will be enrolled at each dose level.  Additional 
eligible subjects may be enrolled at the current dose level at the discretion of the 
Investigators and the AbbVie TA MD.  The dose escalation decisions will be made 
following the completion of the DLT observation period for the evaluable subjects in the 
intended cohort size.  If a cohort is over-enrolled, reported toxicities in additional subjects 
will be taken into consideration.
Dose-Escalation Criteria: 
AEs, clinical laboratory results and vital signs will be assessed throughout the study in 
each dose-escalation cohort.  
DLTs will be assessed in each dose-escalation cohort during DLT observation period 
(Cycle 1 Day –2 to pre-dose Cycle 2 Day 1).  Based on the safety and tolerability of study 


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drugs after the first cycle of treatment has been completed in at least 3 subjects, escalation 
to a subsequent dose level or expansion of the current dose level will occur based upon 
the following criteria (Table 5):
Table 5.
Dose Escalation Guidelines
Number of Subjects with 
DLT in the First Cycle
Escalation Decision Rule
0 out of 3
Enter 3 subjects at the next dose level.
1 out of 3
Add 3 more subjects at current dose level.  If AbbVie or the investigator 
considers the DLT(s) is clinically significant, AbbVie will determine if it is 
appropriate to add more patients at this dose level.
●
If < 2 of 6 subjects (or < 33% of subjects) experience DLT, dose 
escalation will proceed to the next dose level.
●
If ≥ 2 of total 6 subjects (or ≥ 33% of subjects) experience DLTs, then 
dose escalation will be stopped.*
≥ 2 out of 3 or 6
Dose escalation will be stopped.  *Additional subjects will be enrolled at 
the previous lower dose level as needed.  The following exceptions apply 
to Dose Level 1:
●
If 2 of 6 initial subjects at Dose Level 1 experience DLTs, 3 additional 
subjects may be entered and the cohort will be expanded up to 
9 subjects for further DLT assessment.  
o
Enrollment of the 3 additional subjects will depend on a review of 
the specific DLTs observed and discussion with the Investigators.  
●
If 2 of 9 subjects at Dose Level 1 experience DLTs, then escalation to 
the next dose level may proceed.
●
If > 2 of 9 subjects in Dose Level 1 experience DLTs, dose-escalation 
will stop.
*
If 2 out of 6 subjects experience different DLTs, for example nausea and neutropenia, the data will be reviewed by 
the investigators and AbbVie to determine if 3 additional subjects should be added at that dose level.  If 3 subjects 
will be added and none experience DLTs, this dose level will be declared the MTD.
An MTD and/or maximum administered dose (MAD), and RPTD, will be determined.  
The MTD is defined as the maximum dose at which < 2 of 6 or ≤ 2 of 9 subjects 
experience a DLT during the DLT observational period C1D-2 to C2D1.  The MAD is 
defined as the highest dose tested.  Both MAD and MTD may be determined 
independently for each tested dosing schedule of veliparib.  The RPTD and schedule will 
be determined based on the assessment of the observed toxicities, the MTD or MAD, and 


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the overall safety profile of the study drug.  The RPTD cannot exceed the lower of the 
MTD or MAD.  At the RPTD and schedule additional subjects will be added as needed so 
that a total of at least 9 subjects will be treated at the RPTD.
DLT Definition:  DLT is defined as any of the following drug-related toxicities occurring 
during the DLT observation period (Cycle 1 Day –2 to Cycle 2 Day 1) in any of the 
dose-escalation cohorts, with grading according to the National Cancer Institute (NCI) 
Common Toxicity Criteria for Adverse Events (CTCAE), version 4.020:
1.
Cycle 1 events associated with treatment delay > 14 days in initiating Cycle 2 
chemotherapy:
a.
Grade 4 thrombocytopenia (platelets < 25.0 × 109/L)
b. Grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5 × 109/L)
c.
Grade 3 febrile neutropenia with fever lasting for > 7 days
d. Grade 4 febrile neutropenia of any duration
NOTE:  Delay of more than 14 days in initiating Cycle 2 due to factors not directly 
related to treatment emergent toxicity will not be considered a DLT.
2.
Grade ≥ 3 non-hematologic toxicity that represents at least 2 grade increase from 
baseline and is attributed to veliparib treatment:
a.
Exclusion:  nausea and vomiting lasting ≤ 48 hours or inadequately treated
b. Exclusion:  electrolyte abnormalities resolving within ≤ 24 hours
c.
Exclusion:  hypersensitivity reactions
d. Exclusion:  alopecia
3.
Grade 2 non-hematologic toxicity that represents at least 2 grade increase from 
baseline, is attributed to veliparib treatment and requires a treatment delay of 
> 14 days in initiation of Cycle 2
4.
Any toxicity that represents at least 2 grade increase from baseline, is attributed to 
veliparib treatment and requires at least one of:


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a.
Dose modification within Cycle 1
b. Omission of carboplatin, > 1 daily etoposide dose, or > 30% veliparib doses in 
Cycle 1
Subjects experiencing DLT(s) during the DLT observation period will require an 
interruption of study drugs and possible discontinuation from further participation in the 
study.  Veliparib may be reintroduced at a reduced dose, if the toxicity returns to 
≤Grade 1 or to baseline if Grade 2 at study entry.  All decisions regarding continued 
dosing for individual subjects experiencing a DLT will be medically managed by the 
investigator in conjunction with the AbbVie TA MD.
A subject will be considered evaluable for DLT if he/she has completed the DLT 
evaluation period with the assigned regimen (full dose carboplatin, at least two doses of 
etoposide, with ≥80% compliance of veliparib) or discontinued Cycle 1 due to a DLT.  
All cohort sizes and numbers of subjects in the Phase 1 dose escalation criteria section 
above refer to evaluable subjects.  Any subjects who discontinue from study prior to the 
completion of the DLT evaluation period for any reason other than a DLT will be 
replaced.
Phase 1 Pharmacokinetics
Pharmacokinetics of veliparib and etoposide will be assessed to determine the drug-drug 
interactions.  Further pharmacokinetics of carboplatin will be assessed on Day 1 of 
Cycle 1 (please reference Table 10 and Table 11.)
Transition from Phase 1 to Phase 2
Once the veliparib RPTD and schedule is determined, the veliparib RPTD and schedule 
will be communicated to all participating research sites prior to the start of enrollment into 
the Phase 2.  Subjects from the Phase 1 Dose Escalation portion are not eligible for 
enrollment into the Phase 2 portion, but may continue to receive veliparib, carboplatin and 
etoposide at the assigned dose and schedule as long as they tolerate the study drug, show 


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no evidence of disease progression, and do not meet any of the criteria for subject 
discontinuation (Section 5.4.1).
Phase 2 Randomized Double-Blind
The veliparib dose and schedule for the Phase 2 was determined to be 240 mg BID on a 
14 day schedule based on the analysis of Phase 1 data.
Approximately 180 total subjects with treatment-naïve ED SCLC will be enrolled at the 
240 mg BID veliparib/placebo dose and 14 day schedule in the Phase 2 double-blinded 
portion of the study.  They will be randomized in a 1:1:1 ratio to one of three treatment 
arms: 
Arm A:  veliparib 240 mg in combination with carboplatin/etoposide followed by 
veliparib 400 mg BID monotherapy
Arm B:  veliparib 240 mg in combination with carboplatin/etoposide followed by placebo 
monotherapy
Arm C:  placebo in combination with carboplatin/etoposide followed by placebo 
monotherapy
Subjects in all Phase 2 study arms will receive a minimum of 4 cycles of combination 
therapy unless disease progression or unacceptable toxicity warrants earlier 
discontinuation from the treatment.  Additional 2 cycles of combination therapy (e.g., up 
to a total of 6 cycles) may be administered at the investigators discretion if subject status 
at the completion of initial 4 cycles warrants continued combination treatment and/or if 
local SOC guidelines require 6 cycles of platinum-based therapy.  In the combination 
cycles of Arms A and B, subjects will receive veliparib at 240 mg BID on a 14-day 
schedule, Arm C will receive matching placebo.  After completion of the chemotherapy 
combination cycles (at least 4), subjects without evidence of disease progression will 
receive veliparib at 400 mg BID continuous dosing (21-day cycles) (Arms A), or 


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matching placebo (Arms B and C) as per treatment arm assignment, until disease 
progression or unacceptable toxicity occurs (Figure 2).  
Subject randomization for Phase 2 will be stratified by baseline LDH level (> ULN versus 
≤ ULN), and gender.
Table 6.
Treatment Schematic for Combination Cycles in Phase 2
Days
–2
–1
1
2
3
4 – 12
Veliparib/Placebo
240 mg 
BID
240 mg 
BID
240 mg 
BID
240 mg 
BID
240 mg 
BID
240 mg 
BID
Carboplatin 
Once
Etoposide
Once
Once
Once
Notes:
Starting at Maintenance Day 1 veliparib will be dosed at 400 mg BID monotherapy continuous dosing for 
21 days per cycle.
A minimum of 4 cycles of combination treatment are to be administered.  If subject/disease status at the 
completion of Cycle 4 warrants continued combination treatment, up to 2 additional combination cycles 
(e.g., up to a total of 6) may be administered at investigators discretion.
Figure 2.
Phase 2 Treatment and Randomization Schematics


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For subjects who experience toxicities due to veliparib or carboplatin/etoposide, 
appropriate dose modifications or dosing delays should be managed according to 
Section 5.7.  Subsequent cycles of therapy will be administered if there is no evidence of 
disease progression and observed toxicities have recovered adequately as described in 
Section 5.7.
5.2
Selection of Study Population
Subjects will undergo screening procedures within 28 days (tumor assessments within 
21 days) prior to initial study drug administration.  Adult male and female subjects with 
histologically or cytologically confirmed diagnosis of extensive disease SCLC who meet 
the inclusion criteria and who do not meet any of the exclusion criteria will be eligible for 
enrollment into the study.
5.2.1
Inclusion Criteria
A subject will be eligible for study participation if he/she meets the following criteria:
1.
Subject with histologically or cytologically confirmed extensive-stage disease 
small cell lung cancer (ED SCLC), which is newly diagnosed and chemotherapy 
naïve.
Notes:
●
ED SCLC is defined herein as any SCLC except a disease confined to the 
hemithorax of origin, with or without the involvement of regional lymph 
nodes, including ipsilateral and contralateral hilar, ipsilateral and contralateral 
mediastinal, and ipsilateral supraclavicular nodes.
2.
Phase 1 ONLY:  subject with advanced/metastatic solid tumors for which 
carboplatin/etoposide treatment is considered appropriate.
3.
Subject in Phase 2 ONLY:  must have measureable disease per RECIST 1.1.


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4.
Subjects with SCLC must consent to provide available archived FFPE tissue 
sample of SCLC lesion (primary or metastatic) for central review and biomarker 
analysis.
5.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance score 
of 0 to 1.
6.
Subject must be ≥ 18 years of age.
7.
Subject must have adequate hematologic, renal and hepatic function as follows:
●
Bone Marrow:  Absolute neutrophil count ANC ≥ 1,500/mm3 (1.5 × 109/L); 
White blood cells ≥ 3,000/mm3 (3× 109/L); Platelets ≥ 100,000/mm3
(100 × 109/L); Hemoglobin ≥ 9 g/dL (5.58 mmol/L);
●
Renal function: creatinine ≤ ULN or, if > ULN, calculated creatinine 
clearance via the Cockroft Gault formula of ≥ 50 mL/min;
●
Hepatic function:
○
AST and ALT ≤ 2.5 × ULN.  For subjects with liver metastases, AST and 
ALT ≤ 5 × ULN;
○
Bilirubin:  ≤ 1.5 × ULN; for subjects with Gilbert's syndrome bilirubin 
> 1.5 × ULN is allowed if no symptoms of compromised liver function are 
present.
8.
Subject must be able to swallow pills.
9.
Female and male patients of fertile age, and/or their partners should use 
contraception.  If male, subject and subject's female partner(s) of childbearing 
potential must follow the contraception recommendations as described in 
Section 5.2.4.  If female, subject must be either postmenopausal for at least 1 year, 
surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), 
or the subject and the subject's male partner(s) must follow the contraception 
recommendations as described in Section 5.2.4.
Female subjects must have negative results for pregnancy tests performed:
●
Screening on a serum specimen obtained within 7 days prior to initial study 
drug administration, and


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●
prior to dosing on a urine sample obtained C1D-2 unless the serum pregnancy 
test was collected within 7 days of C1D-2.
10.
Must voluntarily sign and date each 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 – 4)  These criteria were selected to ensure the appropriate subject population with 
sufficient disease severity for evaluation.
(5 – 8)  This is standard criteria to ensure general good health and safety of the subjects.
(9)  The impact of veliparib/carboplatin/etoposide on the unborn fetus is unknown, 
therefore, this criteria ensure that adequate precautions are taken to avoid pregnancy.
(10)  This is standard criteria in accordance with harmonized Good Clinical Practice.
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Phase 1 ONLY:  Subject has had any prior anti-cancer therapy other than:
●
Hormonal, non-myelosuppressive, biologic, targeted, or immune therapy (must 
be completed ≥ 4 weeks prior to Cycle 1 Day –2).  See Section 5.2.3.1 for 
details.
●
One line of cytotoxic chemotherapy (must be completed ≥ 4 weeks prior to 
Cycle 1 Day –2).  See Section 5.2.3.1 for details.
●
Adjuvant/neoadjuvant radiotherapy completed ≥ 12 months prior to Cycle 1 
Day –2, with field not involving > 10% of bone marrow reserve.
●
Tumor lesion irradiation with intent of symptom palliation ≥ 4 weeks prior 
Cycle 1 Day –2.


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2.
Phase 2 ONLY:  Subject has had any prior chemotherapy, radiotherapy, 
investigational anti-cancer agents or biologic therapy for the disease under study.  
Single non-target lesion irradiation with intent of symptom palliation is allowed if 
completed ≥ 2 weeks prior Cycle 1 Day –2. 
3.
Subject has known hypersensitivity to etoposide, platinum compounds or veliparib.
4.
Phase 1 ONLY:  Subject has received prior myelopoietic growth factors.
5.
Subject has current or history of central nervous system (CNS) or leptomeningeal 
metastases.  If CNS metastasis is suspected, a head CT should be performed at 
screening.
6.
Subject has a history of seizures within 12 months of Cycle 1 Day–2 or diagnosed 
neurological condition placing subject at the increased risk of seizures.
7.
Subject has received traditional herbal anti-cancer medicine (e.g., Chinese, other 
Asian, etc.) within 14 days prior to Cycle 1 Day –2.
8.
Subject has had major surgery within 6 weeks prior to Cycle 1 Day –2 (subjects 
must have completely recovered from any previous surgery prior Cycle 1 Day –2).
9.
Subject has clinically significant and uncontrolled major medical condition(s) 
including but not limited to:
●
Uncontrolled nausea/vomiting/diarrhea;
●
Active uncontrolled infection;
●
History of hepatitis B (HBV) with surface antigen (HBsAg) positivity within 
3 months prior to the date of informed consent for this study (if HBsAg status 
is unknown it must be tested at screening);
●
History of hepatitis C (HCV) with HCV RNA positivity within 3 months prior 
to the date of informed consent for this study (if HCV RNA status is unknown 
it must be tested at screening);
●
Symptomatic congestive heart failure (NYHA class ≥ II);
●
Unstable angina pectoris or cardiac arrhythmia;


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●
Psychiatric illness/social situation that would limit compliance with study 
requirements;
●
Any other medical condition, which in the opinion of the Investigator, places 
the subject at an unacceptably high risk for toxicities.
10.
Subject is pregnant or lactating.
11.
The subject has a history of another active 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, breast DCIS).
Questions regarding the eligibility of individual subjects should be directed to the AbbVie 
TA MD.
Rationale for Exclusion Criteria
(1 – 3, 11)  To select the adequate subject population with the appropriate disease severity 
for evaluation.
(4 – 10)  For the safety of the subject.
5.2.3
Prior and Concomitant Therapy
If a subject reports taking any over-the-counter or prescription medications, vitamins 
and/or herbal supplements or if administration of any medication becomes necessary from 
2 weeks prior to study drug administration through the end of the study, the name of the 
medication, dosage information including dose, route and frequency, date(s) of 
administration including start and end dates, and reason for use must be recorded.
The AbbVie TA MD should be contacted if there are any questions regarding concomitant 
or prior therapy(ies).


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5.2.3.1
Prior Therapy
Phase 1 Dose Escalation
For Phase 1 subjects, prior hormonal, non-myelosuppressive, biologic, immune, and 
targeted therapy is allowed if completed ≥ 4 weeks prior to Cycle 1 Day –2.  Allowed 
biologic and targeted agents are listed below (List 1).  Other prior biologic, immune or 
targeted agents may be permitted upon review by AbbVie TA MD.
List 1.
Allowable Prior Therapies
Afatinib
Cetuximab
Ficlatuzumab
Lapatinib
Provenge
Sunitinib
Axitinib
Dacomitinib
Gefitinib
Pazopanib
Rilotimumab
Tivozanib
Bevacizumab
Erlotinib
Ipilimumab
Pembrolizumab
Sorafenib
Trastuzumab
For Phase 1 subjects one line of prior cytotoxic chemotherapy is allowed, however 
regimens known to cause significant myelosuppression will not be permitted.  Specific 
prior regimen received must be reviewed and approved by AbbVie TA MD.
For Phase 1 subjects, adjuvant/neoadjuvant radiotherapy is allowed if completed 
≥12 months prior to Cycle 1 Day –2 and the field did not involve > 10% of bone marrow 
reserve.
Phase 2 Randomized Double-Blind
Subjects in the Phase 2 portion of the study are not allowed to have any prior antitumor 
treatment for the disease under study.  For the purposes of this protocol, antitumor 
treatment is defined as systemic anticancer agents (cytotoxic chemotherapy, hormonal 
therapy, immunotherapy, biologic therapy), radiotherapy, and investigational anti-cancer 
agents.  For subjects in Phase 2, radiotherapy to a single lesion with the intent of symptom 
palliation (irradiated lesion will not be used as a target lesion for RECIST evaluations) is 
allowed, if completed at least 2 weeks prior to Cycle 1 Day –2.


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5.2.3.2
Concomitant Therapy
The locally approved product label, institutional guidelines, local practice, or applicable 
Summary of Product Characterizations (SmPC) for carboplatin and etoposide should be 
referenced for any concomitant therapy guidelines.
Premedication:
The prophylactic antiemetics, including 5-HT3 antagonists, according to 
institution, National Comprehensive Cancer Network (NCCN), European 
Society for Medical Oncology (ESMO) or American Society of Clinical 
Oncology (ASCO) guidelines should be given, prior to administration of 
carboplatin and etoposide.  Prophylaxis with anti-emetics (e.g., 5-HT3 
antagonists such as ondansetron) is strongly recommended when initiating 
single agent veliparib/placebo maintenance monotherapy.
Anticancer Agents:
Other anticancer agents are not permitted during the treatment portion of the 
study.  All subjects will receive carboplatin + etoposide with veliparib/placebo 
at specified timepoints during the treatment portion of the study.  The locally 
approved carboplatin and etoposide product labels or SmPCs should be 
referenced to determine if there are any contraindications associated with 
concomitant medications (e.g., phenytoin, etc.).
Supportive Care:
Best supportive care and treatment will be given as appropriate to each subject 
(antiemetics, antibiotics, transfusions, nutritional support, palliative treatment 
for pain, bisphosphonates or denosumab) according to institutional or clinical 
practice guidelines (e.g., ASCO, ESMO, or NCCN).
Growth Factors:
Biologic response modifiers administered for erythropoiesis 
(e.g., erythropoietin, darbepoetin alpha) and colony stimulating factors 
(e.g., neulasta, G-CSF, GM CSF, etc.) may be administered according to 
institutional or clinical practice guidelines (e.g., ASCO, ESMO, or NCCN).  
Growth factors prophylaxis will not be allowed in Cycle 1 (Day –2 through 
Day 21) of the dose escalation cohorts.  Growth factors prophylaxis is 
acceptable in Phase 2.


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Radiation:
Prophylactic cranial irradiation (PCI) is allowed during the study in the 
Maintenance phase of treatment at Investigators discretion.  The dose of PCI 
should be 24 Gy in 8 fractions of 3 Gy each, or per local treatment standards.  
Veliparib or placebo maintenance monotherapy will be held starting 2 days prior 
to the initiation of radiation therapy, throughout the radiation therapy and for 
4 days following radiation therapy.  Palliative radiation to a non-target lesion 
with the intent of symptom control is allowed; non-progressing status of lesion 
to be irradiated must be documented prior to the procedure.  Radiation to non-
target lesions for other reasons will not be allowed during combination treatment 
cycles and generally will not be allowed during maintenance; exceptional 
circumstances that may arise during maintenance must be discussed with 
AbbVie TA MD and non-progressing status of such lesions using the same 
modality as study tumor assessments will have to be documented prior to
procedure.
Surgery:
If the subject requires surgery during the study, then this needs to be discussed 
with the AbbVie TA MD.
Alternate Therapy:
No traditional herbal anti-cancer medicine (e.g., Chinese, Asian, etc.) may be 
taken concurrently with veliparib (a 14-day washout period must be 
documented).
5.2.4
Contraception Recommendations
If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of both) OR a Women of Childbearing Potential, 
practicing at least one of the following methods of birth control, on C1D-2 (or earlier) 
through at least 6 months after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to C1D-2.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
C1D-2.
●
Bilateral tubal occlusion/ligation.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.


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●
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success, and is the sole sexual 
partner of the WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the birth 
control methods listed above (excluding true abstinence).
If the subject or subject's female partner(s) is currently using a hormonal contraceptive, 
she should also use a barrier method during this study and for 6 months (or per local 
label) after study completion.
Male subjects who are sexually active with a WOCBP, even if the male subject has 
undergone a successful vasectomy, must agree from C1D-2 through at least 6 months 
after the last dose of study drug to use condoms and his female partner(s) must use at least 
one of the contraceptive measures (as defined in the protocol for female study subjects of 
childbearing potential).
Male subject agrees not to donate sperm from C1D-2 through at least 6 months after the 
last dose of study drug.


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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 7 and Table 8.  Pharmacodynamic 
(PD) and Pharmacogenetic (PG) assessments will be performed as summarized in Table 9
Pharmacokinetic (PK) assessment will be performed as summarized in Table 10 and 
Table 11.


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Table 7.
Study Activities Phase 1 Dose Escalation
Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 
D8 
and 
D15
C2 
Through 
C4 D1
C2 
Through 
C4 D8
C2 
Through 
C4 D15
Maintenance 
Veliparib 
D1 of Each Cycle 
Starting in C5
Tumor 
Assessments 
Every 6 Weeks 
First 24 Weeks 
Tumor 
Assessments 
Every 9 Weeks 
Thereafter
Final 
Visit
30-Day 
Follow-Up 
Visit
Informed 
Consentb
X
Medical and 
Oncology 
Historyc
X
Physical Exam 
(including 
weight)d
X
X
X
X
X
X
X
X
Performance 
Status (ECOG)
X
X
X
X
X
X
X
12-Lead ECG
X
X
Vital Signs
X
X
X
Cycle 1 only
X
X
X
X
X
X
Pregnancy Test 
Serum (s), Urine 
(u)e
Xe
(s)
Xe
(u)
Hematologyf
X
X
X
X
X
X
X
X
X
Chemistryg
X
X
X
X
X
X
X
X
Coagulation 
Tests
X
X
C3 D1
X
Odd cycles
X
HBsAg, HCV 
RNAn
X


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Table 7.
Study Activities Phase 1 Dose Escalation (Continued)
Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 
D8 
and 
D15
C2 
Through 
C4 D1
C2 
Through 
C4 D8
C2 
Through 
C4 D15
Maintenance 
Veliparib 
D1 of Each Cycle 
Starting in C5
Tumor 
Assessments 
Every 6 Weeks 
First 24 Weeks
Tumor 
Assessments 
Every 9 Weeks 
Thereafter
Final 
Visit
30-Day 
Follow-Up 
Visit
Urinalysis
X
X
Clinical Disease 
Progressionh
X
X
X
Tumor 
Assessmentsi
X
Xi
Xi
Xi
Monitor 
Adverse Events/ 
Concomitant 
Medication 
X
X
X
X
X
X
X
X
X
X
Monitor 
Compliance
X
X
X
Enrollment
X
Dispense 
Veliparibk,m
X
X
Xk
Administer 
Premedicationl
X
Administer 
Etoposidej
X
Administer
Carboplatinj
X
Day 1 only
X
C = Cycle; D = Day; SCR = Screening


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Table 7.
Study Activities Phase 1 Dose Escalation (Continued)
a.
Screening visit must be performed within 28 days of Cycle 1 Day–2.  If the screening visit is performed > 7 days prior to Cycle 1 Day –2 the physical exam, laboratory tests 
(hematology and chemistry) and pregnancy test must be repeated on Cycle 1 Day –2.  Tumor assessments must be performed within 21 Days of Cycle 1 Day –2.  The scanned 
areas will include chest and abdomen (with image of liver and adrenal glands) at all radiographic assessments and head CT at screening visit (if clinical suspicion of CNS 
metastases).
b.
The informed consent must be signed and dated prior to the initiation of any screening or study specific procedure is performed.
c.
A subject's medical history will be reviewed at each visit.  Any changes from baseline will be recorded on the adverse event eCRF.
d.
Height will be assessed at Screening only.
e.
A serum pregnancy test must be performed at Screening, a urine pregnancy test on Cycle 1 Day –2 prior to dosing if > 7 days since obtaining the serum pregnancy test for 
women of childbearing potential.  Pregnancy tests may be repeated at any time during the study at the discretion of the investigator.
f.
Hematology labs do not need to be repeated if screening is within 7 days of Cycle 1 Day –2.  A central laboratory will be used for the study; however, sites may use a certified 
local laboratory to collect a sample to dose the subject.
g.
Chemistry panels do not need to be repeated if screening is within 7 days of Cycle 1 Day –2.  A central laboratory will be used for the study; however, sites may use a 
certified local laboratory to collect a sample to dose the subject.
h.
Clinical progression will include, but not limited to an evaluation of worsening performance status due to progressive disease, requirement for non-palliative radiation 
therapy, chemotherapy or surgery due to progressive disease or death due to progressive disease.
i.
Tumor assessments will be performed until disease progression.  Tumor assessment and assessment of response will occur every 6 weeks (± 1 week) from C1D-2 for the 
first 24 weeks, then every 9 weeks (± 1 week) thereafter.  Tumor Assessments at the end of Cycle 4 should be performed 1 week prior to the conclusion of Cycle 4 with 
radiographic results determined and reported to ensure subjects eligibility prior to subject starting continuous monotherapy veliparib dosing at Cycle 5.  A tumor assessment 
will 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.  The scanned areas will include chest, abdomen and 
pelvis at all tumor assessments.  A head CT will be performed if there is clinical suspicion of CNS metastases.
j.
Etoposide on Days 1, 2 and 3 and carboplatin on Day 1 of Cycles 1 – 4 will be administered IV by site staff after veliparib administration (exception:  veliparib will not be 
administered on Cycle 2 Day 1 of non-continuous dosing schedules).  Etoposide will be given prior to carboplatin, unless institutional guidelines require inverse sequence of 
administration.  
k.
Starting at Cycle 5 Day 1 and all subsequent monotherapy cycles, veliparib will be dispensed on Day 1.  See Section 5.0.
l.
Pre-medication will be given as per institutional guidelines.


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Table 7.
Study Activities Phase 1 Dose Escalation (Continued)
m.
As per cohort and dosing schedule assignment veliparib will be dosed orally on Days –2 to 5 (7-day schedule), or Day –2 to 12 (14-day schedule) or Day –2 – 19 (continuous 
schedule) of each 21-day cycle for up to 4 cycles.  Veliparib will be administered after the pre-medications on all days when given with chemotherapy.  Veliparib will be 
given approximately every 12 hours with a glass of water (approximately 240 mL).  Subjects in Phase 1 dose escalation on non-continuous dosing schedules will receive 
veliparib on Days 2 to 5 during Cycle 2 (for 7-day schedule) or on Days 2 to 12 (for 14-day schedule).  After completing 4 Cycles of combination therapy subjects may 
receive veliparib continuous dosing at 400 mg BID (each cycle will be 21 days) until disease progression or unacceptable toxicity occurs.
n.
If no HBsAg/HCV RNA test has been performed within 3 months prior to the date of informed consent for this study.


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Table 8.
Study Activities in Phase 2
Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 
D8
C2 Through 
Last 
Combination 
Cycle D1
C2 Through 
Last 
Combination 
Cycle D8
Monotherapy 
Veliparib/ 
PBO D1 of 
Each Cycle 
Starting in 
Maintenance
Tumor 
Assessments 
Every 
6 Weeks 
First 
30 Weeks
Tumor 
Assessments 
Every 
9 Weeks 
Thereafter
Post-
Treatment 
Follow-Up
Final 
Visito
30-Day 
Follow-
Up 
Visitp
Survival 
Follow-
Up
Informed Consentb
X
Medical and 
Historyc
X
Physical Exam 
(including weight)d
X
X
X
X
X
X
X
Performance Status 
(ECOG)
X
X
X
X
X
X
12-Lead ECG
X
X
Vital Signs
X
X
X
C1 only
X
X
X
X
X
Pregnancy Test 
Serum (s), Urine 
(u)e
X (s)
X (u)
Hematologyf
X
X
X
X
X
X
X
X
Chemistryf
X
X
X
X
X
X
Coagulation Tests
X
X
HBsAg, HCV 
RNAg
X
Urinalysis
X
X


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Table 8.
Study Activities in Phase 2 (Continued)
Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 
D8
C2 Through 
Last 
Combination 
Cycle D1
C2 Through 
Last 
Combination 
Cycle D8
Monotherapy 
Veliparib/ 
PBO D1 of 
Each Cycle 
Starting in 
Maintenance
Tumor 
Assessments 
Every 
6 Weeks 
First 
30 Weeks
Tumor 
Assessments 
Every 
9 Weeks 
Thereafter
Post-
Treatment 
Follow-Up
Final 
Visito
30-Day 
Follow-
Up 
Visitp
Survival 
Follow-
Up
Clinical Disease 
Progressionh
X
X
X
Tumor 
Assessmentsi
X
Xi
Xi
Xi
X
Monitor Adverse 
Events/Concomitant 
Medications
X
X
X
X
X
X
X
X
Monitor 
Compliance
X
X
X
X
Randomization
X
Dispense Veliparib
X
Xj
Xl
Administer 
Premedicationk
X
X
Administer 
Etoposidem
X
X
Administer 
Carboplatinm
X 
Day 1 only
X
Survival Follow-
Upn
X
C = Cycle; D = Day, SCR = Screening; RND = Randomization; PBO = Placebo; TA = Tumor Assessments; FV = Final Visit; PT = Post-treatment; F/U = Follow-up


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Table 8.
Study Activities in Phase 2 (Continued)
a.
Screening visit must be performed within 28 days of Cycle 1 Day –2.  If the screening visit is performed > 7 days prior to Day –2 the physical exam, laboratory tests 
(hematology and chemistry) and pregnancy test must be repeated on Cycle 1 Day –2.  Tumor assessments must be performed within 21 Days of Cycle 1 Day –2.
b.
The informed consent must be signed and dated prior to the initiation of any screening or study specific procedure being performed.
c.
A subject's medical history will be reviewed at each visit.  Any changes from baseline will be recorded on the adverse event eCRF.
d.
Physical exam does not need to be repeated at Cycle 1 Day –2 if screening physical exam was completed within 7 days of Cycle 1 Day –2.  Physical exams during 
combination cycles must include assessment of hearing if required by the local SmPC for carboplatin.  The Cycle 1 Day 8 physical exam may be symptom directed.  Height 
will be assessed at Screening only.
e.
A serum pregnancy test must be performed at Screening, a urine pregnancy test on Cycle 1 Day –2 prior to dosing if > 7 days since obtaining the serum pregnancy test for 
women of childbearing potential.  Pregnancy tests may be repeated at any time during the study at the discretion of the investigator.
f.
Hematology and Chemistry panels do not need to be repeated at Cycle 1 Day –2 if screening labs were completed within 7 days of Cycle 1 Day –2.  A central laboratory will 
be used for the study; however, sites may use a certified local laboratory to collect a sample to dose the subject.  If local labs are drawn the sample MUST be split and also 
sent to central lab.
g.
Only for subjects with known history of HBV or HCV without prior evidence of active disease-free status and if HBsAg/HCV RNA status within 3 months of the study entry 
is unknown.
h.
If clinical disease progression is suspected, progression must be confirmed radiographically per RECIST 1.1.  Clinical disease progression will include, but will not be limited 
to worsening performance status due to progressive disease, requirement for non-palliative radiation therapy, alternative chemotherapy or surgery due to progressive disease.  
At the Final Visit, a clinical disease progression assessment is required only for subjects who discontinue the study for reasons other than progression (clinical or 
radiographic).
i.
Tumor assessment and assessment of response will occur every 6 weeks (± 1 week) from C1D-2 for the first 30 weeks, then every 9 weeks (± 1 week) thereafter.  A tumor 
assessment will 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 in Post-Treatment Follow-
Up should continue to receive tumor assessments at the protocol defined time points until an event of radiographic progression. 
j.
Veliparib will be dosed orally at 240 mg BID and 14-day schedule for up to 6 cycles.  Veliparib will be administered after the pre medications on all days when given with 
chemotherapy.  Veliparib will be given approximately every 12 hours with a glass of water (approximately 240 mL).
k.
Pre-medication will be given as per institutional guidelines.
l.
Starting at Maintenance Day 1 and all subsequent monotherapy cycles, veliparib or placebo will be dosed orally at 400 mg BID and continuous (21-day) dosing schedule. 
Subjects should remain on veliparib until disease progression or unacceptable toxicity occurs.


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Table 8.
Study Activities in Phase 2 (Continued)
m.
Etoposide on Days 1, 2 and 3 and carboplatin on Day 1 of Combination Cycles will be administered IV by site staff after veliparib administration.  Etoposide will be given 
prior to carboplatin, unless institutional guidelines require inverse sequence of administration.
n.
Survival follow-up will be performed at 2 month intervals after the subject discontinues the study and until the endpoint of death, the subject has become lost to follow-up, the 
subject specifically withdraws consent for survival follow-up or if AbbVie terminates the study.
o.
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.
p.
A 30-Day Follow-Up visit must occur when the subject discontinues all study drugs due to toxicity and will transition to Post-Treatment Follow-Up.  Subjects who 
discontinue treatment due to radiographic progression and have a Final Visit within 30 days of last dose of study drug will have one Follow-Up Visit approximately 30 days 
after the last dose of study drug.


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Table 9.
Schedule of Pharmacogenetic and Pharmacodynamic Assessments for Phase 1 Dose Escalation and Phase 2
Procedure
Visit Schedule
Before Drug 
Administration
After Drug Administration
Sampling Plan
Specimen Matrix
PG Blood Samplinga
Genetic (DNA)
Cycle 1 Day –2
Not Dose Dependent
Not Dose Dependent
Whole Blood
Frozen –20°C or Colder
Plasma Markersb
Cycle 1 Day –2, Cycle 2 Day 1, 
Cycle 3 Day 1, Cycle 4 Day 1 
and Final Visit
Prior to Dose
Prior to Dosing 
Blood →Plasma
Frozen –70°C or Colder
Serum Markersb
Cycle 1 Day –2, Cycle 2 Day 1 
and Final Visit
Prior to Dose
NA
Blood →Serum
Frozen –70°C or Colder
Archived Tissue Sample 
Collectionc
Cycle 1 Day –2
N/A
N/A
FFPE
a.
Perform once at Cycle 1 Day –2.  If not collected at this visit, it may be collected at any time throughout the study.  Subjects must sign a separate informed consent prior to 
obtaining the PG sample.
b
Samples will not be drawn during carboplatin and/or etoposide dose delays.
c.
Subjects must consent to provide available archival tissue for analysis.  It is preferred to send FFPE blocks, however slides prepared by the local pathology laboratory are 
acceptable and should be prepared as described in the study specific laboratory manual.  If there is not enough tissue to provide the number of slides specified in the 
laboratory manual, sites should provide as many slides as possible with the available tissue.


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Table 10.
Schedule of Pharmacokinetic Assessments for Phase 1 Dose Escalation 
Procedure
Visit Schedule
Before Drug 
Administration
After Drug Administration
Sampling Plan
Specimen Matrix
PK Blood Samplinga
Etoposide
Cycle 1 Day 1
55 min (5 min before the end of infusion), 3 h, 5 h, 8 h, and 24 h 
post Day 1 dosing (24 hours is prior to dosing on Cycle 1 Day 2)
Blood →Plasma
Frozen –20°C or Colder
Cycle 2 Day 1b
55 min (5 min before the end of infusion), 3 h, 5 h, 8 h, and 24 h 
post Day 1 dosing (24 hours is prior to dosing on Cycle 2 Day 2)
Blood →Plasma
Frozen –20°C or Colder
PK Blood Samplinga
Carboplatin
Cycle 1 Day 1
25 min, 4 h, and 23 h post the start of Day 1 carboplatin infusion
Blood →Plasma
Frozen –20°C or Colder
PK Blood Sampling for 
Veliparib (ABT-888)a
Cycle 1 Day 1
Pre-dose
1 h, 2 h, 3 h, 5 h, 8 h, and 24 h
Blood →Plasma
Frozen –20°C or Colder
a.
Pharmacokinetic sampling is further discussed in Section 5.3.2.1.  Samples will not be drawn during carboplatin and/or etoposide dose delays.  All timepoints of etoposide 
and carboplatin samples are referred to the start of the infusion.
b.
This sampling will be omitted for subjects receiving continuous veliparib schedule.
Table 11.
Schedule of Pharmacokinetic Assessments in Phase 2
Procedure
Visit Schedule
Before Drug Administration
After Drug 
Administration
Sampling Plan
Specimen Matrix
PK Blood Sampling for 
Velipariba
Cycle 1 Day 1
Pre-dose (0 h)
1 and 2 h
Blood →Plasma
Frozen –20°C or Colder
Cycle 2 Day 1, Cycle 3 Day 1, 
Cycle 4 Day 1
Pre-dose (0 h)
N/A
Blood →Plasma
Frozen –20°C or Colder
a.
Pharmacokinetic sampling is further discussed in Section 5.3.2.1.  Samples will not be drawn during carboplatin and/or etoposide dose delays.


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5.3.1.1
Study Procedures
Unless otherwise stated, the baseline measurement for any given variable will be defined 
as the last value obtained for the variable prior to the first dose of study drug.
The study procedures outlined in Table 7 and Table 8 are discussed in detail in this
section, with the exception of the monitoring of treatment compliance (discussed in 
Section 5.5.7) and adverse event information (discussed in Section 6.0).  All study data 
will be recorded on eCRFs with supporting source documentation.
Screening procedures should be performed within 28 days prior to Cycle 1 Day –2.  If the 
screening visit is performed greater than 7 days prior to Cycle 1 Day –2, the physical 
exam, laboratory tests, and pregnancy test (for female subjects of childbearing potential) 
must be repeated on Cycle 1 Day –2.  Vital signs and performance status assessments will 
be performed on Cycle 1 Day –2 for all subjects.  Baseline radiographic tumor 
assessments per computed tomography (CT) with IV contrast/magnetic resonance 
imaging (MRI) of the chest, abdomen, pelvis and head (if CNS metastases are suspected) 
will be conducted within 21 days prior to Cycle 1 Day –2.  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.
For procedures performed at Screening and repeated, the later procedure performed prior 
to dosing will serve as a baseline for clinical assessment.  Subsequent study procedures 
should be performed approximately within ± 1 day on days of IV infusion of carboplatin 
and etoposide and ± 2 days for all safety visits and first Maintenance visit.  Clinical 
laboratory tests can be performed up to 48 hours prior to dosing.  
Informed Consent
Signed informed consent will be obtained from the subject before any study procedures 
are undertaken or before any prohibited medications are withheld from the subject in 


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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 enter into the study.  The reason for screen failure will be documented in the 
source and will be captured in the eCRF.
Medical History
A complete medical history, including alcohol, tobacco and nicotine-containing product 
use history, will be taken at Screening.  The medical history includes complete medical 
history, including documentation of any clinically significant medical condition; the 
presence and severity of any symptoms/conditions associated with SCLC; and detailed 
SCLC oncology history (histology, staging, date of diagnosis, tumor burden, metastatic 
sites, surgical history).
On Cycle 1 Day –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 7 and 
Table 8.  Physical examination during combination cycles will include hearing assessment 
if required by carboplatin locally approved product label, local practice, or applicable 
SmPC.  If the Screening physical examination is performed within 7 days of Cycle 1 
Day –2, it is not required to repeat the exam on Cycle 1 Day –2 unless clinically indicated.  
The Cycle 1 Day 8 physical examination may be symptom directed.  Clinically significant 
changes from baseline will be documented in the source documentation and eCRFs as 
adverse events.


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Height will be measured at the Screening Visit only.  The subject will wear lightweight 
clothing and no shoes during weighing.
Vital Signs
Vital signs will be performed per Table 7 and Table 8.  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 single ECG will be performed per as per Table 7 and Table 8.  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 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 7 and Table 8 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.


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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 
Cycle 1 Day –2.  A urine pregnancy test should also be performed prior to dosing on 
Cycle 1 Day –2 if > 7 days since obtaining Screening serum test results.  The test results 
must be reviewed and determined to be negative prior to dosing.  A positive urine 
pregnancy test will be confirmed with a serum pregnancy test.  Pregnancy tests may also 
be repeated at the discretion of the investigator at any time during the study.
Should a female study subject become pregnant or suspect she is pregnant while 
participating in this study, she should inform the treating investigator immediately 
(Section 6.7).
Hepatitis Screen
Subjects with history of hepatitis C (HCV) must be tested for HCV RNA at screening if 
no documented test result is available from within 3 months from the date of informed 
consent, and for Phase 2 if status within 3 months of the study entry is unknown.  Subjects 
with history of hepatitis B (HBV) must be tested for HBV surface antigen (HBsAg) at 
screening if no documented test result is available from within 3 months from the date of 
informed consent, and for Phase 2 if status within 3 months of the study entry is unknown.  
Testing will be performed by the sponsor-designated central laboratory.


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Clinical Laboratory Tests
Samples for chemistry, hematology and urinalysis will be collected per Table 7 (Phase 1) 
and Table 8 (Phase 2).  Specific laboratory assessments are outlined in Table 12.
All study samples will be shipped to the central laboratory, and central laboratory results 
will be used for data analysis.  A certified local laboratory may be used to perform 
laboratory analyses for immediate treatment decisions; however, split or concurrent 
samples must be drawn and sent to the central laboratory for analysis.  The central 
laboratory will provide instructions regarding the collection, processing and shipping of 
samples.
Sites will obtain the estimated creatinine clearance locally.
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 6.6.
For any laboratory test value outside the reference range that the investigator considers 
being clinically significant:
●
The investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
●
A laboratory test value that requires a subject to be discontinued from the 
study or requires a subject to receive treatment will be recorded as an adverse 
event.
Study samples for central laboratory analysis may be performed within 48 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.


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Table 12.
Clinical Laboratory Tests
Hematology
Clinical Chemistry
Urinalysis
Hematocrit
Hemoglobin
Red Blood Cell (RBC) count
White Blood Cell (WBC) count
Neutrophils
Bands (if detected)
Lymphocytes
Monocytes
Basophils
Eosinophils (if detected)
Absolute Platelet count
Mean corpuscular hemoglobin 
(MCH)
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin 
concentration (MCHC)
Reticulocyte count
Coagulation
Prothrombin Time (PT)
Activated Partial Thromboplastin 
Time (aPTT)
International Normalized Ratio
(INR)
Blood Urea Nitrogen (BUN)
Serum Creatinine
Total bilirubin
Serum glutamic-pyruvic 
transaminase (SGPT/ALT)
Serum glutamic-oxaloacetic 
transaminase (SGOT/AST)
Alkaline phosphatase
Sodium
Potassium
Chloride
Calcium
Inorganic phosphorus
Uric acid
Total protein
Glucose
Albumin
Magnesium
Bicarbonate
Lactate dehydrogenase (LDH)
Hepatitis C RNA/hepatitis B surface 
antigen (HBsAG)+
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Leukocyte esterase
Microscopic examination (perform 
only if  dipstick results 
warrant)
Serum Pregnancy Test
Human Chorionic Gonadotropin 
(hCG)*
*
At Screening and at any time point in which pregnancy is suspected or following a positive urine pregnancy test.
+
Subjects with history of hepatitis C (HCV) must be tested for HCV RNA at screening if no documented test result 
is available from within 3 months from the date of informed consent.  Subjects with history of hepatitis B (HBV) 
must be tested for HBV surface antigen (HBsAg) at screening if no documented test result is available from within 
3 months from the date of informed consent.  If HBsAg/HCV RNA status is unknown it must be tested at screening 
for Phase 2 subjects.  Testing will be performed by the sponsor-designated central laboratory.
Tumor Assessments (Radiographic)
A CT scan with contrast will be used in the evaluation of tumor responses with RECIST 
version 1.1.  The scanned areas will include chest, abdomen and pelvis at all radiographic 
assessments, and head CT as warranted by clinical suspicion of CNS metastases.
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) 


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can be conducted in cases where local laws/requirements mandate but should have 
Sponsor approval prior to performing the MRI.
Subjects will continue to be monitored by the same methodology unless evidence of 
tumor metastasis warrants otherwise.
Sites may be requested to electronically transfer copies of all CT or MRI scans used for 
radiographic tumor assessments in the Phase 2 part of the study to AbbVie.  Electronic 
copies of scans in DICOM format should be maintained at the sites until notification from 
AbbVie or end of study, whichever comes first.  Instructions regarding procedures for 
transferring scans will be provided separately, if the request for scans becomes necessary.
Tumor Assessments Schedule
Tumor assessments will be performed until radiographic disease progression.  Tumor 
assessment and assessment of response will occur every 6 weeks (± 1 week) from C1D-2 
for the first 24 weeks (Phase 1) or 30 weeks (Phase 2), then every 9 weeks (± 1 week) 
thereafter.  Tumor response will be determined according to the Response Evaluation 
Criteria in Solid Tumors (RECIST), Version 1.1.  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.
For Phase 2, the protocol defined tumor assessment schedule should be maintained 
independent of any treatment delays or changes.
Refer to Appendix C "RECIST (Version 1.1) for Tumor Response (PFS)" for response 
criteria and guidelines. 
Post-Treatment Follow-Up
Subjects who discontinue all study drugs prior to reaching an event of radiographic 
progression must enter into Post-Treatment Follow-Up.  Subjects will remain on study 


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(off study drug) and will continue to receive tumor assessments according to the protocol 
defined tumor assessment schedule until reaching an event of radiographic progression. 
Subjects who discontinue all study drugs due to toxicity should have a 30-day Follow-up 
visit prior to entering into Post-Treatment Follow-Up to ensure all toxicities have 
resolved.  Subjects will have a Final Visit and be discontinued from the study upon 
reaching an event of radiographic progression, if the Investigator determines they should 
be discontinued for any other reason or if the subject withdraws consent.
Survival Follow-Up (Phase 2 Only)
All discontinued subjects will have survival information collected via electronic data 
capture (EDC) at two month intervals (or as requested by sponsor to support data 
analysis) after the subject discontinues the study and continuing until the endpoint of 
death, the subject has become lost to follow-up, or AbbVie terminates the study.  
All subjects will be followed for survival information (i.e., the date and cause of death or 
last known alive date if not deceased) unless the subject requests to be withdrawn 
specifically from study survival follow-up; this request must be documented in the 
subject's medical record and signed by the Investigator.
If known, post treatment anti-cancer therapies, dates of initiation, and end dates will be 
collected.
If the subject withdraws from survival 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.
Randomization and Subject Number Assignment
An Interactive Response Technology System (IRT) will be utilized to register subjects.
The site will access the IRT system at Screening, after the subject signs informed consent 
and a unique subject number will be provided.  Subjects who complete all Screening 


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procedures and meet the eligibility criteria will proceed to dosing.  Subjects who sign 
consent and do not meet the eligibility criteria will be considered a screen failure and the 
reason for screen failure will be documented in the source and in the eCRF.  Subjects will 
also be registered as a screen failure in the IRT system.
Subjects in Phase 2 who complete all Screening procedures and meet the eligibility 
criteria will be randomized in a 1:1:1 ratio to one of three treatment arms:  
Arm A:  veliparib 240 mg in combination with carboplatin/etoposide followed by 
veliparib 400 mg BID monotherapy
Arm B:  veliparib 240 mg in combination with carboplatin/etoposide followed by placebo 
monotherapy
Arm C:  placebo in combination with carboplatin/etoposide followed by placebo 
monotherapy
A bottle number randomization schedule and a subject randomization schedule will be 
generated by the Data and Statistical Science Department at AbbVie prior to the start of 
the study.  A copy of all randomization schedules will be kept by the Data and Statistical 
Science Department at AbbVie and a copy will be forwarded to the IRT vendor.
5.3.1.2
Confinement
Subjects will not be confined in this study.
5.3.1.3
Meals and Dietary Requirements
There are no meal and dietary requirements for this study.
5.3.1.4
Blood Samples for Pharmacogenetic Analysis
One 4 mL whole blood sample for DNA isolation will be collected on Cycle 1 Day –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 


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the sample is not collected on Cycle 1 Day –2, it may be collected at any time throughout 
the study.
The sample collection tubes will minimally be labeled with "PG-DNA," protocol number,
and subject number.  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 study specific laboratory manual.
If pharmacogenetic (PG) testing is performed, results from individual subjects will be kept 
coded and confidential and will not be given to anyone not directly involved with this 
research study.  AbbVie will store the DNA samples in a secure storage space with 
adequate measures to protect confidentiality.  Samples will be coded so that subject 
identities will not be available to the scientists conducting the genotyping analyses.  
Individual subject results will not be provided to the Investigator so that neither the 
subject nor the Investigator will have knowledge of specific subject genotypes.  AbbVie 
will keep the DNA samples until destroyed by AbbVie when this research is completed.  
These samples will not be stored longer than 20 years or per country requirement.
5.3.1.5
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
Twelve (12) mL (Cycle 1 Day –2 or Final Visit) or 6 mL (all other time points) of blood 
will be collected pre-dose by venipuncture at time points outlined in Table 9 in 
conjunction with PK samples, if possible.  The collection, processing and storage should 
be performed as described in the study specific laboratory manual.  The complete process 
of centrifugation, transfer to cryovial and freezing should be accomplished in less than 
1 hour from the time of blood draw.


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Blood Collection for Serum Markers
Approximately 5 mL of blood will be collected pre-dose by venipuncture at time points as 
outlined in Table 9.  The collection, processing and storage should be performed as 
described in the study specific laboratory manual.  The complete process of clot 
formation, centrifugation, transfer to cryovials and freezing should be accomplished in 
less than 90 minutes from the time of blood draw.
Tissue Collection for IHC, ELISA and FISH DNA Mutational/Methylation Analysis
Archived Tissue Specimens:
Subjects must consent to provide available archived tissue for analysis.  It is recognized 
that samples suitable for analysis will not be available from all consenting subjects.  The 
most recent archived biopsy is preferred and should be obtained at Cycle 1 Day –2, if 
possible.  While sending FFPE blocks is preferred, slides prepared by the local pathology 
laboratory are acceptable and should be prepared as described in the study specific 
laboratory manual.  Study specific biopsies are not required for subject participation.
5.3.1.6
Shipment of Pharmacodynamic Samples
All samples should be labeled and shipped as outlined in the study specific laboratory 
manual.  An inventory of the samples being shipped will accompany the package.
5.3.2
Drug Concentration Measurements
5.3.2.1
Collection of Samples for Analysis
Blood Samples for Veliparib Assay
Blood samples for veliparib assay will be collected by venipuncture at the designated time 
points outlined in Table 10 (Phase 1) and Table 11 (Phase 2).  The timing of blood 
collection is fundamental to the success of the study.  The timing of blood collections will 
take priority over all other scheduled study activities except for dosing.  The order of 
blood collections will be maintained to the minute such that the time intervals relative to 


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the preceding dose will be the same for all subjects.  The time that each blood sample is 
collected will be recorded to the minute.  
The date and time of the morning dose of veliparib on PK sampling day will be recorded.  
In Phase 2 portion, the date and time of the two doses of veliparib prior to PK sampling 
on C1D1, C2D1, C3D1 and C4D1 will also be recorded.
The collection, processing and storage should be performed as described in the study 
specific laboratory manual.
Approximately 7 blood samples are planned to be collected per subject in Phase 1 and 
6 samples per subject in Phase 2 for pharmacokinetic analysis.  The approximate number 
of blood samples planned for pharmacokinetic analysis is approximately 1325 for the 
entire study.
Blood Samples for Etoposide Assay
Blood samples for etoposide assay will be collected at the time points specified in 
Table 10.  The date and time of the dose of etoposide on PK sampling day will be 
recorded.  The collection, processing and storage should be performed as described in the 
study specific laboratory manual.  A total of 10 samples per subject will be collected for 
etoposide analysis in Phase 1 Cycles 1 and 2.  Blood samples for etoposide assay will not 
be collected for Phase 2 subjects.
Blood Samples for Unbound Carboplatin Assay 
Plasma concentration-time course of carboplatin will be determined on Cycle 1 Day 1.  
Blood samples will be collected at the time points outlined in Table 10.  The date and time 
of the dose of carboplatin on PK sampling day will be recorded.  The collection, 
processing and storage should be performed as described in the study specific laboratory 
manual.  A total of 3 samples per subject will be collected for carboplatin assay in Phase 1 
Cycle 1 Day 1.  Blood samples for carboplatin assay will not be collected for Phase 2 
subjects.


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Pharmacokinetic variable are discussed in Section 5.3.5.
5.3.2.2
Handling/Processing of Samples
The processing and storage of the PK samples for veliparib, carboplatin and etoposide 
should be performed as described in the study specific laboratory manual.
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.  The 
placebo samples may not be analyzed to confirm the absence of veliparib.  Upon 
completion of this research, AbbVie or a designated laboratory will destroy the samples.
5.3.2.3
Disposition of Samples
The frozen plasma samples for veliparib, carboplatin and etoposide assays will be packed 
in dry ice sufficient to last during transport and shipped from the study site to the central 
laboratory according to instructions in the central laboratory manual.
5.3.2.4
Measurement Methods
Analysis of Plasma Samples
Plasma concentrations of veliparib will be determined under the supervision of the Drug 
Analysis Department at AbbVie.  Placebo samples may or may not be analyzed to confirm 
the absence of veliparib (ABT-888).  Plasma concentrations of etoposide and carboplatin 
will be determined at external laboratories using validated assays under the supervision of 
the Drug Analysis Department at AbbVie.
5.3.3
Efficacy Variables
Efficacy variables are not primary endpoints in the Phase 1 Dose Escalation portion of the 
study.


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The primary efficacy endpoint in Phase 2 is progression free survival (PFS) from the time 
of subject randomization.  The secondary endpoints are objective response rate (ORR), 
overall survival (OS).  The tertiary endpoints are duration of response (DOR) and ECOG 
performance status. 
5.3.3.1
RECIST 1.1 for Tumor Response
Response criteria will be assessed using RECIST (Version 1.1).28 Changes in the 
measurable lesions over the course of therapy must be evaluated using the criteria 
presented in Appendix C.  Tumor assessments will be performed until disease 
progression.  See tumor assessment schedule in Section 5.3.1.1.
5.3.3.2
Definition of Disease Progression
Disease progression will be defined as radiographic progression of disease as determined 
by the investigator by RECIST (Version 1.1) Appendix C.
Clinical progression as determined by the investigator, which may be characterized as, but 
not limited to:
●
Increase in at least two points of ECOG performance status attributable to 
cancer progression;
●
Subject requires non-palliative radiation, chemotherapy or surgery due to 
progressive disease;
●
Death from progressive disease.
In cases where an Investigator determines that a subject has met the criteria for clinical 
disease progression, every effort should be made to confirm the progression 
radiographically.


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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 4.0.21
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
Values for pharmacokinetic parameters of veliparib, including the maximum observed 
plasma concentration (Cmax), the time to Cmax (peak time, Tmax), the area under the plasma 
concentration-time curve from time 0 to time of last measurable concentration (AUCt) 
will be determined for veliparib doses on Day 1 of Cycle 1 using non-compartmental 
methods.
Values for pharmacokinetic parameters of etoposide including Cmax, AUC from time 0 to 
the last measurable concentration (AUCt) and from time 0 to time infinity (AUC∞), 
clearance and terminal half-life will be determined on Day 1 of Cycle 1 and Day 1 of 
Cycle 2 using noncompartmental methods.
Values for compartmental pharmacokinetic parameters of carboplatin in the dose 
escalation cohorts (such as volume of distribution and clearance) and of veliparib in the 
Phase 2 part of the study such as rate of absorption (Ka), apparent volume of distribution 
(V/F) and oral clearance (CL/F) may be estimated using a nonlinear mixed-effect 
population modeling approach with NONMEM software and reported in a separate 
pharmacokinetic report.
5.3.6
Pharmacogenetic Variables
DNA samples may be sequenced and data analyzed for genetic factors contributing to the 
disease or to the subject's response to veliparib, (or other study treatment) in terms of 
pharmacokinetics, efficacy, tolerability, and safety.  Such genetic factors may include 


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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 
related to veliparib, drugs of this class, or the disease state.  The results of 
pharmacogenetic analyses will not be reported to subjects and 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, analysis of proteins, including but not 
limited to proteins involved in DNA repair, such as ERCC1 and XPF, may be performed 
on tumor tissue obtained from each consented subject and associated with response.
Samples collected during the course of this study may be banked and used in the future to 
investigate new scientific questions related to this study.  Additionally, the samples may 
be anonymized and used for diagnostic test development.  AbbVie (or a designated 


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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
5.4.1
Discontinuation of Individual Subjects
Each subject has the right to withdraw from the study at any time.  In addition, the 
investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol.  Subjects who withdraw or are discontinued from the 
study will not be replaced except as described in Section 5.1, unless it is mutually agreed 
upon, in writing, by the investigator and AbbVie.
When a subject discontinuation from the study (without reaching a protocol-defined 
endpoint) is planned, the Investigator is to notify the AbbVie TA MD 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 TA MD may contact the site to discuss the reason for withdrawal from the study.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result 
or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the study, the administration of study drug to that 
subject must be discontinued immediately.  The investigator must report a pregnancy 
within 1 working day of the site being aware to one of the AbbVie representatives listed 
in Section 6.6 or Section 7.0.


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Post-Treatment Follow-Up
Phase 2 subjects who discontinue treatment for reasons other than radiographic 
progression will be monitored in the Post-Treatment Follow-Up period of the study by the 
same imaging method (unless medical contraindication is noted) until disease progression 
(Table 8).
Final Visit
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 7 and Table 8.  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.
30-Day Follow-Up Visit
Subjects who discontinue treatment for reasons other than radiographic progression will 
have a Follow-Up Visit approximately 30 days after the last dose of study drug and will 
transition to Post-Treatment Follow-Up. 
Subjects who discontinue treatment due to radiographic progression and have a Final Visit 
within 30 days of last dose of study drug will have one Follow-Up Visit approximately 
30 days after the last dose of study drug.
Survival Follow-Up
All discontinued subjects will have survival information collected via electronic data 
capture (EDC) at 2 month intervals (or as requested by sponsor to support data analysis) 
after the subject discontinues the study and continuing until the endpoint of death, the 
subject has become lost to follow-up, or AbbVie terminates the study.


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5.4.1.1
Discontinuation of Combination and Maintenance Therapies 
in Phase 2
Subjects will receive veliparib, carboplatin and etoposide up to a maximum of 4 –
6 combination cycles or until reaching a protocol defined event of disease progression or 
experiencing unmanageable toxicity.  Dose reductions of carboplatin and etoposide will 
occur on the basis of the toxicity observed and may result in discontinuation of either 
agent.  The subject may continue on therapy with the remaining agent in combination with 
veliparib.  At the Investigator's discretion, carboplatin and/or etoposide administration 
may continue after veliparib has been discontinued.  Suitable subjects will receive 
veliparib/placebo maintenance monotherapy as per treatment arm assignment 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.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
Phase 1 subjects will receive the following:
●
Designated doses of veliparib BID on Days –2 through 5 or Day –2 through 12 
(14-day schedule) or Day –2 to 19 (continuous schedule) + Carboplatin AUC 


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5 mg/mL*min administered on Day 1 and Etoposide 100 mg/m2 administered 
on Days 1 through 3 of each 21-day cycle for up to 4 cycles.
○
Exception: Phase 1 subjects receiving non-continuous veliparib will have 
their Cycle 2 dosing schedule altered as follows to allow for the evaluation 
of veliparib effect on etoposide exposure:  veliparib BID on Days 2 
through 5 or Days 2 through 12 + Carboplatin AUC 5 mg/mL*min 
administered on Day 1 and Etoposide 100 mg/m2 administered on Days 1 
through 3 of a 21-day cycle.
●
Phase 1 subjects with SD, PR or CR at the completion of all scheduled 
combination therapy cycles will receive veliparib (400 mg) monotherapy, BID 
continuously in 21-day cycles starting on Day 1 of each cycle starting at 
Cycle 5.
Phase 2 subjects will receive the following:
●
Veliparib/Placebo 240 mg BID on Day –2 through 12 (14-day schedule) + 
Carboplatin AUC 5 mg/mL*min administered on Day 1 and Etoposide 
100 mg/m2 administered on Days 1 through 3 of each 21-day cycle for up to 
6 cycles.
●
Phase 2 subjects with SD, PR or CR at the completion of combination therapy 
cycles will receive veliparib (400 mg) or placebo monotherapy, BID 
continuously in 21-day cycles starting on Maintenance Day 1 of each cycle.
The sequence of administration is as follows on days when veliparib is dosed in 
combination with chemotherapy as described in Figure 3:
Figure 3.
Sequence of Administration*
Pre Medication Administration  Veliparib/Placebo  etoposide (60 min infusion) 
carboplatin (30 min infusion)
*
If institutional guidelines mandate inverse sequence of etoposide and carboplatin administration, they may be 
followed.  Infusion times are approximate.


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5.5.1.1
Administration of Veliparib/Placebo
Subjects will self-administer the morning dose of veliparib/placebo and the evening doses 
of veliparib/placebo approximately 12 hours after the morning dose with or without food 
in the same calendar day.  Veliparib dose should be followed by a glass of water 
(approx. 240 mL).
It is recommended that if a subject misses a scheduled dose of veliparib/placebo and less 
than 6 hours have passed since the scheduled dosing time, the dose should be immediately 
taken.  It is recommended that if more than 6 hours have passed since the scheduled 
dosing time, the subject should not take the missed dose but should wait for the next 
regularly scheduled dose.
If the subject vomits within 15 minutes of taking veliparib, 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 the 
remainder 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 Table 15 in Section 5.5.2.3.  
Subjects should return bottles of veliparib (empty, partially filled or full) and the 
completed dosing card to the study site prior to each cycle and at the Final Visit.
5.5.1.2
Administration of Carboplatin and Etoposide
Carboplatin will be administered intravenously on Day 1 of every 21-day cycle.  
Etoposide will be administered intravenously on Days 1, 2 and 3 of every 21-day cycle.  
Carboplatin and Etoposide are to be given only after veliparib/placebo dosing on 
Cycle Day –2 and Day –1 are confirmed.  If veliparib/placebo was not taken by the 
subject on Day –2 and Day –1, a new supply of veliparib is to be dispensed, and Day –2 
and Day –1 are to be repeated for that cycle, if needed.  Etoposide will be administered 


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prior to carboplatin, unless institutional guidelines require inverse sequence of 
administration.  On the days of chemotherapy, veliparib will be administered after the 
premedications are given for etoposide, prior to the infusion of etoposide. 
Investigators should evaluate subjects for carboplatin and etoposide treatment per the 
locally approved product label, local practice, or applicable SmPC.  Carboplatin will be 
administered intravenously over approximately 30 minutes at AUC 5 mg/mL/min.  The 
dose of carboplatin will be calculated using the Calvert formula, with creatinine clearance 
calculated using the modified Cockroft-Gault equation, as specified in the Appendix E.
The maximum allowed doses of carboplatin are:
AUC5 = 750 mg
AUC4 = 600 mg
Etoposide will be administered intravenously over approximately 60 minutes at 
100 mg/m2.
5.5.2
Identity of Investigational Products
Information regarding the veliparib/placebo formulation to be used in this study is 
presented in Table 13.
Table 13.
Identity of Investigational Products
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
Veliparib (ABT-888)
Capsule
40 mg or placebo*
Oral
AbbVie
Veliparib (ABT-888)
Capsule
100 mg or placebo*
Oral
AbbVie
Veliparib (ABT-888)
Capsule
20 mg*
Oral
AbbVie
*
Placebo for Phase 2 ONLY.  20 mg capsule strength for Phase 1 ONLY.


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5.5.2.1
Standard of Care Medicinal Products for Study Treatment
Information regarding carboplatin and etoposide to be used in this study is presented in 
Table 14.
Table 14.
Standard of Care Medicinal Products for Study Treatment
Study Treatment
Dosage Form
Route of Administration
Carboplatin (commercially available)*
Vial
Intravenously
Etoposide (commercially available)*
Vial
Intravenously
*
Carboplatin and etoposide formulations may vary based on the source.
Carboplatin and etoposide are commercially available marketed products and will be 
obtained by the clinical site pharmacy.  Each site will be responsible for tracking the lot 
numbers for all carboplatin and etoposide dispensed.
5.5.2.2
Packaging and Labeling
Phase 1 Dose Escalation
Veliparib (ABT-888) will be supplied by AbbVie in HDPE bottles containing either 
20 mg, 40 mg, 100 mg active capsules.  Bottles will contain either 15, 24 or 50 capsules 
per bottle.  This will allow for the 2, 5, 14, 21, or monotherapy days of administration 
(with one additional dose to cover loss, spillage or replacement due to vomiting within 
15 minutes).  Each bottle will be labelled per country requirements including at a 
minimum the information required by local regulations.  The label is to remain affixed to 
the bottle.  All blank spaces on the label will be completed by site staff prior to dispensing 
to the subject.
Phase 2 Randomized Double-Blind
Veliparib (ABT-888)/placebo will be supplied by AbbVie in HDPE bottles containing 
either 40 mg, 100 mg active or their placebo capsules.  Bottles will contain either 15, 
24 or 50 capsules per bottle.  This will allow for the 14 days combination or continuous 
monotherapy days of administration (with additional doses to cover loss, spillage or 


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replacement due to vomiting within 15 minutes).  Each bottle will be labelled per country 
requirements including at a minimum the information required by local regulations.  The 
label is to remain affixed to the bottle.  All blank spaces on the label will be completed by 
site staff prior to dispensing to the subject.
AbbVie will provide study sites with instructions and training for the proper handling, 
storage and documentation related to all investigational supplies.
5.5.2.3
Storage and Disposition of Study Drug
All sponsor supplied investigational products are for investigational use only and are to be 
used only within the context of this study.  The study drug supplied for this study must be 
maintained under adequate security and stored under the conditions specified on the label 
until dispensed for subject use or returned to the destruction facility.  Veliparib in Phase 1 
and veliparib/placebo in Phase 2 will be designated through the IRT system.  Resupplies 
of veliparib/placebo will be automatically generated through the IRT system based on 
sites active enrollment.
Veliparib or Placebo
Table 15.
Study Drug Storage Conditions
Study Drug
Country
Storage Conditions
Veliparib or Placebo
All countries
Store at 15° to 25°C (59° to 77°F).
Veliparib or Placebo bottles must be stored as presented in Table 15.  A storage 
temperature log is to be maintained to document proper storage conditions.  The storage 
temperature must be recorded on a daily basis.  All Temperature Excursions must be 
reported to the Sponsor immediately.  Investigational product should be quarantined and 
not dispensed until AbbVie GPRD or Abbott Temperature Excursion System (ATEMS) 
deems the medication as acceptable. 


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Storage and Use of Carboplatin and Etoposide
Carboplatin and etoposide are commercially available marketed products and will be 
obtained by the clinical site pharmacy. 
Both carboplatin and etoposide are to be used, stored, and disposed of in accordance with 
their approved commercial product labeling Product Package Insert or Summary of 
Product Characteristics (SmPC) and/or local institutional guidelines.
5.5.3
Method of Assigning Subjects to Treatment Groups 
(Phase 1 Dose Escalation)
In the Phase 1 dose escalation portion of the study, there is no randomization schedule; 
however, an IRT system will still be utilized to assign subject numbers.  Subject numbers 
will be assigned by the IRT as subjects are enrolled in the study.
5.5.4
Method of Assigning Subjects to Treatment Groups 
(Phase 2 Randomized Double-Blind)
All subjects will be randomized using an IRT system.  Before the study is initiated, the 
IRT user manual, which provides instruction on how to use the system via the web or 
phone, will be provided to each site.
Subjects who complete all Screening procedures and meet eligibility criteria may proceed 
to randomization.  Subject randomization will be stratified by:  LDH (≤ ULN versus 
> ULN), and gender; therefore a subject's baseline LDH value must be known prior to 
randomization and when accessing the IRT to perform the randomization transaction.
The site will contact the IRT to obtain a Screening (subject) number once the subject has 
signed the informed consent and a study-specific procedure has been performed 
(i.e., central laboratory samples drawn).  Once the subject number is assigned, if the 
subject is not enrolled/randomized the reason for screen failure will be documented in the 
source document and in the eCRF.  If the subject meets all inclusion and none of the 


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exclusion criteria, the site will access the system to randomize the subject.  The IRT will 
randomize subjects in a 1:1:1 ratio to one of the three treatment arms as follows:
●
Arm A:  veliparib in combination with carboplatin/etoposide followed by 
veliparib monotherapy
●
Arm B:  veliparib in combination with carboplatin/etoposide followed by 
placebo monotherapy
●
Arm C:  placebo in combination with carboplatin/etoposide followed by 
placebo monotherapy
Subject randomization will be stratified by:  LDH (≤ ULN versus > ULN), and gender
5.5.5
Selection and Timing of Dose for Each Subject
Phase 1 Dose Escalation
All Phase 1 subjects will receive veliparib orally.  Depending on the dosing schedule 
assigned, veliparib will be dosed twice a day on Days –2 through 5 (7-day schedule) or 
Days –2 through 12 (14-day schedule) of 1st, 3rd and 4th 21-day cycles and on Days 2 
through 5 or Days 2 through 12 (14-day schedule) of the 2nd 21-day cycle, or on Days –2 
through 19 (continuous schedule) of the 21 day Cycles 1 – 4 at a dose level based on the 
dose escalation cohort assignment.  One dose will be taken in the morning and the second 
dose will be taken in the evening (approximately 12 hours after the morning dose).  The 
morning dose of veliparib should be administered in the clinic prior to etoposide and 
carboplatin, but after chemotherapy premedications on days when administered with 
chemotherapy.  Premedications may be administered per individual institutional 
standards.
After the end of Cycle 4, subjects without evidence of disease progression by radiographic 
assessment (CT) will receive veliparib at 400 mg BID continuous schedule 21 day cycle, 
until disease progression or unacceptable toxicity.


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A "3 + 3" escalation rule will be used for the Phase 1 dose escalation portion of this study, 
with a condition applied for the Dose Level 1, which will allow 3 additional subjects to be 
entered in Dose Level 1 if 2 of 6 initial subjects experience DLTs.  Enrollment of the 
3 additional subjects at all dose levels will depend on a review of the specific DLTs 
observed and discussion with the Investigators.  At the RPTD and schedule, additional 
subjects will be added as needed so that a total of at least 9 subjects will be treated at the 
RPTD.
Phase 2 Randomized Double-Blind
Subjects will complete at least 4 cycles of combination therapy, unless disease 
progression or unacceptable toxicity warrants earlier discontinuation from the 
combination treatment.  Subject whose status at the completion of the 4th cycle of 
combination therapy warrants, in the opinion of the investigator, continued combination 
treatment may receive up to two additional combination therapy cycles (e.g., up to a total 
of 6 cycles) if required by local standard of care.  After the completion of combination 
therapy, subjects without evidence of disease progression by most recent scheduled 
radiographic assessment (CT) will receive veliparib at 400 mg BID or placebo continuous 
schedule in 21-day cycles, until disease progression or unacceptable toxicity.
5.5.6
Blinding
All study site personnel, including the investigator, study coordinator, as well as the 
subjects, will remain blinded to the treatment throughout the course of the Phase 2 portion 
of the study.  The IRT system will provide access to blinded subject treatment information 
during the double-blind period, if needed.
AbbVie must be notified before breaking the blind, unless identification of the study drug 
is required for a medical emergency, i.e., situation in which the knowledge or the specific 
blinded treatment will affect the immediate management of the subject's conditions 
(e.g., antidote is available).  AbbVie must then be notified within 24 hours of the blind 
being broken.  The date and reason that the blind was broken must be recorded in the 
source documentation and on the CRF or eCRF, as applicable.


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5.5.7
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/placebo should be taken as directed by the investigator.  Carboplatin 
and etoposide will be administered intravenously by trained site personnel.
Subjects will be instructed to return all veliparib/placebo bottles (empty, partially filled or 
full) and the completed dosing card to the study site personnel at each combination cycle 
Day 1, each Maintenance cycle Day 1, 30-Day Follow-Up Visit and/or at the Final Visit.  
The Investigator or his/her designated and qualified representatives will document the 
bottles returned and the number of capsules returned per bottle in the IRT system.
Upon completion or termination of the study, all original bottles/cartons containing 
unused veliparib/placebo (empty containers will be defaced and discarded on site) will be 
returned to AbbVie or the destruction facility according to AbbVie's instructions, or if 
pre-arranged between the sponsor and site, destruction of used and unused bottles will be 
performed at the site.
Subjects should be questioned regarding their adherence to the assigned treatment 
schedule at each study visit.  The Investigator or his/her designated and qualified 
representatives will also confirm that the subject took the required number of capsules per 
protocol. 
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.  The 
Investigator or his/her designated and qualified representatives will document compliance 
on the appropriate eCRF.


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5.5.8
Drug Accountability
Upon receipt of a shipment of veliparib, the representative at each site will verify that 
study drug supplies are received intact and in the correct amounts.  This will be 
documented by signing and dating the Proof of Receipt (PoR) or similar document 
respectively via direct recording in the IRT.  The shipment receipt must be acknowledged 
in the IRT in order to become available for dispensation to subjects.  All veliparib/placebo 
must be retained in the designated secure area under proper storage conditions.  The study 
site will record the kit number of veliparib/placebo given to each subject in the source 
documents and on the eCRF.
The IRT will maintain a current and accurate inventory of study drug, accountability, 
reconciliation, returns, and destruction for each site.  The IRT will also include the lot 
number, the bottle/kit numbers, and the date veliparib/placebo was dispensed for each
subject.
In the event the IRT is not operable, the above information will be documented on forms 
provided/approved by the Sponsor.
The Investigator or designee will document the bottles of veliparib/placebo returned and 
the number of capsules on the appropriate form in the IRT.  If the number of capsules 
taken and the number of capsules returned do not add up to the number of capsules 
dispensed, an explanation is required and should be documented in the IRT.
An overall accountability of the study drug will be performed and verified by the AbbVie 
monitor throughout the study and at the site close-out visit.  All study drug unit doses 
must be inventoried, accounted for, and returned to the destruction facility or to AbbVie 
or destroyed per instructions from AbbVie and according to local regulations.  
The investigator and/or named the sub-investigators agree not to supply study medication 
to any persons not enrolled in the study.


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The site will record the dose of carboplatin and etoposide given to each subject in the 
source documents and on the eCRF.  As the investigator will obtain both carboplatin and 
etoposide commercially, site inventory and accountability of carboplatin and etoposide 
will not be performed, and drug accountability for carboplatin and etoposide will not be 
performed in the IRT.  However, each site will be responsible for tracking the lot numbers 
for all carboplatin and etoposide dispensed.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
The carboplatin and etoposide combination chemotherapy is standard first-line treatment 
for ED SCLC.  Veliparib may have a potential benefit for subjects with ED SCLC.  This 
Phase 1 dose escalation/Phase 2 randomized double-blind study will determine the 
recommended Phase 2 dose of veliparib in combination with carboplatin and etoposide 
(Phase 1 portion), and will evaluate the treatment effect due to the addition of veliparib to 
carboplatin/etoposide chemotherapy followed by veliparib monotherapy maintenance in
subjects with ED SCLC (Phase 2 portion).
5.6.2
Appropriateness of Measurements
The Phase 1 dose escalation portion of the study is a standard 3 + 3 design.  Standard 
pharmacokinetic, statistical, clinical, and laboratory procedures will be utilized in this 
study.
The randomized double-blind Phase 2 portion will utilize a well-established surrogate ED 
SCLC and other solid tumor endpoint of progression free survival using RECIST 1.1 as a 
guideline for the measurement of responses in subjects with advanced or metastatic solid 
tumors.28  Secondary and tertiary endpoints of objective response rate, duration of overall 
response and overall survival of subjects receiving veliparib maintenance monotherapy 
will also be evaluated.


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5.6.3
Suitability of Subject Population
Subjects with ED SCLC and advanced/metastatic solid tumors (Phase 1) and with 
treatment-naïve ED SCLC (Phase 2) and meeting inclusion and exclusion selection 
criteria as outlined in the Section 5.2.1 and Section 5.2.2 are appropriate for this study.  
Subjects with advanced/metastatic solid tumors will allow defining the recommended 
Phase 2 dose as the tolerability of the study regimen in this population should be similar 
to the target population with ED-SCLC.  Subjects with treatment-naïve ED SCLC are 
appropriate to define efficacy and safety of the study regimen since carboplatin/etoposide 
is the first line standard of care in this tumor type and SCLC is the intended indication for 
further clinical evaluation of veliparib/carboplatin/etoposide combination.
5.6.4
Selection of Doses in the Study
Phase 1 Dose Escalation
The initial starting dose of 80 mg BID veliparib in the Phase 1 portion of the study was 
derived from the results obtained in the ECOG E2511, GOG 9923 and AbbVie M10-898 
clinical studies, as well as from the non-clinical studies.  
Doses for carboplatin in combination with etoposide will be given as per standard of care 
in first line treatment for extensive stage SCLC as per NCCN guideline 2014.3
The dose for veliparib monotherapy is 400 mg BID. This dose is well characterized for 
safety and tolerability based on the experience from multiple clinical trials.  
Phase 2 Randomized Double-Blind
The RPTD has been defined in the Phase 1 portion of the study as veliparib 240 mg BID 
administered on Days –2 – 12 (14-Day schedule), carboplatin AUC 5 mg/ml*hr 
administered on Day 1, etoposide 100 mg/m2 administered on Days 1 – 3 of 21-Day 
cycles.


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The dose for veliparib/placebo monotherapy is 400 mg BID administered continuously in 
21-Day cycles.
5.7
Dose Reductions or Delays
If a subject experiences an adverse event that results in a delay in starting a cycle or 
requires that study regimen is delayed or interrupted during a cycle, the subject will 
complete the planned activities per Section 5.7.1 until resuming treatment.
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 timing of dose resumption should be at the discretion of 
the Investigator.  Study treatment may be delayed for up to 21 days due to toxicity.  
Toxicity-related delays greater than 21 days will result in study treatment discontinuation.
Table 16.
Guidelines for Veliparib, Carboplatin, and Etoposide Dose 
Reduction Levels During Combination Therapy
Dose Reductions
Carboplatin
Etoposidea
Veliparibb
Starting Dose 
AUC 5
100 mg/m2
Phase 1:  As assigned
Phase 2:  240 mg BID
Dose Reduction 1
AUC 4
75 mg/m2
Phase 1:  Next lower DL (assigned –1)
Phase 2:  200 mg BID
Dose Reduction 2
No Additional 
Reductions Allowed
55 mg/m2
Phase 1:  Next lower DL (assigned –2)
Phase 2:  160 BID
a.
Refer to Section 5.7.2.1.2 for etoposide dose reduction guidelines related to bilirubin.
b.
Refer to Section 5.7.1 for veliparib dose reduction guidelines for maintenance therapy.  "Next lower DL" refers to 
the daily dose levels tested in the dose escalation part of the study.  The dose of each drug can be reduced 
independently based on the observed toxicities.  For veliparib dose level of 80 mg (Phase 1 only), Dose Reduction 
1 is to 60 mg, Dose Reduction 2 is to 40 mg.
5.7.1
Veliparib/Placebo Dose Reductions and Interruptions
The following are guidelines for dose reduction, interruption and discontinuation of 
veliparib/placebo during combination therapy:


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1.
Veliparib/placebo will be discontinued if both carboplatin and etoposide are 
discontinued prior to the completion of the planned number of combination therapy 
cycles.
2.
For any subject who experiences Grade 3/4 toxicity which is not attributable to 
carboplatin/etoposide or the underlying disease, refer to Table 17 for dosing 
guidelines.
3.
Two dose reductions are prospectively allowed during combination therapy for 
subjects who experience toxicity attributable to veliparib/placebo.  Refer to 
Table 16 for dose reduction guidelines.
a.
Veliparib dose reduction at C1D1 is allowed in case of nausea and vomiting 
attributable to C1D-2 and C1D-1 veliparib doses
b. All veliparib/placebo dose reductions within combination therapy cycles are 
permanent.
c.
If further dose reductions (beyond prospectively allowed two) are required, 
sites must contact the AbbVie TA MD.
4.
Any ≥ Grade 2 event of seizure attributed to veliparib/placebo requires 
discontinuation of veliparib/placebo.
5.
Veliparib/placebo interruptions will not affect the schedule of planned study 
procedures and will not be replaced.  If veliparib/placebo-related toxicity 
necessitates the delay in veliparib/placebo re-initiation beyond the scheduled start 
of the next combination therapy cycle, the start of the cycle should be delayed until 
veliparib/placebo can be restarted.  The AbbVie TA MD may be contacted 
(Section 6.6) for subjects who require more than a 2-week delay in the re-initiation 
of the next cycle.
The following are guidelines for dose reduction, interruption and discontinuation of 
veliparib/placebo during Maintenance Therapy:
1.
Dose Reduction 1:  300 mg BID.


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2.
Dose Reduction 2:  200 mg BID.
3.
Subjects requiring dose reduction of veliparib/placebo to below 200 mg BID will 
be discontinued from treatment.
4.
For subjects who experience any Grade 3/4 toxicity during maintenance therapy 
which is attributable to veliparib, refer to Table 18 for dosing guidelines.
Table 17.
Dose Interruption or Reduction Due to Toxicity Attributable to 
Veliparib in the Combination Therapy Cycles
Adverse Event
Veliparib
Any Grade 3 or 4 
toxicity attributable to 
veliparib which is not 
attributable to 
carboplatin/etoposide 
or underlying disease
1.
Interrupt dosing in the current cycle until Grade 1 (or Grade 2 if present at 
baseline)
and
2.
Reduce veliparib dose to next lower dose level upon dosing re-initiation
Table 18.
Veliparib Dose Interruption or Reduction Due to Toxicity 
Attributable to Veliparib in the Maintenance Therapy Cycles
Adverse Event
Veliparib
Any Grade 3 or 4 
toxicity attributable to 
veliparib 
1.
Interrupt dosing in the current cycle until Grade 1 (or Grade 2 if present at 
baseline)
and
2.
At resumption reduce veliparib dose to next lower monotherapy dose level
5.7.2
Carboplatin/Etoposide Dose Reductions and Delays
If a subject experiences an adverse event attributable to carboplatin or etoposide, 
carboplatin or etoposide may either be interrupted or the dose reduced.  
If a dose reduction or delay is required for carboplatin and/or etoposide, the Investigator 
should follow procedures as defined in the locally approved product label or applicable 
Summary of Product Characteristics (SmPC).  Section 5.7.2.1 outlines suggested dose 


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reductions for carboplatin/etoposide if above information is not available.  PD and/or PK 
samples will not be drawn during carboplatin and/or etoposide dose delays.
5.7.2.1
Guidelines for Carboplatin and Etoposide Dose Reductions 
and Delays
The below guidelines are suggested, unless described as mandatory.  If a dose reduction 
or delay is required for carboplatin and/or etoposide, the Investigator should follow 
procedures according to institutional guidelines, the locally approved product label, local 
practice, or applicable SmPC.  If the Investigator considers an event attributable to 
carboplatin and/or etoposide, the Investigator may consider reducing carboplatin and/or 
etoposide, but not veliparib/placebo.  Suggested guidelines for dose reduction, delay, and 
discontinuation are included in Table 16 and Table 19 (if locally approved product label, 
local standard of care guideline or applicable SmPC for carboplatin/etoposide 
combination chemotherapy are not available).
All carboplatin and/or etoposide dose reductions are permanent.  Re-escalation of the dose 
of therapy is not allowed.  All toxicities should have 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 toxicity precludes the initiation of the dosing of carboplatin/etoposide in the cycle, and 
veliparib doses on Days –2 and –1 of the cycle have already been administered, veliparib 
should be administered again once the toxicity resolves for 2 days prior to 
carboplatin/etoposide dosing.  In such a case, a new supply of veliparib/placebo is to be 
dispensed, and Day –2 and Day –1 are to be repeated for that cycle.
For Phase 1 ONLY:  PD and/or PK samples will not be drawn during carboplatin and/or 
etoposide dose delays.  If the Investigator considers an event attributable to carboplatin 
and/or etoposide and not veliparib, the Investigator may consider reducing the dose of 
both agents.


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5.7.2.1.1
Hematologic Toxicity
If chemotherapy must be withheld due to hematologic toxicity, CBC and platelet counts 
should be obtained weekly via central labs (if done locally, sample MUST be split for 
central lab) until the counts reach the lower limits for treatment as outlined.  The 
treatment schedule will then proceed in the usual sequence.
Neutropenia or Febrile Neutropenia
For febrile neutropenia with absolute neutrophil count (ANC) < 500/mm3 and a single 
temperature of > 38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) for more 
than one hour, requiring intravenous antibiotics:
a.
Doses of both carboplatin and etoposide drugs should be reduced to the next lower 
dose level for all subsequent cycles of chemotherapy.  Suggested dose reduction 
levels are outlined in Table 14.
b. Implement dose reductions, as outlined in Table 19.
c.
Initiate prophylactic neutrophil growth factors (e.g., G-CSF) after the first episode 
and in accordance with local SOC practices, ASCO or NCCN guidelines.
d. If ANC counts do not recover within 3 weeks, discontinue all protocol therapy.
For treatment delays of more than 7 days due to neutropenia, carboplatin and etoposide 
should be dose-reduced to next lower dose level for all subsequent cycles of 
chemotherapy, as outlined in Table 19.
For nadir neutropenia in the absence of fever or with fever that is successfully treated by 
oral antibiotics, there will be no dose adjustment. 
ANC must be ≥ 1,500/mm3 on Day 1 of each cycle (mandatory).  If the ANC is lower 
than 1,500/mm3, then dosing of all drugs (carboplatin, etoposide and veliparib) will be 
delayed until recovery to the required ANC.


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Platelets
For Grade 4 nadir platelet count decrease (thrombocytopenia) (platelets < 25,000 mm3), 
the dose of both carboplatin and etoposide should be reduced to next lower dose level 
from the previous dose for all subsequent cycles of chemotherapy.  Implement dose 
reductions 1 and 2 for the first and second episodes, respectively as outlined in Table 19.  
If counts do not recover within 3 weeks, discontinue all protocol therapy.
Platelet count must be > 100,000/mm3 on Day 1 of each cycle (mandatory).  Doses or all 
drugs (carboplatin, etoposide and veliparib) should be delayed until platelet count 
recovers to > 100,000/mm3.
Anemia
No dose reductions will be made for anemia.  Subjects should be supported per the 
treating physician's discretion.  The use of RBC transfusions for anemia will be allowed 
as clinically indicated and as per local standard of care or current NCCN guidelines.  The 
use of growth factors for anemia is not permitted during Phase 1 Cycle 1.
If more than two dose modifications of carboplatin and etoposide are required for 
hematologic toxicity, e.g., in cases where an additional dose modification is needed for a 
toxicity which was not observed earlier, please consult the AbbVie TA MD.
5.7.2.1.2
Non-Hematological Toxicity
Gastrointestinal Toxicity: Nausea and Vomiting
All subjects should receive antiemetics* to prevent nausea and vomiting.  Specific 
antiemetic therapy is left to the discretion of the treating physician (steroids and 5-HT3 
antagonists should be used).  For vomiting Grade ≥ 3, consider hospital admission and/or 
use of aprepitant, if possible.  Nausea/vomiting should have resolved to Grade 1 or less 
prior to initiation of next treatment cycle.  Do not modify carboplatin and/or etoposide 
doses due to nausea/vomiting.


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*
Aprepitant, when given once daily for 14 days as a 100 mg capsule with an oral contraceptive containing 35 mcg of 
ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43% and decreased the 
AUC of norethindrone by 8%.  Women of childbearing potential using pregnancy contraception that includes 
ethinyl estradiol should not receive Aprepitant for the treatment of nausea/delayed emesis.  Subjects may change to 
a different method of contraception if they wish to use Aprepitant.
Hepatic Toxicity
For bilirubin > 1.5 – 3.0 × ULN, not attributable to underlying disease, reduce the dose of 
etoposide to 50 mg/m2.  For bilirubin > 3 – 5 × ULN reduce the dose of etoposide to 
30 mg/m2.  For bilirubin > 5 × ULN hold etoposide or hold all treatment if starting the 
next treatment cycle.  When bilirubin resolves to ≤ 5 × ULN, treatment can be resumed, 
with etoposide dose to 30 mg/m2.  If bilirubin does not improve to ≤ 5 × ULN within 
3 weeks of first occurrence, discontinue protocol therapy.
5.7.2.1.3
Other Grade 3/4 Non-Hematologic Toxicity
Other non-hematologic Grade 3/4 toxicity should be managed as per local SmPC 
guidelines and institutional standard practices.  


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Table 19.
Suggested Guidelines for Carboplatin/Etoposide Dose Delay or 
Reduction
Adverse Event
Carboplatin Dose
Etoposide Dose
ANC < 1,500/mm3 Day 1 of 
Cycle
Hold next cycle until ANC 
≥1,500/mm3.
Hold next cycle until ANC 
≥1,500/mm3.
Treatment delays of > 7 days 
due to neutropenia
Implement Dose Reduction 1 for 
1st episode.
Implement Dose Reduction 1 for 
1st episode and Dose Reduction 2 for 
2nd episode.  
Grade 3/4 febrile 
neutropenia with ANC 
< 500/mm3, requiring IV 
antibiotics
Implement Dose Reduction 1 for 
1st episode.  Initiate Prophylactic G-CSF 
after 1st episode.
Implement Dose Reduction 1 for 
1st episode and Dose Reduction 2 for 
2nd episode.  Initiate Prophylactic 
G-CSF after 1st episode.
Grade 3 nausea, vomiting or 
Grade 4 vomiting
Hold next cycle until resolution to 
Grade 1 or better.  If more than 2 weeks 
dose delay is required consult with 
AbbVie TA MD.
Hold next cycle until resolution to 
Grade 1 or better.  If more than 
2 weeks dose delay is required consult 
with AbbVie TA MD.
Platelets < 100,000/mm3 Day 
1 of Cycle
Hold next cycle until platelets 
≥100,000/mm3.
Hold next cycle until platelets 
≥100,000/mm3.
Grade 4 thrombocytopenia
Implement Dose Reduction 1 for 
1st episode.
Implement Dose Reduction 1 for 
1st episode and Dose Reduction 2 for 
2nd episode.
Bilirubin  > 1.5 – 3.0 × ULN
No Change
Reduce dose to 50 mg/m2
Bilirubin > 3 – 5 × ULN
No Change
Reduce dose to 30 mg/m2
Bilirubin > 5 × ULN
Hold if bilirubin does not improve to 
≤5 × ULN within 3 weeks of 
first occurrence, discontinue protocol 
therapy
Hold if bilirubin does not improve to 
≤ 5 × ULN within 3 weeks of 
first occurrence, discontinue protocol 
therapy
Any other Grade 3/4 toxicity
Per local SmPC/institution guidelines
Per local SmPC/institution guidelines
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 another cause of the event.  For adverse events to be considered 


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intermittent, the events must be of similar nature and severity.  Adverse events, whether in 
response to a query, observed by site personnel, or reported spontaneously by the subject 
will be recorded.
All adverse events will be followed to a satisfactory conclusion.
6.1
Definitions
6.1.1
Adverse Event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment.  An adverse event can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an adverse event.  
Worsening in severity of a reported adverse event should be reported as a new adverse 
event.  Laboratory abnormalities and changes in vital signs are considered to be adverse 
events only if they result in discontinuation from the study, necessitate therapeutic 
medical intervention, (meets protocol specific criteria [see Section 6.8 regarding toxicity 
management]) and/or if the investigator considers them to be adverse events.
An elective surgery/procedure scheduled to occur during a study will not be considered an 
adverse event if the surgery/procedure is being performed for a pre-existing condition and 
the surgery/procedure has been pre planned prior to study entry.  However, if the 
pre-existing condition deteriorates unexpectedly during the study (e.g., surgery is 
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.


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6.1.2
Deaths
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the protocol 
specified adverse event reporting period (Section 6.5) that are attributed by the 
investigator solely to progression of disease under study should be recorded only on the 
Study Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and immediately 
reported to the Sponsor (Section 6.1.4).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be reported.  
The term "sudden death" should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without preexisting
heart disease, within 1 hour of the onset of acute symptoms or, in the case of an 
unwitnessed death, within 24 hours after the patient was last seen alive and stable.  If the 
cause of death is unknown and cannot be ascertained at the time of reporting, 
"unexplained death" should be recorded on the Adverse Event eCRF.  If the cause of 
death later becomes available (e.g., after autopsy), "unexplained death" should be replaced 
by the established cause of death.
During survival follow-up, deaths should be recorded on Survival eCRF.
6.1.3
Lack of Efficacy or Worsening of Disease Under Study
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.  These data will 
be captured as efficacy assessment data only.  Refer to Appendix F for listing of events 
expected with progression of ED SCLC.


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6.1.4
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.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences 
of relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle).


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Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject 
and may require medical or surgical intervention to 
prevent any of the outcomes listed above (i.e., death of 
subject, life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any 
elective or spontaneous abortion or stillbirth is considered 
an important medical event.  Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or 
drug abuse.
For 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 SCLC or Progression of 
SCLC
Adverse events that may be expected from primary SCLC 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 SCLC subjects but will not be subject to expedited reporting.  
These data will be captured as efficacy assessment data only.
6.3
Adverse Event Severity
The 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).21


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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 3/4)
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 SAE supplemental 
eCRFs also need to be updated and need to include the new AE serial number.
6.4
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the adverse 
event to the use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment and potential alternative 
causes there is insufficient evidence (information to suggest a 
causal relationship.


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For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.  For the purposes of this study, causality 
assessments will be attributed to veliparib/placebo or carboplatin or etoposide separately.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, another cause of event must be provided by the investigator for the serious adverse 
event.
6.5
Adverse Event Collection Period
All protocol related serious adverse events and nonserious adverse events must be 
collected from the signing of the study specific informed consent until study drug 
administration.
In addition, all adverse events reported from the time of study drug administration until 
30 days following discontinuation of study drug administration have elapsed will be 
collected, whether solicited or spontaneously reported by the subject.
Serious and nonserious adverse events occurring after the study specific informed consent 
is signed but prior to the initial dose of study drugs will be collected only if they are 
considered by the Investigator to be causally related to the study-required procedures.
Adverse event information will be collected as shown in Figure 4.


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Figure 4.
Adverse Event Collection
Protocol 
Related Serious 
and Nonserious 
Adverse 
Events*
Serious and Nonserious Adverse Events
Elicited and/or Spontaneously Reported
∀
∀
∀
∀
Consent 
Signed
Study 
Drug 
Start
Study 
Drug 
Stopped
30 Days
After Study 
Drug Stopped
*
Only if considered by the Investigator to be causally related to study-required procedures.
6.6
Adverse Event Reporting
In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify  Clinical Pharmacovigilance within 24 hours of the site being 
made aware of the serious adverse event by entering the serious adverse event data into 
the electronic data capture (EDC) system.  Serious adverse events that occur prior to the 
site having access to the RAVE® system or if RAVE is not operable should be sent to 
Clinical Pharmacovigilance within 24 hours of being made aware of the serious adverse 
event using the paper CRF (pCRF).
Serious adverse events which are considered expected due to the underlying disease of 
SCLC would not be expedited as individual safety case reports to regulatory authorities.
FAX to:  
Email to:


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For safety related concerns, contact the Oncology Safety Management Team at:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Office:
Fax:
Email:
Or the physician through the operator at:
Phone:  
For any subject safety concerns, please contact the physician listed below:
Primary TA MD:
Medical Director
AbbVie
381 Plantation Street
Worcester, MA  01605
Phone:
Fax:
Email:


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Alternate Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Office:
Cell:
Fax:
Email:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure for veliparib or 
Summary of Product Characteristics (SmPC) for carboplatin and etoposide.
6.7
Pregnancy
In the event of a positive pregnancy test, subjects must immediately discontinue study 
drug and must be discontinued from the study.  The investigator must report the positive 
pregnancy test to the appropriate contact listed in protocol Section 6.6 within 1 working 
day of the site becoming aware of the pregnancy.
All subjects should be informed that contraceptive measures should be taken throughout 
the study and for 6 months after discontinuing study drug.  Information regarding a 
pregnancy occurrence in a study subject and the outcome of the pregnancy will be 
collected.  The Investigator must follow the pregnancy to completion and provide an 
update to AbbVie after delivery.
Male subjects should be informed that contraceptive measures should be taken by their 
female partners.  If the subject's partner should become pregnant during the study, this 


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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 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
Dose Limiting Toxicities
Dose limiting toxicities for Phase 1 dose escalation purposes will be determined during 
DLT observational period C1D-2 to pre-dose C2D1 in any of the dose-escalation cohorts, 
with grading according to the National Cancer Institute (NCI) Common Toxicity Criteria 
for Adverse Events (CTCAE), version 4.0.  Any of the events described in Section 5.1
considered to have a reasonable possibility of being related to veliparib will be considered 
a dose limiting toxicity (DLT).
Subjects experiencing DLTs during the DLT observational period C1D-2 to pre-dose 
C2D1 will generally be discontinued from further participation in the study, but may 
continue at the same or a reduced dose with written approval by the Sponsor if there is 
evidence of clinical benefit.
6.8.1
Determination of the MTD
If a single subject within a cohort experiences a DLT, a total of 6 subjects will be enrolled 
and dosed at the same dose level.  If these additional subjects do not exhibit a DLT, dose 
escalation may proceed.  If any of the additional subjects exhibits a dose limiting toxicity, 
then dose de-escalation may occur to interrogate lower dose levels.  MTD, if identified, 
will be defined at the highest dose level at which less than 2 of 6 subjects or < 33% of (if 
cohort is expanded beyond 6) subjects experience a DLT.  MTD may be determined 
independently for each veliparib dosing schedule.


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6.8.2
Determination of the RPTD
If an MTD is reached, the RPTD will not be a dose higher than the MTD and will be 
selected based on the types of DLTs which occur and the MTD identified.  If an MTD is 
not reached, then the RPTD will be defined based on the safety and available PK data.
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  Field Monitor or the following 
AbbVie Clinical Monitor(s):


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Primary Contact:
1 North Waukegan Road
North Chicago, IL  60064
Office:
Fax:
Email:
Alternate Contact:
AbbVie
1 North Waukegan Road
North Chicago, IL  60064
Office:
Cell:
Fax:
Email:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analysis Plans
For subjects in the Phase 1 portion, the date of enrollment is defined as the first day of 
study drug administration.  For subjects in the randomized Phase 2 portion, the date of 
randomization (enrollment) is defined as the date that the IRT issued a subject number.
ORR will be performed on all dosed subjects in the Phase 1 portion of the study.
The primary, secondary, and tertiary efficacy analyses will be performed on all subjects in 
the randomized Phase 2 portion of the study.
Safety analyses will be performed separately for the Phase 1 and Phase 2 portions.  All 
subjects who receive at least one dose of the study drug will be included in the safety 
analysis.


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Unless otherwise noted, data will be summarized for Phase 1 and Phase 2 subjects 
separately.
8.1.1
Baseline Characteristics 
All baseline summary statistics and analyses will be based on characteristics obtained 
prior to the initiation of study drug (or randomization for non-treated subjects).  Unless 
otherwise stated, baseline for a given variable will be defined as the last value for that 
variable obtained prior to the first dose of study drug.
8.1.1.1
Demographics
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
means, standard deviations, medians, and minimum and maximum values.  Frequencies 
and percentages will be computed for categorical data (e.g., sex, race, and performance 
status).
Smoking history can be defined as current smoker (subject who has smoked within the 
last 12 months and has more than 100 smoking events [for example, cigarettes] in their 
lifetime), never smoked (subject with a lifetime smoking history of ≤ 100 smoking events 
[for example, cigarettes] in lifetime) and past smoker (subject who has not smoked in past 
12 months and has more than 100 smoking events [for example, cigarettes] in their 
lifetime).
8.1.1.2
Medical History 
Frequencies and percentages will be computed for each medical history parameter.
8.1.2
Efficacy Endpoints
8.1.2.1
Primary Efficacy Endpoint
The primary efficacy endpoint is progression-free survival (PFS). 


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Progression-free survival will be defined as the number of days from the date of 
randomization to the date of earliest disease progression (radiographic progression per 
RECIST version 1.1) or death.  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.  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 available radiographic disease progression assessment.
8.1.2.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints include objective response rate and overall survival.
Objective Response Rate
The proportion of subjects with objective response (CR or PR) as assessed by the 
investigator using RECIST version 1.1 will be evaluated for randomized subjects.
Overall Survival
Overall survival will be defined as the number of days from the date of randomization to 
the date of death.  For subjects who did not die, their data will be censored at the date of 
last study visit or the last known date to be alive, whichever is later.
8.1.2.3
Tertiary Efficacy Endpoints
In addition to the primary and secondary efficacy analyses, tertiary efficacy analyses of 
duration of overall response and performance status will be performed.
Duration of Overall Response
Duration of overall response will be defined as the number of days from the date of 
first response (CR or PR) to the earliest documentation of radiographic progressive 
disease.  If a subject is still responding, then the subject's data will be censored at the date 
of the subject's last available disease assessment (radiographic or clinical).  For subjects 
who never experience response, the subject's data will not be included in the analysis.  


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Performance Status
ECOG performance status will be determined by the investigator at assessment 
throughout therapy and at the final visit.
8.1.3
Primary Analysis of Efficacy
PFS will be analyzed by Kaplan-Meier methodology and compared between Arm A 
(veliparib in combination with carboplatin/etoposide followed by veliparib monotherapy) 
and Arm C (placebo in combination with carboplatin/etoposide followed by placebo 
monotherapy), using a log-rank test stratified by LDH level.  A two-sided, stratified 
log-rank test P value will be provided.  Median PFS time will be calculated and 
95% confidence interval for median PFS time will be presented.  A hazard ratio estimate 
(Arm A versus Arm C) and the corresponding 95% confidence interval will be obtained 
from a Cox proportional hazards model.
8.1.4
Secondary Analysis of Efficacy
8.1.4.1
Progression-Free Survival (Arm B Versus Arm C)
PFS will be analyzed by Kaplan-Meier methodology and compared between Arm B 
(veliparib in combination with carboplatin/etoposide followed by placebo monotherapy) 
and Arm C, using a log-rank test stratified by LDH level.  A two-sided, stratified log-rank 
test P value will be provided.  Median PFS time will be calculated and 95% confidence 
interval for median PFS time will be presented.  A hazard ratio estimate (Arm B versus 
Arm C) and the corresponding 95% confidence interval will be obtained from a Cox 
proportional hazards model.
8.1.4.2
Objective Response Rate
The objective response rate at the time of completion of combination therapy will be 
estimated and compared between Arm A + B combined and Arm C, using a 
Cochran-Mantel-Haenszel test stratified by LDH level.  A two-sided, stratified CMH test 


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P value will be provided.  In addition, a 95% confidence interval will be constructed for 
the estimated proportions.
8.1.4.3
Overall Survival
OS will be analyzed by Kaplan-Meier methodology and compared between Arm A and 
Arm C as well as between Arm B and Arm C, using a log-rank test stratified by LDH 
level.  A two-sided, stratified log-rank test P value will be provided.  Median OS time will 
be calculated and 95% confidence interval for median OS time will be presented.  Hazard 
ratio estimates (Arm A versus Arm C, Arm B versus Arm C) and the corresponding 
95% confidence intervals will be obtained from a Cox proportional hazards model.
8.1.5
Tertiary Analysis of Efficacy
8.1.5.1
Duration of Overall Response
The distribution of duration of overall response (DOR) will be estimated for each 
treatment arm using Kaplan-Meier methodology.  Median DOR will be estimated and a 
95% confidence interval will be presented for each treatment arm.
8.1.5.2
Progression-Free Survival (Arm A Versus Arm B)
PFS will be analyzed by Kaplan-Meier methodology and compared between Arm A and 
Arm B, using a log-rank test stratified by LDH level.  A two-sided, stratified log-rank test 
P value will be provided.  Median PFS time will be calculated and 95% confidence 
interval for median PFS time will be presented.  A hazard ratio estimate (Arm A versus 
Arm B) and the corresponding 95% confidence interval will be obtained from a Cox 
proportional hazards model.
8.1.5.3
Overall Survival (Arm A Versus Arm B)
OS will be analyzed by Kaplan Meier methodology and compared between Arm A and 
Arm B, using a log-rank test stratified by LDH level.  A two-sided, stratified log-rank test 
P value will be provided.  Median OS time will be calculated and 95% confidence interval 
for median OS time will be presented.  A hazard ratio estimate (Arm A versus Arm B) 


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and the corresponding 95% confidence interval will be obtained from a Cox proportional
hazards model.
8.1.5.4
ECOG Performance Status
Changes and/or percent changes from baseline in ECOG performance status will be 
summarized using descriptive statistics for each scheduled post-baseline visit and for the 
final visit.  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.  Changes and/or percent 
changes from baseline to each visit will be compared between Arm A and Arm C as well 
as between Arm B and Arm C using an analysis of covariance with treatment arm as the 
factor and baseline value as a covariate.
8.1.6
Pharmacokinetics
8.1.6.1
Tabulations and Summary Statistics
Plasma concentrations and pharmacokinetic parameter values of veliparib, carboplatin, 
and etoposide will be tabulated for each subject by dose level, and summary statistics will 
be computed for each sampling time and each parameter by dose level.
8.1.6.2
Model and Tests
Dose Proportionality of Veliparib on Phase 1 Cycle 1 Day 1
To address the issue of dose proportionality for designated veliparib doses, a linear mixed 
effects model analysis will be performed for dose-normalized Cmax and AUC0-8 and other 
pharmacokinetic parameters provided that they can be adequately determined from the 
data.  The natural logarithmic transformation will be employed for Cmax and the AUC's 
unless the data clearly indicate that other transformation or the untransformed variable 
provides more nearly symmetric probability distributions and/or more nearly homogenous 
variances across dose levels.  The model will include dose level, this may be done by 
classifying subjects by dose level or, if appropriate, using dose level as a continuous 


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variable.  Some variables such as age, body weight, gender, and perhaps others that might 
explain some of the variability in the population will be included in the model initially as 
covariates.  A necessary condition for a variable to be included in the final model is that 
the regression coefficient be significant at level 0.10.  The dependence among explanatory 
variable candidates will also be considered when selecting the final model.
Within the framework of the final model, the null hypothesis of no difference between the 
means of the highest and lowest veliparib doses will be tested.  Assuming that at least 
four veliparib dose levels are indeed studied, a test will also be performed on a contrast in 
the dose level, with the contrast chosen to be sensitive to an approximately linear function
of dose or the logarithm of dose.
Veliparib Effect on Etoposide Pharmacokinetics Parameters
For the dose escalation subjects, a linear mixed effects model analysis will be performed 
for dose normalized Cmax, AUC0-24 and AUC∞, to compare etoposide pharmacokinetics 
parameters when co-administered with veliparib (Cycle 1 Day 1) relative to etoposide
administered alone (Cycle 2 Day 1).  For Cmax and AUC, the logarithmic transformation 
will be used unless the data indicate that the logarithm has significant non-normality.  The 
model will include effects for visit (Cycle 1 Day 1, Cycle 2 Day 1).  The within-subject 
variability will be accounted for utilizing the repeated statement for the effect of visit.  
Within the repeated measure analysis modeling framework, the null hypothesis of no 
difference between etoposide in combination with veliparib and etoposide alone will be 
tested with a significance level of 0.05.  The relative bioavailability of etoposide 
co-administered with veliparib relative to etoposide alone will be estimated.  Point 
estimates and corresponding 90% confidence intervals for the ratio of etoposide 
co-administered relative to etoposide alone will be provided.  The point estimates will be 
obtained by antilogarithm of the estimate of the difference of the logarithmic means.  The 
90% confidence intervals will be similarly obtained by antilogarithm of the endpoints of 
the corresponding confidence intervals for the difference of mean logarithms obtained 
within the framework of the repeated measure analysis model.


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8.1.6.3
Missing Values and Model Violations
All available data will be included in the mixed effect analyses.  Data exclusion, if any, 
will be documented and justification provided.
Normally values of pharmacokinetic variables (Cmax, AUC, etc.) will be determined 
without replacing missing individual concentration values, simply using the available 
data, and if necessary doing the analysis with some missing values for a pharmacokinetic 
variable.  However, if a missing individual concentration results in a value of a 
pharmacokinetic parameter that may be too low or too high to a meaningful degree, the 
value of the pharmacokinetic parameter will tentatively be considered missing.  In this 
case, a value for the missing individual concentration may be imputed so that an 
appropriate value of the pharmacokinetic parameter can be included in the analysis.  The 
imputed value will be obtained using appropriate methodology that   takes into account 
the individual characteristics of the subject.
If an outlier is identified and/or a pronounced non-normal probability distribution is 
observed (after logarithmic transformation for Cmax and AUC), then a non-parametric 
analysis may also be performed.  Such a model violation may be identified by graphical 
methods, measures of non-normality (e.g., skewness, kurtosis) or other appropriate 
methods.  If the regimens have unequal variances to the extent that conclusions might be 
affected, then approximate methods that allow for unequal variances will be used.
8.1.7
Safety
Safety analyses will be performed for Phase 1 and Phase 2 separately.
8.1.7.1
Duration of Study Drug
A summary of the number of days and/or cycles subjects were exposed to study drug will 
be provided.


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8.1.7.2
Adverse Events
Analyses of adverse events will include only "treatment-emergent" events, i.e., those that 
have an onset on or after the day of the first dose of study drug (veliparib or placebo).  
Analyses will not include those that have an onset greater than 30 days after the last dose 
of study drug.
Treatment-emergent adverse events will be coded and summarized by system organ class 
and preferred term according to the Medical Dictionary for Regulatory Activities 
(MedDRA) adverse event coding dictionary.  The percentage of subjects experiencing an 
adverse event at a given NCI CTCAE version 4.0 grade, and relationship to study drug 
will be provided.  For Phase 1, all summaries will be done by dose level.  For Phase 2, 
comparisons of the percentages of subjects experiencing an adverse event between Arm A 
and Arm C as well as between Arm B and Arm C will be performed using Fisher's exact 
test.
8.1.7.3
Serious Adverse Events
Serious adverse events will be summarized using the same methods as adverse events 
described above in Section 8.1.7.2.
8.1.7.4
Deaths
The number of subject deaths will be summarized 1) for deaths occurring while the 
subject was still receiving study drug in this study, 2) for deaths occurring off treatment 
within 30 days after the last dose of study drug, and 3) for all deaths in this study 
regardless of the number of days after the last dose of study drug.
8.1.7.5
Longitudinal Analyses of Laboratory and Vital Signs Data
Changes from baseline will be analyzed for each scheduled post-baseline visit and for the 
final visit for blood chemistry and hematology parameters, as well as urinalysis and vital 
sign parameters.  If more than one measurement exists for a subject on a particular day, an 
arithmetic average will be calculated.  This average will be considered to be that subject's 


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measurement for that day.  Post-baseline measurements more than 30 days after the last 
dose of randomized study drug will not be included.  Subjects that do not have a baseline 
measurement or do not have any post-baseline measurements will not be included.  For 
Phase 1, changes from baseline will be analyzed by dose level at each scheduled visit.  
For Phase 2, comparisons of the differences in mean changes from baseline between 
Arm A and Arm C as well as between Arm B and Arm C will be made using ANCOVA 
with treatment group as the factor and baseline as a covariate.
8.1.7.6
Analyses of Laboratory Data Using NCI CTCAE
Where applicable, blood chemistry and hematology determinations will be categorized 
according to NCI CTCAE version 4.0 grades, and shifts from baseline NCI CTCAE 
version 4.0 grades to maximum and final post-baseline grades will be assessed.  The 
baseline and final grades will be defined respectively as the grade of the last measurement 
collected prior to the first dose of study drug, and as the grade of the last post-baseline 
measurement collected no more than 30 days after the last dose of study drug.  If multiple 
values are available for a post-baseline measurement, then the value with the highest NCI 
CTCAE grade will be used in the assessment of shift.  Comparisons of the number of 
subjects experiencing a shift from baseline grades of 0 to 2 or no grade to maximum 
post-baseline grades of 3 to 4, and from baseline grades of 0 to 2 or no grade to final 
post-baseline grades of 3 to 4 between Arm A and Arm C as well as between Arm B and 
Arm C will be performed using Fisher's exact tests.  Additional analyses including all 
measurements collected, regardless of the number of days after the last dose of study 
drug, will be performed.
Detailed listings of data for subjects experiencing NCI CTCAE Grade 3 to 4 blood 
chemistry and hematology values will be provided.  All measurements collected, 
regardless of the number of days after the last dose of study drug, will be included in these 
listings.


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8.1.7.7
Analyses of Vital Signs Using Criteria for Potentially 
Clinically Significant Vital Sign Values
Detailed listings of data for subjects experiencing potentially clinically significant vital 
sign values according to the AbbVie-defined criteria for vital sign values will be provided.  
All measurements collected, regardless of the number of days after the last dose of study 
drug, will be included in these listings.
8.1.8
Timing of Efficacy Analyses and Safety Evaluations
When the 126th PFS event is observed, all efficacy and safety data as of this time will be 
retrieved and entered into the clinical database prior to breaking the study blind.  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 study 
blind will be broken and clinical database data will be extracted for documentation and 
statistical analyses of the efficacy and safety data.
Overall survival will be collected on all subjects.  After all survival data have been 
collected and entered into the clinical database, the clinical database will be extracted 
again for documentation and a "Final OS Analysis" will be performed on this dataset.
8.1.9
Data Monitoring Committee (DMC)
A safety DMC will be set up for the Phase 2 portion of the study to review the aggregate 
unblinded safety data.  The initial safety DMC review will occur once the first 30 Phase 2 
subjects complete combination treatment.  Based on this initial safety DMC review, the 
frequency of subsequent safety DMC reviews will be determined.  However, the initial 
safety DMC review may occur sooner:  if the observed rate of DLT-like events in the 
aggregate blinded safety review of the first 15 Phase 2 subjects exceeds the rate observed 
in the MTD/RPTD cohort by more than 10%, the safety DMC will convene immediately 
to review the aggregate unblinded safety data.  The details of the safety DMC setup and 
procedure will be outlined in a separate document.
The DMC will not evaluate efficacy data.


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8.2
Determination of Sample Size
Phase 1 Dose Escalation
The number of subjects required for dose escalation portion will depend upon the 
toxicities observed as the trial progresses.
Phase 2 Randomized Double-Blind
Assuming a median PFS of 5.5 months for placebo in combination with carboplatin and 
etoposide followed by placebo monotherapy (Arm C) and a hazard ratio of 0.63 for 
veliparib in combination with carboplatin and etoposide followed by veliparib 
monotherapy (Arm A) versus Arm C, a total of 85 PFS events will provide an least 80% 
power to detect a statistically significant difference between Arm A and Arm C at a 
one-sided α = 0.1.  Further assuming a hazard ratio of 0.75 for veliparib in combination 
with carboplatin and etoposide followed by placebo monotherapy (Arm B) versus Arm C, 
a total of 126 PFS events will be observed across all three arms at the time when 85 PFS 
events are observed for Arm A and Arm C combined.  A total of approximately 
180 subjects (60 subjects per treatment arm) will be enrolled into the study to obtain the 
126 PFS events.
8.3
Randomization Methods
All subjects in the Phase 2 portion of 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 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 and a unique 
randomization number will be provided.
The IRT will randomize subjects in a 1:1:1 ratio to one of the treatment arms as follows:


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●
Arm A:  veliparib in combination with carboplatin/etoposide followed by 
veliparib monotherapy
●
Arm B:  veliparib in combination with carboplatin/etoposide followed by 
placebo monotherapy
●
Arm C:  placebo in combination with carboplatin/etoposide followed by 
placebo monotherapy
Subject randomization will be stratified by baseline LDH (≤ ULN versus > ULN) and 
gender.  The stratification factors used for the randomization should be the last values on 
or prior to the date of randomization and should be consistent with those on the eCRF.
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.
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.


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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 or any additional reports 
required by local regulations) to the IEC/IRB of any changes that affect the conduct of the 
study and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) GCP guidelines, applicable regulations and guidelines governing 
clinical study conduct and ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.
9.3
Subject Information and Consent
The investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 
the informed consent form will be given to the subject and the original will be placed in 
the subject's medical record.  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.
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 


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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 form, approved by an IRB/IEC, after 
the nature of the testing has been explained and the subject has had the opportunity to ask 
questions.  The subject must provide consent specific to pharmacogenetic testing 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.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.
10.2
Case Report Forms
Case report forms (CRF) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study specific electronic case report forms (eCRFs) will comply with Title 21 CFR 


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Part 11.  The documentation related to the validation of the EDC system is available 
through the vendor, Medidata, while the validation of the study specific eCRFs will be 
conducted by AbbVie and will be maintained in the Trial Master File at AbbVie.
The investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 
investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.


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12.0
Use of Information
All information concerning veliparib and AbbVie operations, such as AbbVie patent 
applications, formulas, manufacturing processes, basic scientific data, or formulation 
information, supplied by AbbVie and not previously published is considered confidential 
information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of veliparib.  
This information may be disclosed as deemed necessary by AbbVie to other clinical 
investigators, other pharmaceutical companies, and to governmental agencies.  To allow 
for the use of the information derived from this clinical study and to ensure complete and 
thorough analysis, the investigator is obligated to provide AbbVie with complete test 
results and all data developed in this study and to provide direct access to source 
data/documents for study-related monitoring, audits, IEC/IRB review and regulatory 
inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study (by name and subject number).  This list will be maintained at the 
site and will not be retrieved by AbbVie.
Any pharmacogenetic research that may be done using DNA samples from this study will 
be experimental in nature and the results will not be suitable for clinical decision-making 
or patient management.  Hence, neither the investigator, the subject, nor the subject's 
physician (if different than 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 


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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 and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The investigator must retain any records related to the study according to local 
requirements.  If the investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory investigator from the investigators who participate in the 
study.  Selection criteria for this investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug and study protocol.  
The signatory investigator for the study will review and sign the final study report in 
accordance with the European Medicines Agency (EMA Guidance on Investigator's 
Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last on-site visit.  The sponsor 
may also end the study upon confirmation that the primary endpoint was statistically met.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for veliparib and the 
product labeling for carboplatin and etoposide.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title:
A Phase 1 Dose Escalation and Phase 2 Randomized Double-Blind 
Study of Veliparib in Combination with Carboplatin and Etoposide as 
a Therapy of Treatment-Naïve Extensive Stage Disease Small Cell 
Lung Cancer
Protocol Date:
22 November 2016
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
Reference List
1.
Jemal A, Siegel R, Xu J, et al.  Cancer statistics.  CA Cancer J Clin.  
2010;60(5):277-300.
2.
Board RE, Thatcher N, Lorigan P.  Novel therapies for the treatment of small-cell 
lung cancer:  a time for cautious optimism?  Drugs.  2006;66(15):1919-31.
3.
Cooper S, Spiro SG.  Small cell lung cancer:  treatment review.  Respirology.  
2006;11(3):241-8.
4.
Ettinger DS, Berkey BA, Abrams RA, et al. Study of paclitaxel, etoposide, and 
cisplatin chemotherapy combined with twice-daily thoracic radiotherapy for 
patients with limited-stage small-cell lung cancer:  a Radiation Therapy Oncology 
Group 9609 phase II study.  J Clin Oncol.  2005;23(22):4991-8.
5.
Greco FA, Thompson DS, Morrissey LH, et al.  Paclitaxel/carboplatin/etoposide 
versus paclitaxel/topotecan for extensive-stage small cell lung cancer:  a Minnie 
Pearl Cancer Research Network randomized, prospective phase II trial.  
Oncologist.  2005;10(9):728-33.
6.
Niell HB, Herndon JE 2nd, Miller AA, et al.  Randomized phase III intergroup trial 
of etoposide and cisplatin with or without paclitaxel and granulocyte colony 
stimulating factor in patients with extensive-stage small-cell lung cancer:  cancer 
and Leukemia Group B Trial 9732.  J Clin Oncol.  2005;23(16):3752-9.
7.
Otto H, Reche PA, Bazan F, et al.  In silico characterization of the family of PARP 
like poly(ADP-ribosyl) transferases (pARTs).  BMC Genomics.  2005;6:139.
8.
Ishizuka S, Martin K, Booth C, et al.  Poly(ADP-ribose) polymerase-1 is a survival 
factor for radiation-exposed intestinal epithelial stem cells in vivo.  Nucleic Acids 
Res.  2003;31(21):6198-205.
9.
Amé JC, Spenlehauer C, de Murcia G.  The PARP superfamily.  Bioessays.  
2004;26(8):882-93.
10.
Masutani M, Nozaki T, Nakamoto K, et al.  The response of Parp knockout mice 
against DNA damaging agents.  Mutat Res.  2000;462(2-3):159-66.


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11.
Alderson T.  New targets for cancer chemotherapy-poly(ADP-ribosylation) 
processing and polyisoprene metabolism.  Biol Rev Camb Philos Soc.  
1990;65(4):623-41.
12.
Wielckens K, Garbrecht M, Kittler M, et al.  ADP-ribosylation of nuclear proteins 
in normal lymphocytes and in low-grade malignant non-Hodgkin lymphoma cells.  
Eur J Biochem.  1980;104(1):279-87.
13.
Hirai K, Ueda K, Hayaishi O.  Aberration of poly(adenosine diphosphate-ribose) 
metabolism in human colon adenomatous polyps and cancers.  Cancer Res.  
1983;43(7):3441-6.
14.
Fernet M, Ponette V, Deniaud-Alexandre E, et al.  Poly(ADP-ribose) polymerase, a 
major determinant of early cell response to ionizing radiation.  Int J Radiat Biol.  
2000;76(12):1621-9.
15.
AbbVie.  ABT-888 Investigator Brochure Edition 7.  2013.
16.
AbbVie.  R&D/10/098.  Effects of veliparib (ABT-888) in syngeneic and xenograft 
tumors series 1.  2010.
17.
Coleman RL, Sill M, Aghajanian CA, et al.  A phase II evaluation of the potent,  
highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent 
epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry 
a germline BRCA1 or BRCA2 mutation – a gynecologic oncology group study.  
Gynecologic Oncology.  2013;130(1):e168.  Presented at:  Society of Gynecologic 
Oncology Annual Meeting on Women's Cancer; March 9-12, 2013; 
Los Angeles CA.
18.
Rugo HS, Olopade O, DiMichele A, et al.  Veliparib/carboplatin plus standard 
neoadjuvant therapy for high-risk breast cancer:  first efficacy results from the 
ISPY 2 TRIAL.  In:  Proceedings of the 2013 San Antonio Breast Cancer 
Symposium; December 13, 2013; San Antonio, TX.  Abstract S5-02.
19.
Appleman LJ, Beumer JH, Jiang Y, et al.  A phase I study of veliparib (ABT-888) 
in combination with carboplatin and paclitaxel in advanced solid malignancies.  
J Clin Oncol.  2012;30(15 suppl):3049.  Abstract 3049.


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20.
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.  Updated Version 4.3.  14 June 2010.  Files available from:  
http://eversusnci.gov/ftp1/CRCAE/About.html.
21.
Taofeek Kunle, Owonikoko, Suzanne Eleanor Dahlberg.  A phase 1 study of 
veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in combination with 
cisplatin and etoposide in extensive-stage small cell lung cancer (SCLC) patients: 
an Eastern Cooperative Oncology Group study (E2511).
22.
Carboplatin [package insert].  Irvine, CA; Teva Parenteral Medicines, Inc., 2010.
23.
National Cancer Institute [updated 2011 May 05].  Available from:  
http://www.cancer.gov/cancertopics/druginfo/carboplatin.
24.
ETOPOPHOS (etoposide phosphate) [package insert].  Deerfield, IL.  Baxter 
Healthcare Corporation, September 2013.
25.
Hermes A, Bergman B, Bremnes R, et al.  Irinotecan plus carboplatin versus oral 
etoposide plus carboplatin in extensive small-cell lung cancer:  a randomized 
phase III trial.  J Clin Oncol.  2008;26(26):4261-7.
26.
Klastersky J, Sculier JP, Lacroix H, et al.  A randomized study comparing cisplatin 
or carboplatin with etoposide in patients with advanced non-small-cell lung cancer:  
European Organization for Research and Treatment of Cancer Protocol 07861.  
J Clin Oncol.  1990;8(9):1556-62.
27.
Schmittel A, Sebastian M, Fischer von Weikersthal L, et al.  A German 
multicenter, randomized phase III trial comparing irinotecan-carboplatin with 
etoposide-carboplatin as first-line therapy for extensive-disease small-cell lung 
cancer.  Ann Oncol.  2011;22(8):1798-804.
28.
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in 
solid tumors:  revised RECIST guideline (version 1.1).  Eur J Cancer.  
2009;45:228-47.


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


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


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


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Appendix C.
RECIST (Version 1.1) for Tumor Response (PFS)
Response criteria will be assessed using RECIST (version 1.1).22  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.


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Special 
Considerations 
Regarding 
Lesion 
Measurability
Bone lesions
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
MRI/CT can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above.
Blastic bone lesions are non-measurable.
Cystic lesions
Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts.
'Cystic lesions' thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.
However, if non-cystic lesions are present in the same patient, 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 21 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 
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 with contrast 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 


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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 that 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 made.  
This decision should be guided by the tumor type under investigation and the anatomic 
location of the disease and the outcome of the decision should be communicated to 
AbbVie.  
For subjects who develop contraindications to contrast after baseline contrast CT is done, 
the decision as to whether non-contrast CT or MRI should be made based upon discussion 
with the AbbVie TA MD.
For accurate objective response evaluation, 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 
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 


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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.
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.


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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.
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 


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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.
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 


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study in an anatomical location that was not scanned at baseline is considered a new 
lesion and will indicate disease progression.  An example of this is the patient who has 
visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases.  The patient's brain metastases are considered evidence of progressive 
disease even if he/she did not have brain imaging at baseline.
If a new lesion is equivocal (e.g., too small to measure), continued therapy and follow-up 
evaluation will clarify if it represents truly new disease.  If repeat scans confirm there is a 
new lesion, then progression should be declared using the date of the initial scan.


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Appendix D.
NYHA Functional Classification
The NYHA classifies heart failure into classes based on functional limitations and 
severity.
Class
Patient Symptoms.
Class I
(Normal)
Few observable symptoms, no limitation in ordinary physical activity.
Class II
(Mild)
Mild observable symptoms and slight limitation during ordinary activity.  Comfortable at 
rest.
Class III
(Moderate)
Marked limitation in physical activity due to symptoms even during less-than-ordinary 
activity.  Comfortable only at rest.
Class IV
(Severe)
End-stage heart failure.  Severe limitations.  Experience symptoms even while at rest.


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Appendix E.
Calculation of Carboplatin Dose
The Cockcroft-Gault formula will be used.
The carboplatin dose will be calculated to reach a target AUC according to the Calvert 
formula using an estimated glomerular filtration rate (GFR) from the Cockcroft-Gault 
formula.
The initial dose of carboplatin must be calculated using GFR.  In the absence of renal 
toxicity greater than or equal to CTCAE Grade 2 (serum creatinine > 1.5 × ULN) or 
toxicity requiring dose modification, the dose of carboplatin will not need to be 
recalculated for subsequent cycles, but will be subject to dose modification for toxicity as 
noted in the protocol.
Carboplatin doses will be based on the subject's weight at baseline and will remain the 
same throughout the study.  However, the doses may be recalculated based on the 
subject's weight at each cycle, and need to be recalculated if the subject has a weight 
change of greater than or equal to 10% from baseline.
In subjects with an abnormally low serum creatinine (less than 0.7 mg/dL), the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dL.
CALVERT FORMULA:
Carboplatin dose (mg) = target AUC × (GFR + 25)
NOTE:  the GFR used in the Calvert formula should not exceed 125 mL/min.
Maximum carboplatin dose (mg) = target AUC (mg/ml × min) × 150 mL/min.
The maximum allowed doses of carboplatin are:
●
AUC5 = 750 mg
●
AUC4 = 600 mg


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For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance.  The estimated creatinine clearance (mL/min) is calculated by the 
method of Cockcroft-Gault using the following formula:
Creatinine Clearance (mL/min) = [140-Age (years)] × Weight (kg) × 
72 × serum creatinine (mg/dL)
For female subjects:  multiply the result above by 0.85.
Notes:
a.
Body mass index (BMI) should be calculated for each subject.  A BMI should be 
calculated using the following formula:
BMI = (Weight in kg) / (Height in meters)2
b. Actual weight should be used for estimation of GFR for subjects with BMI < 25.
c.
Adjusted weight should be used for estimation of GFR for subjects with BMI ≥ 25.
d. Adjusted weight calculation:
i. Ideal weight (kg) = (((Height (cm)/2.54) – 60) × 2.3) + 45.5
ii. Adjusted weight (kg) = ((Actual weight – Ideal weight) × 0.40) + 
Ideal weight
e.
If a patient with BMI of ≥ 25 is currently being dosed using actual weight, adjust 
dose with next planned treatment.
At the time of a dose modification for toxicity:
●
If the creatinine at the time of a dose modification is lower than the creatinine
used to calculate the previous dose, use the previous (higher) creatinine;
●
If the creatinine at the time of a dose modification is higher than the creatinine 
used to calculate the previous dose, use the current (higher) creatinine.  This 
will ensure that the patient is actually receiving a dose reduction. 


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Note that carboplatin dose will be recalculated if the subject has weight change of greater 
than or equal to 10% from baseline.


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Appendix F.
Adverse Events Expected Due to SCLC or Progression of SCLC
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*
   Blood Antidiuretic Hormonal Abnormal (SIADH)
   Cushing's syndrome
   Cachexia
   Shock*
   Septic shock*


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   Deep vein thrombosis*
   Lower respiratory tract infection*
   Respiratory tract infection*
   Upper respiratory tract infection*
   Opportunistic infection*
   Viral infection*
   Fungal infection*
   Bacterial infection*
   Pulmonary haemorrhage*
   Lung abscess*
   Empyema*
   Sepsis*
   Lymphadenopathy
   Decreased appetite
   Malaise
   Weight decreased
   Headache
   Pain excluding chest pain
   Pyrexia
*
Includes life threatening or fatal events.


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Appendix G.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Global Protocol Changes:
"Medical monitor" and "study designated physician" have been changed to read "TA MD" 
throughout the document.  "Interactive Voice/Web Response Technology (IVRS)" has
been changed to read "Interactive Response Technology (IRT)" throughout the document.
Specific Protocol Changes
Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M14-361
Name of Study Drug:  Veliparib
Phase of Development:  1 – 2
Name of Active Ingredient:  Veliparib
Date of Protocol Synopsis:  14 June 2016
Protocol Title:  
A Phase 1 Dose Escalation and Phase 2 Randomized Double-Blind Study of Veliparib in Combination 
with Carboplatin and Etoposide as a Therapy of Treatment-Naïve Extensive Stage Disease Small Cell 
Lung Cancer
Objectives:
Phase 1:
Primary Objectives:
●
To establish the Maximum Tolerated Dose (MTD) and to establish the Recommended Phase 2 
Dose (RPTD) and schedule for veliparib in combination with carboplatin and etoposide.
●
To evaluate the pharmacokinetic interaction between veliparib and etoposide.
Secondary Objective:
●
To evaluate the safety of maintenance veliparib monotherapy at 400 mg twice daily (BID) in 
subjects completing 4 cycles of carboplatin, etoposide and veliparib without evidence of disease 
progression.
Phase 2:
Primary Objective:
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by veliparib 
maintenance monotherapy results in improved progression free survival (PFS) versus placebo in 
combination with carboplatin and etoposide followed by placebo monotherapy in subjects with 
treatment-naïve ED SCLC.


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Objectives (Continued):
Secondary Objectives:
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by placebo 
monotherapy results in improved progression free survival (PFS) versus placebo in combination 
with carboplatin and etoposide followed by placebo monotherapy in subjects with 
treatment-naïve ED SCLC.
●
To evaluate if veliparib in combination with carboplatin and etoposide results in improved 
objective response rate (ORR) versus placebo in combination with carboplatin and etoposide at 
the time of completion of combination therapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by veliparib 
maintenance monotherapy results in improved overall survival (OS) versus placebo in 
combination with carboplatin and etoposide followed by placebo monotherapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by placebo 
monotherapy results in improved overall survival (OS) versus placebo in combination with 
carboplatin and etoposide followed by placebo monotherapy.
To further evaluate the safety of veliparib in combination with carboplatin and etoposide followed by 
veliparib maintenance monotherapy.
Tertiary Objectives:
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by veliparib 
maintenance monotherapy results in improved duration of overall response (DOR) versus
placebo in combination with carboplatin and etoposide followed by placebo monotherapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by placebo 
monotherapy results in improved duration of overall response (DOR) versus placebo in 
combination with carboplatin and etoposide followed by placebo monotherapy. 
●
To compare PFS and OS of subjects treated with veliparib in combination with carboplatin and 
etoposide followed by veliparib maintenance to PFS and OS of subjects treated with veliparib 
in combination with carboplatin and etoposide followed by placebo maintenance.
●
To evaluate performance status.
Investigators:  
Multicenter
Study Sites:  
Approximately 65 globally
Study Population:  
Phase 1:  Histologically or cytologically confirmed extensive stage disease SCLC or any other 
advanced/metastatic solid tumor for which carboplatin/etoposide treatment is considered appropriate.
Phase 2:  Histologically or cytologically confirmed treatment-naïve extensive stage disease SCLC.
Number of Subjects to be Enrolled:  
Dose Escalation Cohort:  Approximately:  35
Phase 2 Portion Approximately:  180


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Methodology:
This is a Phase 1 dose escalation and Phase 2 randomized double-blind study.
Screening Procedures:
Screening procedures should be performed within 28 days of Cycle 1 Day –2.  If the screening visit is 
performed greater than 7 days prior to Cycle 1 Day –2, the physical exam, laboratory tests, and 
pregnancy test (for female subjects of childbearing potential) must be repeated on Cycle 1 Day –2.  Vital 
signs and performance status assessments will be performed on Cycle 1 Day –2 for all subjects.  
Baseline radiographic tumor assessments per computed tomography (CT)/magnetic resonance imaging 
(MRI) of the chest, abdomen, and head will be conducted within 21 days prior to Cycle 1 Day –2.  If 
CNS metastases are suspected, a head CT should also be performed at screening.
Phase 1 Dose Escalation:
For subjects in the dose escalation portion of the study, each subject will participate in only 1 dose group 
and there is no provision for intra-subject dose-escalation.  Study procedures will be provided in the 
Schedule of Assessments and Pharmacokinetic and Pharmacodynamic tables.
The Phase 1 portion of this study will evaluate the safety, tolerability, dose limiting toxicities (DLTs), 
RPTD, pharmacokinetics (PK), and pharmacodynamics (PD), of veliparib/carboplatin/etoposide 
combination in subjects diagnosed with Extensive Stage Disease Small Cell Lung Cancer or, other 
advanced/metastatic solid tumor for which carboplatin/etoposide treatment is considered appropriate.  
Veliparib will be administered on Days –2 to 5 (7-day schedule), and, if the MTD of the 7-day schedule 
is not reached at ≤ 200 mg BID veliparib dose level, may be administered on Days –2 to 12 (14-day 
schedule) and/or Days –2 to 19 (continuous schedule) orally BID, in combination with carboplatin area 
under the curve 5 mg/mL*min administered on Day 1 and etoposide 100 mg/m2 administered on Days 1 
to 3 via intravenous (IV) infusion in 21-day cycles.  An exception would be for the Phase 1 Cycle 2:  In 
the 7-day schedule, veliparib in Cycle 2 will be administered on Days 2 to 5 and for the 14-day schedule, 
Days 2 to 12 (veliparib dose on Cycle 2 Days –2 and –1 and Cycle 2 Day 1 will be omitted to allow for 
the evaluation of drug-drug interaction of veliparib with etoposide).
Upon completion of 4 cycles of combination therapy, subjects without evidence of disease progression 
will continue on veliparib 400 mg BID until disease progression or unacceptable toxicity.  Subjects who 
will be receiving prophylactic cranial irradiation (PCI) will have maintenance veliparib interrupted for 
the duration of radiotherapy.
All subjects will be monitored for DLTs during the DLT observation period (Cycle 1 Day –2 to pre-dose 
Cycle 2 Day 1), and treatment-related adverse events (AEs) will be evaluated throughout the course of 
the study for evidence of acute, delayed, or cumulative toxicities.
The dose levels of veliparib to be evaluated in the dose-escalation portion of this study were determined 
based on the outcome of prior clinical studies of veliparib as well as on pre-clinical toxicology, 
toxicokinetic, and nonclinical anti-tumor efficacy studies.  The following dose levels may be evaluated 
in the dose-escalation portion of the study:  80, 120, 160, 200, and 240 mg BID.  Reduced dose levels 
may be evaluated based upon review of subject safety and PK data.  Intermediate dose levels may be 
evaluated based upon review of subject safety including, but not limited to, Grade 2 study-drug related 
AEs.  If the MTD is not reached at veliparib 200 mg BID dose level, higher dose levels (with no more 
than 25% veliparib dose increments, and not exceeding single agent veliparib RPTD of 400 mg BID) 
may be evaluated at the discretion of the sponsor.  The alternative dosing schedules can include dosing 
veliparib Day –2 to 12 (14-day schedule) and/or Day –2 to 19 (continuous schedule) of 21 day Cycle.  


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Methodology (Continued):
Phase 1 Dose Escalation (Continued):
The initial dose for these schedules will be 200 mg BID or the maximum administered dose (MAD), not 
exceeding the MTD, in the 7-day schedule.  The 14-day schedule will be explored prior to continuous 
dosing schedule.  Reduced or interim dose levels may be evaluated based on review of the safety and 
PK.
A "3 + 3" escalation rule will be used for the dose-escalation portion of this study, with a condition 
applied for the Dose Level 1, which will allow 3 additional subjects to be entered in Dose Level 1 if 2 of 
6 initial subjects experience DLTs.  Enrollment of the 3 additional subjects at all dose levels will depend 
on a review of the specific DLTs observed and discussion with the Investigators.
Dose-Escalation Criteria:
AEs, clinical laboratory results, and vital signs will be assessed throughout the study in each 
dose-escalation cohort.
DLTs will be assessed in each dose-escalation cohort during the DLT observation period
(Cycle 1 Day –2 to pre-dose on Cycle 2 Day 1).  Based on the safety and tolerability of study drugs after 
the first cycle of treatment has been completed in at least 3 subjects, escalation to a subsequent dose 
level or expansion of the current dose level will occur based upon the following criteria:


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Methodology (Continued):
Dose-Escalation Criteria (Continued):
Number of Subjects with 
DLT in the First Cycle
Escalation Decision Rule
0 out of 3
Enter 3 subjects at the next dose level.
1 out of 3
Add 3 more subjects at current dose level.  If AbbVie or the investigator 
considers the DLT(s) clinically significant, AbbVie will determine if it 
is appropriate to add more patients at this dose level.
!
If < 2 of 6 subjects (or < 33% of subjects) experience DLT, dose 
escalation will proceed to the next dose level.
!
If ≥ 2 of total 6 subjects (or ≥ 33% of subjects) experience DLTs, 
then dose escalation will be stopped.*
≥ 2 out of 3 or 6
Dose escalation will be stopped.  *Additional subjects will be enrolled 
at the previous lower dose level as needed.  The following exceptions 
apply to Dose Level 1:
!
If 2 of 6 initial subjects at Dose Level 1 experience DLTs, 
3 additional subjects may be entered and the cohort will be 
expanded up to 9 subjects for further DLT assessment.  
o
Enrollment of the 3 additional subjects will depend on a review 
of the specific DLTs observed and discussion with the 
Investigators.  
!
If 2 of 9 subjects at Dose Level 1 experience DLTs, then escalation 
to the next dose level may proceed.
!
If > 2 of 9 subjects in Dose Level 1 experience drug-related DLTs, 
dose-escalation will stop.
*
If 2 out of 6 subjects experience different DLTs, for example nausea and neutropenia, the data will be reviewed 
by the investigator and AbbVie to determine if 3 additional subjects should be added at that dose level.  If 
3 subjects will be added and none experience DLTs, this dose level will be declared the MTD.
An MTD and/or maximum administered dose (MAD), and RPTD, will be determined.  The MTD is 
defined as the maximum dose at which < 2 of 6 or ≤ 2 of 9 subjects experience a DLT during the DLT 
observation period.  The MAD is defined as the highest dose tested.  Both MAD and MTD may be 
determined independently for each tested dosing schedule of veliparib.  The RPTD and schedule will be 
determined based on the assessment of the observed toxicities, the MTD or MAD, and the overall safety 
profile of the study drug.  The RPTD cannot exceed the lower of MTD or MAD.  At the RPTD and 
schedule, additional subjects will be added as needed so that a total of at least 9 subjects will be treated 
at the RPTD during the dose escalation part of the study.


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Methodology (Continued):
DLT Definition:
DLT is defined as any of the following drug-related toxicities occurring during the DLT observation 
period in any of the dose-escalation cohorts, with grading according to the National Cancer Institute 
(NCI) Common Toxicity Criteria for Adverse Events (CTCAE), Version 4.0:
1.
Cycle 1 events associated with treatment delay > 14 days in initiating Cycle 2:
a.
Grade 4 thrombocytopenia (platelets < 25.0 × 109/L)
b.
Grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5 × 109/L)
c.
Grade 3 febrile neutropenia with fever lasting for > 7 days
d.
Grade 4 febrile neutropenia of any duration
NOTE:  Delay of more than 14 days in initiating Cycle 2 due to factors not directly related to 
treatment-emergent toxicity will not be considered a DLT.
2.
Grade ≥ 3 non-hematologic toxicity that represents at least 2 grade increase from baseline and is 
attributed to veliparib treatment:
a.
Exclusion:  nausea and vomiting lasting ≤ 48 hours or inadequately treated
b.
Exclusion:  electrolyte abnormalities resolving within ≤ 24 hours
c.
Exclusion:  hypersensitivity reactions
d.
Exclusion:  alopecia
3.
Grade 2 non-hematologic toxicity that represents at least 2 grade increase from baseline, is 
attributed to veliparib treatment and requires a treatment delay of > 14 days in initiation of Cycle 2
4.
Any toxicity that represents at least 2 grade increase from baseline, is attributed to veliparib 
treatment and requires at least one of:
a.
Dose modification within Cycle 1
b.
Omission of carboplatin, > 1 daily etoposide dose, or > 30% veliparib doses in Cycle 1
Subjects experiencing DLT(s) during DLT observation period (Cycle 1 Day –2 to pre-dose Cycle 2 
Day 1) will require an interruption and possible discontinuation from further participation in the study.  
Veliparib may be reintroduced at a reduced dose, if the toxicity returns to ≤ Grade 1 or to baseline if 
Grade 2 at study entry.  All decisions regarding continued dosing for individual subjects who experience 
a DLT will be medically managed by the investigator in conjunction with the AbbVie Medical Monitor.
Pharmacokinetics:
Pharmacokinetics of veliparib and etoposide will be assessed to determine the drug-drug interactions.  
Further pharmacokinetics of carboplatin will be assessed on Day 1 of Cycle 1.
Phase 2
In the Phase 2 double-blinded portion of the study subjects with treatment-naïve ED SCLC will be 
randomized to one of three treatment arms in 1:1:1 ratio: 
●
Arm A:  veliparib in combination with carboplatin/etoposide followed by veliparib 
monotherapy
●
Arm B:  veliparib in combination with carboplatin/etoposide followed by placebo monotherapy
●
Arm C:  placebo in combination with carboplatin/etoposide followed by placebo monotherapy


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Methodology (Continued):
Dose-Escalation Criteria (Continued):
Phase 2 (Continued):
Subjects in all Phase 2 study arms will receive a minimum of 4 cycles of combination therapy unless 
disease progression or unacceptable toxicity warrants earlier discontinuation from the treatment.  
Additional 2 cycles of combination therapy (e.g., up to a total of 6 cycles) may be administered at the 
investigators discretion if subject status at the completion of initial 4 cycles warrants continued 
treatment.  In the combination cycles of Arms A and B, veliparib will be administered at the RPTD 
defined in the Phase 1 portion of the study, Arm C will receive matching placebo.  After the completion 
of at least 4 chemotherapy combination cycles subjects without evidence of disease progression will 
receive veliparib at 400 mg BID continuous dosing (Arms A), or matching  placebo (Arms B and C), 
until disease progression or unacceptable toxicity occurs.
Subjects who will be receiving prophylactic cranial irradiation (PCI) will have maintenance veliparib 
interrupted for the duration of radiotherapy.
Subject randomization for Phase 2 will be stratified by baseline LDH level (> ULN versus ≤ ULN), and 
gender.
Pharmacodynamics (Dose Escalation and Phase 2):
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.
Tumor Assessments and Safety Follow-Up
Tumor assessments will be performed until disease progression.  Tumor assessment and assessment of 
response will occur every 6 weeks (± 1 week) for the first 24 weeks after the first dose of study drugs, 
then every 9 weeks (± 1 week) thereafter.  Tumor response will be determined according to the Response 
Evaluation Criteria in Solid Tumors (RECIST), Version 1.1.  Subjects will continue on study until they 
meet defined discontinuation criteria.  When the investigator has determined that a subject should 
discontinue the study, a Final Visit will be conducted.  Subjects will have a 30-Day Safety Follow-Up 
Visit following the last dose of study drugs or placebo (dependent on cohort).  If the subject begins 
another treatment regimen directly following protocol treatment and if a 30-Day Follow-Up Visit is not 
possible, all adverse events ongoing as of the end of study must be followed to a satisfactory conclusion.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Inclusion:
1.
Subject has histologically or cytologically confirmed ED SCLC which is newly diagnosed and 
chemotherapy naïve.
2.
Phase 1 ONLY:  histologically or cytologically confirmed advanced/metastatic solid tumors for 
which carboplatin/etoposide treatment is considered appropriate.
3.
Subject in Phase 2 only:  must have measureable disease per RECIST 1.1.
4.
Subjects with ED SCLC must consent to provide available archived formalin fixed paraffin 
embedded (FFPE) tissue sample of SCLC lesion (primary or metastatic) for central review and 
biomarker analysis.
5.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
6.
Subject must be ≥ 18 years of age.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Inclusion (Continued):
7.
Subject must have adequate hematologic, renal and hepatic function as follows:
●
Bone Marrow:  Absolute neutrophil count ANC ≥ 1,500/mm3 (1.5 × 109/L); White blood cells 
≥ 3,000/mm3 (3 × 109/L); Platelets ≥ 100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9 g/dL 
(5.58 mmol/L)
●
Renal function:  creatinine ≤ ULN or if creatinine > ULN calculated creatinine clearance via 
the Cockroft Gault formula of ≥ 50 mL/min
●
Hepatic function:
o
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper 
limits of normal (ULN).  For subjects with liver metastases, AST and ALT ≤ 5 × ULN;
o
Bilirubin:  ≤ 1.5 × ULN; for subjects with Gilbert's syndrome bilirubin > 1.5 × ULN is 
allowed if no symptoms of compromised liver function are present.
8.
Subject must be able to swallow pills.
9.
Female and male patients of fertile age, and/or their partners should use contraception.  If male, 
subject and subject's female partner(s) of childbearing potential should practice at least one of the 
following methods of birth control.  If female, subject must be either postmenopausal for at least 
1 year, surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy), or the 
subject and the subject's male partner(s) practicing at least one of the following methods of birth 
control:
!
total abstinence from sexual intercourse (if it is the subject's preferred and usual lifestyle; for 
minimum one complete menstrual cycle prior to study drug administration and to extend 
6 months after treatment);
!
vasectomized subject or partner(s);
!
hormonal contraceptives (oral, parenteral or transdermal) for at least 90 days prior to study drug 
administration for the subject or subject's female partner(s);
!
intrauterine device (IUD) for the subject or subject's female partner(s); or
!
double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal ring with 
spermicidal jellies or creams) for the subject or subject's female partner(s).
If hormonal contraceptives are used, the specific contraceptive must have been used for at least 
90 days prior to study drug administration.  If the subject or subject's female partner(s) is currently 
using a hormonal contraceptive, she should also use a barrier method during this study and for 
6 months (or per local label) after study completion.
Female subjects must have negative results for pregnancy tests performed:
!
at Screening on a serum specimen obtained within 7 days prior to initial study drug 
administration, and
●
prior to dosing on a urine sample obtained C1D-2 unless the serum pregnancy test was 
collected within 7 days of C1D-2.
10. Must voluntarily sign and date each informed consent, approved by an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study 
specific procedures.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Exclusion:
1.
Phase 1 ONLY:  Subject has had any prior anti-cancer therapy other than:
●
Hormonal, non-myelosuppressive, biologic, targeted, or immune therapy (must be completed 
≥4 weeks prior to Cycle 1 Day –2).
●
One line of cytotoxic chemotherapy (must be completed ≥ 4 weeks prior to Cycle 1 Day –2).
●
Adjuvant/neoaduvant radiotherapy (must be completed ≥ 12 months prior to Cycle 1 Day –2, 
with field not involving > 10% of bone marrow reserve).
●
Tumor lesion irradiation with intent of symptom palliation ≥ 4 weeks prior Cycle 1 Day –2.
2.
Phase 2 ONLY:  Subject has had any prior chemotherapy, radiotherapy, investigational anti-cancer 
agents or biologic therapy for the disease under study.  Single non-target lesion irradiation with 
intent of symptom palliation is allowed if ≥ 2 weeks prior Cycle 1 Day –2.
3.
Subject has known hypersensitivity to etoposide, platinum compounds or veliparib.
4.
Phase 1 ONLY:  Subject has received prior myelopoietic growth factors.
5.
Subject has current central nervous system (CNS) or leptomeningeal metastases or history of CNS 
or leptomeningeal metastases.  If CNS progression is suspected, a head CT should be performed at 
screening.
6.
Subject has a history of seizures within 12 months of Cycle 1 Day –2 or diagnosed neurological 
condition placing subject at the increased risk of seizures.
7.
Subject has received traditional herbal anti-cancer medicine (e.g., Chinese, Asian etc.) within 
14 days prior to Cycle 1 Day –2.
8.
Subject has had major surgery within 6 weeks prior to Cycle 1 Day –2 (subjects must have 
completely recovered from any previous surgery prior to Cycle 1 Day –2).
9.
Subject has clinically significant and uncontrolled major medical condition(s) including but not 
limited to:
●
Uncontrolled nausea/vomiting/diarrhea;
●
Active uncontrolled infection;
●
History of hepatitis B (HBV) with surface antigen (HBsAg) positivity within 3 months prior to 
the date of informed consent for this study (if no test has been performed within 3 months, it 
must be done at screening);
●
History of hepatitis C (HCV) with HCV RNA positivity within 3 months prior to the date of 
informed consent for this study (if no test has been performed within 3 months it must be done 
at screening);
●
Symptomatic congestive heart failure (New York Heart Association [NYHA] class ≥ II);
●
Unstable angina pectoris or cardiac arrhythmia;
●
Psychiatric illness/social situation that would limit compliance with study requirements;
●
Any other medical condition, which in the opinion of the Investigator, places the subject at an 
unacceptably high risk for toxicities.
10. Subject is pregnant or lactating.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Exclusion (Continued):
11. The subject has a history of another active 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, breast ductal 
carcinoma in situ [DCIS]).
Questions regarding the eligibility of individual subjects should be directed to the AbbVie Medical 
Monitor.
Investigational Products:
Veliparib
Doses:
Dose escalation cohorts:  80, 120, 160 and 200 mg BID (higher doses 
up to 400 mg BID may be tested)
Phase 2:  RPTD;
Continuous monotherapy maintenance:  400 mg BID
Mode of Administration:
Oral
Investigational Products:
Placebo – BID Phase 2 ONLY
Doses:
Matching capsules for RPTD
Monotherapy maintenance:   matching capsules for 400 mg BID 
continuous
Mode of Administration:
Oral
Reference Therapy:
Carboplatin
Doses:
AUC 5 mg/mL*min
Mode of Administration:
Intravenous infusion
Reference Therapy:
Etoposide
Doses:
100 mg/m2
Mode of Administration:
Intravenous infusion
Duration of Treatment:
Subject will remain on study drug until disease progression or unacceptable toxicity. 
Criteria for Evaluation:
Efficacy:
Progression-free survival (PFS) will be derived according to disease progression (radiographic 
progression per RECIST version 1.1 or clinical disease progression) or death.  Radiographic tumor 
assessments for response will be conducted by CT scanning at baseline, every 6 weeks for the 
first 24 weeks after beginning therapy, then every 9 weeks until disease progression.
Objective response rate (ORR) will be derived per RECIST version 1.1.  Radiographic tumor 
assessments for response will be conducted by CT scanning at baseline, every 6 weeks for 24 weeks 
after beginning therapy, then every 9 weeks until disease progression.
Duration of overall response (DOR) will be derived according to disease progression (radiographic 
progression per RECIST version 1.1 or clinical disease progression). 


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Criteria for Evaluation (Continued):
Efficacy (Continued):
Overall survival will be determined by the Investigator at assessments throughout therapy.  After the 
final visit, survival information will be collected via the Interactive Response Technology (IRT) at 
two month intervals (or as requested by sponsor to support data analysis).
ECOG performance status will be determined by the Investigator at each assessment.  
Pharmacokinetic:
Blood samples for pharmacokinetics of veliparib, carboplatin and etoposide will be collected at 
designated time points throughout the study.  Pharmacokinetics of veliparib and etoposide will be 
assessed to determine the drug-drug interactions.  In addition, pharmacokinetics of carboplatin will be 
determined.
Pharmacodynamic:
Research to find biomarkers that may be predictive of veliparib activity will be conducted.  Serum, 
plasma, blood and archived tissue samples will be collected at designated time points throughout the 
study.
Pharmacogenetic:
DNA samples may be analyzed for genetic factors contributing to the subject's response to veliparib, or 
other study treatment, in terms of pharmacokinetics, efficacy, tolerability and safety.
Safety:
Adverse events, laboratory profiles, physical examinations, vital signs and neurological assessments will 
be evaluated and recorded throughout the study.
Statistical Methods:
Efficacy:
The following end point will be analyzed using data obtained from subjects in Phase 1:
Objective Response Rate
The proportion of subjects with objective response as assessed by the investigator using RECIST 1.1 will 
be calculated for all dosed subjects.
The following end point will be analyzed using data obtained from subjects in Phase 2:
Progression-Free Survival
Progression-Free Survival will be defined as the number of days from the date of randomization to the 
date of earliest disease progression or death.  All disease progression will be included regardless whether 
the event occurred while the subject was taking study drug or had previously discontinued study drug.  If 
the subject does not experience disease progression or death, then the data will be censored at the date of 
the last disease assessment.
Overall Survival
Overall survival will be defined as the number of days from the date of randomization to the date of 
death.  For subjects who did not die, their data will be censored at the date of last study visit or the last 
known date to be alive, whichever is later.  
Objective Response Rate
The proportion of subjects with objective response (CR or PR) as assessed by the investigator using 
RECIST 1.1 will be evaluated for randomized subjects.


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Statistical Methods (Continued):
Efficacy (Continued):
Duration of Overall Response
Duration of overall response will be defined as the number of days from the date of first response (CR or 
PR) to the earliest documentation of progressive disease.  If a subject is still responding, then the 
subject's data will be censored at the date of the subject's last available disease assessment.  For subjects 
who never experience response, the subject's data will not be included in the analysis.
Performance Status
Changes and/or percent changes from baseline will be summarized using descriptive statistics for each 
scheduled post-baseline visit and for the Final Visit for ECOG performance status.  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.
Pharmacokinetic:
Plasma concentrations of veliparib, etoposide, and carboplatin and pharmacokinetic parameter values 
will be tabulated for each subject and each dose level, and summary statistics will be computed for each 
sampling time and each parameter.
The effects of co-administration of veliparib on etoposide pharmacokinetics will be addressed by 
analyzing the Cycle 1, Day 1 (veliparib with carboplatin and etoposide) and Cycle 2 Day 1 (carboplatin 
and etoposide alone) etoposide pharmacokinetic variables, including Tmax, dose normalized Cmax and 
dose normalized AUC.
Pharmacodynamic:
Biomarker results will be tabulated for each subject and each regimen, and summary statistics will be 
computed for each sampling time and each parameter.  The relationship between biomarker status and 
clinical outcome or drug exposure may be examined.
Safety:
●
The safety of veliparib in combination with carboplatin/etoposide will be assessed by 
evaluating the study drugs exposure, adverse events, serious adverse events, all deaths, as well 
as changes in laboratory determinations and vital sign parameters.  Safety will be summarized 
per dose level using descriptive statistics for the dose escalation cohorts and per treatment arm 
in Phase 2.
●
RPTD will be determined based on the rate of DLTs and overall tolerability of the combination 
of veliparib, carboplatin and etoposide with at least 9 subjects treated at the RPTD in Phase 1 
and will be further evaluated in Phase 2.


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Has been changed to read:
AbbVie Inc.
Protocol Number:  M14-361
Name of Study Drug:  Veliparib
Phase of Development:  1 – 2
Name of Active Ingredient:  Veliparib
Date of Protocol Synopsis:  22 November 2016
Protocol Title:  
A Phase 1 Dose Escalation and Phase 2 Randomized Double-Blind Study of Veliparib in Combination 
with Carboplatin and Etoposide as a Therapy of Treatment-Naïve Extensive Stage Disease Small Cell 
Lung Cancer
Objectives:
Phase 1 Dose Escalation:
Primary Objectives:
●
To establish the Maximum Tolerated Dose (MTD) and to establish the Recommended Phase 2 
Dose (RPTD) and schedule for veliparib in combination with carboplatin and etoposide.
●
To evaluate the pharmacokinetic interaction between veliparib and etoposide.
Secondary Objective:
●
To evaluate the safety of maintenance veliparib monotherapy at 400 mg twice daily (BID) in 
subjects completing 4 cycles of carboplatin, etoposide and veliparib without evidence of disease 
progression.
Phase 2 Randomized Double-Blind:
Primary Objective:
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by veliparib 
maintenance monotherapy results in improved progression free survival (PFS) versus placebo in 
combination with carboplatin and etoposide followed by placebo monotherapy in subjects with 
treatment-naïve ED SCLC.
Secondary Objectives:
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by placebo 
monotherapy results in improved progression free survival (PFS) versus placebo in combination 
with carboplatin and etoposide followed by placebo monotherapy in subjects with 
treatment-naïve ED SCLC.
●
To evaluate if veliparib in combination with carboplatin and etoposide results in improved 
objective response rate (ORR) versus placebo in combination with carboplatin and etoposide at 
the time of completion of combination therapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by veliparib 
maintenance monotherapy results in improved overall survival (OS) versus placebo in 
combination with carboplatin and etoposide followed by placebo monotherapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by placebo 
monotherapy results in improved overall survival (OS) versus placebo in combination with 
carboplatin and etoposide followed by placebo monotherapy.
●
To further evaluate the safety of veliparib in combination with carboplatin and etoposide 
followed by veliparib maintenance monotherapy.


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Objectives (Continued):
Tertiary Objectives:
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by veliparib 
maintenance monotherapy results in improved duration of overall response (DOR) versus
placebo in combination with carboplatin and etoposide followed by placebo monotherapy.
●
To evaluate if veliparib in combination with carboplatin and etoposide followed by placebo 
monotherapy results in improved duration of overall response (DOR) versus placebo in 
combination with carboplatin and etoposide followed by placebo monotherapy. 
●
To compare PFS and OS of subjects treated with veliparib in combination with carboplatin and 
etoposide followed by veliparib maintenance to PFS and OS of subjects treated with veliparib 
in combination with carboplatin and etoposide followed by placebo maintenance.
●
To evaluate performance status.
Investigators:  
Multicenter
Study Sites:  
Approximately 65 globally
Study Population:  
Phase 1:  Histologically or cytologically confirmed extensive stage disease SCLC or any other 
advanced/metastatic solid tumor for which carboplatin/etoposide treatment is considered appropriate.
Phase 2:  Histologically or cytologically confirmed treatment-naïve extensive stage disease SCLC.
Number of Subjects to be Enrolled:  
Phase 1 Dose Escalation portion:  Approximately:  35
Phase 2 Randomized Double-Blind portion:  Approximately:  180
Methodology:
This is a Phase 1 dose escalation and Phase 2 randomized double-blind study.
Screening Procedures:
Screening procedures should be performed within 28 days of Cycle 1 Day –2.  If the screening visit is 
performed greater than 7 days prior to Cycle 1 Day –2, the physical exam, laboratory tests, and 
pregnancy test (for female subjects of childbearing potential) must be repeated on Cycle 1 Day –2.  Vital 
signs and performance status assessments will be performed on Cycle 1 Day –2 for all subjects.  
Baseline radiographic tumor assessments per computed tomography (CT) with IV contrast/magnetic 
resonance imaging (MRI) of the chest, abdomen, and pelvis will be conducted within 21 days prior to 
Cycle 1 Day –2.  If CNS metastases are suspected, a head CT must also be performed at screening.  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.
Phase 1 Dose Escalation:
For subjects in the dose escalation portion of the study, each subject will participate in only 1 dose group 
and there is no provision for intra-subject dose-escalation.  Study procedures will be provided in the 
Schedule of Assessments and Pharmacokinetic and Pharmacodynamic tables.


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Methodology (Continued):
Phase 1 Dose Escalation (Continued):
The Phase 1 portion of this study will evaluate the safety, tolerability, dose limiting toxicities (DLTs), 
RPTD, pharmacokinetics (PK), and pharmacodynamics (PD), of veliparib/carboplatin/etoposide 
combination in subjects diagnosed with Extensive Stage Disease Small Cell Lung Cancer or, other 
advanced/metastatic solid tumor for which carboplatin/etoposide treatment is considered appropriate.  
Veliparib will be administered on Days –2 to 5 (7-day schedule), and, if the MTD of the 7-day schedule 
is not reached at ≤ 200 mg BID veliparib dose level, may be administered on Days –2 to 12 (14-day 
schedule) and/or Days –2 to 19 (continuous schedule) orally BID, in combination with carboplatin area 
under the curve 5 mg/mL*min administered on Day 1 and etoposide 100 mg/m2 administered on Days 1 
to 3 via intravenous (IV) infusion in 21-day cycles.  An exception would be for the Phase 1 Cycle 2:  In 
the 7-day schedule, veliparib in Cycle 2 will be administered on Days 2 to 5 and for the 14-day schedule, 
Days 2 to 12 (veliparib dose on Cycle 2 Days –2 and –1 and Cycle 2 Day 1 will be omitted to allow for 
the evaluation of drug-drug interaction of veliparib with etoposide).
Upon completion of 4 cycles of combination therapy, subjects without evidence of disease progression 
will continue on veliparib 400 mg BID until disease progression or unacceptable toxicity.  Subjects who 
will be receiving prophylactic cranial irradiation (PCI) will have maintenance veliparib interrupted for 
the duration of radiotherapy.
All subjects will be monitored for DLTs during the DLT observation period (Cycle 1 Day –2 to pre-dose 
Cycle 2 Day 1), and treatment-related adverse events (AEs) will be evaluated throughout the course of 
the study for evidence of acute, delayed, or cumulative toxicities.
The dose levels of veliparib to be evaluated in the dose-escalation portion of this study were determined 
based on the outcome of prior clinical studies of veliparib as well as on pre-clinical toxicology, 
toxicokinetic, and nonclinical anti-tumor efficacy studies.  The following dose levels may be evaluated 
in the dose-escalation portion of the study:  80, 120, 160, 200, and 240 mg BID.  Reduced dose levels 
may be evaluated based upon review of subject safety and PK data.  Intermediate dose levels may be 
evaluated based upon review of subject safety including, but not limited to, Grade 2 study-drug related 
AEs.  If the MTD is not reached at veliparib 200 mg BID dose level, higher dose levels (with no more 
than 25% veliparib dose increments, and not exceeding single agent veliparib RPTD of 400 mg BID) 
may be evaluated at the discretion of the sponsor.  The alternative dosing schedules can include dosing 
veliparib Day –2 to 12 (14-day schedule) and/or Day –2 to 19 (continuous schedule) of 21 day Cycle.  
The initial dose for these schedules will be 200 mg BID or the maximum administered dose (MAD), not 
exceeding the MTD, in the 7-day schedule.  The 14-day schedule will be explored prior to continuous 
dosing schedule.  Reduced or interim dose levels may be evaluated based on review of the safety and 
PK.
A "3 + 3" escalation rule will be used for the dose-escalation portion of this study, with a condition 
applied for the Dose Level 1, which will allow 3 additional subjects to be entered in Dose Level 1 if 2 of 
6 initial subjects experience DLTs.  Enrollment of the 3 additional subjects at all dose levels will depend 
on a review of the specific DLTs observed and discussion with the Investigators.
Dose-Escalation Criteria:
AEs, clinical laboratory results, and vital signs will be assessed throughout the study in each 
dose-escalation cohort.


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Methodology (Continued):
Dose-Escalation Criteria (Continued):
DLTs will be assessed in each dose-escalation cohort during the DLT observation period
(Cycle 1 Day –2 to pre-dose on Cycle 2 Day 1).  Based on the safety and tolerability of study drugs after 
the first cycle of treatment has been completed in at least 3 subjects, escalation to a subsequent dose 
level or expansion of the current dose level will occur based upon the following criteria:
Number of Subjects with 
DLT in the First Cycle
Escalation Decision Rule
0 out of 3
Enter 3 subjects at the next dose level.
1 out of 3
Add 3 more subjects at current dose level.  If AbbVie or the investigator 
considers the DLT(s) clinically significant, AbbVie will determine if it 
is appropriate to add more patients at this dose level.
!
If < 2 of 6 subjects (or < 33% of subjects) experience DLT, dose 
escalation will proceed to the next dose level.
!
If ≥ 2 of total 6 subjects (or ≥ 33% of subjects) experience DLTs, 
then dose escalation will be stopped.*
≥ 2 out of 3 or 6
Dose escalation will be stopped.  *Additional subjects will be enrolled 
at the previous lower dose level as needed.  The following exceptions 
apply to Dose Level 1:
!
If 2 of 6 initial subjects at Dose Level 1 experience DLTs, 
3 additional subjects may be entered and the cohort will be 
expanded up to 9 subjects for further DLT assessment.  
o
Enrollment of the 3 additional subjects will depend on a review 
of the specific DLTs observed and discussion with the 
Investigators.  
!
If 2 of 9 subjects at Dose Level 1 experience DLTs, then escalation 
to the next dose level may proceed.
!
If > 2 of 9 subjects in Dose Level 1 experience drug-related DLTs, 
dose-escalation will stop.
*
If 2 out of 6 subjects experience different DLTs, for example nausea and neutropenia, the data will be reviewed 
by the investigator and AbbVie to determine if 3 additional subjects should be added at that dose level.  If 
3 subjects will be added and none experience DLTs, this dose level will be declared the MTD.
An MTD and/or maximum administered dose (MAD), and RPTD, will be determined.  The MTD is 
defined as the maximum dose at which < 2 of 6 or ≤ 2 of 9 subjects experience a DLT during the DLT 
observation period.  The MAD is defined as the highest dose tested.  Both MAD and MTD may be 
determined independently for each tested dosing schedule of veliparib.  The RPTD and schedule will be 
determined based on the assessment of the observed toxicities, the MTD or MAD, and the overall safety 
profile of the study drug.  The RPTD cannot exceed the lower of MTD or MAD.  At the RPTD and 
schedule, additional subjects will be added as needed so that a total of at least 9 subjects will be treated 
at the RPTD during the dose escalation part of the study.


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Methodology (Continued):
DLT Definition:
DLT is defined as any of the following drug-related toxicities occurring during the DLT observation 
period in any of the dose-escalation cohorts, with grading according to the National Cancer Institute 
(NCI) Common Toxicity Criteria for Adverse Events (CTCAE), Version 4.0:
1.
Cycle 1 events associated with treatment delay > 14 days in initiating Cycle 2:
a.
Grade 4 thrombocytopenia (platelets < 25.0 × 109/L)
b.
Grade 4 neutropenia (absolute neutrophil count (ANC) < 0.5 × 109/L)
c.
Grade 3 febrile neutropenia with fever lasting for > 7 days
d.
Grade 4 febrile neutropenia of any duration
NOTE:  Delay of more than 14 days in initiating Cycle 2 due to factors not directly related to 
treatment-emergent toxicity will not be considered a DLT.
2.
Grade ≥ 3 non-hematologic toxicity that represents at least 2 grade increase from baseline and is 
attributed to veliparib treatment:
a.
Exclusion:  nausea and vomiting lasting ≤ 48 hours or inadequately treated
b.
Exclusion:  electrolyte abnormalities resolving within ≤ 24 hours
c.
Exclusion:  hypersensitivity reactions
d.
Exclusion:  alopecia
3.
Grade 2 non-hematologic toxicity that represents at least 2 grade increase from baseline, is 
attributed to veliparib treatment and requires a treatment delay of > 14 days in initiation of Cycle 2
4.
Any toxicity that represents at least 2 grade increase from baseline, is attributed to veliparib 
treatment and requires at least one of:
a.
Dose modification within Cycle 1
b.
Omission of carboplatin, > 1 daily etoposide dose, or > 30% veliparib doses in Cycle 1
Subjects experiencing DLT(s) during DLT observation period (Cycle 1 Day –2 to pre-dose Cycle 2 
Day 1) will require an interruption and possible discontinuation from further participation in the study.  
Veliparib may be reintroduced at a reduced dose, if the toxicity returns to ≤ Grade 1 or to baseline if 
Grade 2 at study entry.  All decisions regarding continued dosing for individual subjects who experience 
a DLT will be medically managed by the investigator in conjunction with the AbbVie TA MD.
Pharmacokinetics:
Pharmacokinetics of veliparib and etoposide will be assessed to determine the drug-drug interactions.  
Further pharmacokinetics of carboplatin will be assessed on Day 1 of Cycle 1.
Phase 2 Randomized Double-Blind
The veliparib dose and schedule for the Phase 2 was determined to be 240 mg BID on a 14 day schedule 
based on the analysis of Phase 1 data.
Approximately 180 total subjects with treatment-naïve ED SCLC will be enrolled at the 240 mg BID 
veliparib/placebo dose and 14 day schedule in the Phase 2 double-blinded portion of the study.  They 
will be randomized in a 1:1:1 ratio to one of three treatment arms: 
●
Arm A:  veliparib in combination with carboplatin/etoposide followed by veliparib 
monotherapy
●
Arm B:  veliparib in combination with carboplatin/etoposide followed by placebo monotherapy


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Methodology (Continued):
Phase 2 Randomized Double-Blind (Continued)
!
Arm C:  placebo in combination with carboplatin/etoposide followed by placebo monotherapy
Subjects in all Phase 2 study arms will receive a minimum of 4 cycles of combination therapy unless 
disease progression or unacceptable toxicity warrants earlier discontinuation from the treatment.  
Additional 2 cycles of combination therapy (e.g., up to a total of 6 cycles) may be administered at the 
investigators discretion if subject status at the completion of initial 4 cycles warrants continued 
combination treatment and/or if local SOC guidelines require 6 cycles of platinum-based therapy.  In the 
combination cycles of Arms A and B, subjects will receive veliparib at 240 mg BID on a 14-day 
schedule, Arm C will receive matching placebo.  After completion of the chemotherapy combination 
cycles (at least 4), subjects without evidence of disease progression will receive veliparib at 400 mg BID 
continuous dosing (21-day cycles) (Arms A), or matching placebo (Arms B and C) as per treatment arm 
assignment, until disease progression or unacceptable toxicity occurs.  
Subjects who will be receiving prophylactic cranial irradiation (PCI) will have maintenance veliparib 
interrupted for the duration of radiotherapy.
Subject randomization for Phase 2 will be stratified by baseline LDH level (> ULN versus ≤ ULN), and 
gender.
Pharmacodynamics (Phase 1 Dose Escalation and Phase 2 Randomized Double-Blind):
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.
Tumor Assessments and Safety Follow-Up
Tumor assessments will be performed until radiographic disease progression.  Tumor assessment and 
assessment of response will occur every 6 weeks (± 1 week) from C1D-2 for the first 24 weeks (Phase 1) 
or 30 weeks (Phase 2), then every 9 weeks (± 1 week) thereafter.  Tumor response will be determined 
according to the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1.  Subjects will 
continue on study until they meet defined discontinuation criteria.  When the investigator has determined 
that a subject should discontinue the study, a Final Visit will be conducted.  Subjects will have a 30-Day 
Follow-Up Visit following the last dose of study drugs or placebo (Phase 2, dependent on treatment 
arm).  If the subject begins another treatment regimen directly following protocol treatment and if a 
30-Day Follow-Up Visit is not possible, all adverse events ongoing as of the end of study must be 
followed to a satisfactory conclusion.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Inclusion:
1.
Subject has histologically or cytologically confirmed ED SCLC which is newly diagnosed and 
chemotherapy naïve.
2.
Phase 1 ONLY:  histologically or cytologically confirmed advanced/metastatic solid tumors for 
which carboplatin/etoposide treatment is considered appropriate.
3.
Subject in Phase 2 ONLY:  must have measureable disease per RECIST 1.1.
4.
Subjects with ED SCLC must consent to provide available archived formalin fixed paraffin 
embedded (FFPE) tissue sample of SCLC lesion (primary or metastatic) for central review and 
biomarker analysis.  NOTE:  If sufficient tissue is unavailable for analysis, subjects will still be 
allowed to enroll.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Inclusion (Continued):
5.
Subject has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
6.
Subject must be ≥ 18 years of age.
7.
Subject must have adequate hematologic, renal and hepatic function as follows:
●
Bone Marrow:  Absolute neutrophil count ANC ≥ 1,500/mm3 (1.5 × 109/L); White blood cells 
≥ 3,000/mm3 (3 × 109/L); Platelets ≥ 100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9 g/dL 
(5.58 mmol/L)
●
Renal function:  creatinine ≤ ULN or if creatinine > ULN calculated creatinine clearance via 
the Cockroft Gault formula of ≥ 50 mL/min
●
Hepatic function:
o
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper 
limits of normal (ULN).  For subjects with liver metastases, AST and ALT ≤ 5 × ULN;
o
Bilirubin:  ≤ 1.5 × ULN; for subjects with Gilbert's syndrome bilirubin > 1.5 × ULN is 
allowed if no symptoms of compromised liver function are present.
8.
Subject must be able to swallow pills.
9.
Female and male patients of fertile age, and/or their partners should use contraception.  If male, 
subject and subject's female partner(s) of childbearing potential must follow the contraception 
recommendations as described in Section 5.2.4.  If female, subject must be either postmenopausal 
for at least 1 year, surgically sterile (bilateral tubal ligation, bilateral oophorectomy or 
hysterectomy), or the subject and the subject's male partner(s) must follow the contraception 
recommendations as described in Section 5.2.4.
Female subjects must have negative results for pregnancy tests performed:
!
Screening on a serum specimen obtained within 7 days prior to initial study drug 
administration, and 
!
prior to dosing on a urine sample obtained C1D-2 unless the serum pregnancy test was collected 
within 7 days of C1D-2.
10. Must voluntarily sign and date each informed consent, approved by an Independent Ethics 
Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study 
specific procedures.
Exclusion:
1.
Phase 1 ONLY:  Subject has had any prior anti-cancer therapy other than:
●
Hormonal, non-myelosuppressive, biologic, targeted, or immune therapy (must be completed 
≥4 weeks prior to Cycle 1 Day –2).
●
One line of cytotoxic chemotherapy (must be completed ≥ 4 weeks prior to Cycle 1 Day –2).
●
Adjuvant/neoaduvant radiotherapy (must be completed ≥ 12 months prior to Cycle 1 Day –2, 
with field not involving > 10% of bone marrow reserve).
●
Tumor lesion irradiation with intent of symptom palliation ≥ 4 weeks prior Cycle 1 Day –2.


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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Exclusion (Continued):
2.
Phase 2 ONLY:  Subject has had any prior chemotherapy, radiotherapy, investigational anti-cancer 
agents or biologic therapy for the disease under study.  Single non-target lesion irradiation with 
intent of symptom palliation is allowed if ≥ 2 weeks prior Cycle 1 Day –2.
3.
Subject has known hypersensitivity to etoposide, platinum compounds or veliparib.
4.
Phase 1 ONLY:  Subject has received prior myelopoietic growth factors.
5.
Subject has current central nervous system (CNS) or leptomeningeal metastases or history of CNS 
or leptomeningeal metastases.  If CNS metastasis is suspected, a head CT should be performed at 
screening.
6.
Subject has a history of seizures within 12 months of Cycle 1 Day –2 or diagnosed neurological 
condition placing subject at the increased risk of seizures.
7.
Subject has received traditional herbal anti-cancer medicine (e.g., Chinese, Asian etc.) within 
14 days prior to Cycle 1 Day –2.
8.
Subject has had major surgery within 6 weeks prior to Cycle 1 Day –2 (subjects must have 
completely recovered from any previous surgery prior to Cycle 1 Day –2).
9.
Subject has clinically significant and uncontrolled major medical condition(s) including but not 
limited to:
●
Uncontrolled nausea/vomiting/diarrhea;
●
Active uncontrolled infection;
●
History of hepatitis B (HBV) with surface antigen (HBsAg) positivity within 3 months prior to 
the date of informed consent for this study (if HBsAg status is unknown it must be tested at 
screening);
●
History of hepatitis C (HCV) with HCV RNA positivity within 3 months prior to the date of 
informed consent for this study (if HCV RNA status is unknown it must be tested at screening);
●
Symptomatic congestive heart failure (New York Heart Association [NYHA] class ≥ II);
●
Unstable angina pectoris or cardiac arrhythmia;
●
Psychiatric illness/social situation that would limit compliance with study requirements;
●
Any other medical condition, which in the opinion of the Investigator, places the subject at an 
unacceptably high risk for toxicities.
10. Subject is pregnant or lactating.
11. The subject has a history of another active 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, breast ductal 
carcinoma in situ [DCIS]).
Questions regarding the eligibility of individual subjects should be directed to the AbbVie TA MD.


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Investigational Products:
Veliparib
Doses:
Phase 1 Dose Escalation cohorts:  80, 120, 160, 200 and 240 mg BID 
(higher doses up to 400 mg BID may be tested)
Phase 2 Randomized Double-Blind arms:  240 mg BID
Continuous monotherapy maintenance:  400 mg BID
Mode of Administration:
Oral
Investigational Products:
Placebo – BID Phase 2 ONLY
Doses:
Combination therapy:  matching capsules for 240 mg BID
Continuous monotherapy maintenance:  matching capsules for 400 mg 
BID
Mode of Administration:
Oral
Reference Therapy:
Carboplatin
Doses:
AUC 5 mg/mL*min
Mode of Administration:
Intravenous infusion
Reference Therapy:
Etoposide
Doses:
100 mg/m2
Mode of Administration:
Intravenous infusion
Duration of Treatment:
Subject will remain on study drug until disease progression or unacceptable toxicity. 
Criteria for Evaluation:
Efficacy:
Progression-free survival (PFS) will be derived according to disease progression (radiographic 
progression per RECIST version 1.1) or death.  Radiographic tumor assessments for response will be 
conducted by CT scanning at baseline, every 6 weeks from C1D-2 for the first 24 weeks (Phase 1) or 
30 weeks (Phase 2), then every 9 weeks until disease progression.
Objective response rate (ORR) will be derived per RECIST version 1.1.  Radiographic tumor 
assessments for response will be conducted by CT scanning at baseline, every 6 weeks from C1D-2 for 
the first 24 weeks (Phase 1) or 30 weeks (Phase 2), then every 9 weeks until disease progression.
Duration of overall response (DOR) will be derived according to disease progression (radiographic 
progression per RECIST version 1.1). 
Overall survival will be determined by the Investigator at assessments throughout therapy.  After the 
final visit, survival information will be collected via electronic data capture (EDC) at 2 month intervals 
(or as requested by sponsor to support data analysis).
ECOG performance status will be determined by the Investigator at each assessment.  
Pharmacokinetic:
Blood samples for pharmacokinetics of veliparib, carboplatin (Phase 1 Dose Escalation only) and 
etoposide (Phase 1 Dose Escalation only) will be collected at designated time points throughout the 
study.  Pharmacokinetics of veliparib and etoposide will be assessed to determine the drug-drug 
interactions.  In addition, pharmacokinetics of carboplatin will be determined.


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Criteria for Evaluation (Continued):
Pharmacodynamic:
Research to find biomarkers that may be predictive of veliparib activity will be conducted.  Serum, 
plasma, blood and archived tissue samples will be collected at designated time points throughout the 
study.
Pharmacogenetic:
DNA samples may be analyzed for genetic factors contributing to the subject's response to veliparib, or 
other study treatment, in terms of pharmacokinetics, efficacy, tolerability and safety.
Safety:
Adverse events, laboratory profiles, physical examinations, vital signs and neurological assessments will 
be evaluated and recorded throughout the study.
Statistical Methods:
Efficacy:
The following end point will be analyzed using data obtained from subjects in Phase 1 and Phase 2 
separately:
Objective Response Rate
The proportion of subjects with objective response (CR or PR) as assessed by the investigator using 
RECIST 1.1 will be calculated for all dosed subjects.
The following end point will be analyzed using data obtained from subjects in Phase 2:
Progression-Free Survival
Progression-Free Survival will be defined as the number of days from the date of randomization to the 
date of earliest radiographic disease progression or death.  All disease progression will be included 
regardless whether the event occurred while the subject was taking study drug or had previously 
discontinued study drug.  If the subject does not experience disease progression or death, then the data 
will be censored at the date of the last radiographic disease assessment.
Overall Survival
Overall survival will be defined as the number of days from the date of randomization to the date of 
death.  For subjects who did not die, their data will be censored at the date of last study visit or the last 
known date to be alive, whichever is later.  
Duration of Overall Response
Duration of overall response will be defined as the number of days from the date of first response (CR or 
PR) to the earliest documentation of radiographic progressive disease.  If a subject is still responding, 
then the subject's data will be censored at the date of the subject's last available radiographic disease 
assessment.  For subjects who never experience response, the subject's data will not be included in the 
analysis.
Performance Status
Changes and/or percent changes from baseline will be summarized using descriptive statistics for each 
scheduled post-baseline visit and for the Final Visit for ECOG performance status.  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.


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Statistical Methods (Continued):
Pharmacokinetic:
Plasma concentrations of veliparib, etoposide, and carboplatin and pharmacokinetic parameter values 
will be tabulated for each subject and each dose level, and summary statistics will be computed for each 
sampling time and each parameter.
The effects of co-administration of veliparib on etoposide pharmacokinetics will be addressed by 
analyzing the Cycle 1 Day 1 (veliparib with carboplatin and etoposide) and Cycle 2 Day 1 (carboplatin 
and etoposide alone) etoposide pharmacokinetic variables, including Tmax, dose normalized Cmax and 
dose normalized AUC.
Pharmacodynamic:
Biomarker results will be tabulated for each subject and each regimen, and summary statistics will be 
computed for each sampling time and each parameter.  The relationship between biomarker status and 
clinical outcome or drug exposure may be examined.
Safety:
●
The safety of veliparib in combination with carboplatin/etoposide will be assessed by 
evaluating the study drugs exposure, adverse events, serious adverse events, all deaths, as well 
as changes in laboratory determinations and vital sign parameters.  Safety will be summarized 
per dose level using descriptive statistics for the dose escalation cohorts and per treatment arm 
in Phase 2.
●
RPTD was determined based on the rate of DLTs and overall tolerability of the combination of 
veliparib, carboplatin and etoposide with at least 9 subjects treated at the RPTD in Phase 1 and 
will be further evaluated in Phase 2.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:  "DICOM," "IRT," "IUS," "PoR," "TA MD" and "WOCBP"
DICOM
Digital Imaging and Communications in Medicine
IRT
Interactive Response Technology
IUS
Intrauterine hormone-releasing system
PoR
Proof of Receipt
TA MD
Therapeutic Area Medical Director
WOCBP
Women of Childbearing Potential


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Section 3.7  Benefits and Risks
First paragraph, first sentence previously read:
This study proposes to establish the recommended Phase 2 dose and to evaluate clinical 
outcomes for subjects with ED SCLC treated with veliparib added to standard therapy 
with carboplatin and etoposide.  
Has been changed to read:
The Phase 1 Dose Escalation portion of this study proposed to establish the recommended 
Phase 2 dose and veliparib schedule.  These were determined to be veliparib 240 mg BID 
on Days –2 – 12 (14-Day schedule) in combination with carboplatin AUC 5 mg/ml*hr on 
Day 1 and etoposide 100 mg/m2 on Days 1 – 3 of 21-Day cycle.  The Phase 2 portion of 
this study proposes to evaluate clinical outcomes for subjects with ED SCLC treated with 
veliparib added to standard therapy with carboplatin and etoposide.  
Section 5.1  Overall Study Design and Plan:  Description
Subsection Screening Procedures
Delete:  subsection title and text
Screening Procedures 
Screening procedures should be performed within 28 days prior to Cycle 1 Day –2.  If the 
screening visit is performed greater than 7 days prior to Cycle 1 Day –2, the physical 
exam, laboratory tests, and pregnancy test (for female subjects of childbearing potential) 
must be repeated on Cycle 1 Day –2.  Vital signs and performance status assessments will 
be performed on Cycle 1 Day –2 for all subjects.  Baseline radiographic tumor 
assessments per computed tomography (CT)/magnetic resonance imaging (MRI) of the 
chest, abdomen, and head will be conducted within 21 days prior to Cycle 1 Day –2.


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Section 5.1  Overall Study Design and Plan:  Description
Subsection Transition from Phase 1 to Phase 2
Add:  new subsection title and text
Transition from Phase 1 to Phase 2
Once the veliparib RPTD and schedule is determined, the veliparib RPTD and schedule 
will be communicated to all participating research sites prior to the start of enrollment into 
the Phase 2.  Subjects from the Phase 1 Dose Escalation portion are not eligible for 
enrollment into the Phase 2 portion, but may continue to receive veliparib, carboplatin and 
etoposide at the assigned dose and schedule as long as they tolerate the study drug, show 
no evidence of disease progression, and do not meet any of the criteria for subject 
discontinuation (Section 5.4.1).
Section 5.1  Overall Study Design and Plan:  Description
Subsection Randomized Double-Blind Phase 2
Subsection title and text previously read:
Randomized Double-Blind Phase 2
In the Phase 2 double-blinded portion of the study, subjects with treatment-naïve ED 
SCLC will be randomized in a 1:1:1 ratio to one of three treatment arms: 
Arm A:  RPTD of veliparib in combination with carboplatin/etoposide followed by 
veliparib 400 mg BID monotherapy
Arm B:  RPTD of veliparib in combination with carboplatin/etoposide followed by 
placebo monotherapy
Arm C:  placebo in combination with carboplatin/etoposide followed by placebo 
monotherapy
Subjects in all Phase 2 study arms will receive a minimum of 4 cycles of combination 
therapy unless disease progression or unacceptable toxicity warrants earlier 
discontinuation from the treatment.  Additional 2 cycles of combination therapy (e.g., up 


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to a total of 6 cycles) may be administered at the investigators discretion if subject status 
at the completion of initial 4 cycles warrants continued treatment.  In the combination 
cycles of Arms A and B veliparib will be administered at the RPTD defined in the Phase 1 
portion of the study, Arm C will receive matching placebo.  After completion of the 
chemotherapy combination cycles (at least 4), subjects without evidence of disease 
progression will receive veliparib at 400 mg BID continuous dosing (Arms A), or 
matching placebo (Arms B and C), until disease progression or unacceptable toxicity 
occurs (Figure 2).  Subjects who will be receiving prophylactic cranial irradiation (PCI) 
will have maintenance veliparib interrupted for the duration of radiotherapy as described 
in Section 5.2.3.2.
Subject randomization for Phase 2 will be stratified by baseline LDH level (> ULN versus 
≤ ULN), and gender.
Table 6.
Treatment Schematic for Combination Cycles in Phase 2
Days
–2
–1
1
2
3
4
5
6 – 19
Veliparib/Placebo
Twice 
a day
Twice 
a day
Twice 
a day
Twice 
a day
Twice 
a day
Twice 
a day
Twice 
a day
As 
RPTD
Carboplatin 
Once
Etoposide
Once
Once
Once
Notes:
Starting at Maintenance Day 1 veliparib will be dosed at 400 mg BID monotherapy continuous dosing for 21 
days per cycle.
Dosing of veliparib on Days 6 – 19 will depend on the RPTD schedule, as defined in Table 1 and Table 3.
A minimum of 4 cycles of combination treatment are to be administered.  If subject status at the completion of 
Cycle 4 warrants continued combination treatment, 2 additional combination cycles (e.g., up to a total of 6) 
may be administered at investigators discretion.


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Figure 2.
Phase 2 Treatment and Randomization Schematics
For subjects who experience toxicities due to veliparib or carboplatin/etoposide, 
appropriate dose modifications or dosing delays should be managed according to 
Section 5.7.  Subsequent cycles of therapy will be administered if there is no evidence of 
disease progression and observed toxicities have recovered adequately as described in 
Section 5.7.
Has been changed to read:
Phase 2 Randomized Double-Blind
The veliparib dose and schedule for the Phase 2 was determined to be 240 mg BID on a 
14 day schedule based on the analysis of Phase 1 data.
Approximately 180 total subjects with treatment-naïve ED SCLC will be enrolled at the 
240 mg BID veliparib/placebo dose and 14 day schedule in the Phase 2 double-blinded 
portion of the study.  They will be randomized in a 1:1:1 ratio to one of three treatment 
arms: 


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Arm A:  veliparib 240 mg in combination with carboplatin/etoposide followed by 
veliparib 400 mg BID monotherapy
Arm B:  veliparib 240 mg in combination with carboplatin/etoposide followed by placebo 
monotherapy
Arm C:  placebo in combination with carboplatin/etoposide followed by placebo 
monotherapy
Subjects in all Phase 2 study arms will receive a minimum of 4 cycles of combination 
therapy unless disease progression or unacceptable toxicity warrants earlier 
discontinuation from the treatment.  Additional 2 cycles of combination therapy (e.g., up 
to a total of 6 cycles) may be administered at the investigators discretion if subject status 
at the completion of initial 4 cycles warrants continued combination treatment and/or if 
local SOC guidelines require 6 cycles of platinum-based therapy.  In the combination 
cycles of Arms A and B, subjects will receive veliparib at 240 mg BID on a 14-day 
schedule, Arm C will receive matching placebo.  After completion of the chemotherapy 
combination cycles (at least 4), subjects without evidence of disease progression will 
receive veliparib at 400 mg BID continuous dosing (21-day cycles) (Arms A), or 
matching placebo (Arms B and C) as per treatment arm assignment, until disease 
progression or unacceptable toxicity occurs (Figure 2).  
Subject randomization for Phase 2 will be stratified by baseline LDH level (> ULN versus 
≤ ULN), and gender.
Table 6.
Treatment Schematic for Combination Cycles in Phase 2
Days
–2
–1
1
2
3
4 – 12
Veliparib/Placebo
240 mg 
BID
240 mg 
BID
240 mg 
BID
240 mg 
BID
240 mg 
BID
240 mg 
BID
Carboplatin 
Once
Etoposide
Once
Once
Once
Notes:
Starting at Maintenance Day 1 veliparib will be dosed at 400 mg BID monotherapy continuous dosing for 
21 days per cycle.


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A minimum of 4 cycles of combination treatment are to be administered.  If subject/disease status at the 
completion of Cycle 4 warrants continued combination treatment, up to 2 additional combination cycles 
(e.g., up to a total of 6) may be administered at investigators discretion.
Figure 2.
Phase 2 Treatment and Randomization Schematics
For subjects who experience toxicities due to veliparib or carboplatin/etoposide, 
appropriate dose modifications or dosing delays should be managed according to 
Section 5.7.  Subsequent cycles of therapy will be administered if there is no evidence of 
disease progression and observed toxicities have recovered adequately as described in 
Section 5.7.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Tumor Assessments and Safety Follow-Up (Phase 1 Dose Escalation and 
Phase 2)
Delete:  subsection title and text
Tumor Assessments and Safety Follow-Up (Phase 1 Dose Escalation and Phase 2)
Tumor assessments will be performed until progression. Tumor assessment and 
assessment of response will occur every 6 weeks (± 1 week) for the first 24 weeks after 
the first dose of study drugs, then every 9 weeks thereafter (± 1 week).  Tumor response 


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will be determined according to the Response Evaluation Criteria in Solid Tumors 
(RECIST), Version 1.1.
In the Phase 1 portion, subjects will receive veliparib BID in combination with 
carboplatin/etoposide for up to a maximum 4 cycles of treatment.  In the Phase 2 portion, 
subjects will receive veliparib or placebo BID as applicable in combination with 
carboplatin/etoposide for up to 6 cycles of treatment.  In Phase 1, subjects that do not 
progress according to a radiographic assessment (CT) at Cycle 4 may continue in the 
monotherapy portion veliparib or placebo as appropriate starting at Cycle 5 Day 1.  In 
Phase 2, subjects that do not progress according to a radiographic assessment (CT) at 
completion of at least 4 combination chemotherapy Cycles may continue in the 
monotherapy portion veliparib or placebo starting at Maintenance Day 1.  In the Phase 2 
portion, subjects discontinuing both carboplatin and etoposide due to toxicity and without 
evidence of disease progression prior to the completion of 4 cycles of combination 
therapy may transition to monotherapy veliparib/placebo as per treatment arm assignment.  
All subjects will remain on study until reaching a protocol defined event of disease 
progression.  Subjects in the Phase 2 portion of the study, who are discontinued from 
study treatment due to an adverse event, will remain on study/off study drugs until 
reaching an event of disease progression.
When an investigator has determined that a subject has met the protocol defined criteria 
for disease progression, as outlined in Section 5.3.3.1, a Final Visit will be conducted.
All subjects will have one Follow-Up Visit approximately 30 days after the Final Visit.  
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.
In the Phase 2 portion of the study, post treatment tumor assessments (if subject 
discontinues before disease progression is recorded), cancer treatments and survival 


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information will be collected via electronic data capture (EDC) system at monthly 
intervals (or as requested by sponsor to support data analysis) beginning on the date the 
subject is registered off study and continuing for up to 2 years on all subjects until the 
endpoint of death, the subject has become lost to follow up, or if AbbVie terminates the 
study.
Section 5.2.1  Inclusion Criteria
Criterion 9 previously read:
Female and male patients of fertile age, and/or their partners should use contraception.  If 
male, subject and subject's female partner(s) of childbearing potential should practice at 
least one of the following methods of birth control.  If female, subject must be either 
postmenopausal for at least 1 year, surgically sterile (bilateral tubal ligation, bilateral 
oophorectomy or hysterectomy), or the subject and the subject's male partner(s) practicing 
at least one of the following methods of birth control:
●
total abstinence from sexual intercourse (if it is the subject's preferred and 
usual lifestyle; for minimum one complete menstrual cycle prior to study drug 
administration and to extend 6 months after treatment);
●
vasectomized subject or partner(s);
●
hormonal contraceptives (oral, parenteral or transdermal) for at least 90 days 
prior to study drug administration for the subject or subject's female partner(s);
●
intrauterine device (IUD) for the subject or subject's female partner(s);
●
double-barrier method (condoms, contraceptive sponge, diaphragm or vaginal 
ring with spermicidal jellies or creams) for the subject or subject's female 
partner(s).
If hormonal contraceptives are used, the specific contraceptive must have been used 
for at least 90 days prior to study drug administration.  If the subject or subject's 
female partner(s) is currently using a hormonal contraceptive, she should also use a 
barrier method during this study and for 6 months (or per local label) after study 
completion.


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Female subjects must have negative results for pregnancy tests performed:
●
at Screening on a serum specimen obtained within 7 days prior to initial study 
drug administration, and 
●
prior to dosing on a urine sample obtained C1D-2 unless the serum pregnancy 
test was collected within 7 days of C1D-2.
Has been changed to read:
Female and male patients of fertile age, and/or their partners should use contraception.  If 
male, subject and subject's female partner(s) of childbearing potential must follow the 
contraception recommendations as described in Section 5.2.4.  If female, subject must be 
either postmenopausal for at least 1 year, surgically sterile (bilateral tubal ligation, 
bilateral oophorectomy or hysterectomy), or the subject and the subject's male partner(s) 
must follow the contraception recommendations as described in Section 5.2.4.
Female subjects must have negative results for pregnancy tests performed:
●
Screening on a serum specimen obtained within 7 days prior to initial study 
drug administration, and 
●
prior to dosing on a urine sample obtained C1D-2 unless the serum pregnancy 
test was collected within 7 days of C1D-2.
Section 5.2.2  Exclusion Criteria
Criterion 5, last sentence previously read:
If CNS progression is suspected, a head CT should be performed at screening.
Has been changed to read:
If CNS metastasis is suspected, a head CT should be performed at screening.


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Section 5.2.2  Exclusion Criteria
Criterion 9, third and fourth bullet previously read:
●
History of hepatitis B (HBV) with surface antigen (HBsAg) positivity within 
3 months prior to the date of informed consent for this study (if no test has 
been performed within 3 months, it must be done at screening);
●
History of hepatitis C (HCV) with HCV RNA positivity within 3 months prior 
to the date of informed consent for this study (if no test has been performed 
within 3 months it must be done at screening);
Has been changed to read:
●
History of hepatitis B (HBV) with surface antigen (HBsAg) positivity within 
3 months prior to the date of informed consent for this study (if HBsAg status 
is unknown it must be tested at screening);
●
History of hepatitis C (HCV) with HCV RNA positivity within 3 months prior 
to the date of informed consent for this study (if HCV RNA status is unknown 
it must be tested at screening);
Section 5.2.3.1  Prior Therapy
Subsection Phase 1 Dose Escalation
Add:  new subsection title following section title
Phase 1 Dose Escalation
Section 5.2.3.1  Prior Therapy
Subsection Phase 2 Randomized Double-Blind
Add:  new subsection title following third paragraph
Phase 2 Randomized Double-Blind


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Section 5.2.3.2  Concomitant Therapy
In-text table previously read:
Premedication:
The prophylactic antiemetics, including 5-HT3 antagonists, according to 
institution, National Comprehensive Cancer Network (NCCN), European 
Society for Medical Oncology (ESMO) or American Society of Clinical 
Oncology (ASCO) guidelines should be given, prior to administration of 
carboplatin and etoposide.  Prophylaxis with anti-emetics (e.g., 5-HT3 
antagonists such as ondansetron) is strongly recommended when initiating 
single agent veliparib maintenance therapy.
Anticancer Agents:
Other anticancer agents are not permitted during the treatment portion of the 
study.  All subjects will receive carboplatin + etoposide with veliparib/placebo 
at specified timepoints during the treatment portion of the study.  The locally 
approved carboplatin and etoposide product labels or SmPCs should be 
referenced to determine if there are any contraindications associated with 
concomitant medications (e.g., phenytoin, etc.).
Supportive Care:
Best supportive care and treatment will be given as appropriate to each subject 
(antiemetics, antibiotics, transfusions, nutritional support, non-radiation 
palliative treatment for pain, bisphosphonates or denosumab) according to 
institutional or clinical practice guidelines (e.g., ASCO, ESMO, or NCCN).
Growth Factors:
Biologic response modifiers administered for erythropoiesis 
(e.g., erythropoietin, darbepoetin alpha) and colony stimulating factors 
(e.g., neulasta, G-CSF, GM CSF, etc.) may be administered according to 
institutional or clinical practice guidelines (e.g., ASCO, ESMO, or NCCN).  
Growth factors prophylaxis will not be allowed in Cycle 1 (Day –2 through 
Day 21) of the dose escalation cohorts.
Radiation:
Prophylactic cranial irradiation (PCI) is allowed during the study in the 
maintenance phase of treatment at Investigators discretion.  The dose of PCI 
should be 24 Gy in 8 fractions of 3 Gy each, or per local treatment standards.  
Veliparib or placebo maintenance monotherapy will be held starting 2 days prior 
to the initiation of radiation therapy, throughout the radiation therapy and for 
4 days following radiation therapy.  Palliative radiation to a non-target lesion 
with the intent of symptom control is allowed; non-progressing status of lesion 
to be irradiated must be documented prior to the procedure.
Surgery:
If the subject requires surgery during the study, then this needs to be discussed 
with the AbbVie Medical Monitor.
Alternate Therapy:
No traditional herbal anti-cancer medicine (e.g., Chinese, Asian, etc.) may be 
taken concurrently with veliparib (a 14-day washout period must be 
documented).


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Has been changed to read:
Premedication:
The prophylactic antiemetics, including 5-HT3 antagonists, according to 
institution, National Comprehensive Cancer Network (NCCN), European 
Society for Medical Oncology (ESMO) or American Society of Clinical 
Oncology (ASCO) guidelines should be given, prior to administration of 
carboplatin and etoposide.  Prophylaxis with anti-emetics (e.g., 5-HT3 
antagonists such as ondansetron) is strongly recommended when initiating 
single agent veliparib/placebo maintenance monotherapy.
Anticancer Agents:
Other anticancer agents are not permitted during the treatment portion of the 
study.  All subjects will receive carboplatin + etoposide with veliparib/placebo 
at specified timepoints during the treatment portion of the study.  The locally 
approved carboplatin and etoposide product labels or SmPCs should be 
referenced to determine if there are any contraindications associated with 
concomitant medications (e.g., phenytoin, etc.).
Supportive Care:
Best supportive care and treatment will be given as appropriate to each subject 
(antiemetics, antibiotics, transfusions, nutritional support, palliative treatment 
for pain, bisphosphonates or denosumab) according to institutional or clinical 
practice guidelines (e.g., ASCO, ESMO, or NCCN).
Growth Factors:
Biologic response modifiers administered for erythropoiesis 
(e.g., erythropoietin, darbepoetin alpha) and colony stimulating factors 
(e.g., neulasta, G-CSF, GM CSF, etc.) may be administered according to 
institutional or clinical practice guidelines (e.g., ASCO, ESMO, or NCCN).  
Growth factors prophylaxis will not be allowed in Cycle 1 (Day –2 through 
Day 21) of the dose escalation cohorts.  Growth factors prophylaxis is 
acceptable in Phase 2.
Radiation:
Prophylactic cranial irradiation (PCI) is allowed during the study in the 
Maintenance phase of treatment at Investigators discretion.  The dose of PCI 
should be 24 Gy in 8 fractions of 3 Gy each, or per local treatment standards.  
Veliparib or placebo maintenance monotherapy will be held starting 2 days prior 
to the initiation of radiation therapy, throughout the radiation therapy and for 
4 days following radiation therapy.  Palliative radiation to a non-target lesion 
with the intent of symptom control is allowed; non-progressing status of lesion 
to be irradiated must be documented prior to the procedure.  Radiation to non-
target lesions for other reasons will not be allowed during combination treatment 
cycles and generally will not be allowed during maintenance; exceptional 
circumstances that may arise during maintenance must be discussed with 
AbbVie TA MD and non-progressing status of such lesions using the same 
modality as study tumor assessments will have to be documented prior to 
procedure.


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Surgery:
If the subject requires surgery during the study, then this needs to be discussed 
with the AbbVie TA MD.
Alternate Therapy:
No traditional herbal anti-cancer medicine (e.g., Chinese, Asian, etc.) may be 
taken concurrently with veliparib (a 14-day washout period must be 
documented).
Section 5.2.4  Contraception Recommendations
Add:  new section title and text
5.2.4
Contraception Recommendations
If female, subject must be either postmenopausal or permanently surgically sterile (refer 
to inclusion criteria for definitions of both) OR a Women of Childbearing Potential, 
practicing at least one of the following methods of birth control, on C1D-2 (or earlier) 
through at least 6 months after the last dose of study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 1 month prior to C1D-2.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
C1D-2.
●
Bilateral tubal occlusion/ligation.
●
Bilateral tubal occlusion via hysteroscopy (i.e., Essure), provided a 
hysterosalpingogram confirms success of the procedure.
●
Vasectomized partner(s), provided the vasectomized partner verbally confirms 
receipt of medical assessment of the surgical success, and is the sole sexual 
partner of the WOCBP trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject [periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable].


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If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the birth 
control methods listed above (excluding true abstinence).
If the subject or subject's female partner(s) is currently using a hormonal contraceptive, 
she should also use a barrier method during this study and for 6 months (or per local 
label) after study completion.
Male subjects who are sexually active with a WOCBP, even if the male subject has 
undergone a successful vasectomy, must agree from C1D-2 through at least 6 months 
after the last dose of study drug to use condoms and his female partner(s) must use at least 
one of the contraceptive measures (as defined in the protocol for female study subjects of 
childbearing potential).
Male subject agrees not to donate sperm from C1D-2 through at least 6 months after the 
last dose of study drug.


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Table 7.  Study Activities Phase 1 Dose Escalation
Activity "Vital Signs" previously read:
Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 
D8 
and 
D15
C2 
Through 
C4 D1
C2 
Through 
C4 D8
C2 
Through 
C4 D15
Maintenance 
Veliparib 
D1 of Each Cycle 
Starting in C5
Tumor 
Assessments 
Every 6 Weeks 
First 24 Weeks 
Tumor 
Assessments 
Every 9 Weeks 
Thereafter
Final 
Visit
30-Day 
Follow-Up 
Visit
Vital Signs
X
X
X
X
X
X
X
X
X
Has been changed to read:
Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 
D8 
and 
D15
C2 
Through 
C4 D1
C2 
Through 
C4 D8
C2 
Through 
C4 D15
Maintenance 
Veliparib 
D1 of Each Cycle 
Starting in C5
Tumor 
Assessments 
Every 6 Weeks 
First 24 Weeks 
Tumor 
Assessments 
Every 9 Weeks 
Thereafter
Final 
Visit
30-Day 
Follow-Up 
Visit
Vital Signs
X
X
X
Cycle 1 only
X
X
X
X
X
X
Table 7.  Study Activities Phase 1 Dose Escalation
Add:  Activity "HBsAg, HCV RNAn"
Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 
D8 
and 
D15
C2 
Through 
C4 D1
C2 
Through 
C4 D8
C2 
Through 
C4 D15
Maintenance 
Veliparib 
D1 of Each Cycle 
Starting in C5
Tumor 
Assessments 
Every 6 Weeks 
First 24 Weeks 
Tumor 
Assessments 
Every 9 Weeks 
Thereafter
Final 
Visit
30-Day 
Follow-Up 
Visit
HBsAg, HCV 
RNAn
X


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Table 7.  Study Activities Phase 1 Dose Escalation
Table note "i." previously read:
Tumor assessments will be performed until disease progression.  Tumor assessment and 
assessment of response will occur every 6 weeks (± 1 week) for the first 24 weeks after 
the first dose of study drugs, then every 9 weeks (± 1 week) thereafter.  Tumor 
Assessments at the end of Cycle 4 should be performed 1 week prior to the conclusion of 
Cycle 4 with radiographic results determined and reported to ensure subjects eligibility 
prior to subject starting continuous monotherapy veliparib dosing at Cycle 5.  A tumor 
assessment will 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.  The scanned areas will include chest and abdomen 
(with image of liver and adrenal glands) at all tumor assessments.  A head CT at will be 
performed at baseline if there is clinical suspicion of CNS metastases.
Has been changed to read:
Tumor assessments will be performed until disease progression.  Tumor assessment and 
assessment of response will occur every 6 weeks (± 1 week) from C1D-2 for the 
first 24 weeks, then every 9 weeks (± 1 week) thereafter.  Tumor Assessments at the end 
of Cycle 4 should be performed 1 week prior to the conclusion of Cycle 4 with 
radiographic results determined and reported to ensure subjects eligibility prior to subject 
starting continuous monotherapy veliparib dosing at Cycle 5.  A tumor assessment will 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.  The scanned areas will include chest, abdomen and pelvis at all 
tumor assessments.  A head CT will be performed if there is clinical suspicion of CNS 
metastases.


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Table 7.  Study Activities Phase 1 Dose Escalation
Add:  table note "n."
If no HBsAg/HCV RNA test has been performed within 3 months prior to the date of 
informed consent for this study.


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Table 8.  Study Activities in Phase 2
Previously read:
Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 D8
C2 Through 
Last 
Combination 
Cycle D1
C2 Through 
Last 
Combination 
Cycle D8
C2 
Through 
C D15
Monotherapy 
Veliparib/ 
PBO D1 of 
Each Cycle 
Starting in 
Maintenance 
per SOC
Tumor 
Assessments 
Every 
6 Weeks 
First 24 
Weeks
Tumor 
Assessments 
Every 
9 Weeks 
Thereafter
Final 
Visit
30-Day 
Follow-
Up Visit
Post 
Treatment 
Follow-Up
Informed 
Consentb
X
Medical and 
Historyc
X
Physical Exam 
(including 
weight)d
X
X
Xo
X
X
X
X
X
Performance 
Status (ECOG)
X
X
X
X
X
X
X
12-Lead ECG
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
Pregnancy 
Test Serum (s), 
Urine (u)e
X (s)
X (u)
Hematologyf
X
X
X
X
X
X
X
X
X
Chemistryg
X
X
X
X
X
X
X
Coagulation 
Tests
X
X 
C3 D1 only
X 
Odd cycles
X


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Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 D8
C2 Through 
Last 
Combination 
Cycle D1
C2 Through 
Last 
Combination 
Cycle D8
C2 
Through 
C D15
Monotherapy 
Veliparib/ 
PBO D1 of 
Each Cycle 
Starting in 
Maintenance 
per SOC
Tumor 
Assessments 
Every 
6 Weeks 
First 24 
Weeks
Tumor 
Assessments 
Every 
9 Weeks 
Thereafter
Final 
Visit
30-Day 
Follow-
Up Visit
Post 
Treatment 
Follow-Up
Urinalysis
X
X
Clinical 
Disease 
Progressionh
Xh
X
Xh
X
Tumor 
Assessmentsi
X
Xi
Xi
X
Xp
Monitor 
Adverse 
Events/ 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
Monitor 
Compliance
X
X
X
X
Randomization
X
Dispense 
Veliparibj,l
X
X
Xl
Administer 
Premedicationk
X
X
Administer 
Etoposidem
X


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Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 D8
C2 Through 
Last 
Combination 
Cycle D1
C2 Through 
Last 
Combination 
Cycle D8
C2 
Through 
C D15
Monotherapy 
Veliparib/ 
PBO D1 of 
Each Cycle 
Starting in 
Maintenance 
per SOC
Tumor 
Assessments 
Every 
6 Weeks 
First 24 
Weeks
Tumor 
Assessments 
Every 
9 Weeks 
Thereafter
Final 
Visit
30-Day 
Follow-
Up Visit
Post 
Treatment 
Follow-Up
Administer 
Carboplatinm
X 
Day 1 only
Survival 
Follow-Upn
X
C = Cycle; D = Day, SCR = Screening; RND = Randomization; PBO = Placebo; TA = Tumor Assessments; FV = Final Visit; PT = Post-treatment; F/U = Follow-up
a.
Screening visit must be performed within 28 days of Cycle 1 Day –2.  If the screening visit is performed > 7 days prior to Day –2 the physical exam, laboratory tests 
(hematology and chemistry) and pregnancy test must be repeated on Day –2.  Tumor assessments must be performed within 21 Days of Cycle 1 Day –2.
b.
The informed consent must be signed and dated prior to the initiation of any screening or study specific procedure is performed.
c.
A subject's medical history will be reviewed at each visit.  Any changes from baseline will be recorded on the adverse event eCRF.
d.
Height will be assessed at Screening only.
e.
A serum pregnancy test must be performed at Screening, a urine pregnancy test on Cycle 1 Day –2 prior to dosing if > 7 days since obtaining the serum pregnancy test for 
women of childbearing potential.  Pregnancy tests may be repeated at any time during the study at the discretion of the investigator.
f.
Hematology labs do not need to be repeated if screening is within 7 days of Cycle 1 Day –2.  A central laboratory will be used for the study; however, sites may use a certified 
local laboratory to collect a sample to dose the subject.
g.
Chemistry panels do not need to be repeated if screening is within 7 days of Cycle 1 Day –2.  A central laboratory will be used for the study; however, sites may use a 
certified local laboratory to collect a sample to manage subject therapy.
h.
Clinical disease progression will include, but will not be limited to an evaluation of worsening performance status due to progressive disease, requirement for non-palliative 
radiation therapy, alternative chemotherapy or surgery due to progressive disease or death due to progressive disease.
i.
Tumor assessments will be performed from the first dose of the study drugs until disease progression.  Tumor assessment and assessment of response will occur every 
6 weeks (± 1 week) for the first 24 weeks after the first dose of study drug, then 9 weeks (± 1 week) thereafter.  A tumor assessment will 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.


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j.
Veliparib will be dosed orally at the RPTD schedule in 21-day cycles for up to 6 cycles.  Veliparib will be administered after the pre medications on all days when given with 
chemotherapy.  After completing combination therapy subjects may receive veliparib continuous dosing at 400 mg BID or placebo (each cycle will be 21 days) until disease 
progression or unacceptable toxicity occurs.  Veliparib will be given approximately every 12 hours with a glass of water (approximately 240 mL).
k.
Pre-medication will be given as per institutional guidelines.
l.
Starting at Maintenance Day 1 and all subsequent monotherapy cycles, veliparib or placebo will be dispensed on Day 1.
m.
Etoposide on Days 1, 2 and 3 and carboplatin on Day 1 of Combination Cycles will be administered IV by site staff after veliparib administration.  Etoposide will be given 
prior to carboplatin, unless institutional guidelines require inverse sequence of administration.
n.
Survival follow-up will be performed beginning on the date the subject is registered off study monthly and continuing for up to 2 years on all subjects until the endpoint of 
death, the subject has become lost to follow-up, or if AbbVie terminates the study.
o.
The Cycle 1 Day 8 physical examination may be "symptom-directed."
p.
Post treatment tumor assessments will be collected for up to 2 years or until progression.


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Has been changed to read:
Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 
D8
C2 Through 
Last 
Combination 
Cycle D1
C2 Through 
Last 
Combination 
Cycle D8
Monotherapy 
Veliparib/ 
PBO D1 of 
Each Cycle 
Starting in 
Maintenance
Tumor 
Assessments 
Every 
6 Weeks 
First 
30 Weeks
Tumor 
Assessments 
Every 
9 Weeks 
Thereafter
Post-
Treatment 
Follow-Up
Final 
Visito
30-Day 
Follow-
Up 
Visitp
Survival 
Follow-
Up
Informed Consentb
X
Medical and 
Historyc
X
Physical Exam 
(including weight)d
X
X
X
X
X
X
X
Performance Status 
(ECOG)
X
X
X
X
X
X
12-Lead ECG
X
X
Vital Signs
X
X
X
C1 only
X
X
X
X
X
Pregnancy Test 
Serum (s), Urine 
(u)e
X (s)
X (u)
Hematologyf
X
X
X
X
X
X
X
X
Chemistryf
X
X
X
X
X
X
Coagulation Tests
X
X
HBsAg, HCV 
RNAg
X
Urinalysis
X
X


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Activity
SCRa
C1 
D-2
D1 through 
D3 
Combination 
Cycles
C1 
D8
C2 Through 
Last 
Combination 
Cycle D1
C2 Through 
Last 
Combination 
Cycle D8
Monotherapy 
Veliparib/ 
PBO D1 of 
Each Cycle 
Starting in 
Maintenance
Tumor 
Assessments 
Every 
6 Weeks 
First 
30 Weeks
Tumor 
Assessments 
Every 
9 Weeks 
Thereafter
Post-
Treatment 
Follow-Up
Final 
Visito
30-Day 
Follow-
Up 
Visitp
Survival 
Follow-
Up
Clinical Disease 
Progressionh
X
X
X
Tumor 
Assessmentsi
X
Xi
Xi
Xi
X
Monitor Adverse 
Events/Concomitant 
Medications
X
X
X
X
X
X
X
X
Monitor 
Compliance
X
X
X
X
Randomization
X
Dispense Veliparib
X
Xj
Xl
Administer 
Premedicationk
X
X
Administer 
Etoposidem
X
X
Administer 
Carboplatinm
X 
Day 1 only
X
Survival Follow-
Upn
X
C = Cycle; D = Day, SCR = Screening; RND = Randomization; PBO = Placebo; TA = Tumor Assessments; FV = Final Visit; PT = Post-treatment; F/U = Follow-up
a.
Screening visit must be performed within 28 days of Cycle 1 Day –2.  If the screening visit is performed > 7 days prior to Day –2 the physical exam, laboratory tests 
(hematology and chemistry) and pregnancy test must be repeated on Cycle 1 Day –2.  Tumor assessments must be performed within 21 Days of Cycle 1 Day –2.


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b.
The informed consent must be signed and dated prior to the initiation of any screening or study specific procedure being performed.
c.
A subject's medical history will be reviewed at each visit.  Any changes from baseline will be recorded on the adverse event eCRF. 
d.
Physical exam does not need to be repeated at Cycle 1 Day –2 if screening physical exam was completed within 7 days of Cycle 1 Day –2.  Physical exams during 
combination cycles must include assessment of hearing if required by the local SmPC for carboplatin.  The Cycle 1 Day 8 physical exam may be symptom directed.  Height 
will be assessed at Screening only.
e.
A serum pregnancy test must be performed at Screening, a urine pregnancy test on Cycle 1 Day –2 prior to dosing if > 7 days since obtaining the serum pregnancy test for 
women of childbearing potential.  Pregnancy tests may be repeated at any time during the study at the discretion of the investigator.
f.
Hematology and Chemistry panels do not need to be repeated at Cycle 1 Day –2 if screening labs were completed within 7 days of Cycle 1 Day –2.  A central laboratory will 
be used for the study; however, sites may use a certified local laboratory to collect a sample to dose the subject.  If local labs are drawn the sample MUST be split and also 
sent to central lab.
g.
Only for subjects with known history of HBV or HCV without prior evidence of active disease-free status and if HBsAg/HCV RNA status within 3 months of the study entry 
is unknown.
h.
If clinical disease progression is suspected, progression must be confirmed radiographically per RECIST 1.1.  Clinical disease progression will include, but will not be limited 
to worsening performance status due to progressive disease, requirement for non-palliative radiation therapy, alternative chemotherapy or surgery due to progressive disease.  
At the Final Visit, a clinical disease progression assessment is required only for subjects who discontinue the study for reasons other than progression (clinical or 
radiographic).
i.
Tumor assessment and assessment of response will occur every 6 weeks (± 1 week) from C1D-2 for the first 30 weeks, then every 9 weeks (± 1 week) thereafter.  A tumor 
assessment will 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 in Post-Treatment Follow-
Up should continue to receive tumor assessments at the protocol defined time points until an event of radiographic progression. 
j.
Veliparib will be dosed orally at 240 mg BID and 14-day schedule for up to 6 cycles.  Veliparib will be administered after the pre medications on all days when given with 
chemotherapy.  Veliparib will be given approximately every 12 hours with a glass of water (approximately 240 mL).
k.
Pre-medication will be given as per institutional guidelines.
l.
Starting at Maintenance Day 1 and all subsequent monotherapy cycles, veliparib or placebo will be dosed orally at 400 mg BID and continuous (21-day) dosing schedule. 
Subjects should remain on veliparib until disease progression or unacceptable toxicity occurs.
m.
Etoposide on Days 1, 2 and 3 and carboplatin on Day 1 of Combination Cycles will be administered IV by site staff after veliparib administration.  Etoposide will be given 
prior to carboplatin, unless institutional guidelines require inverse sequence of administration.
n.
Survival follow-up will be performed at 2 month intervals after the subject discontinues the study and until the endpoint of death, the subject has become lost to follow-up, the 
subject specifically withdraws consent for survival follow-up or if AbbVie terminates the study.


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o.
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.
p.
A 30-Day Follow-Up visit must occur when the subject discontinues all study drugs due to toxicity and will transition to Post-Treatment Follow-Up.  Subjects who 
discontinue treatment due to radiographic progression and have a Final Visit within 30 days of last dose of study drug will have one Follow-Up Visit approximately 30 days 
after the last dose of study drug.
Table 9.  Schedule of Pharmacogenetic and Pharmacodynamic Assessments for Phase 1 Dose Escalation and Phase 2
Previously read:
Procedure
Visit Schedule
Before Drug 
Administration
After Drug Administration
Sampling Plan
Specimen Matrix
PG Blood Samplinga
Genetic (DNA)
Cycle 1 Day 1
Not Dose Dependent
Not Dose Dependent
Whole Blood
Frozen –20°C or Colder
Plasma Markers
Screening, Cycle 2 Day 1, 
Cycle 3 Day 1, Cycle 4 Day 1 
and Final Visit
Prior to Dose
Prior to Dosing 
Blood →Plasma
Frozen –70°C or Colder
Serum Markers
Screening, Cycle 2 Day 1 and 
Final Visit
Prior to Dose
NA
Blood →Serum
Frozen –70°C or Colder
Archived Tissue Sample 
Collectionb
Screening
N/A
N/A
FFPE
a.
Perform once at either screening or on Cycle 1 Day 1.  If not collected at this visit, it may be collected at any time throughout the study.  Subjects must sign a separate 
informed consent prior to obtaining the PG sample.
b.
Subjects must consent to provide available archival tissue for analysis.  It is preferred to send FFPE blocks, however slides prepared by the local pathology laboratory are 
acceptable and should be prepared as described in the study specific laboratory manual.


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Has been changed to read:
Procedure
Visit Schedule
Before Drug 
Administration
After Drug Administration
Sampling Plan
Specimen Matrix
PG Blood Samplinga
Genetic (DNA)
Cycle 1 Day –2
Not Dose Dependent
Not Dose Dependent
Whole Blood
Frozen –20°C or Colder
Plasma Markersb
Cycle 1 Day –2, Cycle 2 Day 1, 
Cycle 3 Day 1, Cycle 4 Day 1 
and Final Visit
Prior to Dose
Prior to Dosing 
Blood →Plasma
Frozen –70°C or Colder
Serum Markersb
Cycle 1 Day –2, Cycle 2 Day 1 
and Final Visit
Prior to Dose
NA
Blood →Serum
Frozen –70°C or Colder
Archived Tissue Sample 
Collectionc
Cycle 1 Day –2
N/A
N/A
FFPE
a.
Perform once at Cycle 1 Day –2.  If not collected at this visit, it may be collected at any time throughout the study.  Subjects must sign a separate informed consent prior to 
obtaining the PG sample.
b.
Samples will not be drawn during carboplatin and/or etoposide dose delays.
c.
Subjects must consent to provide available archival tissue for analysis.  It is preferred to send FFPE blocks, however slides prepared by the local pathology laboratory are 
acceptable and should be prepared as described in the study specific laboratory manual.  If there is not enough tissue to provide the number of slides specified in the 
laboratory manual, sites should provide as many slides as possible with the available tissue.


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Table 10.  Schedule of Pharmacokinetic Assessments for Phase 1 Dose Escalation
Table note "a."
Add:  new second and third sentence 
Samples will not be drawn during carboplatin and/or etoposide dose delays.  All 
timepoints of etoposide and carboplatin samples are referred to the start of the infusion.
Table 11.  Schedule of Pharmacokinetic Assessments in Phase 2
Table note "a."
Add:  new last sentence 
Samples will not be drawn during carboplatin and/or etoposide dose delays.
Section 5.3.1.1  Study Procedures
Last paragraph previously read:
Screening procedures and assessments will occur within 28 days prior to Cycle 1 Day –2 
except for radiographic assessments that are to be performed within 21 days of Cycle 1 
Day –2.  For procedures performed at Screening and repeated, the later procedure 
performed prior to dosing will serve as a baseline for clinical assessment.  Subsequent 
study procedures should be performed approximately within ± 1 day on days of IV 
infusion of carboplatin and etoposide and ± 2 days for all safety visits and Cycle 5 of 
monotherapy and maintenance surrounding the scheduled study visit date.  Clinical 
laboratory tests can be performed up to 24 hours prior to dosing.
Has been changed to read:
Screening procedures should be performed within 28 days prior to Cycle 1 Day –2.  If the 
screening visit is performed greater than 7 days prior to Cycle 1 Day –2, the physical 
exam, laboratory tests, and pregnancy test (for female subjects of childbearing potential) 
must be repeated on Cycle 1 Day –2.  Vital signs and performance status assessments will 
be performed on Cycle 1 Day –2 for all subjects.  Baseline radiographic tumor 
assessments per computed tomography (CT) with IV contrast/magnetic resonance 
imaging (MRI) of the chest, abdomen, pelvis and head (if CNS metastases are suspected) 
will be conducted within 21 days prior to Cycle 1 Day –2.  If the subject is unable to 


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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.
For procedures performed at Screening and repeated, the later procedure performed prior 
to dosing will serve as a baseline for clinical assessment.  Subsequent study procedures 
should be performed approximately within ± 1 day on days of IV infusion of carboplatin 
and etoposide and ± 2 days for all safety visits and first Maintenance visit.  Clinical 
laboratory tests can be performed up to 48 hours prior to dosing.
Section 5.3.1.1  Study Procedures
Subsection Physical Examination
First paragraph, first and second sentence previously read:
A physical examination, including body weight, will be performed per Table 7 and 
Table 8.  If the Screening physical examination is performed within 7 days of Cycle 1 Day 
–2, it is not required to repeat the exam on Cycle 1 Day 1 unless clinically indicated. 
Has been changed to read:
A physical examination, including body weight, will be performed per Table 7 and 
Table 8.  Physical examination during combination cycles will include hearing assessment 
if required by carboplatin locally approved product label, local practice, or applicable 
SmPC. If the Screening physical examination is performed within 7 days of Cycle 1 
Day –2, it is not required to repeat the exam on Cycle 1 Day –2 unless clinically indicated. 
Section 5.3.1.1  Study Procedures
Subsection Hepatitis Screen
Previously read:
Subjects with history of hepatitis C (HCV) must be tested for HCV RNA at screening if 
no documented test result is available from within 3 months from the date of informed 
consent.  Subjects with history of hepatitis B (HBV) must be tested for HBV surface 
antigen (HBsAg) at screening if no documented test result is available from within 


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3 months from the date of informed consent.  The hepatitis test panel will be performed by 
a certified laboratory.
Has been changed to read:
Subjects with history of hepatitis C (HCV) must be tested for HCV RNA at screening if 
no documented test result is available from within 3 months from the date of informed 
consent, and for Phase 2 if status within 3 months of the study entry is unknown.  Subjects 
with history of hepatitis B (HBV) must be tested for HBV surface antigen (HBsAg) at 
screening if no documented test result is available from within 3 months from the date of 
informed consent, and for Phase 2 if status within 3 months of the study entry is unknown.  
Testing will be performed by the sponsor-designated central laboratory.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
First and second paragraph previously read:
Samples for chemistry, hematology and urinalysis will be collected per Table 7 and 
Table 8.  Specific laboratory assessments are outlined in Table 12.
A certified local laboratory may be used to perform laboratory analyses for treatment 
decisions.  All study samples indicated in Table 12 are to be shipped to the central 
laboratory, and central laboratory results will be used for data analysis.  The central 
laboratory will provide instructions regarding the collection, processing and shipping of 
samples.
Has been changed to read:
Samples for chemistry, hematology and urinalysis will be collected per Table 7 (Phase 1) 
and Table 8 (Phase 2).  Specific laboratory assessments are outlined in Table 12.
All study samples will be shipped to the central laboratory, and central laboratory results 
will be used for data analysis.  A certified local laboratory may be used to perform 
laboratory analyses for immediate treatment decisions; however, split or concurrent 


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samples must be drawn and sent to the central laboratory for analysis.  The central 
laboratory will provide instructions regarding the collection, processing and shipping of 
samples.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Delete:  first bullet 
The investigator will repeat the test to verify the out-of-range value.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Add:  new sixth paragraph
Study samples for central laboratory analysis may be performed within 48 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.
Table 12.  Clinical Laboratory Tests
Table note "+"
Add:  new third sentence
If HBsAg/HCV RNA status is unknown it must be tested at screening for Phase 2 
subjects.  
Section 5.3.1.1  Study Procedures
Subsection Tumor Assessments (Radiographic)
First paragraph previously read:
A CT scan will be used in the evaluation of tumor responses with RECIST version 1.1.  
The scanned areas will include chest and abdomen (with image of liver and adrenal 
glands) at all radiographic assessments, and head CT as warranted by clinical symptoms 
suspicion of CNS metastases.


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Has been changed to read:
A CT scan with contrast will be used in the evaluation of tumor responses with RECIST 
version 1.1.  The scanned areas will include chest, abdomen and pelvis at all radiographic 
assessments, and head CT as warranted by clinical suspicion of CNS metastases.
Section 5.3.1.1  Study Procedures
Subsection Tumor Assessments (Radiographic)
Add:  new last paragraph
Sites may be requested to electronically transfer copies of all CT or MRI scans used for 
radiographic tumor assessments in the Phase 2 part of the study to AbbVie.  Electronic 
copies of scans in DICOM format should be maintained at the sites until notification from 
AbbVie or end of study, whichever comes first.  Instructions regarding procedures for 
transferring scans will be provided separately, if the request for scans becomes necessary.
Section 5.3.1.1  Study Procedures
Subsection Tumor Assessments Schedule
Previously read:
Tumor assessments will be performed until disease progression.  Tumor assessment and 
assessment of response will occur every 6 weeks (± 1 week) for the first 24 weeks after 
the first dose of study drugs, then every 9 weeks (± 1 week) thereafter.  Tumor response 
will be determined according to the Response Evaluation Criteria in Solid Tumors 
(RECIST), Version 1.1.  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.
For Phase 2, calendar of tumor assessments should be maintained independent of any 
treatment schedule delays or changes.


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Has been changed to read:
Tumor assessments will be performed until radiographic disease progression.  Tumor 
assessment and assessment of response will occur every 6 weeks (± 1 week) from C1D-2 
for the first 24 weeks (Phase 1) or 30 weeks (Phase 2), then every 9 weeks (± 1 week) 
thereafter.  Tumor response will be determined according to the Response Evaluation 
Criteria in Solid Tumors (RECIST), Version 1.1.  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.
For Phase 2, the protocol defined tumor assessment schedule should be maintained 
independent of any treatment delays or changes.
Refer to Appendix C "RECIST (Version 1.1) for Tumor Response (PFS)" for response 
criteria and guidelines. 
Post-Treatment Follow-Up
Subjects who discontinue all study drugs prior to reaching an event of radiographic 
progression must enter into Post-Treatment Follow-Up.  Subjects will remain on study 
(off study drug) and will continue to receive tumor assessments according to the protocol 
defined tumor assessment schedule until reaching an event of radiographic progression. 
Subjects who discontinue all study drugs due to toxicity should have a 30-day Follow-up 
visit prior to entering into Post-Treatment Follow-Up to ensure all toxicities have 
resolved.  Subjects will have a Final Visit and be discontinued from the study upon 
reaching an event of radiographic progression, if the Investigator determines they should 
be discontinued for any other reason or if the subject withdraws consent.


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Section 5.3.1.1  Study Procedures
Subsection Survival Information (Phase 2 Only)
Subsection title and text previously read:
Survival Information (Phase 2 Only)
Subjects no longer undergoing clinical assessments will have survival information 
collected 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.  
All subjects will be followed for survival information (i.e., the date and cause of death or 
last known alive date if not deceased) unless the subject requests to be withdrawn 
specifically from study survival follow-up; this request must be documented in the 
subject's medical record and signed by the Investigator.
If known, post treatment anti-cancer therapies, dates of initiation, and end dates will be 
collected.
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.
Has been changed to read:
Survival Follow-Up (Phase 2 Only)
All discontinued subjects will have survival information collected via electronic data 
capture (EDC) at two month intervals (or as requested by sponsor to support data 
analysis) after the subject discontinues the study and continuing until the endpoint of 
death, the subject has become lost to follow-up, or AbbVie terminates the study.  
All subjects will be followed for survival information (i.e., the date and cause of death or 
last known alive date if not deceased) unless the subject requests to be withdrawn 


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specifically from study survival follow-up; this request must be documented in the 
subject's medical record and signed by the Investigator.
If known, post treatment anti-cancer therapies, dates of initiation, and end dates will be 
collected.
If the subject withdraws from survival 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.
Section 5.3.1.1  Study Procedures
Subsection Randomization and Subject Number Assignment
Previously read:
An Interactive Voice/Web Response System (IVRS/IWRS) will be utilized to register 
subjects and receive a screening number.
Subjects who complete all Screening procedures and meet the eligibility criteria will 
proceed to dosing.  The site will access the IVR/IWR system at Screening and a unique 
subject number will be provided.
Subjects in Phase 2 will be randomized in a 1:1:1 ratio to carboplatin, etoposide, placebo, 
followed by placebo maintenance, or carboplatin, etoposide, veliparib followed by either 
veliparib or placebo maintenance.  A subject number will be assigned after the subject 
signs the informed consent.  The site can contact the system up to 4 calendar days prior to 
or on the subject's Cycle 1 Day –2 to obtain a Screening (subject) number.  Subjects who 
complete all Screening procedures and meet the eligibility criteria will proceed to 
randomization.  The site will contact the system prior to the subject's Cycle 1 Day –2 and 
a unique randomization number will be provided.
A bottle number randomization schedule and a subject randomization schedule will be 
generated by the Data and Statistical Science Department at AbbVie prior to the start of 
the study.  A copy of all randomization schedules will be kept by the Data and Statistical 
Science Department at AbbVie and a copy will be forwarded to the IVRS/IWRS vendor.


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Has been changed to read:
An Interactive Response Technology System (IRT) will be utilized to register subjects.
The site will access the IRT system at Screening, after the subject signs informed consent 
and a unique subject number will be provided.  Subjects who complete all Screening 
procedures and meet the eligibility criteria will proceed to dosing.  Subjects who sign 
consent and do not meet the eligibility criteria will be considered a screen failure and the 
reason for screen failure will be documented in the source and in the eCRF.  Subjects will 
also be registered as a screen failure in the IRT system.
Subjects in Phase 2 who complete all Screening procedures and meet the eligibility 
criteria will be randomized in a 1:1:1 ratio to one of three treatment arms:  
Arm A:  veliparib 240 mg in combination with carboplatin/etoposide followed by 
veliparib 400 mg BID monotherapy
Arm B:  veliparib 240 mg in combination with carboplatin/etoposide followed by placebo 
monotherapy
Arm C:  placebo in combination with carboplatin/etoposide followed by placebo 
monotherapy
A bottle number randomization schedule and a subject randomization schedule will be 
generated by the Data and Statistical Science Department at AbbVie prior to the start of 
the study.  A copy of all randomization schedules will be kept by the Data and Statistical 
Science Department at AbbVie and a copy will be forwarded to the IRT vendor.
Section 5.3.1.4  Blood Samples for Pharmacogenetic Analysis
First paragraph previously read:
One 4 mL whole blood sample for DNA isolation will be collected on Cycle 1 Day 1 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 


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the sample is not collected on Cycle 1 Day 1, it may be collected at any time throughout 
the study.
Has been changed to read:
One 4 mL whole blood sample for DNA isolation will be collected on Cycle 1 Day –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 Cycle 1 Day –2, it may be collected at any time throughout 
the study.
Section 5.3.1.5  Collection and Handling of Pharmacodynamic Variables
Subsection Blood Collection for Plasma Markers
First sentence previously read:
Twelve (12) mL (Screening or Final Visit) or 6 mL (all other time points) of blood will be 
collected pre-dose by venipuncture at time points outlined in Table 9 in conjunction with 
PK samples, if possible.  
Has been changed to read:
Twelve (12) mL (Cycle 1 Day –2 or Final Visit) or 6 mL (all other time points) of blood 
will be collected pre-dose by venipuncture at time points outlined in Table 9 in 
conjunction with PK samples, if possible.  
Section 5.3.1.5  Collection and Handling of Pharmacodynamic Variables
Subsection Tissue Collection for IHC, ELISA and FISH DNA 
Mutational/Methylation Analysis
Heading "Archived Tissue Specimens:"
First, second and third sentence previously read:
In order for subjects' samples to be analyzed, only subjects who consent to provide 
available archival tissue for analysis will be included.  It is recognized that samples 
suitable for analysis will not be available from all consenting subjects.  The most recent 
archived biopsy is preferred and should be obtained during screening if possible.  


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Has been changed to read:
Subjects must consent to provide available archived tissue for analysis.  It is recognized 
that samples suitable for analysis will not be available from all consenting subjects.  The 
most recent archived biopsy is preferred and should be obtained at Cycle 1 Day –2, if 
possible.  
Section 5.3.2.1  Collection of Samples for Analysis
Subsection Blood Samples for Veliparib Assay Dose Escalation
Subsection title previously read:
Blood Samples for Veliparib Assay Dose Escalation
Has been changed to read:
Blood Samples for Veliparib Assay
Section 5.3.2.1  Collection of Samples for Analysis
Subsection Blood Samples for Veliparib Assay Dose Escalation
First paragraph, first sentence previously read:
Blood samples for veliparib assay will be collected by venipuncture at the designated time 
points outlined in Table 10 and Table 11.  
Has been changed to read:
Blood samples for veliparib assay will be collected by venipuncture at the designated time 
points outlined in Table 10 (Phase 1) and Table 11 (Phase 2).  
Section 5.3.2.1  Collection of Samples for Analysis
Subsection Blood Samples for Veliparib Assay Dose Escalation
Last paragraph, first sentence previously read:
Approximately 7 blood samples are planned to be collected per subject in Phase 1 and 
8 samples per subject in Phase 2 for pharmacokinetic analysis. 


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Has been changed to read:
Approximately 7 blood samples are planned to be collected per subject in Phase 1 and 
6 samples per subject in Phase 2 for pharmacokinetic analysis.
Section 5.3.2.1  Collection of Samples for Analysis
Subsection Blood Samples for Etoposide Assay
Add:  new last sentence 
Blood samples for etoposide assay will not be collected for Phase 2 subjects.
Section 5.3.2.1  Collection of Samples for Analysis
Subsection Blood Samples for Unbound Carboplatin Assay
Add:  new last sentence
Blood samples for carboplatin assay will not be collected for Phase 2 subjects.
Section 5.3.3.2  Definition of Disease Progression
Add:  new last paragraph
In cases where an Investigator determines that a subject has met the criteria for clinical 
disease progression, every effort should be made to confirm the progression 
radiographically.
Section 5.4.1  Discontinuation of Individual Subjects
Second, third, fourth and fifth paragraph previously read:
In the event that a subject withdraws or is discontinued from the study, the primary reason 
for discontinuation and any other reason(s) for the discontinuation from the study will be 
recorded and a physical examination, body weight, vital signs measurement, laboratory 
analyses, and an assessment of adverse events will be performed as soon as possible after 
discontinuation from the study.  If a subject discontinues for reasons other than 
radiographic progression and if no tumor assessment has been performed within the last 
4 weeks, a tumor assessment will be performed at the Final Visit.  Phase 2 subjects who 
discontinue treatment for reasons other than radiographic progression will continue to be 


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monitored by the same methods (unless medical contraindication is noted) until the earlier 
of disease progression or initiation of next line of treatment.
If a subject discontinues for reasons other than radiographic progression and if no tumor 
assessment has been performed with the last 4 weeks, a tumor assessment will be 
performed at the Final Visit.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result 
or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the study, the administration of study drug to that 
subject must be discontinued immediately.  The investigator must report a pregnancy 
within 1 working day of the site being aware to one of the AbbVie representatives listed 
in Section 6.6 or Section 7.0.
Has been changed to read:
When a subject discontinuation from the study (without reaching a protocol-defined 
endpoint) is planned, the Investigator is to notify the AbbVie TA MD 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 TA MD may contact the site to discuss the reason for withdrawal from the study.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until a satisfactory clinical resolution of the laboratory result 
or adverse event is achieved.
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the study, the administration of study drug to that 


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subject must be discontinued immediately.  The investigator must report a pregnancy 
within 1 working day of the site being aware to one of the AbbVie representatives listed 
in Section 6.6 or Section 7.0.
Post-Treatment Follow-Up
Phase 2 subjects who discontinue treatment for reasons other than radiographic 
progression will be monitored in the Post-Treatment Follow-Up period of the study by the 
same imaging method (unless medical contraindication is noted) until disease progression 
(Table 8).
Final Visit
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 7 and Table 8.  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.
30-Day Follow-Up Visit
Subjects who discontinue treatment for reasons other than radiographic progression will 
have a Follow-Up Visit approximately 30 days after the last dose of study drug and will 
transition to Post-Treatment Follow-Up. 
Subjects who discontinue treatment due to radiographic progression and have a Final Visit 
within 30 days of last dose of study drug will have one Follow-Up Visit approximately 
30 days after the last dose of study drug.


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Survival Follow-Up
All discontinued subjects will have survival information collected via electronic data 
capture (EDC) at 2 month intervals (or as requested by sponsor to support data analysis) 
after the subject discontinues the study and continuing until the endpoint of death, the 
subject has become lost to follow-up, or AbbVie terminates the study.
5.4.1.1
Discontinuation of Combination and Maintenance Therapies 
in Phase 2
Subjects will receive veliparib, carboplatin and etoposide up to a maximum of 4 –
6 combination cycles or until reaching a protocol defined event of disease progression or 
experiencing unmanageable toxicity.  Dose reductions of carboplatin and etoposide will 
occur on the basis of the toxicity observed and may result in discontinuation of either 
agent.  The subject may continue on therapy with the remaining agent in combination with 
veliparib. At the Investigator's discretion, carboplatin and/or etoposide administration 
may continue after veliparib has been discontinued.  Suitable subjects will receive 
veliparib/placebo maintenance monotherapy as per treatment arm assignment until 
reaching a protocol defined event of disease progression or experiencing unmanageable 
toxicity.
Section 5.5.1  Treatments Administered
First paragraph and bullet list previously read:
Subjects will receive the following:
●
Designated doses of veliparib BID on Days –2 through 5 or Day –2 through 12 
(14-day schedule) or Day –2 to 19 (continuous schedule) + Carboplatin AUC 
5 mg/mL*min administered on Day 1 and Etoposide 100 mg/m2 administered 
on Days 1 through 3 of each 21-day cycle for up to 4 cycles in Phase 1 and up 
to 6 cycles in Phase 2.
○
Exception: Phase 1 subjects receiving non-continuous veliparib will have 
their Cycle 2 dosing schedule altered as follows to allow for the evaluation 
of veliparib effect on etoposide exposure:  veliparib BID on Days 2 
through 5 or Days 2 through 12 + Carboplatin AUC 5 mg/mL*min 


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administered on Day 1 and Etoposide 100 mg/m2 administered on Days 1 
through 3 of a 21-day cycle.
●
Phase 1 subjects with SD, PR or CR at the completion of all scheduled 
combination therapy cycles will receive veliparib (400 mg) monotherapy, BID 
continuously in 21-day cycles starting on Day 1 of each cycle.  Phase 2 
subjects with SD, PR or CR at the completion of combination therapy cycles 
will receive veliparib (400 mg) or placebo monotherapy, BID continuously in 
21-day cycles starting on Day 1 of each cycle.
Has been changed to read:
Phase 1 subjects will receive the following:
●
Designated doses of veliparib BID on Days –2 through 5 or Day –2 through 12 
(14-day schedule) or Day –2 to 19 (continuous schedule) + Carboplatin AUC 
5 mg/mL*min administered on Day 1 and Etoposide 100 mg/m2 administered 
on Days 1 through 3 of each 21-day cycle for up to 4 cycles.
○
Exception: Phase 1 subjects receiving non-continuous veliparib will have 
their Cycle 2 dosing schedule altered as follows to allow for the evaluation 
of veliparib effect on etoposide exposure:  veliparib BID on Days 2 
through 5 or Days 2 through 12 + Carboplatin AUC 5 mg/mL*min 
administered on Day 1 and Etoposide 100 mg/m2 administered on Days 1 
through 3 of a 21-day cycle.
●
Phase 1 subjects with SD, PR or CR at the completion of all scheduled 
combination therapy cycles will receive veliparib (400 mg) monotherapy, BID 
continuously in 21-day cycles starting on Day 1 of each cycle starting at 
Cycle 5.
Phase 2 subjects will receive the following:
●
Veliparib/Placebo 240 mg BID on Day –2 through 12 (14-day schedule) + 
Carboplatin AUC 5 mg/mL*min administered on Day 1 and Etoposide 
100 mg/m2 administered on Days 1 through 3 of each 21-day cycle for up to 
6 cycles.


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●
Phase 2 subjects with SD, PR or CR at the completion of combination therapy 
cycles will receive veliparib (400 mg) or placebo monotherapy, BID 
continuously in 21-day cycles starting on Maintenance Day 1 of each cycle.
Section 5.5.1.1  Administration of Veliparib/Placebo
Third paragraph, last sentence previously read:
The subject is to contact the Investigator if additional veliparib is needed to complete BID 
dosing through Day 5 of the cycle.
Has been changed to read:
The subject is to contact the Investigator if additional veliparib is needed to complete BID 
dosing through the remainder of the cycle.
Section 5.5.1.1  Administration of Veliparib/Placebo
Last paragraph, last sentence previously read:
Subjects should return bottles of veliparib (empty, partially filled or full) to the study site 
prior to each cycle and at the Final Visit.
Has been changed to read:
Subjects should return bottles of veliparib (empty, partially filled or full) and the 
completed dosing card to the study site prior to each cycle and at the Final Visit.
Section 5.5.1.2  Administration of Carboplatin and Etoposide
First paragraph
Add:  new third and fourth sentence
Carboplatin and Etoposide are to be given only after veliparib/placebo dosing on 
Cycle Day –2 and Day –1 are confirmed.  If veliparib/placebo was not taken by the 
subject on Day –2 and Day –1, a new supply of veliparib is to be dispensed, and Day –2 
and Day –1 are to be repeated for that cycle, if needed.  


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Section 5.5.1.2  Administration of Carboplatin and Etoposide
Subsection Calculation of Carboplatin Dose
Delete:  subsection title and text
Calculation of Carboplatin Dose
The below guidance recommendation for carboplatin dose calculation is intended to 
reduce variability of carboplatin doses between sites. 
The initial dose of carboplatin must be calculated using GFR.  In the absence of renal 
toxicity greater than or equal to CTCAE Grade 2 (serum creatinine > 1.5 × ULN) or 
toxicity requiring dose modification, the dose of carboplatin does not need to be 
recalculated for subsequent cycles, but will be subject to dose modification for toxicity as 
noted in the protocol.
Carboplatin doses will be based on the subject's weight at baseline and should remain the 
same throughout the study.  However, the doses may be recalculated based on the 
subject's weight at each cycle, and need to be recalculated if the subject has a weight 
change of greater than or equal to 10% from baseline.
In subjects with an abnormally low serum creatinine (less than 0.7 mg/dL), the creatinine 
clearance should be estimated using a minimum value of 0.7 mg/dL.
CALVERT FORMULA:
Carboplatin dose (mg) = target AUC × (GFR + 25)
NOTE:  the GFR used in the Calvert formula cannot exceed 125 mL/min.
For the purposes of this protocol, the GFR is considered to be equivalent to the estimated 
creatinine clearance.  The estimated creatinine clearance (mL/min) is calculated by the 
method of Cockcroft-Gault using the following formula:
Creatinine Clearance (mL/min) = [140-Age (years)] × Weight (kg) / 
(72 × Ser Cr (mg/dL))


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For female subjects:  multiply the result above by 0.85.
Notes:
Body mass index (BMI) should be calculated for each subject.  A BMI should be 
calculated using the following formula:
BMI = (Weight in kg) / (Height in meters)2
Actual weight should be used for estimation of GFR for subjects with BMI < 25.
Adjusted weight should be used for estimation of GFR for subjects with BMI 
≥25.
Adjusted weight calculation:
Ideal weight (kg) = (((Height (cm)/2.54) – 60) × 2.3) + 45.5
Adjusted weight (kg) = ((Actual weight – Ideal weight) × 0.40) + Ideal 
weight
If a patient with BMI of ≥ 25 is currently being dosed using actual weight, adjust 
dose with next planned treatment.
At the time of a dose modification for toxicity:
If the creatinine at the time of a dose modification is lower than the creatinine 
used to calculate the previous dose, use the previous (higher) creatinine; 
If the creatinine at the time of a dose modification is higher than the creatinine 
used to calculate the previous dose, use the current (higher) creatinine.  This will 
ensure that the patient is actually receiving a dose reduction. 
Note that carboplatin dose will be recalculated if the subject has weight change of greater 
than or equal to 10% from baseline.


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Section 5.5.2  Identity of Investigational Products
First paragraph previously read:
Information regarding the veliparib formulation to be used in this study is presented in 
Table 13.
Has been changed to read:
Information regarding the veliparib/placebo formulation to be used in this study is 
presented in Table 13.
Table 13.  Identity of Investigational Products
Last row previously read:
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
Veliparib (ABT-888)
Capsule
20 mg or placebo*
Oral
AbbVie
Has been changed to read:
Study Drug
Dosage Form
Strength
Route of 
Administration
Manufacturer
Veliparib (ABT-888)
Capsule
20 mg*
Oral
AbbVie
Table 13.  Identity of Investigational Products
Table note "*"
Add:  new last sentence  
20 mg capsule strength for Phase 1 ONLY.
Section 5.5.2.2  Packaging and Labeling
Previously read:
Veliparib (ABT-888) will be supplied by AbbVie in HDPE bottles containing either 
20 mg, 40 mg, 100 mg active or their placebo capsules.  Bottles will contain either 15, 
24 or 50 capsules per bottle.  This will allow for the 2, 5, 14, 21, or monotherapy days of 
administration (with one additional dose to cover loss, spillage or replacement due to 
vomiting within 15 minutes).  Each bottle will be labelled per country requirements 


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including at a minimum the information required by local regulations.  The label is to 
remain affixed to the bottle.  All blank spaces on the label will be completed by site staff 
prior to dispensing to the subject.
AbbVie will provide study sites with instructions and training for the proper handling, 
storage and documentation related to all investigational supplies.
Has been changed to read:
Phase 1 Dose Escalation
Veliparib (ABT-888) will be supplied by AbbVie in HDPE bottles containing either 
20 mg, 40 mg, 100 mg active capsules.  Bottles will contain either 15, 24 or 50 capsules 
per bottle.  This will allow for the 2, 5, 14, 21, or monotherapy days of administration 
(with one additional dose to cover loss, spillage or replacement due to vomiting within 
15 minutes).  Each bottle will be labelled per country requirements including at a 
minimum the information required by local regulations.  The label is to remain affixed to
the bottle.  All blank spaces on the label will be completed by site staff prior to dispensing 
to the subject.
Phase 2 Randomized Double-Blind
Veliparib (ABT-888)/placebo will be supplied by AbbVie in HDPE bottles containing 
either 40 mg, 100 mg active or their placebo capsules.  Bottles will contain either 15, 
24 or 50 capsules per bottle.  This will allow for the 14 days combination or continuous 
monotherapy days of administration (with additional doses to cover loss, spillage or 
replacement due to vomiting within 15 minutes).  Each bottle will be labelled per country 
requirements including at a minimum the information required by local regulations.  The 
label is to remain affixed to the bottle.  All blank spaces on the label will be completed by 
site staff prior to dispensing to the subject.
AbbVie will provide study sites with instructions and training for the proper handling, 
storage and documentation related to all investigational supplies.


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Section 5.5.3  Method of Assigning Subjects to Treatment Groups (Dose Escalation 
Portion)
Section title previously read:
Method of Assigning Subjects to Treatment Groups (Dose Escalation Portion)
Has been changed to read:
Method of Assigning Subjects to Treatment Groups (Phase 1 Dose Escalation)
Section 5.5.4  Method of Assigning Subjects to Treatment Groups (Randomized 
Phase 2 Portion)
Section title and text previously read:
5.5.4
Method of Assigning Subjects to Treatment Groups 
(Randomized Phase 2 Portion)
All subjects 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 within 
4 calendar days prior to or on the subject's Cycle 1 Day –2 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 enrolled in the study or is not randomized (as applicable), 
the reason for screen failure will be documented in the source document and in the eCRF.  
For others, the site will access the system and a unique randomization number will be 
provided.
The IRT will randomize subjects in a 1:1:1 ratio to one of the three treatment arms as 
follows:
●
Arm A: veliparib in combination with carboplatin/etoposide followed by 
veliparib monotherapy
●
Arm B:  veliparib in combination with carboplatin/etoposide followed by 
placebo monotherapy
●
Arm C:  placebo in combination with carboplatin/etoposide followed by 
placebo monotherapy


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Subject randomization will be stratified by:  LDH (≤ ULN versus > ULN), and gender.
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.
Has been changed to read:
5.5.4
Method of Assigning Subjects to Treatment Groups 
(Phase 2 Randomized Double-Blind)
All subjects will be randomized using an IRT system.  Before the study is initiated, the 
IRT user manual, which provides instruction on how to use the system via the web or 
phone, will be provided to each site.
Subjects who complete all Screening procedures and meet eligibility criteria may proceed 
to randomization.  Subject randomization will be stratified by:  LDH (≤ ULN versus 
> ULN), and gender; therefore a subject's baseline LDH value must be known prior to 
randomization and when accessing the IRT to perform the randomization transaction.
The site will contact the IRT to obtain a Screening (subject) number once the subject has 
signed the informed consent and a study-specific procedure has been performed 
(i.e., central laboratory samples drawn).  Once the subject number is assigned, if the 
subject is not enrolled/randomized the reason for screen failure will be documented in the 
source document and in the eCRF.  If the subject meets all inclusion and none of the 
exclusion criteria, the site will access the system to randomize the subject.  The IRT will 
randomize subjects in a 1:1:1 ratio to one of the three treatment arms as follows:
●
Arm A:  veliparib in combination with carboplatin/etoposide followed by 
veliparib monotherapy
●
Arm B:  veliparib in combination with carboplatin/etoposide followed by 
placebo monotherapy


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●
Arm C:  placebo in combination with carboplatin/etoposide followed by 
placebo monotherapy
Subject randomization will be stratified by:  LDH (≤ ULN versus > ULN), and gender.
Section 5.5.5  Selection and Timing of Dose for Each Subject
Subsection Phase 2
Subsection title and text previously read:
Phase 2
Subjects will be randomized in a 1:1:1 ratio to receive carboplatin, etoposide, placebo 
followed by placebo maintenance or carboplatin, etoposide, veliparib followed by either 
veliparib or placebo maintenance for at least 4 cycles of combination treatment, unless 
disease progression or unacceptable toxicity warrants earlier discontinuation from the 
treatment.  Subject whose status at the completion of the 4th cycle of combination therapy 
warrants, in the opinion of the investigator, continued combination treatment may receive 
up to two additional combination therapy cycles (e.g., up to a total of 6 cycles).  After the 
completion of combination therapy, subjects without evidence of disease progression by 
most recent scheduled radiographic assessment (CT) will receive veliparib at 400 mg BID 
or placebo continuous schedule in 21-day cycles, until disease progression or 
unacceptable toxicity.
Has been changed to read:
Phase 2 Randomized Double-Blind
Subjects will complete at least 4 cycles of combination therapy, unless disease 
progression or unacceptable toxicity warrants earlier discontinuation from the 
combination treatment.  Subject whose status at the completion of the 4th cycle of 
combination therapy warrants, in the opinion of the investigator, continued combination 
treatment may receive up to two additional combination therapy cycles (e.g., up to a total 
of 6 cycles) if required by local standard of care.  After the completion of combination 
therapy, subjects without evidence of disease progression by most recent scheduled 


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radiographic assessment (CT) will receive veliparib at 400 mg BID or placebo continuous 
schedule in 21-day cycles, until disease progression or unacceptable toxicity.
Section 5.5.6  Blinding
First paragraph previously read:
Phase 1 is the open-label portion of the trial.  Phase 2 is the randomized; double-blinded 
portion of the study.  Placebo capsules will be identical in appearance to the veliparib 
capsules.  All study site personnel, including the investigator, study coordinator, as well 
as the subjects, will remain blinded to the treatment.  Subjects will be randomized via 
IVRS/IWRS.
Has been changed to read:
All study site personnel, including the investigator, study coordinator, as well as the 
subjects, will remain blinded to the treatment throughout the course of the Phase 2 portion 
of the study.  The IRT system will provide access to blinded subject treatment information 
during the double-blind period, if needed.
Section 5.5.7  Treatment Compliance
Previously read:
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/placebo (placebo in randomized portion of the study) should be taken 
as directed by the investigator.  Carboplatin and etoposide will be administered 
intravenously by trained site personnel.
Subjects will be instructed to return all veliparib/placebo bottles (empty, partially filled or 
full) to the study site personnel prior to each cycle and at the Final Visit.  The site staff 
will document the bottles returned and the number of capsules per bottle on the 
appropriate form.


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Upon completion or termination of the study, all original bottles/cartons containing 
unused veliparib/placebo (empty containers will be defaced and discarded on site) will be 
returned to AbbVie or the destruction facility according to AbbVie's instructions, or if 
pre-arranged between the sponsor and site, destruction of used and unused bottles will be 
performed at the site.
Unless otherwise directed by the investigator, a subject will be considered compliant with 
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.
Has been changed to read:
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/placebo should be taken as directed by the investigator.  Carboplatin 
and etoposide will be administered intravenously by trained site personnel.
Subjects will be instructed to return all veliparib/placebo bottles (empty, partially filled or 
full) and the completed dosing card to the study site personnel at each combination cycle 
Day 1, each Maintenance cycle Day 1, 30-Day Follow-Up Visit and/or at the Final Visit.  
The Investigator or his/her designated and qualified representatives will document the 
bottles returned and the number of capsules returned per bottle in the IRT system.
Upon completion or termination of the study, all original bottles/cartons containing 
unused veliparib/placebo (empty containers will be defaced and discarded on site) will be 
returned to AbbVie or the destruction facility according to AbbVie's instructions, or if 
pre-arranged between the sponsor and site, destruction of used and unused bottles will be 
performed at the site.
Subjects should be questioned regarding their adherence to the assigned treatment 
schedule at each study visit.  The Investigator or his/her designated and qualified 


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representatives will also confirm that the subject took the required number of capsules per 
protocol. 
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.  The 
Investigator or his/her designated and qualified representatives will document compliance 
on the appropriate eCRF.
Section 5.5.8  Drug Accountability
Previously read:
Upon receipt of a shipment of veliparib, the representative at each site will verify that 
study drug supplies are received intact and in the correct amounts.  This will be 
documented by signing and dating the Proof of Receipt or similar document respectively 
via direct recording in the IVRS.  An accurate (running) inventory of study drug will be 
kept by the site, and will include the lot number, shipment number and the number of 
capsules dispensed, subject initials, initials of person who dispensed the drug, and the date 
study drug was dispensed for each subject.  An overall accountability of the study drug 
will be performed and verified by the AbbVie monitor throughout the study and at the site 
close-out visit.  All study drug unit doses must be inventoried, accounted for, and returned 
to the destruction facility or to AbbVie or destroyed per instructions from AbbVie and 
according to local regulations.  A copy of the Drug Accountability Form, in accordance 
with instructions provided by the AbbVie monitor, will also be included in the shipment.
The investigator and/or named the sub-investigators agree not to supply study medication 
to any persons not enrolled in the study.
The site will record the dose of carboplatin and etoposide given to each subject in the 
source documents and on the eCRF.  As the investigator will obtain both carboplatin and 
etoposide commercially, site inventory and accountability of carboplatin and etoposide 
will not be performed, and drug accountability forms will not be provided.  However, 


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each site will be responsible for tracking the lot numbers for all carboplatin and etoposide 
dispensed.
Has been changed to read:
Upon receipt of a shipment of veliparib, the representative at each site will verify that 
study drug supplies are received intact and in the correct amounts.  This will be 
documented by signing and dating the Proof of Receipt (PoR) or similar document 
respectively via direct recording in the IRT.  The shipment receipt must be acknowledged 
in the IRT in order to become available for dispensation to subjects.  All veliparib/placebo 
must be retained in the designated secure area under proper storage conditions.  The study 
site will record the kit number of veliparib/placebo given to each subject in the source 
documents and on the eCRF.
The IRT will maintain a current and accurate inventory of study drug, accountability, 
reconciliation, returns, and destruction for each site.  The IRT will also include the lot 
number, the bottle/kit numbers, and the date veliparib/placebo was dispensed for each 
subject.
In the event the IRT is not operable, the above information will be documented on forms 
provided/approved by the Sponsor.
The Investigator or designee will document the bottles of veliparib/placebo returned and 
the number of capsules on the appropriate form in the IRT.  If the number of capsules 
taken and the number of capsules returned do not add up to the number of capsules 
dispensed, an explanation is required and should be documented in the IRT.
An overall accountability of the study drug will be performed and verified by the AbbVie 
monitor throughout the study and at the site close-out visit.  All study drug unit doses 
must be inventoried, accounted for, and returned to the destruction facility or to AbbVie 
or destroyed per instructions from AbbVie and according to local regulations.  


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The investigator and/or named the sub-investigators agree not to supply study medication 
to any persons not enrolled in the study.
The site will record the dose of carboplatin and etoposide given to each subject in the 
source documents and on the eCRF.  As the investigator will obtain both carboplatin and 
etoposide commercially, site inventory and accountability of carboplatin and etoposide 
will not be performed, and drug accountability for carboplatin and etoposide will not be 
performed in the IRT.  However, each site will be responsible for tracking the lot numbers 
for all carboplatin and etoposide dispensed.
Section 5.6.4  Selection of Doses in the Study
Previously read:
The initial starting dose of 80 mg BID veliparib in the Phase 1 portion of the study was 
derived from the results obtained in the ECOG E2511, GOG 9923 and AbbVie M10-898 
clinical studies, as well as from the non-clinical studies.  
Doses for carboplatin in combination with etoposide will be given as per standard of care 
in first line treatment for extensive stage SCLC as per NCCN guideline 2014.3
The recommended dose for veliparib monotherapy is 400 mg BID.  This dose is well 
characterized for safety and tolerability based on the experience from multiple clinical 
trials.  The maximum dose for 100 mg veliparib capsule will not exceed 400 mg BID, the
maximum dose for 40 mg veliparib capsules will not exceed 1000 mg/day, and for 20 mg 
capsule will not exceed 1000 mg/day.
Has been changed to read:
Phase 1 Dose Escalation
The initial starting dose of 80 mg BID veliparib in the Phase 1 portion of the study was 
derived from the results obtained in the ECOG E2511, GOG 9923 and AbbVie M10-898 
clinical studies, as well as from the non-clinical studies.  


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Doses for carboplatin in combination with etoposide will be given as per standard of care 
in first line treatment for extensive stage SCLC as per NCCN guideline 2014.3
The dose for veliparib monotherapy is 400 mg BID.  This dose is well characterized for 
safety and tolerability based on the experience from multiple clinical trials.  
Phase 2 Randomized Double-Blind
The RPTD has been defined in the Phase 1 portion of the study as veliparib 240 mg BID 
administered on Days –2 – 12 (14-Day schedule), carboplatin AUC 5 mg/ml*hr 
administered on Day 1, etoposide 100 mg/m2 administered on Days 1 – 3 of 21-Day 
cycles.
The dose for veliparib/placebo monotherapy is 400 mg BID administered continuously in 
21-Day cycles.
Table 16.  Guidelines for Veliparib, Carboplatin, and Etoposide Dose Reduction 
Levels
Table title and table previously read:
Table 16.
Guidelines for Veliparib, Carboplatin, and Etoposide Dose Reduction 
Levels
Dose Reductions
Carboplatin
Etoposide
Veliparib
Starting Dose 
AUC 5
100 mg/m2
As assigned
Dose Reduction 1
AUC 4
75 mg/m2
Next lower DL (assigned –1)
Dose Reduction 2
No Additional 
Reductions 
Allowed
55 mg/m2
Next lower DL (assigned –2)
Notes:
For combination therapy cycles only; for monotherapy cycles see Section 5.7.1.  "Next lower DL" refers to the 
daily dose levels tested in the dose escalation part of the study.  The dose of each drug can be reduced 
independently based on the observed toxicities.  For veliparib dose level of 80 mg, Dose Reduction 1 is to 
60 mg, Dose Reduction 2 is to 40 mg.


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Has been changed to read:
Table 16.
Guidelines for Veliparib, Carboplatin, and Etoposide Dose Reduction 
Levels During Combination Therapy
Dose Reductions
Carboplatin
Etoposidea
Veliparibb
Starting Dose 
AUC 5
100 mg/m2
Phase 1:  As assigned
Phase 2:  240 mg BID
Dose Reduction 1
AUC 4
75 mg/m2
Phase 1:  Next lower DL (assigned –1)
Phase 2:  200 mg BID
Dose Reduction 2
No Additional 
Reductions Allowed
55 mg/m2
Phase 1:  Next lower DL (assigned –2)
Phase 2:  160 BID
a.
Refer to Section 5.7.2.1.2 for etoposide dose reduction guidelines related to bilirubin.
b.
Refer to Section 5.7.1 for veliparib dose reduction guidelines for maintenance therapy.  "Next lower DL" refers to 
the daily dose levels tested in the dose escalation part of the study.  The dose of each drug can be reduced 
independently based on the observed toxicities.  For veliparib dose level of 80 mg (Phase 1 only), Dose Reduction 
1 is to 60 mg, Dose Reduction 2 is to 40 mg.
Section 5.7.1  Veliparib/Placebo Dose Reductions and Delays
Section title and text previously read:
5.7.1
Veliparib/Placebo Dose Reductions and Delays
The following are guidelines for dose reduction, delay and discontinuation of 
veliparib/placebo:
1.
Veliparib/placebo part of combination therapy will be discontinued if both 
carboplatin and etoposide are discontinued prior to the completion of the planned 
number of combination therapy cycles.
2.
For any subject who experiences Grade 3/4 toxicity which is not attributable to 
carboplatin/etoposide or the underlying disease, the Veliparib/placebo dose will be 
held until the toxicity resolves to Grade 1 or lower or to baseline if Grade 2 is 
present at the time of study entry.  Upon toxicity resolution re-start veliparib at a 
reduced dose level.


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3.
Two dose reductions are allowed:
a.
Combination treatment cycles:  For Dose Reduction 1, the dose of 
Veliparib/placebo will be reduced to next lower dose level (assigned dose 
level -1).  Veliparib/placebo may be reduced again (Dose Reduction 2, assigned 
dose level –2) due to toxicity (Table 16).  If further dose reductions are 
required, this should be discussed with the AbbVie Study Designated 
Physician.  All veliparib/placebo dose reductions within combination 
treatment cycles are permanent.  Veliparib/placebo cannot be dose-reduced 
below 40 mg BID.
b. Monotherapy cycles:  Dose Reduction 1 to 300 mg BID, Dose Reduction 2 to 
200 mg BID.  Subjects requiring dose reduction of veliparib/placebo to below 
200 mg BID will be discontinued from the treatment.
4.
Any ≥ Grade 2 event of seizure attributed to veliparib/placebo requires 
discontinuation of veliparib/placebo.
5.
Veliparib/placebo doses held will not affect the study calendar and will not be 
replaced.  If veliparib/placebo-related toxicity necessitates the delay in 
veliparib/placebo re-initiation beyond the scheduled start of the next combination 
treatment cycle, the start of the cycle should be delayed until veliparib/placebo can 
be restarted.  The AbbVie study designated physician may be contacted 
(Section 6.6) for subjects who require more than a 2-week delay in the re-initiation 
of the next cycle.


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Table 17.
Dose Delay or Reduction Due to Toxicity Attributable to Veliparib in 
the Combination Treatment Cycles
Adverse Event
Veliparib*
Any Grade 3 or 4 
toxicity attributable to 
veliparib which is not 
attributable to 
carboplatin/etoposide 
or underlying disease
1.
Interrupt dosing in the current cycle until Grade 1 (or Grade 2 if present at 
baseline)
and
2.
Reduce veliparib dose to next lower dose level upon dosing re-initiation
*
Two dose reductions of veliparib are allowed.  Veliparib dose cannot be reduced below 40 mg BID.  All veliparib 
dose reductions in the combination treatment cycles are considered permanent.  For continuous schedule of 
veliparib administration in cases of delayed  (> 7 days) hematologic recovery or late onset (after Day 12 of the 
Cycle) GI toxicity skipping Days 13 – 19 doses in subsequent cycles can be considered in place of reducing the 
daily dose level.  
Table 18.
Veliparib Dose Delay or Reduction Due to Toxicity in the 
Monotherapy Cycles
Adverse Event
Veliparib*
Any Grade 3 or 4 
toxicity attributable to 
veliparib 
1.
Interrupt dosing in the current cycle until Grade 1 (or Grade 2 if present at 
baseline)
and
2.
At resumption reduce veliparib dose to next lower monotherapy dose level
*
Two dose reductions of veliparib are allowed.
Has been changed to read:
5.7.1
Veliparib/Placebo Dose Reductions and Interruptions
The following are guidelines for dose reduction, interruption and discontinuation of 
veliparib/placebo during combination therapy:
1.
Veliparib/placebo will be discontinued if both carboplatin and etoposide are 
discontinued prior to the completion of the planned number of combination therapy 
cycles.


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2.
For any subject who experiences Grade 3/4 toxicity which is not attributable to 
carboplatin/etoposide or the underlying disease, refer to Table 17 for dosing 
guidelines.
3.
Two dose reductions are prospectively allowed during combination therapy for 
subjects who experience toxicity attributable to veliparib/placebo.  Refer to 
Table 16 for dose reduction guidelines.
a.
Veliparib dose reduction at C1D1 is allowed in case of nausea and vomiting 
attributable to C1D-2 and C1D-1 veliparib doses
b. All veliparib/placebo dose reductions within combination therapy cycles are 
permanent.
c.
If further dose reductions (beyond prospectively allowed two) are required, 
sites must contact the AbbVie TA MD.
4.
Any ≥ Grade 2 event of seizure attributed to veliparib/placebo requires 
discontinuation of veliparib/placebo.
5.
Veliparib/placebo interruptions will not affect the schedule of planned study 
procedures and will not be replaced.  If veliparib/placebo-related toxicity 
necessitates the delay in veliparib/placebo re-initiation beyond the scheduled start 
of the next combination therapy cycle, the start of the cycle should be delayed until 
veliparib/placebo can be restarted.  The AbbVie TA MD may be contacted 
(Section 6.6) for subjects who require more than a 2-week delay in the re-initiation 
of the next cycle.
The following are guidelines for dose reduction, interruption and discontinuation of 
veliparib/placebo during Maintenance Therapy:
1.
Dose Reduction 1:  300 mg BID.
2.
Dose Reduction 2:  200 mg BID.


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3.
Subjects requiring dose reduction of veliparib/placebo to below 200 mg BID will 
be discontinued from treatment.
4.
For subjects who experience any Grade 3/4 toxicity during maintenance therapy 
which is attributable to veliparib, refer to Table 18 for dosing guidelines.
Table 17.
Dose Interruption or Reduction Due to Toxicity Attributable to 
Veliparib in the Combination Therapy Cycles
Adverse Event
Veliparib
Any Grade 3 or 4 
toxicity attributable to 
veliparib which is not 
attributable to 
carboplatin/etoposide 
or underlying disease
1.
Interrupt dosing in the current cycle until Grade 1 (or Grade 2 if present at 
baseline)
and
2.
Reduce veliparib dose to next lower dose level upon dosing re-initiation
Table 18.
Veliparib Dose Interruption or Reduction Due to Toxicity Attributable 
to Veliparib in the Maintenance Therapy Cycles
Adverse Event
Veliparib
Any Grade 3 or 4 
toxicity attributable to 
veliparib 
1.
Interrupt dosing in the current cycle until Grade 1 (or Grade 2 if present at 
baseline)
and
2.
At resumption reduce veliparib dose to next lower monotherapy dose level
Section 5.7.2  Carboplatin/Etoposide Dose Reductions and Delays
Previously read:
If a subject experiences an adverse event attributable to carboplatin or etoposide, 
carboplatin or etoposide may either be held or dose reduced for that cycle.  At the 
Investigator's discretion, carboplatin and etoposide administration may continue as 
scheduled.
If a dose reduction or delay is required for carboplatin and/or etoposide, the Investigator 
should follow procedures as defined in the locally approved product label or applicable 
Summary of Product Characteristics (SmPC).  Section 5.7.2.1 outlines suggested dose 


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reductions for carboplatin/etoposide if above information is not available.  PD and/or PK 
samples will not be drawn during carboplatin and/or etoposide dose delays.  If the 
Investigator considers an event attributable to carboplatin and/or etoposide and not 
veliparib, the Investigator may consider reducing the dose of both agents.
All toxicity will be graded by the National Cancer Institute Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE).  All carboplatin and/or etoposide 
dose reductions are permanent.  Re-escalation of the dose of therapy is not allowed.  
All toxicities should have 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.
If toxicity precludes the initiation of the dosing of carboplatin/etoposide in the cycle, and 
veliparib doses on Days –2 and –1 of the cycle have already been administered, veliparib 
should be administered again once the toxicity resolves for two days prior to 
carboplatin/etoposide dosing.
Has been changed to read:
If a subject experiences an adverse event attributable to carboplatin or etoposide, 
carboplatin or etoposide may either be interrupted or the dose reduced.  
If a dose reduction or delay is required for carboplatin and/or etoposide, the Investigator 
should follow procedures as defined in the locally approved product label or applicable 
Summary of Product Characteristics (SmPC).  Section 5.7.2.1 outlines suggested dose 
reductions for carboplatin/etoposide if above information is not available.  PD and/or PK 
samples will not be drawn during carboplatin and/or etoposide dose delays. 


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Section 5.7.2.1  Guidelines for Carboplatin and Etoposide Dose Reductions and 
Delays
Previously read:
The below guidelines are suggested, unless described as mandatory.  If a dose reduction 
or delay is required for carboplatin and/or etoposide, the Investigator should follow 
procedures according to institutional guidelines, the locally approved product label, local 
practice, or applicable SmPC.  If the Investigator considers an event attributable to 
carboplatin and/or etoposide, the Investigator may consider reducing carboplatin and/or 
etoposide, but not veliparib/placebo.  Suggested guidelines for dose reduction, delay, and 
discontinuation are included in Table 19 (if locally approved product label, local standard 
of care guideline or applicable SmPC for carboplatin/etoposide combination 
chemotherapy are not available).
Hematologic Toxicity
Neutropenia or Febrile Neutropenia
For febrile neutropenia with absolute neutrophil count (ANC) < 500/mm3 and a single 
temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more 
than one hour, requiring intravenous antibiotics, the doses of both carboplatin and 
etoposide drugs should be reduced to the next lower dose level for all subsequent cycles 
of chemotherapy (Table 14).  Implement dose reductions 1 and 2 for first and second 
episodes, respectively, as outlined in Table 19.  Consider initiating prophylactic 
neutrophil growth factors (e.g., G-CSF) after the first episode.  If ANC counts do not 
recover within 3 weeks, discontinue all protocol therapy.
For treatment delays of more than 7 days due to neutropenia, carboplatin and etoposide 
should be dose-reduced to next lower dose level for all subsequent cycles of 
chemotherapy, as outlined in Table 19.
For nadir neutropenia in the absence of fever or with fever that is successfully treated by 
oral antibiotics, there will be no dose adjustment.


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ANC must be ≥ 1,500/mm3 on Day 1 of each cycle (mandatory).  If the counts are lower 
than the limit, then dosing of all drugs (carboplatin, etoposide and veliparib) should be 
delayed until recovery to the required ANC.
If the subject experiences fever with neutropenia, then neutrophil growth factors 
(e.g., G-CSF) should be given based on local standard of care guidelines, ASCO or 
NCCN guidelines.  
Platelets
For Grade 4 nadir platelet count decrease (thrombocytopenia) (platelets < 25,000 mm3), 
the dose of both carboplatin and etoposide should be reduced to next lower dose level 
from the previous dose for all subsequent cycles of chemotherapy.  Implement dose 
reductions 1 and 2 for the first and second episodes, respectively as outlined in Table 19.  
If counts do not recover within 3 weeks, discontinue all protocol therapy.
Platelet count must be > 100,000/mm3 on Day 1 of each cycle.  Doses or all drugs 
(carboplatin, etoposide and veliparib) should be delayed until platelet count recovers to 
> 100,000/mm3.
Anemia
No dose reductions will be made for anemia.  Subjects should be supported per the 
treating physician's discretion.  The use of RBC transfusions for anemia will be allowed 
as clinically indicated and as per local standard of care or current NCCN guidelines.  The 
use of growth factors for anemia is not permitted during Phase 1 Cycle 1.
If more than two dose modifications of carboplatin and etoposide are required for 
hematologic toxicity, e.g., in cases where an additional dose modification is needed for a 
toxicity which was not observed earlier, please consult the Study Designated Physician.


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Non-Hematological Toxicity
Gastrointestinal Toxicity:  Nausea and Vomiting
All subjects should receive antiemetics* to prevent nausea and vomiting.  Specific 
antiemetic therapy is left to the discretion of the treating physician (steroids and 5-HT3 
antagonists should be used).  For vomiting Grade ≥ 3, consider hospital admission and/or 
use of aprepitant, if possible.  Nausea/vomiting should have resolved to Grade 1 or less 
prior to initiation of next treatment cycle.  Do not modify carboplatin and/or etoposide 
doses due to nausea/vomiting.
*
Aprepitant, when given once daily for 14 days as a 100 mg capsule with an oral contraceptive containing 35 mcg of 
ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43% and decreased the 
AUC of norethindrone by 8%.  Women of childbearing potential using pregnancy contraception that includes 
ethinyl estradiol should not receive Aprepitant for the treatment of nausea/delayed emesis.  Subjects may change to 
a different method of contraception if they wish to use Aprepitant.
Hepatic Toxicity
For bilirubin > 1.5 – 3.0 × ULN, not attributable to underlying disease, reduce the dose of 
etoposide to 50 mg/m2.  For bilirubin > 3 – 5 × ULN reduce the dose of etoposide to 
30 mg/m2.  For bilirubin > 5 × ULN hold etoposide or hold all treatment if starting the 
next treatment cycle.  When bilirubin resolves to ≤ 5 × ULN, treatment can be resumed, 
with etoposide dose to 30 mg/m2.  If bilirubin does not improve to ≤ 5 × ULN within 
3 weeks of first occurrence, discontinue protocol therapy.
Other Grade 2/4 Non-Hematologic Toxicity
Other non-hematologic Grade 3/4 toxicity should be managed as per local SmPC 
guidelines and institutional standard practices.  


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Table 19.
Suggested Guidelines for Carboplatin/Etoposide Dose Delay or 
Reduction
Adverse Event
Carboplatin Dose
Etoposide Dose
ANC < 1,500/mm3 Day 1 of 
Cycle
Hold next cycle until ANC 
≥1,500/mm3.
Hold next cycle until ANC 
≥1,500/mm3.
Treatment delays of > 7 days 
due to neutropenia
Implement Dose Reduction 1 for 
1st episode.
Implement Dose Reduction 1 for 
1st episode and Dose Reduction 2 for 
2nd episode.  
Grade 3/4 febrile 
neutropenia with ANC 
< 500/mm3, requiring IV 
antibiotics
Implement Dose Reduction 1 for 
1st episode.  Consider Prophylactic 
G-CSF after 1st episode.
Implement Dose Reduction 1 for 
1st episode and Dose Reduction 2 for 
2nd episode.  Consider Prophylactic 
G-CSF after 1st episode.
Grade 3 nausea, vomiting or 
Grade 4 vomiting
Hold next cycle until resolution to 
Grade 1 or better.  If more than 2 weeks 
dose delay is required consult with 
AbbVie medical monitor.
Hold next cycle until resolution to 
Grade 1 or better.  If more than 
2 weeks dose delay is required consult 
with AbbVie medical monitor.
Platelets < 100,000/mm3 Day 
1 of Cycle
Hold next cycle until platelets 
≥100,000/mm3.
Hold next cycle until platelets 
≥100,000/mm3.
Grade 4 thrombocytopenia
Implement Dose Reduction 1 for 
1st episode.
Implement Dose Reduction 1 for 
1st episode and Dose Reduction 2 for 
2nd episode.
Bilirubin  > 1.5 – 3.0 × ULN
No Change
Reduce dose to 50 mg/m2
Bilirubin > 3 – 5 × ULN
No Change
Reduce dose to 30 mg/m2
Bilirubin > 5 × ULN
Hold if bilirubin does not improve to 
≤5 × ULN within 3 weeks of 
first occurrence, discontinue protocol 
therapy
Hold if bilirubin does not improve to 
≤ 5 × ULN within 3 weeks of 
first occurrence, discontinue protocol 
therapy
Any other Grade 3/4 toxicity
Per local SmPC/institution guidelines
Per local SmPC/institution guidelines
Has been changed to read:
The below guidelines are suggested, unless described as mandatory.  If a dose reduction 
or delay is required for carboplatin and/or etoposide, the Investigator should follow 
procedures according to institutional guidelines, the locally approved product label, local 
practice, or applicable SmPC.  If the Investigator considers an event attributable to 
carboplatin and/or etoposide, the Investigator may consider reducing carboplatin and/or 
etoposide, but not veliparib/placebo.  Suggested guidelines for dose reduction, delay, and 
discontinuation are included in Table 16 and Table 19 (if locally approved product label, 


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local standard of care guideline or applicable SmPC for carboplatin/etoposide 
combination chemotherapy are not available).
All carboplatin and/or etoposide dose reductions are permanent.  Re-escalation of the dose 
of therapy is not allowed.  All toxicities should have 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 toxicity precludes the initiation of the dosing of carboplatin/etoposide in the cycle, and 
veliparib doses on Days –2 and –1 of the cycle have already been administered, veliparib 
should be administered again once the toxicity resolves for two days prior to 
carboplatin/etoposide dosing.  In such a case, a new supply of veliparib/placebo is to be 
dispensed, and Day –2 and Day –1 are to be repeated for that cycle.
For Phase 1 ONLY:  PD and/or PK samples will not be drawn during carboplatin and/or 
etoposide dose delays.  If the Investigator considers an event attributable to carboplatin 
and/or etoposide and not veliparib, the Investigator may consider reducing the dose of 
both agents.
5.7.2.1.1
Hematologic Toxicity
If chemotherapy must be withheld due to hematologic toxicity, CBC and platelet counts
should be obtained weekly via central labs (if done locally, sample MUST be split for 
central lab) until the counts reach the lower limits for treatment as outlined.  The 
treatment schedule will then proceed in the usual sequence.
Neutropenia or Febrile Neutropenia
For febrile neutropenia with absolute neutrophil count (ANC) < 500/mm3 and a single 
temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more 
than one hour, requiring intravenous antibiotics:


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a.
Doses of both carboplatin and etoposide drugs should be reduced to the next lower 
dose level for all subsequent cycles of chemotherapy.  Suggested dose reduction 
levels are outlined in Table 14.
b. Implement dose reductions, as outlined in Table 19.
c.
Initiate prophylactic neutrophil growth factors (e.g., G-CSF) after the first episode 
and in accordance with local SOC practices, ASCO or NCCN guidelines.
d. If ANC counts do not recover within 3 weeks, discontinue all protocol therapy.
For treatment delays of more than 7 days due to neutropenia, carboplatin and etoposide 
should be dose-reduced to next lower dose level for all subsequent cycles of 
chemotherapy, as outlined in Table 19.
For nadir neutropenia in the absence of fever or with fever that is successfully treated by 
oral antibiotics, there will be no dose adjustment. 
ANC must be ≥ 1,500/mm3 on Day 1 of each cycle (mandatory).  If the ANC is lower 
than 1,500/mm3, then dosing of all drugs (carboplatin, etoposide and veliparib) will be 
delayed until recovery to the required ANC.
Platelets
For Grade 4 nadir platelet count decrease (thrombocytopenia) (platelets < 25,000 mm3), 
the dose of both carboplatin and etoposide should be reduced to next lower dose level 
from the previous dose for all subsequent cycles of chemotherapy.  Implement dose 
reductions 1 and 2 for the first and second episodes, respectively as outlined in Table 19.  
If counts do not recover within 3 weeks, discontinue all protocol therapy.
Platelet count must be > 100,000/mm3 on Day 1 of each cycle (mandatory).  Doses or all 
drugs (carboplatin, etoposide and veliparib) should be delayed until platelet count 
recovers to > 100,000/mm3.


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Anemia
No dose reductions will be made for anemia.  Subjects should be supported per the 
treating physician's discretion.  The use of RBC transfusions for anemia will be allowed 
as clinically indicated and as per local standard of care or current NCCN guidelines.  The 
use of growth factors for anemia is not permitted during Phase 1 Cycle 1.
If more than two dose modifications of carboplatin and etoposide are required for 
hematologic toxicity, e.g., in cases where an additional dose modification is needed for a 
toxicity which was not observed earlier, please consult the AbbVie TA MD.
5.7.2.1.2
Non-Hematological Toxicity
Gastrointestinal Toxicity:  Nausea and Vomiting
All subjects should receive antiemetics* to prevent nausea and vomiting.  Specific 
antiemetic therapy is left to the discretion of the treating physician (steroids and 5-HT3 
antagonists should be used).  For vomiting Grade ≥ 3, consider hospital admission and/or 
use of aprepitant, if possible.  Nausea/vomiting should have resolved to Grade 1 or less 
prior to initiation of next treatment cycle.  Do not modify carboplatin and/or etoposide 
doses due to nausea/vomiting.
*
Aprepitant, when given once daily for 14 days as a 100 mg capsule with an oral contraceptive containing 35 mcg of 
ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43% and decreased the 
AUC of norethindrone by 8%.  Women of childbearing potential using pregnancy contraception that includes 
ethinyl estradiol should not receive Aprepitant for the treatment of nausea/delayed emesis.  Subjects may change to 
a different method of contraception if they wish to use Aprepitant.
Hepatic Toxicity
For bilirubin > 1.5 – 3.0 × ULN, not attributable to underlying disease, reduce the dose of 
etoposide to 50 mg/m2.  For bilirubin > 3 – 5 × ULN reduce the dose of etoposide to 
30 mg/m2.  For bilirubin > 5 × ULN hold etoposide or hold all treatment if starting the 
next treatment cycle.  When bilirubin resolves to ≤ 5 × ULN, treatment can be resumed, 
with etoposide dose to 30 mg/m2.  If bilirubin does not improve to ≤ 5 × ULN within 
3 weeks of first occurrence, discontinue protocol therapy.


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5.7.2.1.3
Other Grade 3/4 Non-Hematologic Toxicity
Other non-hematologic Grade 3/4 toxicity should be managed as per local SmPC 
guidelines and institutional standard practices.  
Table 19.
Suggested Guidelines for Carboplatin/Etoposide Dose Delay or 
Reduction
Adverse Event
Carboplatin Dose
Etoposide Dose
ANC < 1,500/mm3 Day 1 of 
Cycle
Hold next cycle until ANC 
≥1,500/mm3.
Hold next cycle until ANC 
≥1,500/mm3.
Treatment delays of > 7 days 
due to neutropenia
Implement Dose Reduction 1 for 
1st episode.
Implement Dose Reduction 1 for 
1st episode and Dose Reduction 2 for 
2nd episode.  
Grade 3/4 febrile 
neutropenia with ANC 
< 500/mm3, requiring IV 
antibiotics
Implement Dose Reduction 1 for 
1st episode.  Initiate Prophylactic G-CSF 
after 1st episode.
Implement Dose Reduction 1 for 
1st episode and Dose Reduction 2 for 
2nd episode.  Initiate Prophylactic 
G-CSF after 1st episode.
Grade 3 nausea, vomiting or 
Grade 4 vomiting
Hold next cycle until resolution to 
Grade 1 or better.  If more than 2 weeks 
dose delay is required consult with 
AbbVie TA MD.
Hold next cycle until resolution to 
Grade 1 or better.  If more than 
2 weeks dose delay is required consult 
with AbbVie TA MD.
Platelets < 100,000/mm3 Day 
1 of Cycle
Hold next cycle until platelets 
≥100,000/mm3.
Hold next cycle until platelets 
≥100,000/mm3.
Grade 4 thrombocytopenia
Implement Dose Reduction 1 for 
1st episode.
Implement Dose Reduction 1 for 
1st episode and Dose Reduction 2 for 
2nd episode.
Bilirubin  > 1.5 – 3.0 × ULN
No Change
Reduce dose to 50 mg/m2
Bilirubin > 3 – 5 × ULN
No Change
Reduce dose to 30 mg/m2
Bilirubin > 5 × ULN
Hold if bilirubin does not improve to 
≤5 × ULN within 3 weeks of 
first occurrence, discontinue protocol 
therapy
Hold if bilirubin does not improve to 
≤ 5 × ULN within 3 weeks of 
first occurrence, discontinue protocol 
therapy
Any other Grade 3/4 toxicity
Per local SmPC/institution guidelines
Per local SmPC/institution guidelines
Section 6.1.2  Deaths
Last paragraph previously read:
During survival follow-up, deaths attributed to progression of disease under study should 
be recorded only on the Study Completion/Early Discontinuation eCRF.


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Has been changed to read:
During survival follow-up, deaths should be recorded on Survival eCRF.
Section 6.1.3  Lack of Efficacy or Worsening of Disease Under Study
Add:  new last sentence
Refer to Appendix F for listing of events expected with progression of ED SCLC.
Section 6.1.4  Serious Adverse Events
In-text table, "Death of Subject" previously read:
An event that results in the death of a subject when not related to ED SCLC.
Has been changed to read:
An event that results in the death of a subject.
Section 6.2  Adverse Events Expected Due to SCLC or Progression of SCLC
Last paragraph previously read:
These adverse events may occur alone or in various combinations and are considered 
expected adverse events in SCLC subjects.
Has been changed to read:
These adverse events may occur alone or in various combinations and are considered 
expected adverse events in SCLC subjects but will not be subject to expedited reporting.  
These data will be captured as efficacy assessment data only.
Section 6.3  Adverse Event Severity
Last paragraph previously read:
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.


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Has been changed to read:
For all reported serious adverse events that increase in severity, the SAE supplemental 
eCRFs also need to be updated and need to include the new AE serial number.
Section 6.4  Relationship to Study Drug
In-text table previously read:
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.
Has been changed to read:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment and potential alternative 
causes there is insufficient evidence (information to suggest a 
causal relationship.
Section 7.0  Protocol Deviations
"Primary Contact:" previously read:
Primary Contact:
1 North Waukegan Road
North Chicago, IL  60064
Office:
Fax:
Email:


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Has been changed to read:
Primary Contact:
1 North Waukegan Road
North Chicago, IL  60064
Office:
Fax:
Email:
Section 8.1.1.1  Demographics
Previously read:
All baseline summary statistics and analyses will be based on characteristics obtained 
prior to the initiation of study drug (or randomization for non-treated subjects).  Unless 
otherwise stated, baseline for a given variable will be defined as the last value for that 
variable obtained prior to the first dose of study drug.
Has been changed to read:
Continuous demographic data (e.g., age, height, and weight) will be summarized with 
means, standard deviations, medians, and minimum and maximum values.  Frequencies 
and percentages will be computed for categorical data (e.g., sex, race, and performance 
status).
Smoking history can be defined as current smoker (subject who has smoked within the 
last 12 months and has more than 100 smoking events [for example, cigarettes] in their 
lifetime), never smoked (subject with a lifetime smoking history of ≤ 100 smoking events 
[for example, cigarettes] in lifetime) and past smoker (subject who has not smoked in past 
12 months and has more than 100 smoking events [for example, cigarettes] in their 
lifetime).


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Section 8.1.2.1  Primary Efficacy Endpoint
Last paragraph previously read:
Progression-free survival will be defined as the number of days from the date of 
randomization to the date of earliest disease progression (radiographic progression per 
RECIST version 1.1 or clinical disease progression) or death.  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.  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 available disease progression assessment 
(radiographic or clinical).
Has been changed to read:
Progression-free survival will be defined as the number of days from the date of 
randomization to the date of earliest disease progression (radiographic progression per 
RECIST version 1.1) or death.  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.  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 available radiographic disease progression assessment.
Section 8.1.2.3  Tertiary Efficacy Endpoints
Subsection Duration of Overall Response
First sentence previously read:
Duration of overall response will be defined as the number of days from the date of 
first response (CR or PR) to the earliest documentation of progressive disease 
(radiographic or clinical).  
Has been changed to read:
Duration of overall response will be defined as the number of days from the date of 
first response (CR or PR) to the earliest documentation of radiographic progressive 
disease.  


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Section 8.2  Determination of Sample Size 
Subsection Phase 2
Subsection title previously read:
Phase 2
Has been changed to read:
Phase 2 Randomized Double-Blind
Section 13.0  Completion of the Study
Last paragraph, first sentence previously read:
The end-of-study is defined as the date of the last subject's last visit.  
Has been changed to read:
The end-of-study is defined as the date of the last subject's last on-site visit.  
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
GDSM
Clinical
Clinical
Clinical
Biometrics
Statistics
Pharmacokinetics


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Has been changed to read:
Name
Title
Functional Area
GDSM
Clinical
Clinical
Clinical
Biometrics
Statistics
Pharmacokinetics
Appendix C.  RECIST (Version 1.1) for Tumor Response (PFS)
Subsection Methods of Measurement
First and second paragraph previously read:
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.
Has been changed to read:
Conventional CT with contrast 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.


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If prior to enrollment, it is known that 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 made.  
This decision should be guided by the tumor type under investigation and the anatomic 
location of the disease and the outcome of the decision should be communicated to 
AbbVie.



SAP_001.pdf: 
Veliparib
M14-361 – Statistical Analysis Plan
Version 1.0 – 15 Nov 2018
1
1.0
Title Page
Statistical Analysis Plan
Study M14-361
A Phase 1 Dose Escalation and Phase 2 Randomized 
Double-Blind Study of Veliparib in Combination with 
Carboplatin and Etoposide as a Therapy of 
Treatment-Naïve Extensive Stage Disease Small Cell 
Lung Cancer (ED SCLC)
Date:  15 Nov 2018
Version 1.0
NCT02289690


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M14-361 – Statistical Analysis Plan
Version 1.0 – 15 Nov 2018
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2.0
Table of Contents
1.0
Title Page ...............................................................................1
2.0
Table of Contents ..................................................................2
3.0
Introduction...........................................................................5
4.0
Study Objectives, Design and Procedures............................6
4.1
Objectives .............................................................................................. 6
4.2
Design Diagram ..................................................................................... 7
4.3
Sample Size............................................................................................ 9
4.4
Interim Analysis..................................................................................... 9
5.0
Analysis Populations ...........................................................10
5.1
Definition for Analysis Population ....................................................... 10
5.2
Variables Used for Stratification of Randomization .............................. 10
6.0
Analysis Conventions ..........................................................10
7.0
Demographic and baseline characteristics, medical 
history, prior oncological therapies, and concomitant 
medications ..........................................................................13
7.1
Demographic and Baseline Characteristics ........................................... 13
7.2
Medical History.................................................................................... 14
7.3
Prior oncological therapies, concomitant medications, and Post-
Treatment Therapies............................................................................. 14
8.0
Subjects Disposition ............................................................15
9.0
Study Drug Exposure..........................................................16
10.0
Efficacy Analysis .................................................................19
10.1
General considerations ......................................................................... 19
10.2
Testing Hierarchy................................................................................. 20
10.3
Definition of Efficacy Endpoints .......................................................... 21
10.4
Primary Efficacy Analysis.................................................................... 23
10.4.1
Progression-Free Survival (Arm A versus Arm C)................................ 23
10.5
Secondary Efficacy Analyses ............................................................... 23
10.5.1
Progression-Free Survival (Arm B versus Arm C) ................................ 23
10.5.2
Objective Response Rate (Arm A vs Arm C and Arm B vs 
Arm C)................................................................................................. 24


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10.5.3
Overall Survival (Arm A versus Arm C and Arm B versus 
Arm C)................................................................................................. 24
10.6
Tertiary Efficacy Analyses ................................................................... 24
10.6.1
Duration of Overall Response............................................................... 24
10.6.2
Progression-Free Survival (Arm A versus Arm B)................................ 24
10.6.3
Overall Survival (Arm A versus Arm B)............................................... 24
10.6.4
ECOG Performance Status (Arm A vs Arm C and Arm B vs 
Arm C)................................................................................................. 25
10.7
Efficacy Subgroup Analysis ................................................................. 25
10.8
Additional Efficacy Analysis................................................................ 26
11.0
Safety Analysis.....................................................................26
11.1
General considerations ......................................................................... 26
11.2
Analysis of Adverse Events.................................................................. 26
11.3
Deaths.................................................................................................. 27
11.4
Analysis of Laboratory......................................................................... 28
12.0
Timing of Efficacy Analyses and Safety Evaluations ........28
13.0
References............................................................................29
14.0
Appendix..............................................................................30
14.1
DMC Charter 2017............................................................................... 30
14.1.1
Introduction.......................................................................................... 33
14.1.2
Membership ......................................................................................... 33
14.1.2.1
Members .............................................................................................. 33
14.1.2.2
Duration of Membership....................................................................... 34
14.1.3
Role of the DMC.................................................................................. 34
14.1.3.1
Safety Monitoring Guidelines............................................................... 35
14.1.4
ORGANIZATIONAL FLOW............................................................... 36
14.1.5
MEETINGS ......................................................................................... 36
14.1.5.1
Organizational Meeting ........................................................................ 36
14.1.5.2
DMC Review Meetings........................................................................ 36
14.1.5.2.1
Open Session........................................................................................ 37
14.1.5.2.2
Closed Session ..................................................................................... 37
14.1.6
Communication.................................................................................... 38
14.1.6.1
Meeting minutes................................................................................... 38


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14.1.6.2
Recommendations ................................................................................ 38
14.1.7
APPENDIX.......................................................................................... 40
14.1.8
APPENDIX.......................................................................................... 42
14.2
List of Abbreviations............................................................................ 42
List of Tables
Table 1.
Treatment Schema for Combination Cycles in Phase 2 ........................... 8
Table 2.
Time Windows for ECOG performance status...................................... 13
Table 3.
Definition of Actual Total Dose, Planned Total Dose, And Dose 
Intensity for Study Drugs Prior To Maintenance Period........................ 17
Table 4.
Definition of Actual Total Dose, Planned Total Dose, And Dose 
Intensity for Veliparib/Placebo in Maintenance Period ......................... 18
Table 5.
Alpha-spending Boundary (One-sided p-value) for Each Ranked 
Endpoint............................................................................................... 20


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3.0
Introduction
Veliparib is a novel small molecule and also a potent oral PARP inhibitor that delays the 
repair of DNA damage induced by chemotherapeutic agents, including 
alkylating/methylation agents (TMZ, cyclophosphamide), crosslinking agents (cisplatin, 
carboplatin), platinum agents, topoisomerase inhibitors (irinotecan), and radiation.  
Nonclinical efficacy with veliparib in combination with these agents has been 
demonstrated across an array of tumor types, including melanoma, glioma, prostate, 
breast, and colon.
Preclinical studies data suggest the addition of veliparib to carboplatin would enhance the 
efficacy of carboplatin 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.  On the other hand, etoposide in combination with other approved 
chemotherapeutic agents is FDA approved as first-line treatment in subjects with SCLC.  
Carboplatin in combination with etoposide (both IV and oral formulations) has been 
extensively tested in randomized clinical trials in SCLC as well as in other tumor types.
Therefore, this study (Study M14-361) is being conducted to assess efficacy and toxicity 
of veliparib versus placebo in combination with carboplatin and etoposide in the treatment 
of subjects with ED SCLC who are previously untreated.
This 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.  Analyses will be performed using 
SAS® Version 9.3 (SAS Institute, Inc., Cary, NC) or later under the UNIX operating 
system.


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4.0
Study Objectives, Design and Procedures
4.1
Objectives
The primary objective of the study is to evaluate if the addition of veliparib in 
combination with carboplatin and etoposide followed by veliparib maintenance 
monotherapy results in improved progression free survival (PFS) versus placebo in 
combination with carboplatin and etoposide followed by placebo monotherapy in subjects 
with treatment-naïve ED SCLC. 
The secondary objectives of the study are to evaluate (1) if veliparib in combination with 
carboplatin and etoposide followed by placebo monotherapy results in improved PFS 
versus placebo in combination with carboplatin and etoposide followed by placebo 
monotherapy in subjects with treatment-naïve ED SCLC; (2) if veliparib in combination 
with carboplatin and etoposide results in improved objective response rate (ORR) versus 
placebo in combination with carboplatin and etoposide, at the time of completion of 
maintenance therapy, or completion of combination therapy if subject was not involved in 
maintenance phase.  In protocol v.5 dated 22 NOV 2016, Chapter 4.0, objective response 
rate is to be evaluated by the combination therapy for all subjects.  We modified the 
analysis period by adding maintenance phase following ITT (intent-to-treat) population 
principle to avoid observation bias; (3) if veliparib in combination with carboplatin and 
etoposide followed by veliparib maintenance monotherapy results in improved overall 
survival (OS) versus placebo in combination with carboplatin and etoposide followed by 
placebo monotherapy; (4) if veliparib in combination with carboplatin and etoposide 
followed by placebo monotherapy results in improved OS versus placebo in combination 
with carboplatin and etoposide followed by placebo monotherapy; (5) to further evaluate 
the safety of veliparib in combination with carboplatin and etoposide followed by 
veliparib maintenance monotherapy.
The tertiary objectives are to (1) evaluate if veliparib in combination with carboplatin and 
etoposide followed by veliparib maintenance monotherapy results in improved duration of 
overall response (DOR) versus placebo in combination with carboplatin and etoposide 


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followed by placebo monotherapy; (2) evaluate if veliparib in combination with 
carboplatin and etoposide followed by placebo monotherapy results in improved DOR 
versus placebo in combination with carboplatin and etoposide followed by placebo 
monotherapy; (3) compare PFS and OS of subjects treated with veliparib in combination 
with carboplatin and etoposide followed by veliparib maintenance to PFS and OS of 
subjects treated with veliparib in combination with carboplatin and etoposide followed by 
placebo maintenance; (4) evaluate ECOG performance status.
4.2
Design Diagram
This is a Phase 1 dose escalation and Phase 2 randomized double-blind study of veliparib 
in combination with carboplatin and etoposide and maintenance veliparib monotherapy.  
The veliparib dose and schedule for the Phase 2 was determined to be 240 mg BID (twice 
a day) on a 14-day schedule for up to 6 cycles (21 days per cycle) based on the analysis of 
Phase 1 data.  This SAP is only for Phase II part of the study.  Analysis for Phase I part 
will be presented in CSR Phase I portion and when the study is complete PK analysis will 
be drafted in Appendix 16.1__9.1.
Approximately 180 adult male or female subjects with treatment-naïve ED SCLC will be 
selected to participate in the study to meet scientific and regulatory objectives without 
enrolling an undue number of subjects in alignment with ethical considerations.  Subjects 
will be randomized in a 1:1:1 ratio to one of three treatment arms:
Arm A:  veliparib 240 mg BID in combination with carboplatin/etoposide for up to 
6 cycles followed by veliparib 400 mg BID monotherapy;
Arm B:  veliparib 240 mg BID in combination with carboplatin/etoposide for up to 
6 cycles followed by placebo monotherapy;
Arm C:  placebo in combination with carboplatin/etoposide for up to 6 cycles followed by 
placebo monotherapy;


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Subject randomization for Phase 2 will be stratified by gender and baseline lactate 
dehydrogenase (LDH) level, that is, > Upper Limit of Normal (ULN) versus ≤ ULN.  The 
stratification factors used for the randomization should be the last values on or prior to the 
date of randomization and should be consistent with those on the eCRF.
The detailed dosing schedules for these three groups of the study are presented below in 
Table 1.
Table 1.
Treatment Schema for Combination Cycles in Phase 2
Days
–2
–1
1
2
3
4 - 12
Veliparib/Placebo
240 mg 
BID
240 mg 
BID
240 mg 
BID
240 mg 
BID
240 mg 
BID
240 mg 
BID
Carboplatin
Once
Etoposide
Once
Once
Once
Subjects in all Phase 2 study arms will receive a minimum of 4 cycles of combination 
therapy unless disease progression or unacceptable toxicity warrants earlier 
discontinuation from the treatment. Additional 2 cycles of combination therapy (e.g., up 
to a total of 6 cycles) may be administered at the investigators discretion if subject status 
at the completion of initial 4 cycles warrants continued combination treatment and/or if 
local SOC guidelines require 6 cycles of platinum-based therapy.  Subjects enrolled in 
these additional 2 cycles of combination therapy will receive veliparib at 400 mg BID 
continuous dosing (21-day cycles) (Arms A), or matching placebo (Arms B and C) as per 
treatment arm assignment, until disease progression (PD) or unacceptable adverse events 
(AEs) occur.
All subjects will remain on study until reaching a protocol-defined event of PD or AE due 
to veliparib or carboplatin/etoposide.  Otherwise, appropriate dose modifications or 
dosing delays should be managed according to protocol.  Subsequent cycles of therapy 
will be administered if there is no evidence of PD and observed toxicities have recovered 
adequately as described in protocol.


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4.3
Sample Size
Assuming a median PFS of 5.5 months for placebo in combination with carboplatin and 
etoposide followed by placebo monotherapy (Arm C) and a hazard ratio of 0.63 for 
veliparib in combination with carboplatin and etoposide followed by veliparib 
monotherapy (Arm A) versus Arm C, a total of 85 PFS events will provide an least 
80% power to detect a statistically significant difference between Arm A and Arm C at a 
one-sided α = 0.1.
Further assuming a hazard ratio of 0.75 for veliparib in combination with carboplatin and 
etoposide followed by placebo monotherapy (Arm B) versus Arm C, a total of 126 PFS 
events will be observed across all three arms at the time when 85 PFS events are observed 
for Arm A and Arm C combined.  A total of approximately 180 subjects (60 subjects per 
treatment arm) will be enrolled into the study to obtain the 126 PFS events.
4.4
Interim Analysis
A safety DMC (Data Monitoring Committee) was set up for the Phase 2 portion of the 
study to review the aggregate unblinded safety data.  The initial safety DMC review will 
occur once at least 30 Phase 2 subjects have met criterion 1) and 2), or 3), or 4).
1). Received at least one dose of veliparib/placebo;
2). Started Cycle 5; or
3). Discontinued (not death) prior to Cycle 5 due to AE not related disease progression; or
4). Death prior to Cycle 5 not due to disease progression. 
Data cutoff date was Aug. 25th, 2017 and the safety DMC meeting was held on 
Oct. 18th, 2017.  Based on this initial safety DMC review, it's decided that it's not 
necessary to have another safety review before DB lock.  The details of the safety DMC 
setup and procedure was outlined in Appendix 14.1.7. 


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5.0
Analysis Populations
5.1
Definition for Analysis Population
Two study populations will be analyzed, respectively defined as follows:
Intent-To-Treat (ITT) population – all subjects who were randomized using an IRT 
(interactive response technology) system.  The data from ITT population will be analyzed 
by the treatment group assignment given at the time of randomization, even if the subject 
takes the incorrect drugs that do not match the assigned treatment, or does not receive any 
treatment, or does not follow the protocol until completion.
As-Treated (AST) population – all subjects who were randomized by IRT system and 
took at least 1 dose of study drug (veliparib/placebo).  The data from AST population will 
be analyzed by the actual treatment that subject received.
5.2
Variables Used for Stratification of Randomization
Subject randomization were stratified by LDH level (> ULN versus ≤ ULN), and gender 
(female versus male).
6.0
Analysis Conventions
Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a one-sided P value ≤ 0.1 (when rounded to one decimal place).  The date 
of randomization is defined as the date that the IRT issued a subject number.
Unless otherwise specified, demographic and baseline characteristics, medical history, 
prior oncological therapies, and other medications, as well as all efficacy analyses will be 
performed on Phase 2 ITT population, and all safety analyses will be performed on 
Phase 2 AST population.  Summary data will be presented for each of the three treatment 
arms (A, B, C), or as indicated otherwise.


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Definition of Study Drug
Unless otherwise specified, the study drug in this document refers to veliparib/placebo, 
and carboplatin/etoposide.  The first dose date of study drug for combination period is 
defined as the date of the 1st dose of veliparib/placebo or carboplatin/etoposide received 
during combination period, whichever occurs first.  The last dose date of study drug for 
combination period is defined as the date of the last dose of veliparib/placebo or 
carboplatin/etoposide received during combination period, whichever occurs later.  The 
first dose date of study drug for maintenance period is defined as the date of the 1st dose 
of veliparib/placebo received during maintenance period.  The last dose date of study drug 
for maintenance period is defined as the date of the last dose of veliparib/placebo received 
during maintenance period. 
Definition of Post-Treatment Therapy
Unless otherwise specified, the post-treatment therapy (excluding surgical and radiation 
therapy) in this document refers to the therapy after the last dose of study drug.
Stratification Factor for Efficacy Analyses
Baseline LDH (≤ ULN versus > ULN) will be used in all stratified analyses of the 
efficacy endpoints.  The stratification factor value under which the subject is randomized 
by the IRT will be used in the efficacy analyses.
Dealing with Multiple Values on the Same Day
If multiple lab values on the same day are available for a post-baseline measurement, then 
the value with the highest NCI CTCAE grade (or worst scenario) will be used in the 
assessment of shift from baseline to post-baseline.  Arithmetic averages will be taken for 
the mean change analyses in lab values and vital signs values.


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Definition of Baseline
All baseline summary statistics and analyses will be based on baseline for each variable.  
Unless otherwise stated, baseline for a given variable will be defined as the last value for 
that variable obtained on or prior to the date of first dose of study drug (or randomization 
date for untreated subjects). 
Unless otherwise specified, baseline in rest of the document refers to the Baseline defined 
here.
Definition of Final Value 
For ECOG, laboratory and vital signs variables, final value is defined as the last non-
missing observation collected after the first dose of study drug in combination period to 
the 30 days after the last dose of study drug in combination period, or the last dose of 
veliparib/placebo in maintenance period if subject received any maintenance 
monotherapy.
Unless otherwise specified, final value in rest of the document refers to the Final Value 
defined here.
Definition of Analysis Windows
All time points and corresponding time windows are defined for each cycle are based on 
Cycle Rx Day 1 of each cycle.
Visit-wise longitudinal analyses such as change from baseline to all post-baseline 
assessments will be performed for blood chemistry and hematology parameters, as well as 
urinalysis and vital sign parameters.  If more than one measurement exists for a subject on 
a particular day, an arithmetic average will be calculated.  This average will be considered 
to be that subject's measurement for that day. 


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The time windows specified in Table 2 describe how the data will be assigned to the 
protocol specified visits.  Analysis time windows are constructed using the following 
algorithm:
●
Determine the nominal Cycle Rx Day for each scheduled visit.
●
Determine the window around a specific nominal Cycle Rx Day as in Table 2.
●
If more than one assessment is included in a time window, the assessment 
closest to the nominal day should be used.  If there are two observations 
equally distant to the nominal day, the later one will be used in analyses.
Table 2.
Time Windows for ECOG performance status
Scheduled Visit
Nominal Cycle Rx Day
Time Window
(Cycle Rx Day Range)
Baseline
Baseline
Per baseline definition
Combination Cycle X Day 1
Rx day of Combination 
Cycle X Day 1
[–5, 1]
Combination Cycle X Day 8*
Rx day of Combination 
Cycle X Day 8
[–3, +3]
Maintenance Cycle XX Day 1
Rx day of Maintenance 
Cycle 1 Day 1
[–5, +5]
Final Value
NA
From baseline to final value per 
definition
Note:
X refers to 2, 3, 4 … XX refers to 1, 2, 3, 4 … 
7.0
Demographic and baseline characteristics, medical 
history, prior oncological therapies, and 
concomitant medications 
7.1
Demographic and Baseline Characteristics
Categorical demographic and baseline characteristic variables will be summarized with 
the number and percentage of subjects, including those with missing information.  
Continuous demographic and baseline variables will be summarized with summary 


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statistics (mean, standard deviation, median, minimum and maximum).  There will be no 
statistical comparison for demographic and baseline characteristics.
Continuous demographic variables include age, baseline height, weight.  Categorical 
demographic variables include gender (male, female) and race (White, Black, Asian, 
American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander).
Continuous baseline characteristics include baseline tumor burden (based on the sum of 
baseline target lesion sizes (mm)), and number of baseline lesion sites (for one subject, 
one site counts as one regardless of the number of lesions that it carries).
Categorical baseline characteristics include baseline LDH value (≤ ULN, > ULN), 
baseline ECOG performance (0, 1), medical/surgical history (yes, no), history of other 
cancer (yes, no), number of metastatic sites (0/1, ≥ 2), baseline diagnose stage M (M0, 
M1, unknown), tobacco use (former, current, never, unknown), and alcohol use (former, 
current, never, unknown). 
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 number and percentage of subjects with a particular PT will be summarized by 
alphabetical order of SOCs and alphabetical order of PTs within each SOC.
Subjects reporting more than one PTs within a SOC will be counted only once for that 
SOC.  There will be no statistical comparison for medical history.
7.3
Prior oncological therapies, concomitant medications, and 
Post-Treatment Therapies 
The number and percentage of subjects who took at least one dose of concomitant 
medication other than study drug, and subjects who received any post treatment therapy, 


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will be summarized separately by the generic medication name coded by WHO 
dictionary.
The number and percentage of subjects who have prior oncological therapies will be 
summarized by generic medication name and treatment setting (adjuvant, neo-adjuvant, 
metastatic).  In addition, the best response of any therapies prior to study drug (or 
randomization for non-treated subjects) will be summarized.
There will be no statistical comparison for prior oncological therapies and other 
medications.
8.0
Subjects Disposition 
Analyses for the subject disposition will be performed on ITT population.  The screen 
failure reasons will be summarized for the screen failure subjects separately.  The number 
and percentage of subjects will be summarized overall, by treatment arm, and by country 
for each of the following categories:
●
Subjects who screen failed
●
Subjects who were randomized into the study
●
Subjects who never received any study drug
●
Subjects who received randomized study drug
●
Subjects who received study drug other than randomized
●
Subjects who were in maintenance phase
●
Subjects who discontinued study drug due to all reasons and primary reason
●
Subjects who discontinued carboplatin due to all reasons and primary reason
●
Subjects who discontinued etoposide due to all reasons and primary reason
●
Subjects who discontinued maintenance veliparib/placebo due to all reasons 
and primary reason
●
Subjects who discontinued study due to all reasons and primary reason


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9.0
Study Drug Exposure 
Analyses for the study drug exposure will be performed on AST population.  Some 
definitions are provided as follows.
1.
Combination therapy period
The following calculations only include data prior to maintenance monotherapy.
a.
Total number of cycles a certain subject exposed to veliparib/placebo:  total
number of cycles during which subject received at least one dose of 
veliparib/placebo.
b. Duration of veliparib/placebo of a certain subject:  last dose date of 
veliparib/placebo of this subject minus the first dose date of veliparib/placebo of 
this subject plus 1.
c.
Total number of days a certain subject exposed to veliparib/placebo overall, and 
by cycle, respectively:  total number of days this subject received 
veliparib/placebo (excluding days not on study drug) overall, and by cycle, 
respectively.
d. Average daily dose of veliparib/placebo of a certain subject overall, and by cycle, 
respectively:  total administered dose of veliparib/placebo of this subject divided 
by total number of days this subject exposed to veliparib/placebo overall, and by 
cycle, respectively. 
e.
Dose intensity (DI) of veliparib/placebo of a certain subject is defined as the ratio 
of ATD (actual total dose) of veliparib/placebo of this subject and PTD (planned 
total dose) of veliparib/placebo of this subject, expressed as a percentage (%).  
ATD and PTD of veliparib/placebo will be defined in Table 3.
For carboplatin and etoposide, analysis of DI will be performed.  Dose intensity (DI) of 
carboplatin/etoposide of a certain subject is defined as ratio of ATD of 
carboplatin/etoposide of this subject and PTD of carboplatin/etoposide of this subject, 


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expressed as a percentage (%).  ATD and PTD of carboplatin/etoposide will be defined in 
Table 3.
Descriptive statistics (mean, standard deviation, median, and range) will be used to 
summarize total number of cycles, duration, and total number of days, average daily dose, 
and DI of veliparib/placebo in combination phase, and DI of carboplatin/etoposide in 
combination phase.  The actual total dose (ATD), planned total dose (PTD), and dose 
intensity (DI) for veliparib/placebo, carboplatin and etoposide prior to maintenance 
monotherapy period are presented in Table 3.
Table 3.
Definition of Actual Total Dose, Planned Total Dose, And Dose 
Intensity for Study Drugs Prior To Maintenance Period
ATD
(Actual Total Dose)
PTD
(Planned Total Dose)
DI (Dose Intensity)
Veliparib/placebo
Actual total dose (mg)
480 mg* 14* (actual 
number of 
veliparib/placebo 
combination cycles –1) 
+480 mg* actual 
veliparib/placebo dosed 
days in the last 
combination cycle
100*ATD/PTD
Carboplatin
Actual total AUC 
(mg/mL/min)
5 mg/mL/min* actual 
number of chemo 
cycles
100*ATD/PTD
Etoposide
Actual total dose 
(mg/m2)
3*100 mg/m2* actual 
number of chemo 
cycles
100*ATD/PTD
Actual number of veliparib/placebo combination cycles refers to the number of cycles 
subjects are exposed to veliparib/placebo prior to the initiation of maintenance therapy (if 
any) as captured on drug administration pages in EDC.
Actual total dose of veliparib/placebo in combination cycles is calculated excluding 
premature veliparib/placebo doses, that being said, we exclude any veliparib/placebo dose 
that was administered 2 days (not necessarily continuous doses) before the start date of 


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carboplatin or etoposide in that cycle, whichever occurs first.  If a subject received no 
carboplatin and etoposide in a cycle, which indicates a protocol deviation, then 
veliparib/placebo administered in this cycle will be excluded.
Actual number of chemo cycles refers to the number of cycles subjects exposed to 
carboplatin/etoposide as captured on drug administration pages in EDC.
2.
Maintenance monotherapy period
Duration, total number of days, average daily dose, and DI of veliparib/placebo as 
described above will be summarized by descriptive statistics for veliparib/placebo in 
maintenance monotherapy.
The actual total dose (ATD), planned total dose (PTD), and dose intensity (DI) for 
veliparib/placebo in the maintenance monotherapy period is presented in the Table 4.
Table 4.
Definition of Actual Total Dose, Planned Total Dose, And Dose 
Intensity for Veliparib/Placebo in Maintenance Period
ATD
(Actual Total Dose)
PTD
(Planned Total Dose)
DI
(Dose Intensity)
veliparib/placebo
Actual total dose (mg)
800 mg* duration of 
maintenance therapies
100*ATD/PTD
Duration of maintenance therapy is calculated by subtracting the start date of maintenance 
therapy from the end date of maintenance therapy plus 1.
3.
Dose reduction, delay, and interruption,
The numbers and percentages of subjects having dose reduction or interruption or delay 
for each study drug will be summarized for each treatment arm prior to maintenance 
monotherapy period.  If a subject has any dose reduction from the previous dose of a 
certain drug, this subject will be considered as having experienced dose reduction of this 
drug.  If the difference between the first dose dates of two adjacent cycles of a certain 


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drug is more than 21 days, the subject will be considered as having experienced a dose 
delay of this drug.  If a subject skips one or more consecutive dosing days of any drug 
within a cycle, then this subject is considered as having dose interruption of this drug. 
10.0
Efficacy Analysis
10.1
General considerations
Unless otherwise noted, for all statistical analyses, statistical significance will be 
determined by a one-sided P value ≤ 0.1 (when rounded to two decimal places).  
Confidence intervals will be two-sided 80% for all descriptive statistics.  The date of 
randomization is defined as the date that the IRT issued a subject number.
The efficacy analyses will be performed on Phase 2 ITT population and presented by 
treatment arm.  All randomized subjects will be included unless otherwise specified.  The 
dosing schedules for each of the three arms are listed in detail in Section 4.2.
After observing 95 PFS events (75% of 126), a model-based prediction was performed to 
estimate the approximate date of the 126th PFS events across all 3 arms.  The prediction 
estimated Sep. 14th, 2018 as the date of 126 PFS events across the three arms.  Unless 
otherwise specified, Sep. 14th, 2018 will be the cutoff date for all efficacy analyses.
For all efficacy endpoints except OS, if a subject's blind has prematurely broken by sites 
before cutoff date, the date of premature blind break will be set as the cutoff date for that 
subject.
If a subject starts any systemic anti-cancer therapy post-discontinuation of study therapy, 
then PFS and DOR will be censored at last non-missing tumor assessment prior to the 
initiation date of the new systemic anti-cancer therapy; similarly ORR/DOR will be based 
only on tumor assessment prior to the initiation of any new systemic anti-cancer therapy.


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10.2
Testing Hierarchy 
This is a single primary efficacy endpoint (PFS, Arm A vs Arm C) study.  Survival data (a 
total of approximately 136 death events targeted across all three treatment arms) will not 
be mature at the PFS primary analysis time, thus OS analysis at the time of PFS primary 
analysis will be considered as an interim analysis.  If statistical test is significant 
(one-sided P value ≤ 0.1) for the primary efficacy endpoint, then the fixed sequence 
testing procedure will be performed with a significance level of 0.1 (one-sided) for key 
secondary efficacy endpoints sequentially.  If primary PFS (Arm A vs. Arm C) is not 
significant, then statistical significance will not be declared for any of the secondary 
efficacy endpoints. 
Hierarchical ranking and alpha spending for primary and each secondary endpoint at the 
time of PFS primary analysis and OS primary analysis is presented in Table 5.
Table 5.
Alpha-spending Boundary (One-sided p-value) for Each Ranked 
Endpoint
Endpoint
Timing
PFS Primary Analysis
(approximately 126 PFS events 
across all 3 arms)
OS Primary Analysis
(approximately 136 deaths 
across all 3 arms)
PFS (A vs C)
0.1
NA
OS (A vs C)
0.0001 (administrative purpose)
0.1
PFS (B vs C)*
0.1
OS (B vs C)
0.0001 (administrative purpose)
0.1
ORR (A vs C)*
0.1
ORR (B vs C)*
0.1
(A, B, and C correspond to the three treatment arms, respectively.)
*
Analysis sets for these three tests are the same as PFS (A vs C).


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10.3
Definition of Efficacy Endpoints
PFS (progression-free survival):  the number of days from the date of randomization to 
the date of earliest radiographic disease progression or death provided no radiographic 
disease progression occurred.
All events of disease progression before the initiation of anti-cancer post-treatment 
therapy 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 immediately after a subject misses two or more consecutive 
disease progression assessments (e.g., 84 days = 12 weeks if previous tumor scan were 
prior to or on Week 24 Day 7 (Day 168), 105 days = 15 weeks if previous tumor scan 
were in between of Week 25 Day 1 and Week 30 Day 7 (Day 210), and 126 days = 
18 weeks if previous tumor scan were on or after Week 31 Day 1), then this subject's data 
will be censored at the last disease progression assessment prior to the missing disease 
progression assessments, or at randomization if disease progression occurred at the first 
post-baseline disease assessment.  All events of death before the initiation of anti-cancer 
post-treatment therapy will be included for subjects (whether had post-baseline tumor 
assessment or not) who had not experienced disease progression, regardless of whether 
the event occurred while the subject was still taking study drug or had previously 
discontinued study drug.  Similar to disease progression, if a death event occurs 
immediately after a subject misses two or more consecutive disease progression 
assessments (length of gap is calculated the same way as disease progression), then this 
subject's data will be censored at the last tumor assessment before death, or at 
randomization provided subject did not have any post-baseline disease assessment.
If a subject did not have an event of disease progression nor has the subject died on or 
prior to the cutoff of PFS analysis, this subject's data will be censored at the date of 
his/her last disease assessment or randomization date provided subject did not have any 
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OS (overall survival):  the number of days from the date of randomization to the date of 
death.  All events of death will be included. 
If a subject did not die on or prior to the cutoff of OS analysis, this subject's data will be 
censored at the date of his/her last known alive date, which is defined as the last date of 
the last survival follow-up visit, the start date of the last AE, the start date or end date of 
the last dose of any study drugs, the last lab and vital sign collection date, or the last 
disease assessment date, whichever occurs the last.
ORR (objective response rate):  the proportion of randomized subjects with objective 
response (confirmed) as assessed by the investigator using RECIST version 1.1.  
Response includes both CR (complete response) and PR (partial response).  Confirmation 
is required to determine objective response.  Confirmation rules are described as follows,
Confirmed CR:  After the first tumor assessment showing CR, the CR will be considered 
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.
Confirmed PR:  After first tumor assessment showing PR, the PR will be considered 
confirmed if a subsequent tumor assessment also shows CR/PR (irrespective of tumor 
assessment in between that show stable disease) and if the duration of the first PR and the 
next CR/PR is greater than or equal to 28 days.
All ITT subjects will be included in the ORR analysis.  Subjects with no post-baseline 
confirmed response will be identified as non-responders.  Data after the first appearance 
of PD, or the start date of any anti-cancer post-treatment therapy, whichever comes 
earlier, will not be included.
DOR (duration of overall response):  the number of days from the date of the first 
confirmed response (CR or PR) to the earliest documentation of radiographic progressive 
disease or death.  The inclusion and exclusion criteria for PD and death, as well as event 
censoring strategy, are the same as described in PFS endpoint. 


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If a subject is still responding on or prior to the cutoff of DOR analysis, then the subject's 
data will be censored at the date of the subject's last available disease assessment.
Subjects with no post-baseline confirmed response will not be included in the DOR 
analysis.  Data after the first appearance of PD, or the start date of any anti-cancer post-
treatment therapy, whichever comes earlier, will not be included.
10.4
Primary Efficacy Analysis
10.4.1
Progression-Free Survival (Arm A versus Arm C)
Time to PFS will be analyzed by Kaplan-Meier methodology and compared between 
Arm A and Arm C using a two-sided log-rank test stratified by LDH level.  KM plots of 
these two treatment arms will be presented.  Median PFS time and the corresponding 
80% confidence interval will be calculated and constructed via Brookmeyer and Crowley 
(1982).  A hazard ratio estimate of Arm A vs. Arm C and the corresponding 
80% confidence interval will be obtained from a Cox proportional hazards model 
stratified by LDH level.  In addition, progression free survival rates at Month 3 and 6 with 
their corresponding 80% CIs will also be provided using Kaplan-Meier estimation. 
10.5
Secondary Efficacy Analyses
10.5.1
Progression-Free Survival (Arm B versus Arm C)
Time to PFS will be analyzed by Kaplan-Meier methodology and compared between 
Arm B and Arm C using a two-sided log-rank test stratified by LDH level.  KM plots of 
these two treatment arms will be presented.  Median PFS time and the corresponding 
80% confidence interval will be calculated and constructed via Brookmeyer and Crowley 
(1982).  A hazard ratio estimate of Arm B vs. C and the corresponding 80% confidence 
interval will be obtained from a Cox proportional hazards model stratified by LDH level. 


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10.5.2
Objective Response Rate (Arm A vs Arm C and Arm B vs
Arm C)
The objective response rate and corresponding 80% confidence interval will be estimated 
and compared between Arm A and Arm C as well as between Arm B and Arm C, 
respectively, using a two-sided Cochran-Mantel-Haenszel test stratified by LDH level.  In 
addition, waterfall plots depicting best percentage of change in each subject's sum of 
target lesion sizes will be displayed by each treatment arm.
10.5.3
Overall Survival (Arm A versus Arm C and Arm B versus
Arm C)
OS will be analyzed by Kaplan-Meier methodology and compared between Arm A and 
Arm C as well as between Arm B and Arm C using a two-sided log-rank test stratified by 
LDH level.  Median survival time for all three arms will be calculated and corresponding 
80% confidence intervals will be presented.  Hazard ratio estimates (Arm A versus 
Arm C, Arm B versus Arm C) and their corresponding 80% confidence intervals will be 
obtained from a Cox proportional hazards model stratified by LDH level.
10.6
Tertiary Efficacy Analyses
10.6.1
Duration of Overall Response
The distribution of DOR will be estimated for each treatment arm using Kaplan-Meier 
methodology.  Median DOR will be estimated and an 80% confidence interval will be 
presented for each treatment arm.
10.6.2
Progression-Free Survival (Arm A versus Arm B)
A hazard ratio estimate of Arm A vs. Arm B and the corresponding 80% confidence 
interval will be obtained from a Cox proportional hazards model stratified by LDH level.
10.6.3
Overall Survival (Arm A versus Arm B) 
Hazard ratio estimate of Arm A vs. Arm B for OS and the corresponding 80% confidence 
interval will be obtained from a Cox proportional hazards model stratified by LDH level.


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10.6.4
ECOG Performance Status (Arm A vs Arm C and Arm B vs
Arm C)
Mean Change (80% CI) from baseline to each scheduled post-baseline visit (as defined in 
Table 2) will be compared between Arm A and Arm C as well as between Arm B and 
Arm C using ANCOVA with treatment arm as a factor and baseline ECOG value as a 
covariate.
Subjects that do not have a baseline measurement or do not have any post-baseline 
measurements will not be included.  Post-baseline measurements will be excluded after 
30 days of the last dose of veliparib/placebo (including both combination period and 
maintenance period), carboplatin, or etoposide, whichever occurs the last. 
10.7
Efficacy Subgroup Analysis
To evaluate the impact of demographic and baseline characteristics on efficacy, subgroup 
analyses may be performed for OS and PFS between Arm A and Arm C, and presented in 
forest plots with hazard ratio estimate (80% CI) using Cox proportional hazard model for 
each subgroup.  Subgroups defined below may be used for the subgroup analyses:
1.
Schlafen-11 (SLFN11) expression (+, –) via IHC
2.
LP-52 biomarker status (+, –) as determined by HTG technology
3.
Gender (Male, Female)
4.
Age (< 65 years, ≥ 65 years)
5.
Region (US, EU, and the rest of world)
6.
Baseline ECOG performance status (0, 1)
7.
Smoking history (current smoker, never smoked, and past smoker as defined in 
Section 8.1.1.1 in protocol)
8.
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9.
Four cross-over subgroups per gender and LDH categories (LDH > ULN in male, 
LDH > ULN in female, LDH ≤ ULN in male, LDH ≤ ULN in female)
10.
Number of metastatic sites (1, ≥ 2)
10.8
Additional Efficacy Analysis
The following additional efficacy analysis may be performed:
1.
Modified PFS analysis for Arm A & Arm C to consider the initiation of any anti-
cancer post-treatment therapy as an event.
2.
Modified ORR analysis for Arm A & Arm C and DOR analysis for all 3 arms 
where both confirmed and unconfirmed responses are to be considered. 
11.0
Safety Analysis
11.1
General considerations
All safety analyses will be performed on Phase 2 AST population, and will be 
summarized by each treatment arm (A & B & C) for combination period alone.  Safety 
analyses will include all data in the extracted database (no cutoff).  For visit-wise safety 
analyses, the analysis visit widows as described in Table 2 will be used to align data.  
There will be no statistical comparison for safety analysis unless otherwise specified.
11.2
Analysis of Adverse Events
Analyses of adverse events will include only "treatment-emergent" events (TEAE), 
i.e., those that have an onset (worst CTC grade) prior to or on the 30 days of last dose of 
study drug in combination period.  TEAEs will be coded and summarized by preferred 
term according to the Medical Dictionary for Regulatory Activities (MedDRA) adverse 
event coding dictionary.  Subjects reporting more than one AE will be counted only once 
in the overall analysis.  Summary data by each treatment arm will be presented by but not 
limited to the following statistics:


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●
The numbers and percentage of subjects experiencing any TEAE;
●
The numbers and percentage of subjects experiencing grade 3 or 4 TEAEs;
●
The numbers and percentage of subjects experiencing TEAES that investigator 
found having a reasonable possibility related to veliparib/placebo;
●
The numbers and percentage of subjects experiencing grade 3 or 4 TEAES that 
investigator found having a reasonable possibility related to veliparib/placebo;
●
The numbers and percentage of subjects experiencing TEAEs that led to study 
discontinuation due to disease progression or not due to disease progression;
●
The numbers and percentage of subjects experiencing TEAEs that led to 
veliparib/placebo/carboplatin/etoposide discontinuation due to disease 
progression or not due to disease progression;
●
The numbers and percentage of subjects experiencing TEAEs that led to 
veliparib/placebo/carboplatin/etoposide reduction, interruption, or delay.  If an 
AE led to more than one actions, consider them as one;
●
The numbers and percentage of subjects experiencing any serious TEAE;
●
The numbers and percentage of subjects experiencing any serious TEAE that 
investigator found having a reasonable possibility related to veliparib/placebo;
●
The numbers and percentage of subjects experiencing any TEAE of special 
interest;
●
The numbers and percentage of subjects experiencing any grade 3 or 4 TEAE 
of special interest;
●
Listing of TEAEs that led to death;
●
The numbers and percentage of subjects experiencing TEAEs that led to death;
●
The numbers and percentage of subjects experiencing TEAEs that led to death 
that investigator found having a reasonable possibility related to 
veliparib/placebo;
11.3
Deaths
The number of subject deaths will be summarized 1) for deaths occurring within 30 days 
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30 days of last dose of study drug in combination period, 3) for all deceased subjects.  
Death causes under each category will also be summarized.
11.4
Analysis of Laboratory 
Subjects that do not have a baseline measurement or do not have any post-baseline 
measurements will not be included.  Post-baseline measurements collected 30 days after 
last dose of study drug in combination period will not be included.  Last dose here will be 
determined by each analysis period.
Analyses of Shift from Baseline in Clinical Laboratory Data
Where applicable, blood chemistry and hematology determinations will be categorized 
according to NCI CTCAE version 4.0 grades.  The baseline and maximum grades are 
defined respectively as the baseline grade and as the highest (worst) grade during post-
baseline visit on or prior to 30 days of last study drug.  Section 6.0 describes the analysis 
convention for laboratory values used in summary of shift from baseline analyses.  
Baseline NCI CTCAE version 4.0 grades and maximum post-baseline grades, as well as 
shifts from baseline grade 0 - 2 to maximum grade 3 - 4, will be assessed by cross-
tabulation for both chemistry and hematology.  Shifts from baseline grade 0 - 2 to final 
grade 3 - 4 will be assessed by cross-tabulation for Proteinuria. 
Detailed listings of all measurements collected in the extracted database 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.
12.0
Timing of Efficacy Analyses and Safety Evaluations
The model-based prediction estimated Sep. 14th, 2018 as the date of 126 PFS events 
across the three arms.  To operationalize the data acquisition and cleaning efforts in a 
timely manner, all efficacy and safety data through Sep. 14th, 2018 will be retrieved and 
entered into the clinical database prior to breaking the study blind.  When the data 


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collection is completed and reviewed for completeness and all data management quality 
assurance (QA) and quality control (QC) procedures are performed, the study blind will 
be broken and clinical database data will be extracted for documentation and statistical 
analyses of the efficacy and safety data.
13.0
References
1.
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.goveliparib/placeborotocolDevelopment/electronic_applications/
docs/ctcaev4.pdf.  Updated Version 4.3.  14 June 2010.  Available from:  
http://eversusnci.gov/ftp1/CRCAE/About.html.
2.
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in 
solid tumors:  revised RECIST guideline (version 1.1).  Eur J Cancer.  
2009;45(2):228-47.


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14.0
Appendix
14.1
DMC Charter 2017
DATA MONITORING COMMITTEE (DMC) AGREEMENT
TITLE:
A Phase 1 Dose Escalation and Phase 2 Randomized 
Double-Blind Study of Veliparib in Combination with 
Carboplatin and Etoposide as a Therapy of Treatment-Naïve 
Extensive Stage Disease Small Cell Lung Cancer
PROTOCOL:
M14-361
AUTHORS:
VERSION:
2.0
DATE:
24 Apr 2017


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M14-361 DMC CHARTER SIGNATURES
TITLE:
A Phase 1 Dose Escalation and Phase 2 Randomized 
Double-Blind Study of Veliparib in Combination with 
Carboplatin and Etoposide as a Therapy of Treatment-
Naïve Extensive Stage Disease Small Cell Lung Cancer
STUDY NUMBER:
M14-361
I have read this DMC Agreement and confirm that to the best of my knowledge it 
accurately describes the conduct of the DMC.
Data Monitoring Committee Members
Date
Date
Date


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Table 1
Terms and Abbreviations
Study Team
Composed of AbbVie employees directly involved in the implementation, 
execution, analysis or reporting of AbbVie Study M14-361
Asset Leadership Board 
(ALB)
AbbVie senior management team responsible for the veliparib 
development strategy
DMC
Data Monitoring Committee composed of personnel noted in 
Section 14.1.2
IRT
Interactive response technologies
IRB/EC
Institutional Review Board/Ethics Committee
SME
Subject Matter Expert
Asset Development Team 
(ADT)
AbbVie team responsible for executing the development strategy 
developed by the ALB
DSS
Data and Statistical Sciences
Clinical Strategy Team
AbbVie multi-disciplinary team, responsible for establishing and 
executing the clinical development strategy for a compound (overall by 
indication)
Project Leader
AbbVie senior manager responsible for veliparib development and 
strategy
Therapeutic Area 
Medical/Scientific Director 
(TA MD/SD)
Refers to a Medical or Scientific Director from either Pharmaceutical 
Development or Global Medical Affairs Therapeutic Area (TA)
Clinical Scientist
AbbVie Clinical Scientist responsible for assisting the TA MD/SD with 
execution of AbbVie Study M14-361, including the design, conduct, 
analysis, and reporting of clinical trial results


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14.1.1
Introduction
AbbVie Study M14-361 is a Phase 1, open-label, dose escalation/Phase 2 randomized 
double-blind clinical trial of veliparib in combination with carboplatin and etoposide and 
maintenance veliparib monotherapy.  Subjects enrolled in the Phase 2 portion will be 
randomized in a 1:1:1 ratio to the following three treatment arms:
●
Arm A:  veliparib + carboplatin and etoposide followed by veliparib 
monotherapy; 
●
Arm B:  veliparib + carboplatin and etoposide followed by placebo 
monotherapy; and
●
Arm C:  placebo + carboplatin and etoposide followed by placebo 
monotherapy.
A safety Data Monitoring Committee (DMC) will be set up for the Phase 2 portion of the 
study to review the aggregate unblinded safety data.
Phase 2 portion of the study:
Primary Objective of the DMC:
To evaluate the safety of veliparib in combination with carboplatin and etoposide 
followed by veliparib maintenance monotherapy.
This DMC Agreement defines the roles and responsibilities of the DMC, including its 
membership, scope, timing of meetings, and communication plan.
14.1.2
Membership
14.1.2.1
Members
The DMC consists of a Senior Medical Director who will serve as the Chair, as well as an 
Associate Medical Director and a Statistician who will serve as DMC members.  No 


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DMC members will be from the Study Team responsible for conduct of the AbbVie 
Study M14-361.
The DMC members will review unblinded aggregate safety data by treatment group.  In 
general, these data will not be shared outside the DMC.  However, if deemed necessary by 
the DMC, ALB members (excluding any who are also Study Team members) may be 
asked to review the unblinded results with the DMC and these unblinded data can be 
shared with ALB members (excluding any who are also Study Team members) to support 
critical program needs.  ALB members who are also Clinical Strategy Team members will 
not share any reviewed results with non-ALB Clinical Strategy Team members until study 
completion.
DMC Members
Member Name
Title
14.1.2.2
Duration of Membership
DMC membership will extend from the initiation of the Phase 2 portion of the study 
through completion of the trial.  If a DMC member leaves the committee, a replacement 
will be selected by the TA MD/SD.
14.1.3
Role of the DMC
The DMC will provide an independent internal review and assessment of the unblinded 
aggregate safety data from AbbVie Study M14-361.  The primary role of the DMC is to 
make a recommendation to the AbbVie Contact based on the unblinded analysis of 
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The DMC will not evaluate efficacy data such as Progression Free Survival (PFS) and 
Overall Survival (OS).  However, the incidence (rate) of subject death is considered a 
safety endpoint.  A significant imbalance in death rate favoring the control arm (ARM C) 
may require action.
During the conduct of the study, the medical and safety team will monitor blinded subject 
laboratory results and serious adverse event data on a real-time basis.  The TA MD/SD 
will also review blinded aggregate safety data on a regular basis and may enlist the 
assistance of the DMC at any time to evaluate any identified safety trend.  The timeframe 
for trend analysis will be defined by the TA MD/SD in consultation with the DMC Chair 
on a case-by-case basis, depending on the nature of the safety signal.
14.1.3.1
Safety Monitoring Guidelines
The following safety data recorded in the clinical trial database will be reviewed overall 
and between treatment arms: 
●
Subject disposition;
●
Dose intensity and dose reduction/interruption summary for study drug 
(veliparib);
●
Treatment-emergent adverse events (AEs);
●
AEs/SAEs relationship to study drug (veliparib);
●
Treatment-emergent serious adverse events (SAEs);
●
AEs leading to dose reduction/interruption of study drug (veliparib);
●
Discontinuation of study drug (veliparib) due to AEs not related to disease 
progression;
●
AEs leading to dose reduction/interruption of chemotherapy;
●
Rates of death; and
●
Laboratory data.


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14.1.4
ORGANIZATIONAL FLOW
The DMC statistician member will be responsible for providing the unblinded analysis of 
the safety data required by the DMC.  When the data collection and cleaning is completed 
for interim analysis, the clinical database will be extracted (versioned) for statistical 
analysis at least 10 business days prior to a scheduled DMC meeting.  The DMC 
statistician will receive access to the necessary randomization information and statistical 
programs needed to generate unblinded information (tables, figures and listings) at least 
7 business days prior to a scheduled DMC meeting.  In turn, the DMC statistician will 
communicate the unblinded information to other DMC members through use of a private, 
limited-access SharePoint folder approximately 5 business days prior to the scheduled 
DMC meeting.
14.1.5
MEETINGS
14.1.5.1
Organizational Meeting
The first meeting of the DMC will be an organizational meeting.  Attendees will include, 
but may not be limited to, the DMC members and the appropriate representatives from the 
Clinical Strategy Team, including the TA MD/SD, as well as Study Team members.  This 
meeting will formally establish the DMC, thoroughly acquaint the DMC with the protocol 
and the DMC Agreement, and review the analysis plan for interim safety monitoring.
14.1.5.2
DMC Review Meetings
The initial DMC review meeting is planned to occur once the first 30 Phase 2 subjects 
complete combination treatment.  Based on this initial safety DMC review, the frequency 
of subsequent safety DMC review meetings will be determined.
The initial safety DMC review may occur sooner than planned if the observed rate of 
dose-limiting toxicity (DLT)-like events in the aggregate blinded safety review of the first 
15 Phase 2 subjects exceeds the rate observed in the Maximum Tolerated 
Dose/Recommended Phase 2 Dose (MTD/RPTD) cohort from the Phase 1 portion of the 
study by more than 10%.  If that occurs, the DMC will convene as soon as possible to 


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review the aggregate unblinded safety data.  A minimum of one Medical Director DMC 
member and the DMC statistician will have to be present to review the unblinded safety 
data if an immediate DMC meeting is called and other members cannot attend in the 
required timeframe.
The DMC Chair may request additional meetings as needed for safety reasons only.
14.1.5.2.1
Open Session
The open session attendees will include, but may not be limited to, the DMC members 
and the appropriate representatives from the Clinical Strategy Team, including the TA 
MD/SD, as well as Study Team members.  The study statistician will produce and 
distribute Open reports to the Open Session attendees.  Open reports will include tables to 
summarize subject accountability (number of subjects randomized, treated, discontinued 
and ongoing, demographic characteristics, reasons for study discontinuation and adverse 
event summaries).  These Open reports will be aggregated across treatment arms.  No 
unblinded information will be provided in the Open reports.
During the Open Session, the TA MD/SD and/or Clinical Scientist will provide a general 
update on the study and any relevant new information regarding the product under 
investigation, including any relevant recent literature.  The TA MD/SD and/or Clinical 
Scientist will review the Open report with the DMC.  The Study M14-361 study team can 
attend Open Sessions.
14.1.5.2.2
Closed Session
The DMC statistician member will provide the unblinded analysis results of the safety 
data as indicated in the safety monitoring guidelines (Section 14.1.3.1) to the meeting 
attendee's approximately 5 business days prior to the scheduled review meeting.  Closed 
Sessions in which unblinded safety data are reviewed will be restricted to DMC members, 
however, the DMC may invite additional AbbVie subject matter experts (SMEs) to attend 
the closed sessions if the DMC determines they need to consult with AbbVie personnel 


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having expertise not represented on the DMC.  If an SME is asked to join the closed 
session, the SME must not be participating in the Veliparib program. 
14.1.6
Communication
The DMC members are to treat all communications regarding this clinical study, 
including reports, data, review meeting discussions, teleconferences, and meeting 
minutes, as confidential material.
A private, limited-access SharePoint folder will be created to facilitate communication 
between DMC members.  The DMC will not share the study results with external parties 
or to the non-ALB Clinical Strategy Team members/Study Team until study completion; 
only the DMC recommendation may be disseminated, as applicable.
14.1.6.1
Meeting minutes
The DMC Chair or a designated member of the DMC will prepare meeting minutes for 
both the open and closed sessions.  Draft open session minutes will be distributed to the 
meeting attendees for review within one week of the meeting.  Draft closed section 
minutes will be distributed to DMC members only, within one week of the meeting.  
Formal open and closed session minutes will be available within one month following the 
meeting(s).  The DMC Chair or designee is responsible for archiving the 
recommendations, the meeting materials, and minutes in the private, limited-access 
SharePoint folder.
The Study Project Manager will be responsible for documenting the outcome of each 
meeting in the trial master file at the end of the study (after the study has been unblinded).
14.1.6.2
Recommendations
After completing its review, the DMC may recommend to:
●
Continue the trial without modification;
●
Continue the trial with modification(s);


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●
Suspend opinion pending additional analyses;*
●
Terminate the trial due to safety-related concerns;
●
Other action with justification**
*
The study statistician will generate any additional requested blinded analyses.  The DMC statistician will generate 
any additional requested unblinded analyses.
**
For example, communication of findings to Investigators and/or IRB/EC if there is urgency beyond what is 
achievable with a protocol amendment.
The Project Leader for veliparib will serve as the AbbVie Contact for this study.  The 
DMC will provide a completed recommendation form (see Appendix 14.1.7) to the 
AbbVie Contact via email immediately after the completion of the closed session.
The AbbVie Contact will have the responsibility for reviewing and communicating with 
the veliparib ALB in order to decide whether to accept, modify or reject the DMC 
recommendation.  If the DMC recommendation is to continue the trial without 
modification, then the AbbVie Contact should communicate this information to the 
Study M14-361 study team directly.
If the DMC recommendation is to (a) terminate the trial due to safety-related concerns or 
(b) continue the study with modification(s) (e.g.,:  implement "major" unplanned changes 
to the study protocol), the AbbVie Contact will communicate the DMC recommendation 
to the veliparib ALB within 24 hours, who will make a final decision regarding the 
necessary action to be taken based on the DMC recommendation.  The ALB meeting must 
include Jiang Qian as an ad-hoc member to represent Data and Statistical Sciences (DSS).  
If the ALB determination is to either (a) accept with modification or (b) reject the DMC's 
recommendation, the ALB should meet with the DMC to review this decision.  The ALB 
may need to review the same unblinded information that was made available to the DMC 
when they formulated their recommendation.  The ALB decision will be communicated to 
the Study M14-361 study team, who will be responsible for executing the directive from 
the ALB.  Affected members of the veliparib ADT and CST will be notified of this 
decision in a timely manner.


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14.1.7
APPENDIX
Documentation of Recommendation
TITLE:  A Phase 1 Dose Escalation and Phase 2 Randomized Double-Blind Study of 
Veliparib in Combination with Carboplatin and Etoposide as a Therapy of Treatment-
Naïve Extensive Stage Disease Small Cell Lung Cancer
STUDY NUMBER:  M14-361
After reviewing the unblinded interim safety data (Version X, XXX 201X), the DMC 
recommends to:
☐
Continue the trial without modification
☐
Continue the trial with modification(s) (as described below)
☐
Suspend opinion pending additional analyses
☐
Terminate the trial due to safety-related concerns
☐
Other action with justification (as described below)


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Version 1.0 – 15 Nov 2018
41
I acknowledge that this is the joint recommendation of the Data Monitoring Committee.
Date
Date
Date


Veliparib
M14-361 – Statistical Analysis Plan
Version 1.0 – 15 Nov 2018
42
14.1.8
APPENDIX
Changes from Previous Version
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Title page:  Updated version number from 1,0 to 2.0; updated version date 
from 27 Mar 2017 to 24 Apr 2017; Updated footer to reflect new date 
24 Apr 2017
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Table of Contents:  Added new Appendix II, Changes from Previous Version
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Page 1:  Updated footer to reflect new version/date; Updated Data Monitoring 
Committee Member from 
 
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Pages 4 and 9:  Updated Data Monitoring Committee Member from 
 
14.2
List of Abbreviations
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AE:  Adverse Event
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ANCOVA:  Analysis of Covariance
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AST:  As-Treated
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ATDI:  Actual total dose intensity
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BID:  Twice A Day
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CMH:  Cochran-Mantel-Haenszel
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CR:  Complete Response
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CTCAE:  Common Terminology Criteria for Adverse Events
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DI:  Dose intensity
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DLT:  Dose Limiting Toxicity
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DMC:  Data Monitoring Committee
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DOR:  Duration of Overall Response
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ECOG:  Eastern Cooperative Oncology Group
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eCRF:  Electronic Case Report Form


Veliparib
M14-361 – Statistical Analysis Plan
Version 1.0 – 15 Nov 2018
43
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ED SCLC:  Extensive Stage Disease Small Cell Lung Cancer
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FDA:  Food and Drug Administration
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IRT:  Interactive Response Technology
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ITT:  Intent-To-Treat
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IV:  Intravenous
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LDH:  Lactate Dehydrogenase
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MTD:  Maximum Tolerated Dose
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NCI:  National Cancer Institute
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ORR:  Objective Response Rate
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OS:  Overall Survival 
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PD:  Disease Progression
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PFS:  Progression Free Survival
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PR:  Partial Response
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PTDI:  Planned total dose intensity
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QA:  Quality Assurance 
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QC:  Quality Control
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RPTD:  Recommended Phase Two Dose
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Rx:  Medical Prescription
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SAE:  Serious adverse event
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SmPC:  Summary of Product Characterizations
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ULN:  Upper Limit of Normal