A Dose Finding Study Followed by Phase II Randomized, Placebo-Controlled Study of Veliparib (ABT-888) Added to Chemoradiotherapy With Carboplatin and Paclitaxel for Unresectable Stage III Non-small Cell Lung Cancer (NSCLC), (NCI Study Number 8811)
Phase: PHASE1
Conditions: Lung Adenocarcinoma, Lung Adenocarcinoma, Mixed Subtype, Lung Large Cell Carcinoma, Lung Squamous Cell Carcinoma, Minimally Invasive Lung Adenocarcinoma, Stage III Lung Non-Small Cell Cancer AJCC v7, Stage IIIA Lung Non-Small Cell Cancer AJCC v7, Stage IIIB Lung Non-Small Cell Cancer AJCC v7
Sponsor: National Cancer Institute (NCI)

 
 
 
1 
 
 
 
 
 
 
 
 
 
 
 
Distribution Date: 
TBD 
Version Date: 
June 12, 2017 
 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
Dawne 
Wenzel, 
M.A., 
Protocol 
Coordinator 
(E-mail:  
dwenzel@swog.org) 
 
RE: 
S1206, “A Dose Finding Study Followed by Phase II Randomized, 
Placebo-Controlled Study of Veliparib (ABT-888) Added to 
Chemoradiotherapy with Carboplatin and Paclitaxel for Unresectable 
Stage III Non-Small Cell Lung Cancer (NSCLC), (NCI Study Number 
8811).” Study Chairs: Drs. A. Argiris, M. Cristea, A.M. Chen and J .M. 
Sands 
 
REVISION #7 
 
Study Chair: Athanassios Argiris, M.D. 
Phone number: (30) 210/686 ext. 7692 
E-mail: athanassios.argiris@gmail.com 
 
IRB Review Requirements 
(  ) Expedited review allowed 
 
Protocol changes 
(  )  Treatment / Dose Modification / Study Calendar changes  
(  ) Editorial / Administrative changes 
 
 
REVISION #7 
 
Please note that this study is referenced as “8811” in the OPEN, RSS and SpecTrac 
systems. Please use the protocol number “8811” when accessing these databases. 
 
1. 
The Version Date of the protocol and Model Consent Form have been 
updated. 
 
2. 
Page 29, Section 7.3b:  In the chart the route of administration for 
carboplatin has been changed from “IV 30 minutes after completion of 
paclitaxel” to “30 minute IV infusion immediately following paclitaxel.” 
 
3. 
Page 37, Section 7.8:  The following has been removed from this 
paragraph ”Sites utilizing the CIRB must use the intake calendar provided.” 
In the next sentence, “not utilizing the CIRB” has been removed as this is 
not a study which utilizes the CIRB. 
 
4. 
Page 45, Section 8.4d:  In the chart for Hepatic Toxicity (Paclitaxel dose 
modification only), the symbol ≤ in the Bilirubin column for Grade 3 has 
been changed to >. 
 

 
Revision #7 (contd.) 
 
Page 2 
 
 
5. 
Page 51, Section 9.2: Footnote 5 has been added to indicate that the EKG must be 
performed within 28 days prior to registration.  All other numbered footnotes have 
been renumbered accordingly. 
 
6. 
Page 62, Section 13.2:  This section has been deleted as slot reservation is no longer 
necessary in the current Phase II portion of the study.  Subsequent sections have 
been renumbered accordingly. 
 
 
7. 
Page 63, Section 13.2c.1:  The entire second paragraph about using the CIRB has 
been removed from this section as this is not a study which utilizes the CIRB. 
 
8. 
Page 64, Section 13.2c.3:  “For sites not participating via the NCI CIRB” has been 
removed from this section as this is not a study which utilizes the CIRB. 
 
This memorandum serves to notify the NCI and SWOG Statistical Center. 
 
cc:  
PROTOCOL & INFORMATION OFFICE 
 

 
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PRIVILEGED COMMUNICATION 
Activation Date:  October 1, 2012 
FOR INVESTIGATIONAL USE ONLY 
 
 
 
SWOG 
 
A DOSE FINDING STUDY FOLLOWED BY PHASE II RANDOMIZED, PLACEBO-CONTROLLED 
STUDY OF  VELIPARIB (ABT-888) ADDED TO CHEMORADIOTHERAPY WITH CARBOPLATIN AND 
PACLITAXEL FOR UNRESECTABLE STAGE III NON-SMALL CELL LUNG CANCER (NSCLC), (NCI 
STUDY NUMBER 8811) 
 
NCT #01386385 
 
STUDY CHAIRS: 
AGENTS: 
 
Athanassios Argiris, M.D. 
NCI Supplied Investigational Agent: 
Medical Oncologist, Hygeia Hospital 
ABT-888 (veliparib, NSC 737664) 
5 Erythrou Stavrou 
 
6th Floor, Office 6.12 
IND Exempt Agents (Commercially Supplied): 
Marousi 15123 Athens, Greece 
Carboplatin (CBDCA) (NSC-241240) 
Phone: 011 30 210 6867692 
Paclitaxel, Taxol® (NSC-673089) 
FAX: 011 30 210 6845089 
 
E-mail: athanassios.argiris@gmail.com 
STUDY CHAIRS (contd.): 
 
 
Mihaela Cristea, M.D. (Medical Oncology) 
Jacob M. Sands, M.D. (Medical Oncology) 
City of Hope 
Lahey Hospital & Medical Center 
1500 E. Duarte Road 
41 Burlington Mall Road 
 
Duarte, CA 91010 
Burlington, MA  01805 
 
Phone: 626/256-4673 
Phone:  781/744-8400 
 
FAX: 626/930-5461 
FAX:  781/744-5192 
 
E-mail: mcristea@coh.org 
E-mail:  Jacob.M.Sands@lahey.org 
 
 
Allen M. Chen, M.D. (Radiation Oncology) 
BIOSTATISTICIANS: 
Professor and Chairman 
 
Department of Radiation Oncology 
Mary Redman, Ph.D. 
University of Kansas Cancer Center 
James Moon, M.S. 
University of Kansas School of Medicine 
Jieling Miao, M.S. 
MS 4033, 3901 Rainbow Boulevard 
SWOG Statistical Center 
Kansas City, KS 66160 
1100 Fairview Ave N, M3-C102 
Phone: 913/588-3612 
PO BOX 190204 
FAX: 913/588-3663 
Seattle, WA 98109-1024 
E-mail: achen5@kumc.edu 
Phone: 206/667-4623 
 
FAX: 206/667-4408 
 
E-mail: mredman@fredhutch.org 
 
E-mail: jmoon@fredhutch.org 
 
E-mail:  jmiao@fredhutch.org 
 
Phase I PARTICIPANTS:  ARIZONA (including AZ017 & AZ110), CEDARS-SINAI, CITY OF HOPE, 
CLEVELAND CLINIC, HENRY FORD, LOYOLA, MD ANDERSON, PSOC, UC DAVIS, U OF 
COLORADO, U OF KANSAS, U OF KENTUCKY, U OF MICHIGAN, USC, UTHSCSA, WAYNE STATE, 
YALE 
 
 
 
 
 
 
 
 
 
 
PHASE II PARTICIPATING ORGANIZATIONS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 

 
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TABLE OF CONTENTS 
 
 
Page 
PHASE II PARTICIPATING ORGANIZATIONS................................................................. 1 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT  INFORMATION...... 4 
SCHEMA ..................................................................................................................... 5 
1.0 
OBJECTIVES ................................................................................................... 6 
1.1 
Phase I Portion Objectives .................................................................................. 6 
1.2 
Phase II Portion Objectives ................................................................................. 6 
1.3 
Tertiary Objectives ............................................................................................. 6 
2.0 
BACKGROUND ................................................................................................. 6 
3.0 
DRUG INFORMATION ....................................................................................... 11 
3.1  
Carboplatin (CBDCA) (NSC-241240) .................................................................... 11 
3.2 
Paclitaxel, Taxol® (NSC-673089) .......................................................................... 13 
3.3  
Veliparib (ABT-888) (NSC 737664) ....................................................................... 15 
4.0 
STAGING CRITERIA ......................................................................................... 21 
5.0 
ELIGIBILITY CRITERIA ..................................................................................... 23 
5.1 
REGISTRATION #1 ............................................................................................ 23 
5.2 
REGISTRATION #2 – PRIOR TO CONSOLIDATION CHEMOTHERAPY ................... 25 
6.0 
STRATIFICATION FACTORS ............................................................................. 27 
7.0 
TREATMENT PLAN .......................................................................................... 27 
7.1  
Treatment Overview ........................................................................................... 27 
7.2 
Pre-Medication .................................................................................................. 27 
7.3 
Concurrent Chemoradiation................................................................................. 28 
7.4 
Radiotherapy..................................................................................................... 32 
7.5 
Consolidation Chemotherapy ............................................................................... 36 
7.6 
Supportive Care Measures .................................................................................. 36 
7.7 
General Concomitant Medical and Supportive Care Guidelines ................................. 37 
7.8 
Drug Compliance Documentation ......................................................................... 37 
7.9 
Full CDUS Reporting Requirements...................................................................... 37 
7.10 
Criteria for Removal from Protocol Treatment ......................................................... 37 
7.11 
Discontinuation of Treatment ............................................................................... 37 
7.12 
Follow Up Period ............................................................................................... 37 
8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS ....................... 38 
8.1 
NCI Common Terminology Criteria for Adverse Events ............................................ 38 
8.2 
General Dose Modification Guidelines................................................................... 38 
8.3 
Dose Modifications During Concurrent Therapy (common for the Phase I and Phase II) 38 
8.4 
Dose Modifications During Consolidation Therapy................................................... 41 
8.5 
Assessment and Management of Esophageal Toxicity............................................. 47 
8.6 
Colony Stimulating Factors .................................................................................. 47 
8.7 
Dose Modification Contacts ................................................................................. 47 
8.8 
Adverse Event Reporting .................................................................................... 47 
9.0 
STUDY CALENDAR .......................................................................................... 48 
9.1 
Phase I Study Calendar ...................................................................................... 48 
9.2 
Phase II Study Calendar ..................................................................................... 51 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS .............................. 54 
10.1  
Measurability of Lesions...................................................................................... 54 
10.2  
Objective Status at Each Disease Evaluation ......................................................... 55 
10.3  
Best Response .................................................................................................. 56 
10.4 
Performance Status............................................................................................ 57 
10.5 
Time to Treatment Failure ................................................................................... 57 
10.6 
Time to Death.................................................................................................... 57 
10.7 
Progression-Free Survival ................................................................................... 57 
11.0 
STATISTICAL CONSIDERATIONS...................................................................... 58 
11.1 
Accrual ............................................................................................................. 58 
11.2 
Phase I Study: ................................................................................................... 58 
11.3 
Phase II Study ................................................................................................... 58 
11.4 
Sample Size and Power Justification..................................................................... 58 

 
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11.5 
Analyses and Timepoints .................................................................................... 58 
11.6 
Adverse Event Monitoring ................................................................................... 59 
11.7 
Data and Safety Monitoring ................................................................................. 59 
12.0 
DISCIPLINE REVIEW ........................................................................................ 59 
12.1 
Radiation Therapy Review .................................................................................. 59 
12.2 
Required Benchmarks ........................................................................................ 60 
12.3 
Quality Assurance Documentation ........................................................................ 60 
12.4 
Definitions of Deviations in Protocol Performance ................................................... 61 
13.0 
REGISTRATION GUIDELINES............................................................................ 62 
13.1 
Registration Timing ............................................................................................ 62 
13.2 
Investigator/Site Registration ............................................................................... 62 
13.3 
OPEN Registration Requirements ........................................................................ 64 
13.4 
Registration Procedures...................................................................................... 66 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................ 66 
14.0 
DATA SUBMISSION SCHEDULE........................................................................ 66 
14.1 
Data Submission Requirements ........................................................................... 66 
14.2 
Master Forms .................................................................................................... 67 
14.3 
Data Submission Procedures............................................................................... 67 
14.4 
Data Submission Overview and Timepoints ........................................................... 67 
15.0 
SPECIAL INSTRUCTIONS ................................................................................. 71 
15.1 
Rapid Reporting................................................................................................. 71 
15.2 
Paraffin Embedded Tissue Specimens (Required Submission) for correlative studies  ..  
 
and banking ...................................................................................................... 71 
15.3 
Peripheral Blood (Optional Submission) for Circulating Tumor Cells for γH2Ax 
determination. ................................................................................................... 72 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS .............................................. 75 
16.1 
Adverse Event Reporting Requirements ................................................................ 78 
17.0 
BIBLIOGRAPHY ............................................................................................... 83 
18.0 
APPENDIX ....................................................................................................... 84 
18.1  
Intake Form....................................................................................................... 85 
18.2 
Correlative/Special Studies.................................................................................. 86 
18.3 
Carboplatin Dosing Worksheet............................................................................. 90 
18.4 
Emergency Unblinding Guidelines ........................................................................ 91 
18.5 
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4 ..................... 93 
 
 

 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation can 
be submitted to the CTSU via: 
 
ONLINE: 
Regulatory Submission Portal 
(Sign in at www.ctsu.org,            
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
EMAIL: 
CTSURegulatory@ctsu.coccg.o
rg (regulatory documentation 
only) 
FAX:  
215-569-0206 
MAIL:  
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
 
For regulatory questions call the 
CTSU Regulatory Help Desk at 
1-866-651-CTSU 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with 
any OPEN-related questions at 
ctsucontact@westat.com. 
 
 
Data collection for this study 
will be done exclusively 
through SWOG CRA Workbench 
at 
https://crawb.crab.org/TXWB/cts
ulogon.aspx.  Please see the 
data submission section of the 
protocol for further instructions. 
 
SWOG 
Operations Office, SWOG 
4201 Medical Dr., Ste. 250 
San Antonio, TX 78229-5631 
Phone: 210-614-8808 
 
Do not submit study data or 
forms to CTSU Data Operations. 
Do not copy the CTSU on data 
submissions. 
 
Other Tools and Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG 
Workbench. Access this by 
using your active CTEP-IAM 
userid and password at the 
following url: 
 
https://crawb.crab.org/TXWB/cts
ulogon.aspx 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS.   
Note:  Non-lead group institutions will order the following supplies from the CTSU Operations Office:    
For patient eligibility or data submission questions contact the SWOG Data Operations Center by 
phone or email: 
206/652-2267 
lungquestion@crab.org  
 
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study Chairs by email: 
Athanassios Argiris, M.D. at: athanassios.argiris@gmail.com, Mihaela Cristea, M.D. at 
mcristea@coh.org, or Jacob Sands, M.D. at Jacob.M.Sands@lahey.org 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 

 
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SCHEMA 
 
 
Phase I portion (open to limited institutions as listed on the Title Page): 
First Registration 
 
 
 
Chemoradiation Phase 
6 weeks of external beam radiation + paclitaxel + carboplatin + ABT-888 
at assigned dose level (see Section 7.3a) 
 
 
 
Re-evaluation and Second Registration 
 
 
 
 
Consolidation Phase (ABT-888 + carboplatin + paclitaxel) 
(Two 21-day cycles) 
 
 
 
 
 
Phase II portion (open to all SWOG institutions): 
First Registration/Randomization 
 
 
 
Chemoradiation Phase 
6 weeks of external beam radiation + paclitaxel + carboplatin + ABT-888/placebo 
at assigned dose level (see Section 7.3b) 
 
 
 
Re-evaluation and Second Registration 
 
 
or 
 
ABT-888 
 
 
 
 
 
Placebo 
 
 
 
Carboplatin 
 
 
 
 
 
Carboplatin 
 
 
 
Paclitaxel 
 
 
 
 
 
Paclitaxel 
 
(2 cycles) 
(2 cycles) 
 
 
 
 
 
 
 
 
A patient may be enrolled to either the Phase I portion or the Phase II portion, not both. 
 

 
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1.0 
OBJECTIVES 
 
 
This study will be conducted in two different parts: 
 
 
1.1 
Phase I Portion Objectives 
 
To establish the MTD and the recommended Phase II dose of ABT-888 when given 
concurrently with standard carboplatin/paclitaxel and radiotherapy in patients with 
unresectable Stage III non-small cell lung cancer (NSCLC). 
 
1.2 
Phase II Portion Objectives 
 
a. 
To assess whether carboplatin/paclitaxel plus ABT-888 compared with 
carboplatin/paclitaxel plus placebo improves progression-free survival (PFS) in 
patients with unresectable Stage III NSCLC. 
 
b. 
To compare overall survival (OS) in patients treated with carboplatin/paclitaxel 
and radiotherapy plus ABT-888 to those treated with carboplatin, paclitaxel and 
radiotherapy plus placebo. 
 
c.  
To assess the response rate (confirmed and unconfirmed, complete and partial 
responses) and disease control rate in the subset of patients with measurable 
disease by RECIST criteria 
 
d. 
To assess the safety and toxicity profile of the regimen 
 
1.3 
Tertiary Objectives 
 
a. 
To collect tumor tissue from pretreatment biopsies (archival samples) for 
biomarker studies, including PARP activity by measuring the levels of poly-ADP-
ribose, γ-H2AX, and mRNA expression levels of DNA repair enzymes such as 
ERCC1/XRCC1. 
 
b. 
To collect blood samples for evaluation of γ-H2AX (circulating tumor cells) and 
other relevant future studies. 
 
2.0 
BACKGROUND 
 
Locally Advanced Non-Small Cell Cancer 
 
Combined modality therapy with chemotherapy and radiation has become the standard of care 
for the treatment of patients with locally advanced NSCLC. A number of Phase III randomized 
trials have established chemotherapy with concurrent radiation to be superior to sequential 
administration of chemotherapy and radiation. (1-2) The RTOG conducted a 3-arm, randomized 
Phase III trial in patients with Stage III NSCLC (RTOG 9410). Sequential therapy (Arm 1) 
consisted of 2 cycles of cisplatin and vinblastine, followed by 6,000 cGy external beam radiation, 
administered in once-daily fractions, beginning on Day 501. In Arm 2, the same chemotherapy 
regimen was used but radiation was administered concurrently starting on Day 1 of 
chemotherapy cycle. In Arm 3, hyperfractionated radiation therapy with 6,920 cGy was 
administered with twice-daily fractions. Patients in Arm 3 received concurrent chemotherapy that 
consisted of cisplatin and oral etoposide. The median survival was superior (17.0 months vs 14.6 
months, p=0.038) for patients with concurrent chemoradiation (Arm 2) compared to the sequential 
arm, whereas hyperfractionated radiation did not result in improved survival compared to the 
sequential arm (15.6 months vs 14.6 months). Esophagitis and pneumonitis were the principal 
toxicities associated with concurrent chemoradiation. 
 
 

 
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The LAMP (Locally Advanced Multimodality Protocol) Trial was a randomized 3- arm Phase II 
study in patients with Stage III NSCLC. (3) In Arm 1, patients received 2 cycles of induction 
chemotherapy with carboplatin (AUC =6 mg/ml.min) and paclitaxel (200 mg/m2) followed by 
6,300 cGy external beam radiotherapy (sequential); Arm 2 consisted of 2-cycles of induction 
chemotherapy with carboplatin and paclitaxel which was followed by concurrent chemoradiation 
with weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) for 7 weeks (induction-concurrent); 
Arm 3 consisted of initial concurrent chemoradiation with weekly carboplatin and paclitaxel, 
followed by consolidation chemotherapy with 2 cycles of carboplatin and paclitaxel (concurrent -
consolidation). The study enrolled 276 patients. Among patients randomized to Arm 2, less than 
60% received the planned combined therapy after induction. An interim analysis projected an 
inferior median survival for patients on Arm 2 and this arm was closed to accrual. There was no 
statistically significant difference in survival between the study arms. 
 
The Cancer and Leukemia Group B (CALGB) conducted a randomized Phase II study of two 
cycles of induction chemotherapy followed by two additional cycles of  the same drugs with 
concomitant radiotherapy for patients with locally advanced NSCLC. (4) Cisplatin was 
administered in combination with gemcitabine, paclitaxel or vinorelbine as induction therapy 
followed by chemoradiotherapy. Median survival for all patients was 17 months. Subsequently, 
CALGB conducted a Phase III trial that compared induction chemotherapy with carboplatin and 
paclitaxel followed by concurrent chemoradiation versus chemoradiation alone. The results of this 
trial demonstrated similar survival rates between the 2 arms. (5) 
 
SWOG evaluated the role of consolidation chemotherapy following concurrent chemoradiation in 
a Phase II trial (SWOG-9504). (6) Initial therapy consisted of cisplatin and etoposide with 
concurrent radiation (6,100 cGy) followed by three cycles of consolidation chemotherapy with 
docetaxel. This study enrolled 83 eligible patients and demonstrated a median survival of 26 
months. The 2-year and 3-year survival rates were 53% and 40% respectively. The treatment 
was well tolerated with an incidence of Grade 3 esophageal toxicity during concurrent 
chemoradiation of 11%. Based on the results noted in this study, the SWOG investigators 
adopted the treatment regimen from SWOG-9504 as the control arm for their future trials for 
patients with locally advanced NSCLC. However, the benefit of consolidation chemotherapy has 
been questioned. A more recent Phase III study by HOG showed that the addition of 
consolidation docetaxel to concurrent radiation, cisplatin, and etoposide does not improve 
survival. (7) In an ongoing Phase III trial (RTOG 0617), RTOG is using weekly carboplatin and 
paclitaxel with concurrent chest radiotherapy followed by 2 cycles of consolidation chemotherapy 
with carboplatin and paclitaxel as the reference regimen. This ongoing Phase III trial is a 4-arm 
randomized trial that is evaluating standard versus high dose (6,000 vs 7,400 cGy) chest 
radiotherapy as well as treatment with or without the addition of cetuximab in patients with Stage 
III NSCLC. 
 
Despite these improvements in treatment of unresectable, locally advanced NSCLC, long- term 
survival is achieved in less than 25% of patients. Therefore there is a major need to investigate 
novel approaches in this clinical setting.  
 
Clinical Investigations 
 
A single-dose pharmacokinetic and pharmacodynamic endpoint study in cancer patients was 
initiated under an exploratory IND by the National Cancer Institute as the initial study in their 
Phase 0 program. (9) In this study, participants had baseline assessments of PAR in peripheral 
blood mononuclear cells (PBMCs) and at higher dose levels, in tumor from needle biopsies, 
assessed by a validated immunoassay. Participants received a single dose of ABT-888 at 10, 25, 
or 50 mg. PBMCs were collected over a 24 hour period at all dose levels, and tumor biopsies 
were obtained at the 25 mg dose level, approximately 3 to 6 hours after administration of ABT-
888. A total of 6 patients have been studied so far, 3 each for the 10 mg and 25 mg cohorts. No 
treatment related adverse events have been observed. The target plasma Cm ax of 210 nM was  
 
 

 
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exceeded in 2 of 3 patients at the 10 mg dose level, and in all three patients for at least 4 hours at 
the 25 mg dose level. Levels of PAR were reduced 80-99% from baseline levels after 
administration of ABT-888 in both the PBMCs and tumor samples at the 25 mg dose level. Thus, 
there is reason to believe that target inhibition is seen at least at the 25 mg dose level, and may 
be occurring at doses lower than 25 mg. 
 
Currently, several combination Phase I trials are underway. Also, single agent trials have been 
initiated in patients with BRCA mutations. 
 
Experience with ABT-888 plus carboplatin and paclitaxel 
 
At the University of Pittsburgh and CCCP two Phase I clinical trials of carboplatin, paclitaxel plus 
ABT-888 in patients with advanced solid tumors are near completion. In the first Phase I trial, an 
every-3-week schedule of carboplatin and paclitaxel is being used. In this study the first cycle is 
administered without ABT-888. ABT-888 is initiated on Day 1 of Cycle 2 and carboplatin and 
paclitaxel are given on Day 3 of Cycle 2 and all subsequent cycles (cycle duration is 21 days). 
DLT is determined during Cycle 2 only. Currently, patients are being treated at a dose of ABT-888 
of 100 mg BID for 7 days, Days 1-7 of the cycle with standard doses of carboplatin and paclitaxel 
(AUC of 6 and 200 mg/m2, respectively). A dose of 80 mg was safe and will be used in the 
consolidation chemotherapy part. However, dose-limiting myelotoxiticy occurred at a dose of 120 
mg. Additional patients are being treated at 100 mg.  
 
Another ongoing Phase I study at the University of Pittsburgh is evaluating weekly carboplatin 
and paclitaxel in combination with ABT-888. The dose of carboplatin is ACUS of 2 and paclitaxel 
80 mg/m2. Patients receive carboplatin and paclitaxel on Days 3, 10, and 17 and ABT-888 BID on 
Days 1-5, 8-12, and 15-19. The 50 mg and 100 mg dose levels were safe (3 patients treated at 
each without DLT). The current dose level is 150 mg of ABT-888 twice daily. One patient 
developed Grade 4 thrombocytopenia which was DLT and this cohort is expanded (S. Puhalla, 
personal communication).  
 
Rationale 
 
Investigation of new CTEP-sponsored agents plus radiotherapy usually lags far behind that of 
new drug-chemotherapy combinations. From a clinical standpoint, study designs adding a new 
agent to a standard radiation (or chemoradiation) backbone are most desirable. Although 
combined modality therapy with concurrent chemoradiation is considered st andard of care in 
unresectable Stage III NSCLC, long-term survival is low and recent advances have been limited, 
creating an area of major need for new therapeutic strategies. We propose to use a backbone of 
standard chemoradiotherapy with carboplatin and paclitaxel to investigate the addition of oral 
ABT-888. ABT-888 potentiates the anti-cancer effects of various cytotoxic agents including 
carboplatin in preclinical studies. Albert et al have shown that ABT-888 has a synergistic effect 
when combined with radiation in lung cancer models. (8) The primary mechanism of action of 
carboplatin involves formation of platin-DNA adducts and subsequent DNA damage. While repair 
of platin-induced DNA damage is likely multifactoral, nucleotide excision repair (NER) is 
prominent. Pre-clinical studies suggest overlap between PARP-induced repair and other 
mechanisms such as NER or BER. As shown here, preclinical studies by our collaborators at 
Karmanos Cancer Center (unpublished) of ABT-888 show variable effects in regard to 
potentiation of cytotoxicity of the DNA-damaging agent irinotecan. In particular, in ovarian cancer 
cell lines, potentiaton by ABT-888 occurs exclusively in a high ERCC1-expressing cell line (NER-
mediated), whereas ABT-888 shows no potentiation in HOP62 or H226 lung cancer lines, 
regardless of ERCC1 expression. 
 

 
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We believe that these observations should be studied further in preclinical models, and in an 
exploratory way, in this trial. We hypothesize that co-administration with ABT-888 with carboplatin 
and radiation is likely to result in enhanced DNA damage and therefore, greater anti-tumor 
activity, and that this potentiation can be determined by assessing baseline DNA repair genes in 
either the tumor or the host (polymorphisms in DNA repair genes). We further hypothesize that 
selectivity of ABT-888 to tumor cells will also be advantageous. This study will evaluate the 
toxicities and establish the optimal doses of ABT-888 given with standard chemoradiotherapy 
with weekly carboplatin and paclitaxel. 
 
Correlative Studies Background 
 
With the limitations of patient numbers in this Phase I trial, the correlative data are not likely to 
provide a statistically significant finding, however these studies are expected to be hypothesis 
supporting or generating for studies of larger patient cohorts, as a result of identifying trends in 
the data. 
 
Immunoassay for poly-ADP-ribosylated (PAR) substrates 
 
Because the product of the PARP enzyme is poly-ADP-ribosylated (PAR) molecules, an 
immunoassay to quantify the amount of cellular PAR was developed as a clinical biomarker of 
PARP inhibition. Abbott Laboratories and the NCI-Frederick laboratories developed and cross-
validated a quantitative immunoassay for PAR. (9-10) The validated assay is a sandwich enzyme 
chemiluminescence immunoassay employing commercially obtained antibodies to PAR, and pure 
PAR as a standard. Assay dynamic range is 31 to 2000 pg/ml PAR, with a lower limit of 
quantization of approximately 15 pg/ml PAR. The standard curve is linear throughout the range 
(with an adjusted R2 typically better than 0.98). The assay uses high, midrange, and low controls 
produced from the human melanoma line Colo829. Specimen handling was optimized for both  
 
 

 
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PBMCs and tumor needle biopsies (18 ga), and harmonized for use with the same standards and 
controls. Specimens could be subjected to at least 3 freeze-thaw cycles without a detectable loss 
of antigen binding. Assay precision was determined at both Abbott Laboratories and the NCI-
Frederick, to be better than 80% (estimated total imprecision at Abbott Laboratories, 7% or less). 
Accuracy, as assessed by spike recovery of pure PAR into PBMC lysates, was 100% +/ - 20%. 
Assay dilution linearity was established for the Colo829 controls and tumor lysates, although 
deviations from linearity are observed in some tumor homogenates, and assay conditions are 
controlled to compensate for that lack of linearity. The validated assay was used to measure PAR 
levels in PBMCs of healthy donors, in animal models after administration of a single and multiple 
dosing of ABT-888, and has been used successfully in real time to measure PAR in PBMCs and 
tumor biopsies in a Phase 0 clinical trial at the NCI. 
 
The level of PARP activity is determined by measuring the levels of poly-ADPribose. The 
enzymatic assay for PARP activity provides enzyme substrates in excess to achieve zero -order 
kinetics such that enzyme product formation is directly proportional to amount of active enzyme. 
The enzyme product will be poly-ADP-ribose that will be quantified using the capture antibody 
configuration for the immunoassay of poly-adenylated PARP. 
 
mRNA expression levels of DNA repair genes 
 
RNA from laser-captured microdissected FFPE tumor samples will be analyzed by the UC Davis 
group together with their long-term collaborator, Response Genetics, Inc. (RGI) using a patented 
quantitative RT-PCR assay as previously described in a CLIA-certified laboratory. Recently, 
Gandara et al (ASCO, 2010) have reported ERCC1 mRNA expression levels in 2,540 patients 
and correlated results with NSCLC histologic subtype. As shown, ERCC1 mRNA expression 
levels are strongly correlated with NSCLC histologic subtype, with higher levels in SCC compared 
with ADCA (median 2.5 versus 1.8, p=0.001). These data, representing 2,540 NSCLC patients 
(the largest patient-based ERCC1 study yet reported), translate into differences in estimated 
platinum responsiveness between these histologies, with 46% of ADCA below the ERCC 
reference sensitivity level of < 1.7, compared with only 31% of SCC. These studies, conducted by 
our group in collaboration with RGI, set the stage for the current trial incorporating the PARP 
inhibitor into combined modality therapy in Stage III NSCLC. 
 
ERCC1 mRNA Expression Levels in NSCLC (N=2,540):  
Adenoca (AC) versus Squamous (SCCA)
ERCC1 (N=1,438) 
1,002 AC, 436 SCCA 
RRM1 (N=1,104)      
678 AC, 426 SCCA
TS (N=965)      
649 AC, 316 SCCA
ERCC1
ERCC1
(Reference <1.7)
(Reference <1.7)
% Below 
% Below 
Reference Level
Reference Level
NSCLC
NSCLC-Total
Total
43.4%
43.4%
NSCLC
NSCLC-Adenoca
Adenoca
46%
46%
NSCLC
NSCLC-SCCA
SCCA
30.7%
30.7%
p=0.001
 
 

 
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Assessment of host genomic DNA from PBMC/plasma for DNA repair SNPs, including ERCC1 
and ERCC2 
 
Assessment of host DNA repair capacity for relevant polymorphisms will be done as previously 
described (See also Correlative Science section in Appendix 18.2). For example, previous studies 
by our group (Gandara et al: JCO, 2009) have shown an association of ERCC2 K751Q for 
response to carboplatin-paclitaxel chemotherapy in advanced NSCLC (HR, 0.33; 95% CI, 0.13 to 
0.83; p= .02). These associations will be evaluated in an exploratory manner in this trial. 
 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex 
categories is shown in the table below.   
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
2 
2 
4 
Not Hispanic or Latino 
81 
77 
158 
Total Ethnic 
83 
79 
162 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
2 
2 
4 
Black or African American 
8 
9 
17 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
73 
68 
141 
Racial Category: Total of all Subjects 
83 
79 
162 
 
The total number of subjects above assume 30 patients enrolled on the Phase I portion and 132 
patients enrolled on the Phase II portion. 
 
 
3.0 
DRUG INFORMATION 
 
For information regarding Investigator’s Brochure, please refer to SWOG Policy 15. 
 
For this study, carboplatin and paclitaxel are commercially available; therefore, Investigator 
Brochures are not applicable to these drugs.  Information about commercial drugs is publicly 
available in the prescribing information and other resources. 
 
For this study, ABT-888 is investigational and is being provided under an IND held by the 
National Cancer Institute.  The Investigator Brochure may be obtained by contacting the NCI’s 
Pharmaceutical Management Branch (PMB) at 240/276-6575. 
 
3.1  
Carboplatin (CBDCA) (NSC-241240) 
 
a. 
DESCRIPTION 
 
Carboplatin (CBDCA) is a hydrophilic platinum coordination compound and is an 
analog of cisplatin, producing intrastrand DNA cross-links. 

 
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b. 
TOXICOLOGY 
 
Human Toxicology:  Side effects of carboplatin (CBDCA) include 
myelosuppression, nausea, vomiting, abdominal pain, diarrhea and constipation.  
Other toxicities include allergic reaction (including hypersensitivity, i.e., rash, 
urticaria, erythema, pruritus, bronchospasm and hypotension), peripheral 
neuropathy, paresthesia, loss of hair, hearing loss, visual disturbances and 
change in taste.  Serum creatinine elevations and blood urea elevations have 
occurred as well as abnormal liver function tests and decreased serum 
electrolyte values.  Although rare, pain, asthenia, cardiovascular, respiratory, 
genitourinary and mucosal side effects have occurred in some patients.  Cancer-
associated hemolytic uremic syndrome has been reported rarely.  The renal 
effects of nephrotoxic compounds may be potentiated by carboplatin.  
Carboplatin is contraindicated in patients with a history of severe allergic 
reactions to cisplatin or other platinum-containing compounds or mannitol.  This 
drug should not be used in patients with severe bone marrow depression or 
significant bleeding.  The occurrence of acute leukemia has been reported rarely 
in patients treated with anthracycline/alkylator combination chemotherapy.  
 
Pregnancy and Lactation:  Carboplatin may cause fetal harm, therefore women 
of childbearing potential should be advised to avoid becoming pregnant. 
 
c. 
PHARMACOLOGY 
 
Kinetics:  The differences in potencies of carboplatin and cisplatin are due to 
differences in aquation rates.  The initial half-life is 1.1 - 2.0 hours and the post-
distributional half-life is 2.6 - 5.9 hours.  Sixty-five percent of the dose is excreted 
in the urine within twelve hours.  Carboplatin is not bound to plasma proteins. 
 
Formulation:  Carboplatin is supplied as a sterile lyophilized powder available in 
single-dose vials containing 50 mg, 150 mg and 450 mg of carboplatin for 
administration by intravenous injection.  Each vial contains equal parts by weight 
of carboplatin and mannitol.  Immediately before use, the content of each vial 
must be reconstituted with either Sterile Water for Injection, USP, 5% Dextrose in 
Water, or 0.9% Sodium Chloride Injection, USP, according to the following 
schedule: 
 
Vial Strength 
Diluent Volume 
 
 
50 mg 
5 ml 
150 mg 
15 ml 
450 mg 
45 ml 
 
 
These dilutions all produce a carboplatin concentration of 10 mg/mL.  Carboplatin 
can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in 
Water or 0.9% Sodium Chloride Injection, USP (NS). 
 
Carboplatin is also supplied as a solution for injection in vials containing 50 mg, 
150 mg, 450 mg and 600 mg with a concentration of 10 mg/mL. 
 
Storage and Stability:  Unopened vials of carboplatin for injection are stable for 
the life indicated on the package when stored at controlled room temperature 15° 
- 30°C, and protected from light.  When reconstituted as directed, the solution of 
carboplatin exhibits no decomposition for 8 hours at room temperature (25°C).  
Like cisplatin, this drug should not be given through aluminum needles.  

 
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CAUTION:  The single-use lyophilized dosage form contains no antibacterial 
preservatives.  Therefore, it is advised that the reconstituted product be 
discarded eight hours after dilution. 
 
Administration:  Intravenous. 
 
Supplier:  Carboplatin is commercially available for purchase by the third party.  
This drug will not be supplied by the NCI. 
 
Please refer to the Physician Desk Reference and package insert for complete 
information. 
 
3.2 
Paclitaxel, Taxol® (NSC-673089) 
 
a. 
DESCRIPTION 
 
Chemistry:  Paclitaxel is a diterpene plant product found in the needles and bark 
of the western yew, Taxus brevifolia.  The marketed formulation is prepared in a 
semi-synthetic process. 
 
Molecular Weight: 853.9 
 
Empirical Formula: C47H51NO14 
 Description: 
Clear viscous fluid 
 
b. 
TOXICOLOGY 
 
Human Toxicity: 
 
Dose-limiting toxicity is myelosuppression with reversible granulocytopenia, 
anemia, and thrombocytopenia.  Allergic reactions occur in up to 8% of patients 
receiving paclitaxel as an intravenous infusion over 6 to 24 hours.  These can be 
acute anaphylactoid reactions to include flushing, hypotension, and 
bronchospasm; dermatitis and pruritus are also observed.  Hypertension has also 
been seen, and may be related to concomitant medication with dexamethasone.  
Premedication with diphenhydramine, cimetidine, and dexamethasone appears 
to diminish the incidence of these reactions.  Neurotoxicity can include distal 
painful paresthesias.  Rarely, this toxicity has required discontinuation of drug 
due to pain, impairment of fine motor skills, or difficulty ambulating.  Experience 
to date suggests that this neuropathy is reversible.  Rarely, associated forms of 
neurotoxicity have included taste perversion, seizures, and mood changes.  
Some patients have reported vision abnormalities such as blurred vision, 
"flashing lights" and scintillating scotomata.  Ischemic or infarcted colon, 
sometimes with involvement of other parts of the gastrointestinal tract, has also 
been seen.  Patients reporting abdominal discomfort should be monitored 
closely.  These events generally occurred while the patients were severely 
neutropenic.  They may be most consistent with neutropenic enterocolitis 
(typhlitis).  Although increased SGOT, SGPT, bilirubin and alkaline phosphatase, 
as well as hepatic failure and hepatic necrosis have been seen, one patient 
receiving this drug has also experienced hepatic encephalopathy, and two 
incidences of pancreatitis have been noted.  Neuroencephalopathy has also 
been reported.  Pulmonary toxicities that have occurred are pneumonitis and 
radiation pneumonitis (following concomitant paclitaxel and radiation). 
 

 
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Other non-hematologic reactions include:  diarrhea, alopecia, myalgias and 
arthralgias, nausea or vomiting, mucositis (stomatitis and pharyngitis), light-
headedness, myopathy and fatigue.  Less commonly, cardiotoxicity has been 
associated with paclitaxel administration, to include arrhythmias (sinus 
bradycardia, ventricular tachycardia, atrial arrhythmia, and heart block), and 
myocardial infarction.  Skin reactions including erythema, induration, tenderness, 
ulceration, radiation recall, rash and nail changes have occurred including 
discoloration of fingernails and separation from nail bed. 
 
Pregnancy and Lactation:  Paclitaxel may cause fetal harm when administered to 
a pregnant woman.  Paclitaxel has been shown to be embryo- and fetotoxic in 
rats and rabbits and to decrease fertility in rats.  In these studies, paclitaxel was 
shown, to result in abortions, decreased corpora lutea, a decrease in 
implantations and live fetuses, and increased resorption and embryo-fetal 
deaths.  No information is available on the excretion of this drug in human milk.  
Because many drugs are excreted in human milk and because of the potential for 
serious adverse reactions in nursing infants, it is recommended that nursing be 
discontinued. 
 
c. 
PHARMACOLOGY 
 
Formulation:  Sterile solution containing 6 mg/ml in a 5 ml vial (30 mg per vial) in 
polyoxyethylated castor oil (Cremaphor EL) 50% and dehydrated alcohol, USP, 
50%.  There are also vial sizes of 100 mg and 300 mg. 
 
Solution Preparation:  Paclitaxel is reconstituted by diluting the total dose in 0.9% 
Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP (D5W) to 
maintain a paclitaxel concentration between 0.3 and 1.2 mg/ml.  Paclitaxel must 
be prepared in glass or polyolefin containers due to leaching of 
diethylhexlphthalate (DEHP) plasticizer from polyvinyl chloride (PVC) bags and 
intravenous tubing by the Cremaphor vehicle in which paclitaxel is solubilized.  
Each bag/bottle should be prepared immediately before administration. 
 
NOTE:  Formation of a small number of fibers in solution (within acceptable limits 
established by the USP Particulate Matter Test for LVPs) has been observed 
after preparation of paclitaxel.  Therefore, in-line filtration is necessary for 
administration of paclitaxel solutions.  In-line filtrations should be accomplished 
by incorporating a hydrophilic, microporous filter of pore size not greater than 
0.22 microns (e.g.:  IVEX-II or IVEX-HP or equivalent) into the IV fluid pathway 
distal to the infusion pump.  Although particulate formation does not indicate loss 
of drug potency, solutions exhibiting excessive particulate matter formation 
should not be used. 
 
Administration of Paclitaxel:  Paclitaxel, at the appropriate dose, will be given as 
an intravenous infusion as specified in the protocol, diluted in 0.9% Sodium 
Chloride Injection, USP, or 5% Dextrose Injection.  Paclitaxel will be administered 
via an infusion control device (pump) using non-PVC tubing and connectors, 
such as the IV administration sets (polyethylene or polyolefin) which are used to 
infuse parenteral nitroglycerin.  Nothing else is to be infused through the line 
where paclitaxel is being administered. 
 
Storage and stability:  The intact vials of paclitaxel should be stored between 2 - 
25°C.  Based on stability data for Taxol® made from either natural or semi-
synthetic paclitaxel, stored for up to 12 months at 40°C, potency losses were 
within the range of 2.0 to 2.4 percent per year.  Samples stored for up to 3  

 
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months at 60°C lost potency at rates corresponding to 20 to 40% per year.  
Accordingly, vials left out in a warm place for a few days should still be 
satisfactory for use.  All solutions of paclitaxel exhibit a slight haziness directly 
proportional to the concentration of drug and the time elapsed after preparation, 
although when prepared as described above, solutions of paclitaxel (0.3 - 1.2 
mg/ml) are physically and chemically stable for 27 hours.  Vials will be labeled 
with a firm expiration date. 
 
Supplier:  Paclitaxel is commercially available for purchase by the third party.  
This drug will not be supplied by the NCI. 
 
Please refer to the Physician Desk Reference and package insert for complete 
information. 
 
3.3  
Veliparib (ABT-888) (NSC 737664) 
 
a. 
DESCRIPTION 
 
Chemical Name: 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide 
 
Other Names: A-861695.0, Veliparib 
 
Classification: Poly (ADP-ribosome) polymerase (PARP) Inhibitor 
 
Molecular Formula: C13H16N4O  
 
Molecular Weight: 244.29 
 
Description: Light orange opaque capsule with black bands 
 
b. 
TOXICOLOGY 
 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for ABT-888 
(NSC 737664) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI (except as noted below).  Refer 
to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf for further clarification. Frequency is provided based on 2310 patients. 
Below is the CAEPR for ABT-888 (Veliparib). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE listed 
on different SPEERs, use the lower of the grades to determine if expedited 
reporting is required. 

 
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Version 2.3, March 4, 20161 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of revision.  
The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
Adverse Events with Possible  
 Relationship to ABT-888 (Veliparib) 
 (CTCAE 4.0 Term) 
[n= 2310] 
 
Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 Anemia (Gr 3) 
 
Febrile 
neutropenia 
 Febrile neutropenia 
(Gr 3) 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
 
Constipation 
 Constipation (Gr 2) 
 
Diarrhea 
 Diarrhea (Gr 3) 
Nausea 
 Nausea (Gr 3) 
 
Vomiting 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
Fatigue 
 Fatigue (Gr 3) 
INVESTIGATIONS 
 
 
Lymphocyte count 
decreased 
 Lymphocyte count 
decreased  
(Gr 4) 
 
Neutrophil count 
decreased 
 Neutrophil count 
decreased (Gr 4) 
Platelet count decreased 
 Platelet count 
decreased (Gr 4) 
 
Weight loss 
 Weight loss (Gr 2) 
 
White blood cell 
decreased 
 White blood cell 
decreased (Gr 4) 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 Anorexia (Gr 2) 
 
Dehydration 
 Dehydration (Gr 3) 
 
Hypophosphatemi
a 
 Hypophosphatemia 
(Gr 3) 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
Dysgeusia 
 Dysgeusia (Gr 2) 
 
Headache 
 Headache (Gr 3) 
 
Seizure 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Rash maculo-
papular 
 
VASCULAR DISORDERS 
 
 
Thromboembolic 
event2 
 

 
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2 Thromboembolic events, including deep vein thrombosis and pulmonary 
embolism, have been observed at a higher frequency compared to control arm 
when administered in combination with temozolomide. 
 
Adverse events reported on ABT-888 (Veliparib) trials, but for which there 
is insufficient evidence to suggest that there was a reasonable possibility 
that ABT-888 (Veliparib) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic 
system disorders - Other (bone marrow failure); Blood and lymphatic system 
disorders - Other (pancytopenia) 
CARDIAC 
DISORDERS 
- 
Cardiac 
disorders 
- 
Other 
(Takotsubo 
cardiomyopathy); Heart failure; Left ventricular systolic dysfunction; Palpitations; 
Sinus bradycardia; Sinus tachycardia 
EAR AND LABYRINTH DISORDERS - Vertigo 
EYE DISORDERS - Blurred vision 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; 
Colonic obstruction; Dental caries; Dry mouth; Duodenal ulcer; Dyspepsia; 
Dysphagia; Enterocolitis; Esophagitis; Flatulence; Gastritis; Gastroesophageal 
reflux disease; Lower gastrointestinal hemorrhage; Mucositis oral; Obstruction 
gastric; Rectal hemorrhage; Rectal pain; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; 
Edema limbs; Fever; Flu like symptoms; Malaise; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatobiliary disorders - Other 
(cirrhosis) 
INFECTIONS AND INFESTATIONS - Appendicitis; Catheter related infection; 
Infections and infestations - Other (peritonsillar abscess); Infections and 
infestations - Other (shingles); Lung infection; Lymph gland infection; Mucosal 
infection; Sepsis; Skin infection; Upper respiratory infection; Urinary tract 
infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; 
Dermatitis radiation; Injury, poisoning and procedural complications - Other 
(radiation proctitis) 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase 
increased; Aspartate aminotransferase increased; Blood bilirubin increased; 
Cardiac troponin I increased; Creatinine increased; Electrocardiogram QT 
corrected interval prolonged; Lipase increased 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Hyperglycemia; 
Hypernatremia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hypokalemia; 
Hypomagnesemia; Hyponatremia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; 
Arthritis; Back pain; Bone pain; Generalized muscle weakness; Musculoskeletal 
and connective tissue disorder - Other (muscle spasms); Myalgia; Neck pain; 
Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Myelodysplastic syndrome; Treatment related secondary malignancy; 
Tumor pain 
NERVOUS SYSTEM DISORDERS – Ataxia; Cognitive disturbance; Depressed 
level of consciousness; Dysarthria; Extrapyramidal disorder; Intracranial 
hemorrhage; 
Lethargy; 
Memory impairment; Movements involuntary; 
Paresthesia; Peripheral motor neuropathy; Peripheral sensory neuropathy; 
Presyncope; Reversible posterior leukoencephalopathy syndrome; Stroke; 
Syncope; Tremor 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; 
Insomnia; Psychiatric disorders - Other (emotional instability); Psychosis; 
Restlessness 

 
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RENAL AND URINARY DISORDERS - Hematuria; Proteinuria; Renal and 
urinary disorders - Other (dysuria) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; 
Dyspnea; Epistaxis; Hypoxia; Nasal congestion; Pharyngolaryngeal pain; Pleural 
effusion; Pneumonitis; Respiratory failure 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; Palmar-plantar erythrodysesthesia syndrome; Pruritus; Purpura; 
Rash acneiform; Skin and subcutaneous tissue disorders - Other (nail bed 
changes) 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension; 
Vascular disorders - Other (brainstem infarction)  
 
Note: ABT-888 (Veliparib) in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other 
agent, or the combination may result in events never previously associated with 
either agent. 
 
c. 
PHARMACOLOGY 
 
Storage:  Store intact bottles between 15 and 25C (59–77F). 
 
Stability:  Shelf-life stability studies for ABT-888 capsules are ongoing. 
 
Route(s) of Administration: Oral.  ABT-888 and matching placebo capsules may 
be administered without regard to meals. 
 
d. 
SUPPLIER 
 
ABT-888 is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 
ABT-888 and matching placebo are provided to the NCI under a Collaborative 
Agreement between Abbott Laboratories and the DCTD, NCI (see Section 16.0). 
 
Clinical Supplies:  ABT-888(NSC 737664) and matching Placebo will be 
provided free of charge by Abbott Laboratories and distributed by the 
Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation 
Program (CTEP), Division of Cancer Treatment and Diagnosis (DCTD), National 
Cancer Institute (NCI). 
 
ABT-888 20 mg and 0 mg matching placebo for ABT-888 will be supplied as 
immediate release capsules.  The ABT-888 capsule contains ABT-888, 
microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, gelatin, 
sodium lauryl sulfate, and titanium dioxide. May contain FD&C blue #1, FD&C 
yellow #6, or FD&C yellow #5.  The matching placebo capsule contains 
microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, gelatin, 
sodium lauryl sulfate, and titanium dioxide. May contain FD&C blue #1, FD&C 
yellow #6, or FD&C yellow #5. 
 
ABT-888 and matching Placebo will be supplied in bottles containing 64 – 20 mg 
capsules (ABT-888) or 64 – 0 mg capsules (Placebo for ABT-888) with a child-
resistant cap and a tamper-evident seal.   
 
Note: In order to dispense a single cycle at a time, ABT-888(veliparib)/placebo 
capsules may be repackaged from the supplied HDPE bottles into amber (or 
other low-actinic) child resistant pharmacy dispensing bottles.  The bottles should 
be labeled according to State regulations and also include the information from  

 
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the original patient specific bottle sent from the PMB.  Expiration will be 30 days 
from the repackaging date (or the original retest date, whichever is earlier) when 
stored at 15°C to 25°C (59°F to 77°F).  
 
Each blinded, patient-specific bottle will be labeled with … 
• 
the protocol number (i.e., “8811”) 
• 
the bottle number (i.e., “Bottle 1 of 2” and “Bottle 2 of 2”) 
• 
the number of capsules (i.e., “64 capsules”) 
• 
the patient ID number (e.g.,"XXXXXX", where “XXXXXX” represents the 
protocol number and sequence number which is the unique patient 
identifier assigned at registration) 
• 
the patient initials (i.e., first initial, last initial [e.g., "LFM"]) 
• 
the agent identification (i.e., “ABT-888  20  mg”  or  “ABT-888  20  mg  or 
Placebo”) 
• 
a blank line for the pharmacist to enter the patient’s name 
• 
 administration instructions  (i.e.,  “Take        capsules two times daily as 
directed.”) 
• 
storage instructions (i.e., “Store at room temperature (15ºC to 25ºC; 59ºF 
to 77ºF).” 
• 
emergency contact instructions 
• 
a Julian date 
 
The Julian date indicates the day the bottle was labeled and shipped and 
is composed of the last two digits of the calendar year (e.g., 2009 = 09, 2010 = 
10) and a day count (e.g., January 1 = 001, December 31 = 365). For 
example, a bottle labeled and shipped on January 1, 2009 would have a 
Julian date of ‘09001’ and a bottle labeled and shipped on December 31, 
2009 would have a Julian date of ‘09365’. The Julian date will be used by PMB 
for recalls. When a lot expires, PMB will determine the last date the expired lot 
was shipped and will recall all bottles (i.e., both ABT-888 and Placebo) shipped 
on or before that date thus eliminating any chance of breaking the blind. 
 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240/276-6575 Monday through Friday 
between 8:30am and 4:30pm Eastern Time. You may also contact the PMB 
via e-mail at PMBAfterHours@mail.nih.gov. 
 
Agent Orders: No starter supplies will be available for the open-label 
(Phase I) or blinded (Phase II) portion of this study. Patient-specific supplies 
will 
be 
sent 
to 
the 
registering 
investigator 
at 
the 
time 
of 
registration/randomization and should arrive within 3 to 5 days. Patients will be 
registered/randomized by the SWOG Statistical Center in Seattle, WA. The 
assigned patient ID number must be recorded by the registering institution at 
the time of randomization for proper clinical supply dispersion. Once a 
patient has been randomized, the SWOG Statistical Center will electronically 
transmit a clinical drug request for that patient to the PMB. This request will be 
entered and transmitted by the SWOG Statistical Center the day the patient 
is randomized and will be processed by PMB the next business day and 
shipped the following business day. Shipments within the United States will be 
sent by FedEx (generally one to two business day delivery). Thus, if a 
patient is registered on Monday, the SWOG Statistical Center would enter a 
clinical drug request for that patient on Monday and PMB would process that 
request on Tuesday and ship the drug on Wednesday.  Sites could expect to 
receive their order approximately Thursday or Friday. Shipments to United 
States sites can be expedited (i.e., receipt on Thursday in example above) 
by the provision of an express courier account name and number to the 
SWOG Statistical Center at the time the patient is randomized. 

 
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Phase I: The initial request will be for a sufficient supply to complete ABT-
888 treatment for the initial 6 weeks of radiation treatment. If a patient is 
found to be eligible to continue on to consolidation treatment (4-6 weeks 
after radiation ends), sites may reorder an additional 2 – 64 capsule bottles 
(a 2-cycle / 6-week supply at a dose of 80 mg BID on days 1-7 of a 21 day 
cycle).  This supply (2 x 64 capsule bottles) will be sufficient to complete 
the prescribed two cycles of consolidation therapy.  Orders must be 
submitted through the PMB Online Agent Order Processing (OAOP) 
application (https://eappsctep.nci.nih.gov/OAOP/pages/login.jspx). Access to 
OAOP requires 
the establishment of a CTEP Identity and Access 
Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the 
maintenance of an “active” account status and a “current” password. The 
assigned patient ID number (e.g., "XXXXXX") and the patient initials (e.g., 
"LFM") should be entered in the "Patient or Special Code" field. All drug 
orders should be shipped directly to the physician responsible for treating the 
patient. 
 
Phase II: The initial request will be for a suf ficient supply to complete 
ABT-888/placebo treatment at the recommended Phase II dose (120 mg BID for 
43 days – 9 x 64 capsule bottles) for the initial 6 weeks of radiation treatment. 
If a patient is found to be eligible to continue on to consolidation 
treatment (4-6 weeks after radiation ends), sites may reorder an 
additional 2 – 64 capsule bottles (a 2-cycle / 6-week supply at a dose of 
80 mg BID on days 1-7 of a 21 day cycle).  This supply (2 x 64 capsule 
bottles) will be sufficient to complete the prescribed two cycles of 
consolidation therapy.  Orders must be submitted through the PMB Online 
Agent 
Order 
Processing 
(OAOP) 
application 
(https://eappsctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP 
requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an 
“active” account status and a “current” password. The assigned patient ID 
number (e.g., "XXXXXX") and the patient initials (e.g., "LFM") should be 
entered in the "Patient or Special Code" field. The agent name for the ABT-
888 must be written on the order form as “ABT-888 or Placebo”. All drug 
orders should be shipped directly to the physician responsible for treating the 
patient. 
 
Agent Transfers: Bottles MAY NOT be transferred from one patient to another 
patient or from one protocol to another protocol. All other transfers (e.g., a 
patient moves from one participating clinical site to another participating 
clinical site, the principal investigator at a given clinical site changes) must be 
approved in advance by the PMB. To obtain an approval for transfer, 
investigators should complete and submit to the PMB (fax number 240/276-
7893) a Transfer Investigational Agent Form available on the CTEP home 
page (http://ctep.cancer.gov). The patient  ID  number (e.g.,  "XXXXXX"') and  
the patient initials (e.g., "LFM”) should be entered in the "Received on NCI 
Protocol No." and the "Transferred to NCI Protocol No." fields in addition to 
the protocol number (i.e., "8811"). 
 
Agent Returns: Only undispensed clinical supplies should be returned to 
the PMB. When it is necessary to return study drug (e.g., sealed bottles 
remaining when a patient permanently discontinues protocol treatment, 
expired bottles recalled by the PMB), investigators should return the study 
drug to the PMB using the NCI Return Drug List available on the CTEP home 
page (http://ctep.cancer.gov) or by calling the PMB at 240/276-6575. The  

 
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patient ID number (e.g., "XXXXXX") and the patient initials (e.g., "LFM") should 
be entered in the "Lot Number" field. Opened bottles with remaining capsules 
should be documented in the patient-specific NCI Oral Drug Accountability 
Record Form (i.e., logged in as “returned by patient” and logged out as 
“destroyed on site”) and destroyed on-site in accordance with institutional policy. 
 
Agent Accountability: The investigator, or a responsible party designated by 
the investigator, must maintain a careful record of the receipt, disposition, 
and return of all drugs received from the PMB using the NCI Oral Drug 
Accountability Record Form available on the CTEP home page 
(http://ctep.cancer.gov). A separate NCI Oral Drug Accountability Record Form 
must be maintained for each patient ID number (e.g., "XXXXXX") on this 
protocol. 
 
Emergency Unblinding: 
In  the  event  of  an  emergency  or  severe  adverse  reaction  necessitating 
identification of the medication for the welfare of the patient, please contact the 
Washington Poison Center (WPC) at 206-526-2121 (see Appendix 18.4).  This 
service is available 24 hours a day, 365 days a year.  The WPC will require the 
protocol number (i.e., “8811 or S1206”), the patient ID number (e.g., “XXXXXX”), 
and the patient initials (e.g., “LFM”) to unblind the patient.  Please note that, if a 
patient is emergently unblinded, he/she is considered to be off-therapy and must 
discontinue protocol treatment. 
 
 
4.0 
STAGING CRITERIA 
 
Definition of TNM (AJCC Cancer Staging Manual, 7th edition) 
 
Primary Tumor (T) 
 
T1  
A tumor that is 3.0 cm or less in greatest dimension, surrounded by lung or visceral 
pleura, and without evidence of invasion proximal to a lobar bronchus at bronchoscopy. 
 
T2  
Tumor more than 3 cm but 7 cm or less or tumor with any of the following features: 
involves main bronchus, 2 cm or more distal to the carina; invades visceral pleura; 
associated with atelectasis or obstructive pneumonitis that extends to the hilar region but 
does not involve the entire lung.  
 
T3  
Tumor more than 7 cm or one that directly invades any of the following: parietal pleural 
(PL3), chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, 
mediastinal pleura, parietal pericardium; or tumor in the main bronchus less than 2 cm 
distal to the carina1 but without involvement of the carina; or associated atelectasis or 
obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.  
 
T4  
Tumor of any size that invades any of the following: mediastinum, heart, great vessels, 
trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor 
nodule(s) in a different ipsilateral lobe. 
 
Regional Lymph Nodes (N) 
 
N0  
No demonstrable metastasis to regional lymph nodes. 
 
N1  
Metastasis to lymph nodes in the peribronchial or the ipsilateral hilar region, or both, 
including direct extension. 
 
N2 
Metastasis to ipsilateral mediastinal lymph nodes or subcarinal lymph nodes. 
 
N3  
Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, 
ipsilateral or contralateral scalene or supraclavicular lymph nodes 

 
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Distant Metastasis (M) 
 
M0 
No known distant metastasis* 
 
Stage Grouping of the TNM Subsets 
 
Stage IIIA  
T4 N0-1 M0 
T3 N1 M0 
T1-3 N2 M0 
 
Stage IIIB  
T4 N2 M0 
T1-4 N3 M0 
 
* In AJCC 7th edition, pleural and pericardial are now considered Stage M1a disease.  
 
 

 
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5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the S1206 Prestudy Form and submit to the Data 
Operations Center in Seattle (see Section 14.0).  Any potential eligibility issues should be addressed to 
the Data Operations Center in Seattle at 206/652-226, lungquestion@crab.org prior to registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be considered Day 28.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 28 or 42 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.1 
REGISTRATION #1 
 
a. 
Patients must have histologically or cytologically-proven new diagnosis of 
unresectable Stage IIIA/IIIB*, non-small cell lung cancer (adenocarcinoma, 
bronchioloalveolar cell carcinoma, large cell carcinoma, squamous cell 
carcinoma, or mixed).  
 
* Per the AJCC 7th edition, pleural and pericardial are now considered Stage 
M1a disease. When pleural fluid is visible on the CT scan or on a chest x-ray, a 
thoracentesis is required to confirm that the pleural fluid is cytologically 
negative. Patients with exudative pleural effusions are excluded, regardless of 
cytology. Patients with effusions that are minimal (i.e. not visible on chest x-
ray) that are too small to safely tap are eligible. A small effusion that has 
positive FDG uptake on PET has to be proven to be malignant per standard of 
care diagnostic procedures for the patient to be excluded. 
 
b. 
Patients must have measurable or non-measurable disease (see Section 10.1) 
documented by CT, MRI or PET/CT. The CT from a combined PET/CT may be 
used to document only non-measurable disease unless the scan is of diagnostic 
quality as defined in Section 10.1a. Measurable disease must be assessed by 
CT within 28 days prior to registration. Pleural effusions, ascites and laboratory 
parameters are not acceptable as the only evidence of disease. Non-measurable 
disease must be assessed within 42 days prior to registration. All disease must 
be assessed and documented on the Baseline Tumor Assessment Form. 
 
c. 
Patients with brain metastases are ineligible. All patients must have a 
pretreatment CT or MRI scan of the brain to evaluate for CNS disease within 42 
days prior to registration. 
 
d. 
Patients must not have received any prior systemic therapy (chemotherapy or 
other biologic therapy) for lung cancer.  
 
e. 
Patients must not have received prior chest radiation therapy for NSCLC.  
 
f. 
Patients must not have had a previous surgical resection. However, patients may 
have undergone exploratory thoracotomy, mediastinoscopy, excisional biopsy or 
similar surgery for the purpose of determining the diagnosis, stage or potential 
resectability of newly diagnosed lung tumor. At least 28 days must have elapsed 
since thoracic surgery (excluding mediastinoscopy or other minor surgeries) and 
patients should have recovered from all associated toxicities at the time of 
registration. Patients must not be planning to undergo a minor surgical procedure 
while on this study.  

 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
g. 
Patients must be ≥ 18 years old. 
 
h. 
Patients must have Zubrod performance status 0-1 (See Section 10.4). 
 
i. 
Patients must have tumor tissue available for submission to assess gene 
expression of ERCC1 and XRCC1. (See Section 15.2) Patients must also be 
offered participation in banking for future use of specimens as described in 
Section 15.3. 
 
j. 
Patients must have adequate bone marrow function as evidenced by all of the 
following:    absolute neutrophil count ≥ 1,500/ mcl; platelets ≥ 100,000/mcl; 
hemoglobin ≥ 9.0 g/dl. These results must have been obtained within 28 days 
prior to registration. 
 
k. 
Patients must have adequate hepatic function as defined by total bilirubin within 
Institutional Upper Limit of Normal (IULN) and SGOT (AST) or SGPT (ALT) ≤ 2.5 
x IULN. These results must be obtained within 28 days prior to registration. 
 
l. 
Patients must not be pregnant or nursing because of increased risk of harm to a 
nursing infant or fetus including fetal death from the chemotherapeutic and 
biologic agents.  Women/men of reproductive potential must have agreed to use 
an effective contraceptive method.  A woman is considered to be of "reproductive 
potential" if she has had menses at any time in the preceding 12 consecutive 
months.  In 
addition 
to 
routine 
contraceptive 
methods, 
"effective 
contraception" also includes heterosexual celibacy and surgery intended to 
prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a 
hysterectomy, bilateral oophorectomy or bilateral tubal ligation.   However, if at 
any point a previously celibate patient chooses to become heterosexually active 
during the time period for use of contraceptive measures outlined in the protocol, 
he/she is responsible for beginning contraceptive measures. 
 
m. 
Patients must have a serum creatinine ≤ the IULN AND measured or calculated 
creatinine clearance ≥ 60 cc/min using the following Cockroft-Gault Formula: 
 
Calculated Creatinine Clearance = (140 - age) X (actual body weight in kg) 
 
72 x serum creatinine 
 
Multiply this number by 0.85 if the patient is a female. These tests must have 
been performed within 28 days prior to registration. 
 
n. 
Patients must have pulmonary function tests (PFTs) including FEV1 within 84 
days prior to registration; for FEV1, the best value obtained pre- or post 
bronchodilator must be ≥ 1.2 liters/second and/or ≥ 50% predicted. 
 
o. 
Patients may not be planning to receive any other investigational agents. 
 
p. 
Patients must not have more than 10% weight loss in the past 6 months. 
 
q. 
Patients must not have a history of allergic reactions attributed to compounds of 
similar chemical or biologic composition to ABT-888, carboplatin, paclitaxel or 
other agents used in study. 

 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
r. 
No other prior malignancy is allowed except for the following:  adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately 
treated Stage I or II cancer from which the patient is currently in complete 
remission, or any other cancer from which the patient has been disease free for 
five years. 
 
s. 
Patient must not have any uncontrolled intercurrent illness including, but not 
limited to ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
t. 
Patients must not currently have a > Grade 1 symptomatic neuropathy-sensory 
(NCI Common Terminology Criteria Version 4.0). 
 
u. 
Patients must not have a history of seizures. 
 
 
v. 
Patients must not have any known immune deficiencies. Patients with immune 
deficiency are at increased risk of lethal infections when treated with marrow-
suppressive therapy. Therefore, known HIV positive patients receiving 
combination anti-retroviral therapy are excluded from the study because of 
possible pharmacokinetic interactions with carboplatin, paclitaxel and ABT-888 or 
other agents administered during the study.  
 
w. 
Patients must be able to swallow whole capsules.  
 
x. 
Prestudy history and physical must be obtained within 28 days prior to 
registration. 
 
y. 
All patients must be informed of the investigational nature of this study and must 
sign and give written informed consent in accordance with institutional and 
federal guidelines. 
 
z.  
As a part of the OPEN registration process (see Section 13.2 for OPEN access 
instructions) the treating institution’s identity is provided in order to ensure that 
the current (within 365 days) date of institutional review board approval for this 
study has been entered in the system. 
 
5.2 
REGISTRATION #2 – PRIOR TO CONSOLIDATION CHEMOTHERAPY 
 
Following completion of chemoradiotherapy, patients without local progression of disease or 
distant metastases will receive consolidation chemotherapy. Patients must be reregistered to 
consolidation chemotherapy within 6 weeks after completing chemoradiotherapy. 
 
a. 
Patients must have completed chemoradiotherapy per protocol and at least four 
weeks but no more than six weeks must have elapsed from the last day of 
induction therapy (the last day of radiation). 
 
b. 
Patients must have undergone restaging tests according to the study calendar 
and determined to have no evidence of disease progression (as defined in 
Section 10.2d).  
 

 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.2 
REGISTRATION #2 – PRIOR TO CONSOLIDATION CHEMOTHERAPY (Contd.) 
 
c. 
Patients must have a serum creatinine ≤ (IULN) AND measured of calculated 
creatinine clearance ≥ 60 cc/min using the following Cockroft-Gault Formula: 
 
Calculated Creatinine Clearance = (140 - age) X (actual body weight in kg) 
 
 72 x serum creatinine 
 
Multiply this number by 0.85 if the patient is a female. These tests must have 
been performed within 14 days prior to re-registration. 
 
d. 
Patients must have adequate bone marrow function as evidenced by all of the 
following: absolute neutrophil count ≥ 1,500 mcl; platelets ≥ 100,000/mcl; 
hemoglobin ≥ 9.0 g/dl. These results must have been obtained within 14 days 
prior to re-registration. 
 
e. 
Patients must have adequate hepatic function as defined by total bilirubin ≤ IULN 
and SGOT (AST) or SGPT (ALT) ≤ 2.5 x IULN. These results must be obtained 
within 14 days prior to re-registration. 
 
f. 
Patients must have Zubrod performance status 0-1 (See Section 10.4). 
 
 

 
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6.0 
STRATIFICATION FACTORS 
 
For the Phase II portion of the trial, patients will be randomized using a dynamic balancing 
algorithm with stratification based on (12): 
 
1. 
Stage IIIA vs. IIIB 
 
2. 
Histologic subtype: Squamous cell vs. Non-squamous 
 
 
7.0 
TREATMENT PLAN 
 
For chemotherapy-related treatment or dose modification questions, please contact Dr. Argiris at 
athanassios.argiris@gmail.com, Dr. Cristea at 626/256-4673 or mcristea@coh.org or Dr. Sands 
at 781/744-8400 or Jacob.M.Sands@lahey.org. For radiation therapy-related treatment or dose 
modification questions, please contact Dr. Chen at achen5@kumc.edu.  For dosing principles or 
questions, please consult the SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" 
at http://swog.org (then click on "Policies and Manuals" under the "Visitors" menu and choose 
Policy 38). 
 
7.1  
Treatment Overview 
 
The study will be conducted in two sequential parts. A patient may be enrolled to 
either the Phase I portion or the Phase II portion, but not both. 
 
Phase I – Details are in Section 7.3a. 
 
Phase II – Details are in Section 7.3b. 
 
7.2 
Pre-Medication 
 
a.    
Premedications: Paclitaxel 
 
All patients should be premedicated with: 
 
AGENT 
DOSE 
ROUTE 
DURATION 
 
 
Dexamethasone 
20 mg* 
PO/IV 
12 and 6 hours 
 
 
 
 
prior to paclitaxel** 
 
Diphenhydramine 
50 mg 
IV 
30 minutes prior to 
 
 
 
paclitaxel 
 
plus one of the following 
 
Ranitidine  
50 mg 
IV 
30 minutes prior to 
 
 
paclitaxel 
or 
 
Cimetidine 
300 mg 
IV 
 
 
Famotidine 
20 mg 
PO/IV 
30 minutes prior 
 
 
 
To paclitaxel 
 
 
*  20 mg is the dose for each administration. 
** Alternatively, a single intravenous dose of 20 mg may be given 30 minutes 
prior to paclitaxel injection.   

 
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Following the initial cycle of paclitaxel, if the patient has not experienced a 
hypersensitivity reaction to paclitaxel, then the investigator, at his/her discretion, 
may decrease dexamethasone and/or diphenhydramine as follows: 
 
• 
Dexamethasone 8 mg or 10 mg i.v. 
• 
Diphenhydramine 25 mg i.v. 
• 
H2 blocker i.v. (e.g. ranitidine 50 mg or cimetidine 300 mg) 
 
b.  
Premedications: Carboplatin 
 
Patients should receive antiemetics of the treating physician's choice prior to 
carboplatin administration.  Dose modifications in the antiemetic regimen may be 
made at the discretion of the treating physician as clinically indicated. 
 
c.  
Other Ancillary Therapy 
 
Patients should receive full supportive care including transfusions of blood 
products, antibiotics, antiemetics, antidiarrheals, etc., when appropriate.  The 
reason(s) for treatment, dosage, and the dates of treatment should be noted in 
the "Comments" portion of the S1206 Concurrent Chemotherapy Treatment 
Form or S1206 Consolidation Chemotherapy Treatment Form. 
 
7.3 
Concurrent Chemoradiation 
 
Chemotherapy and radiotherapy to begin within 24 hours of each other. Day 1 of 
radiotherapy must be on a Monday or a Tuesday. 
 
Protocol will allow a +/- 24 hour window for chemotherapy and correlatives for Week 1. 
 
a. 
Phase I Drug Administration Schedule During Concurrent Radiation Therapy 
 
Each proceeding dose level will not open until all patients enrolled on the prior 
dose level have completed radiation and have been followed for 2 weeks (total of 
9 weeks). 
 
AGENT 
DOSE 
DAYS 
ROUTE 
SCHEDULE  
 
Paclitaxela 
45 mg/m2 during 
1 
IV over 1 
Weekly 
 
RT over 1 hour 
 
hour 
during RT 
 
 
 
during RT 
 
 
 
 
Carboplatin 
AUC = 2 during RT 
1 
IV 30 minutes Weekly  
 
over 30 minutesb 
 
after 
during RT 
 
 
 
completion of  
 
 
 
 
paclitaxel 
 
 
 
 
ABT-888c 
20 mg (Level -1*) 
1-43 
PO twice 
Daily 
 
40 mg (Level 0) 
 
 
Daily 
continuously 
 
(Starting Dose)    
 
throughout 
 
 
80 mg (Level 1) 
 
 
RT and one 
 
120 mg (Level 2)  
 
day after RT 
 
 
 
 
completion 
 
Radiotherapy  
6,000 cGy x 30 fractions     
 
6 weeks 
                       
(see Section 7.4)                                
 
 
* Per dose 
a See paclitaxel premedication guidelines in Section 7.2a. 

 
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b AUC=2 by modified Calvert formula. Carboplatin is given after paclitaxel 
infusion is   completed. In patients whose serum creatinine is < 0.8 mg/dl, 0.8 
mg/dl must be substituted in the Cockroft-Gault formula to calculate the 
estimated creatinine clearance for carboplatin dosing. This change is an 
addition to the requirement not to exceed a maximum dose of carboplatin of 
300 mg (see Appendix 18.3 for the Carboplatin Dosing Worksheet). See also 
premedication guidelines in Section 7.2b. 
c ABT-888 capsules are supplied as 20 mg capsules. Capsules may be taken 
without regard to meals. 
 
b. 
Phase II Drug Administration Schedule During Concurrent Radiation Therapy 
 
After defining the MTD for ABT-888, patients will be randomized 1:1 between the 
control arm (concurrent chemoradiotherapy + placebo followed by consolidation 
chemotherapy + placebo) versus the investigational arm (concurrent 
chemoradiotherapy + ABT-888 followed by consolidation chemotherapy + ABT-
888). 
 
AGENT 
DOSE 
DAYS 
ROUTE 
SCHEDULE 
 
Paclitaxela 
45 mg/m2 during 
1 
IV over 1 
Weekly 
 
RT over 1 hour 
 
hour 
during RT 
 
 
 
during RT 
up to 6  
 
 
 
 
doses 
 
Carboplatin 
AUC = 2 during RT 
1 
30 minute 
Weekly  
 
over 30 minutesb 
 
IV infusion 
during RT 
 
 
 
immediately  up to 6 
 
 
 
following 
doses 
 
 
 
paclitaxel 
 
 
 
ABT-888 or 
120 mgc 
1-43 
PO twice 
Daily 
Placebo 
 
 
daily 
continuously 
 
 
 
 
throughout  
 
 
 
 
RT and one 
 
 
 
 
day after RT 
 
 
 
 
Completion 
 
Radiotherapy 
6,000 cGy x 30 fractions                          
6 weeks 
 
(see Section 7.4)                              
 
 
a  See paclitaxel premedication guidelines in Section 7.2a. 
b AUC=2 by modified Calvert formula. Carboplatin is given after paclitaxel 
infusion is   completed. In patients whose serum creatinine is < 0.8 mg/dl, 0.8 
mg/dl must be substituted in the Cockroft-Gault formula to calculate the 
estimated creatinine clearance for carboplatin dosing. This change is an 
addition to the requirement not to exceed a maximum dose of carboplatin of 
300 mg (see Appendix 18.3 for the Carboplatin Dosing Worksheet and 
premedication guidelines in Section 7.2b). 
c ABT-888/placebo capsules are supplied as 20 mg capsules. Capsules may be 
taken without regard to meals. 
 
c. 
ABT-888 will be administered orally without regards to meals.  
 
On the Phase I, ABT-888 will be given twice a day starting the first day of RT and 
continuously during RT until one day after RT completion.  
 
 

 
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During the consolidation chemotherapy part (that will start 4-6 weeks after 
RT completion) ABT-888 will be given on days 1-7 of each of the 2 cycles 
(every 21 days) of carboplatin and paclitaxel.   
 
On the Phase II portion of the study patients will be randomized 1:1 to ABT-
888 versus placebo during concurrent chemoradiotherapy and during 
consolidation chemotherapy. 
 
 
Missed doses should not be made up.  
 
On the days when the patient is scheduled to undergo sampling of blood for 
correlative studies, the dose of ABT-888 will be administered under supervision 
(to record the time and coordinate collection of subsequent samples). Please see 
Appendix 18.1. 
 
Because there is a potential for interaction of ABT-888 with other concomitantly 
administered drugs, the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies should be noted in the patients chart.   
 
ABT-888 is not known to be a potent inhibitor of the major human CYPs in vitro, 
indicating a low risk for drug-drug interactions at the proposed dosing 
concentrations. 
 
d. 
Definition of Dose-Limiting Toxicity 
 
Toxicities will be graded according to the Version 4.0 of the NCI Common 
Terminology Criteria for Adverse Events. This can be reviewed at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
Toxicities must be attributable to the study regimen (i.e. possibly, probably 
or definitely related to one of the 3 study drugs or to radiation therapy) to 
constitute a Dose-Limiting Toxicity (DLT). Only adverse events which occur 
during RT or during the 2 weeks following completion of RT will be counted as 
DLTs:  
 
Dose-limiting toxicities will be defined as follows 
 
1. 
Radiation esophagitis or dermatitis radiation Grade 3 that lasts > 7 
consecutive days or Grade 4.  
 
2. 
Grade 4 neutropenia for more than 7 days or neutropenic fever (defined 
as ANC < 500 and a temperature of 38.50 C or above).   
 
3. 
Grade 4 thrombocytopenia. 
 
4. 
Grade 4 nausea/vomiting despite appropriate antiemetic therapy. 
 
5. 
Delays in radiotherapy or chemotherapy or ABT-888 due to toxicity of 
more than 3 weeks. 
 
6. 
All other non-hematologic toxicities of Grade 3 or higher, with the 
following exceptions: 
 
a. 
anorexia 
 
b. 
fatigue 
 
c. 
infection without neutropenia 
 

 
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d. 
Grade 3 AST/ALT elevations ≤ 7 days 
 
e. 
Infusion reactions. Patients with Grade 3 or worse infusion 
reactions will be removed from study and replaced and will not 
be considered evaluable for DLT. 
 
f. 
Grade 3 or 4 lymphopenia 
 
g. 
Grade 3 or 4 electrolyte abnormalities that are corrected to 
Grade 2 or less in less than 48 hours.  
 
h. 
Grade 3 dehydration lasting less than 7 days in duration. 
 
Any laboratory abnormalities should be considered clinically relevant and 
related to the study drugs to be considered DLT.  
 
Patients will be considered evaluable for DLT if they receive at least 66% of 
the planned doses of ABT-888 at the assigned dose level, and at least one 
dose each of carboplatin and paclitaxel, and began radiation therapy 
during the concurrent chemoradiotherapy step, or if they experience a DLT. 
Patients who are not evaluable for DLT will be replaced. Patients with Grade 
3 or worse infusion reactions will be removed from study and replaced and will 
not be considered evaluable for DLT. 
 
Management and dose modifications associated with the above adverse events 
are outlined in Section 8.0. 
 
Dose escalation will proceed within each cohort according to the following 
scheme.  Dose-limiting toxicity (DLT) is defined above.   
 
No intra-patient dose escalation is allowed. 
 
Number of Patients 
with DLT at a Given 
Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥ 2 
Dose escalation will be stopped.  This dose level will be declared 
the maximally administered dose (highest dose administered).  
Three (3) additional patients will be entered at the next lowest 
dose level if only 1 out of 3 patients were treated previously at that 
dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the next 
dose level. 
• If 1 or more of this group suffer DLT, then dose escalation is 
stopped, and this dose is declared the maximally administered 
dose.  Three (3) additional patients will be entered at the next 
lowest dose level if only 3 patients were treated previously at 
that dose. 
≤ 1 out of 6 at highest 
dose level below the 
maximally administered 
dose 
This is generally the recommended Phase II dose. At least 5 
patients evaluable for DLT must be entered at the recommended 
Phase II dose. If no DLTs are observed among the first 5 patients 
evaluable for DLT enrolled at the maximum dose, then accrual to 
the Phase I portion may be terminated at 5 evaluable patients.  
However, if one (1) DLT is observed among the first 5, the total 
accrual must be 6 evaluable patients. 
 

 
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Each proceeding dose level will not open until patient of the prior level have 
completed radiation and have been followed for 2 weeks (total of 9 weeks). 
 
7.4 
Radiotherapy 
 
a. 
Introduction 
 
Patients will receive a total dose of 6,000 cGy in 30 fractions over 6 weeks 
utilizing standard fractionation (one fraction per day). Either 3D conformal 
treatment planning or IMRT will be utilized. Each institution must complete 
applicable benchmarks prior to entering patients on trial, and all treatment plans 
must be submitted to QARC within 3 days of the start of radiation therapy for 
review.  See Section 12.0 for benchmark and data submission requirements. 
 
IMRT is allowed on this study as long as the method of motion 
management is documented. 
Proton therapy is not allowed on this study. 
NOTE: Digital submission of treatment plans is required on this study. 
 
b. 
Localization, Simulation, Immobilization 
 
CT simulation is required.  Portal verification shall be done at the initiation of 
treatment and thereafter for all treatment fields every 5 fractions. 
 
1. 
Each patient will be positioned in an immobilization device in the 
treatment position on a flat table. Contiguous CT slices with slice 
thickness less than or equal to 3 mm are to be obtained starting from the 
level of the cricoid cartilage and extending inferiorly through the entire 
liver volume. The GTV, CTV, and PTV and normal organs will be 
outlined on all appropriate CT slices. 
 
2. 
A treatment planning FDG PET/CT scan (or FDG-PET alone) with the 
patient in the treatment position is encouraged to assist with target 
delineation. In the case where the PET/CT is obtained in the treatment 
position, the CT from this study may be used as the planning CT scan. 
 
3. 
Intravenous (i.v.) contrast during the planning CT is optional provided a 
diagnostic chest CT was done with contrast to delineate the major blood 
vessels. If not, i.v. contrast should be given during the planning CT. If  
contrast is used, the densities can be over-ridden or the contrast scan 
must be registered to a non-contrast scan for planning purposes. Optimal 
immobilization is critical for this protocol. Immobilization to assure 
reproducibility of the set up is necessary. 
 
4. 
The use of four-dimensional radiation treatment planning is highly 
encouraged. Acceptable methods of accounting for tumor motion 
include: design of the PTV to cover the excursion of the lung primary 
cancer and nodes during breathing such as an ITV approach, a 
maximum intensity projection (MIP) approach, automatic breath-hold 
(i.e., Elekta ABC device) or a gating approach (e.g., Varian RPM 
system). 
 
c. 
Target Volumes 
 
The nomenclature and definitions of ICRU Reports 50 and 62 shall be followed in 
this study. 

 
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1. 
Definition of the GTV: The primary tumor and clinically positive lymph 
nodes seen either on the planning CT (> 1 cm short axis diameter) or 
pretreatment PET scan (SUV > 3) will constitute the GTV. This volume(s) 
may be disjointed. In the event of a collapsed lobe or lung segment, the 
use of PET to distinguish tumor from fluid/atelectasis is encouraged. The 
ITV includes the envelope that encompasses the tumor motion for a 
complete respiratory cycle. 
 
2. 
Definition of the CTV: The CTV is defined to be the GTV plus a 0.5 cm to 
1 cm margin as appropriate to account for microscopic tumor extension. 
If an ITV approach is used then the ITV plus 0.5 cm to 1 cm is added to 
the ITV to form the CTV. Elective treatment of the mediastinum and 
supraclavicular fossae will not be done. 
 
Ipsilateral supraclavicular irradiation is allowed when needed for primary 
tumor coverage.  Contralateral hilar or supraclavicular coverage (of 
uninvolved nodes) is not allowed (elective nodal irradiation will not be 
performed).  Any mediastinal node detected by CT scan >1.0 cm (short 
axis) or with SUV > 3 on pre-treatment PET scan should be included as 
GTV, with the appropriate margin to create the CTV. 
 
3. 
Definition of the PTV: The planning target volume (PTV) is the CTV plus 
a margin to ensure that the prescribed dose is actually delivered to the 
GTV.  This margin is a geometric concept, which accounts for variations 
in treatment delivery, including variations in set-up between treatments, 
patient motion during treatment, movement of the tissues that contain the 
GTV, and size variations in the tissue containing the GTV. The PTV 
should be within a range of 0.5 to 1.5 cm, depending on the above 
factors.  This margin should include consideration for, most notably, 
organ motion. 
 
4. 
PTV guidelines when 4D planning is used: 
 
Free-breathing non-ITV approach (i.e. standard CT simulation without 
4DCT or fusion of inhalation and exhalation scans): 
 
There are two components to the PTV expansion. the internal motion (IM 
margin) which should be at least 1 cm in the inferior-superior direction, 
and 0.5 cm in the axial plane and an additional set-up margin (SU 
margin) of 0.5 cm. Thus, the total PTV includes the CTV plus a total 
margin of at least 1.5 cm to the superior-inferior dimensions and at least 
1.0 cm in the axial plane. 
 
Breath-hold or gating non-ITV approach: 
For breath-hold or gating approaches, the PTV margin should be at least 
1 cm in the inferior-superior direction and 0.5 cm in the axial plane. It is 
expected that daily imaging will be used for both breath-hold and gating 
techniques. 
 
ITV approach: 
If the ITV approach is used, then the PTV margin should account for 
setup uncertainties and may be individualized but should not be less 
than 1.0 cm. If daily imaging is used to align the vertebral bodies, then 
the margins for setup margins may be reduced to 0.5 cm. For institutions 
not using 4DCT, the use of fluoroscopy to determine the margin for 
motion in the inferior superior direction is encouraged. For institutions 
with gating technology, the use of respiratory gating is encouraged. 

 
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d. 
Target Doses 
 
Prescribed Dose:   The prescribed dose to the PTV is 6,000 cGy delivered in 200 
cGy/day over 30 fractions.  
 
Dose Uniformity: 
The prescribed isodose volume will cover at least 95% of 
the PTV. The minimum PTV dose must not fall below 95% of the prescription 
dose. The maximum PTV dose must not exceed a value that is 130% of the 
prescribed dose.  The minimum and maximum doses will be defined as the dose 
to a 1 cc volume of the PTV.   
 
Acceptable and Unacceptable Variations: 
See Section 12.4 for Definitions 
of Deviations in Protocol Performance. 
 
Tissue Heterogeneity: All dose calculations will account for the density 
differences within the irradiated volume.   
 
Approved Dose Algorithms: 
Planning must be performed using an approved 
dose calculation algorithm. Approved algorithms include: convolution 
superposition, collapsed cone convolution, and Monte Carlo. Contact QARC 
(physics@qarc.org) for information regarding approved dose algorithms. 
 
e. 
Technical Factors 
 
Beam energy:  Megavoltage equipment is required with minimum peak photon 
energy of 6 MV. 
 
Treatment distance:  Minimal treatment distance should be 100 cm for SAD 
techniques.  SSD techniques should not be used. 
 
Blocking:  Blocking will be required for the shaping of ports to exclude volume of 
tissues that are not to be irradiated. Multi-leaf collimation (MLC) or individually-
shaped custom blocks should be used to protect normal tissues outside of the 
target volume. 
 
Filter or Wedges:  In the case of large sloping contours (as is often encountered 
when treating thoracic tumors in patients with larger body habitus), compensating 
filters are recommended.  Therefore, wedges may be used as a 2 dimensional 
tissue compensator.  If necessary, appropriate reduction in field size must be 
performed to avoid excessive irradiation of critical structures. 
 
f. 
Radiation Therapy Interruptions 
 
Total dose, number of fractions, and elapsed days should be carefully reported.  
Every effort should be made to minimize the length of treatment interruptions. 
 
g. 
Treatment Planning 
 
3D Conformal Therapy: The PTV is to be treated with any combination of 
coplanar or noncoplanar 3-dimensional conformal fields shaped to deliver the 
specified dose while restricting the dose to the normal tissues. Field 
arrangements will be determined by 3D planning to produce the optimal  
 
 

 
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conformal plan in accordance with volume definitions. The treatment plan used 
for each patient will be based on an analysis of the volumetric dose including 
DVH analyses of the PTV and critical normal structures. Each field is to be 
treated daily. 
 
Intensity-Modulated Radiotherapy (IMRT):  IMRT is allowed as long as a method 
of motion management is utilized.  Acceptable approaches include abdominal 
compression, breath hold using ABC device or other computed controlled 
spirometry, gating, image-guidance or other techniques. 
   
h. 
Organs at Risk 
 
Normal anatomy to be identified: The normal anatomy to be outlined on each CT 
image will include the lungs (right and left done separately), heart, skin, 
esophagus and spinal cord. The heart should be contoured from its base to apex, 
beginning at the CT slice where the ascending aorta originates. The esophagus 
should be contoured from the bottom of the cricoid to the gastroesophageal 
junction. The skin and spinal cord should be contoured on each CT slice. 
 
Normal tissue constraints shall be prioritized in the following order for treatment 
planning: 1=spinal cord, 2=lungs, 3=esophagus, and 4=heart 
 
1.  
Spinal Cord: The spinal cord dose limitation is the highest priority dose 
constraint and thus must be met irrespective of other constraints. Total 
“direct” plus “scatter” dose to the spinal cord must not exceed 5,050 cGy. 
 
2.  
Lungs: The dose-volume constraint to the lungs is the second highest 
priority and must be met, except if it conflicts with the cord dose 
constraints. The volume of both lungs that receive more than 2,000 cGy 
(the V20) should not exceed 37% of the total lung volume. Alternatively, 
the mean lung dose should optimally be ≤ 2,000 cGy. (By total lung 
volume we mean the total lung minus the CTV). 
 
3.  
If either of these constraints is exceeded, several solutions can be 
entertained. First, one might increase the weighting of AP / PA 
treatments by one and reduce the obliques. This can be done as long as 
the cord dose (above), which takes precedence, is not exceeded. 
Second, one can reduce the CTV to the minimum range suggested 
above. Third, one can try to reduce the PTV by using respiratory gating 
techniques. If after all attempts to decrease the V20 to below 37%, the 
V20 value still exceeds this limit, the patient should be treated as 
outlined in these guidelines.  However, this will be classified as a minor 
protocol deviation if V20 is greater than 37% but less than 40%.  If the 
V20 lies between 40% and 50%, this will be classified as a major 
protocol deviation.  NOTE:  Patients with V20 of greater than 50% will be 
removed from protocol treatment. 
 
4.  
Esophagus: The mean dose to the esophagus is optimally kept below 
3,400 cGy. This is not an absolute requirement, but is strongly 
recommended unless other, more critical constraints force the situation. 
The V60 (% volume of esophagus exceeding 6,000 cGy) should be 
calculated for each patient. 
 
5.  
Heart: The following limits are recommended 6,000 cGy to < 1/3, 4,500 
cGy to < 2/3, and 4,000 cGy to < 100% of the heart. 
 
i. 
Documentation Requirements 
 
See Section 12.3 for documentation requirements. 

 
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j. 
Variation of Dose Prescription 
 
See Section 12.4 for definitions of deviation in protocol performance. 
 
7.5 
Consolidation Chemotherapy 
 
All patients without disease progression after completion of chemoradiation will 
continue with 2 cycles (every 21 days) of consolidation therapy with paclitaxel 200 
mg/m2, carboplatin 6 AUC and ABT-888 80 mg or placebo BID  (dose of ABT-888 
established at the ongoing Phase I trial of  carboplatin, paclitaxel, and ABT-888). 
 
Consolidation chemotherapy should start within 4-6 weeks of completion of RT, assuming 
criteria for initiating treatment are met, see Section 8.3. 
 
Qualifying laboratory tests can be obtained up to 72 hours before planned initiation of 
therapy. 
 
AGENT 
DOSE 
ROUTE 
SCHEDULE 
 
Paclitaxela 
200 mg/m2 over 
IV over 3 
Day 1 and 
 
3 hours 
hours 
Day 22 (Cycle 2) 
 
 
Carboplatin 
AUC=6 over 30 
IV 30 minutes 
Day 1 and  
 
minutes during 
after 
Day 22 (Cycle 2) 
 
consolidationb 
completion 
 
 
of paclitaxel 
 
 
 
 
 
 
 
 
 
Phase I: ABT-888 
80mgc 
PO twice 
Days 1-7 
 
 
Daily 
(Cycle 1), 
 
 
 
Days 22-28 
 
 
 
(Cycle 2) 
 
Phase II: ABT-888 
80mgc 
PO twice 
Days 1-7 
or Placebo 
 
Daily 
(Cycle 1), 
 
 
 
Days 22-28 
 
 
 
 
(Cycle 2) 
 
NOTE: ABT-888 doses are “flat” and not calculated based on weight or BSA. 
a See paclitaxel premedication guidelines in Section 7.2a. 
b AUC=6 by modified Calvert formula. Carboplatin is given after paclitaxel infusion is 
completed. In patients whose serum creatinine is < 0.8 mg/dl, 0.8 mg/dl must be 
substituted in the Cockroft-Gault formula to calculate the estimated creatinine 
clearance for carboplatin dosing. This change is an addition to the requirement not to 
exceed a maximum dose of carboplatin of 900 mg (see Appendix 18.3 for the 
Carboplatin Dosing Worksheet and premedication guidelines in Section 7.2b). 
c ABT-888/placebo capsules are supplied as 20 mg capsules. Capsules may be taken 
without regard to meals. 
 
Patients are expected to start on a Monday. Protocol will allow a +/- 24 hour window for 
chemotherapy and correlatives for Week 1. 
 
7.6 
Supportive Care Measures 
 
See Section 8.4 regarding the use of prophylactic granulocyte colony stimulating factor 
during RT and during consolidation therapy. The use of growth factors for the treatment 
of anemia is not allowed.  

 
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7.7 
General Concomitant Medical and Supportive Care Guidelines 
  
Because there is a potential for interaction of carboplatin and paclitaxel with other 
concomitantly administered drugs through the cytochrome P450 system, the concurrent 
use of all other drugs, over-the-counter medications, or alternative therapies  must be 
noted in the patients chart.  The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential to affect selected CYP450 
isoenzymes. (See Appendix 18.5) 
 
7.8 
Drug Compliance Documentation 
 
Drug compliance will be recorded by patients in the Intake Calendar (see Appendix 18.1). 
Institutional CRAs will review and ascertain patient adherence with protocol therapy at 
the end of treatment for each cycle.  Calendar should be kept in the patient's clinic chart.  
Sites may utilize institutional pill diaries or other source documentation in place of the 
Intake Calendar at the discretion of the treating physician. 
 
7.9 
Full CDUS Reporting Requirements 
 
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4d and 14.4g, the S1206 
Concurrent Chemotherapy Treatment Form, the S1206 Consolidation Chemotherapy 
Treatment Form, and the S1206 Adverse Event Form.  A cycle is defined as 21 days. 
During the Phase I portion of the trial, the S1206 Concurrent Chemotherapy Treatment 
Form and the S1206 Adverse Event Form must be submitted every 7 days (see Section 
14.4i). 
 
7.10 
Criteria for Removal from Protocol Treatment  
 
a. 
Progression of disease or symptomatic deterioration as defined in Section 10.2d.  
  
b.  
Grade 3 or worse infusion reactions  
 
c.  
Ineligible for Second Registration (see Sections 5.2a-f ) 
 
d. 
Completion of protocol treatment. 
 
e. 
Unacceptable toxicity. 
 
f.  
Treatment delay for any reason > 3 weeks. 
 
g. 
Normal lung V20 greater than 50% (see Section 7.4). 
 
h. 
The patient may withdraw from the study at any time for any reason. 
 
7.11 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.12 
Follow Up Period 
 
All patients will be followed until death or 5 years after registration, whichever occurs first. 
 
 

 
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8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE 
Version 4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4.0. 
 
8.2 
General Dose Modification Guidelines 
 
If multiple toxicities are experienced, use the worst grade.  
 
8.3 
Dose Modifications During Concurrent Therapy (common for the Phase I and Phase II) 
 
 No dose reductions of chemotherapeutic agents are required during concurrent 
chemoradiotherapy.  Doses that are missed during the weekly schedule concurrent with 
radiation therapy will not be made up. Any treatment delays will be documented.  
 
a. 
ABT- 888 Dose Levels 
 
 
Dose level 2 
120 mg* 
Dose level 1 
80 mg* 
Dose level 0 
(Starting Dose) 
40 mg* 
Dose level -1 
20 mg* 
Dose level -2 
Permanently remove patient from protocol treatment. 
* Dose given twice a day. 
 
NOTE: Carboplatin and paclitaxel doses missed will not be made up.  All 
dose reductions are permanent. 
 
b. 
Paclitaxel/Carboplatin Dose Modifications for Hematologic Toxicity During 
Concurrent Therapy (same for both Phase I and Phase II parts of the study) 
 
Toxicity 
NCI CTCAE Grade 
(CTCAE v4.0) on the 
day of due 
treatment* 
Paclitaxel Dose 
At Start of 
Subsequent 
Cycles 
Of Therapya 
Carboplatin Dose at 
Start of Subsequent 
Cycles Of Therapya 
ABT-888 
Versus 
Placebo 
Neutropenia 
1 (1500-1999/mm3) 
Maintain dose 
level 
Maintain dose level 
No change 
2 (1000-1499/ mm3 
Maintain dose 
level 
Maintain dose level 
No change 
3 (500-999/ mm3 
Hold therapyb 
Hold therapyb 
Hold therapyb 
4 < 500/mm3 
Hold therapyb 
Hold therapyb 
Hold therapyb 

 
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Toxicity 
NCI CTCAE Grade 
(CTCAE v4.0) on the 
day of due 
treatment* 
Paclitaxel Dose 
At Start of 
Subsequent 
Cycles 
Of Therapya 
Carboplatin Dose at 
Start of Subsequent 
Cycles Of Therapya 
ABT-888 
Versus 
Placebo 
Neutropenic fever 
Hold therapyb 
Hold therapyb 
Hold therapyb 
Thrombocytopenia 
1 (< LLN-
75,000/mm3) 
Maintain dose 
level 
Maintain dose level 
Maintain 
dose level 
2 (50,000-
74,999/mm3) 
Hold therapyb 
Hold therapyb 
Hold therapyb 
3 (25,000-
49,999/mm3) 
Hold therapyb 
Hold therapyb 
Hold therapyb 
4 (< 24,999/mm3) 
Hold therapyb 
Hold therapyb 
Hold therapyb 
 
* RT should be held for all Grade 4 hematologic toxicity except for Grade 4 
lymphopenia, (at the discretion of the treating physician).  RT should be 
resumed when hematologic toxicity is ≤ Grade 3. 
a Dose levels are relative to the starting dose in the previous cycle. For 
concurrent therapy, paclitaxel and carboplatin doses will not be adjusted. 
b Repeat lab work weekly and resume chemotherapy and ABT-888 based on 
this table. 
 
If paclitaxel and/or carboplatin doses must be withheld for greater than 3 
consecutive weeks, the drug(s) will be held permanently for the duration of 
concurrent therapy. 
 
c. 
Paclitaxel/Carboplatin Dose Modifications for Non-Hematologic Toxicity During 
Concurrent Therapy (same for both Phase I and Phase II parts of the study) 
 
Dose reductions in ABT-888/placebo will be permanent during concurrent 
therapy 
 
Worst 
Toxicity 
NCI CTCAE 
Grade 
(CTCAE 
v4.0)a 
Paclitaxel Dose 
At Start of 
Subsequent 
Cycles 
Of Therapyb 
Carboplatin 
Dose at 
Start of 
Subsequent 
Cycles Of 
Therapyb 
ABT-888 
Versus 
placebo 
Neuropathy 
≤ Grade 1 
Maintain dose level 
Maintain dose 
level 
Maintain dose level 
Grade 2 
Hold therapy until 
Grade ≤ 1; restart 
at full dose 
Maintain dose 
level 
Maintain dose level 
Grade 3 or 4 
Discontinue 
therapy 
Hold therapy, 
until ≤ Grade 2 
Hold therapy , until ≤ 
Grade 2 

 
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Worst Toxicity 
NCI CTCAE 
Grade 
(CTCAE v4.0)a 
Paclitaxel 
Dose 
At Start of 
Subsequent 
Cycles 
Of Therapyb 
Carboplatin 
Dose at 
Start of 
Subsequent 
Cycles Of 
Therapyb 
ABT-888 
Versus 
placebo 
Other non-
hematologic 
toxicitiesc 
Grade 3 or 4 
Hold therapy 
until ≤ Grade 2 
Hold therapy 
until ≤ Grade 2 
 
Hold therapy until ≤ 
Grade 2 and decrease 
ABT-888/placebo by 1 
dose level, unless not 
possibly attributable to 
ABT-888/placebo 
For in-field toxicities please see Section 8.3d. 
a For ≤ CTCAE Grade 2 non-hematologic toxicity not described above, excluding 
neuropathy, maintain dose level of all study.  For neuropathy, follow the 
guidelines listed above. 
b Dose levels are relative to the starting dose in the previous cycle.  For 
concurrent therapy, paclitaxel and carboplatin doses will not be adjusted. 
c Radiation therapy should continue to be delivered for ≤ Grade 3 non-
hematologic toxicities in or outside the radiation treatment field, with the 
exceptions noted in Table 8.2d. RT should be held for all Grade 4 non-
hematologic toxicity in or outside the treatment field and resumed only when 
toxicity is ≤ Grade 2. 
 
NOTE: If there is a decline in performance status to ≥ 2 for greater than 2 
weeks while under treatment, radiotherapy should be held with no further 
chemotherapy administered.  Re-evaluate patient after one week for 
resumption of radiotherapy. 
 
d. 
Paclitaxel/Carboplatin/RT Dose Modifications for in RT In-Field, Non-
Hematologic Toxicity During Concurrent Therapy (same for both Phase I and 
Phase II parts of the study). 
 
Treatment Modification for In-field Non-Hematologic Toxicity 
In-field 
CTCAE 
Toxicity 
Grade 
XRT 
Paclitaxel 
Carboplatin 
Esophagus/pharynx* 
(on day of XRT) 
4 
Hold 
treatment 
Until ≤ 
Grade 2 
Hold treatment 
Until ≤ Grade 2 
Hold treatment 
Until ≤ Grade 2 
Esophagus/pharynx* 
(on day of chemo) 
3 
No change 
or hold ≤ 5 
days 
Hold treatment 
Until ≤ Grade 2 
Hold treatment 
Until ≤ Grade 2 
Esophagus/pharynx* 
(on day of chemo) 
2 
No change 
No change 
No change 

 
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Treatment Modification for In-field Non-Hematologic Toxicity 
Pulmonary 
4 
Discontinue 
Discontinue 
Discontinue 
Pulmonary 
3 
Hold 
treatment 
Until ≤ 
Grade 2 
Hold treatment 
Until ≤ Grade 2 
Hold treatment 
Until ≤ Grade 2 
Skin 
4 
Hold 
treatment 
Until ≤ 
Grade 2 
Hold treatment 
Until ≤ Grade 2 
Hold treatment 
Until ≤ Grade 2 
Skin 
3 
No change 
No change 
No change 
* Radiation esophagitis or dermatitis radiation will use CTCAE v4.0.  
 
The grading for esophagitis as per CTCAE v4.0  is: 
 
Grade 1:  Asymptomatic; clinical or diagnostic observations only; intervention not 
indicated.  
 
Grade 2: Symptomatic; altered eating/swallowing; oral supplements indicated.  
 
Grade 3: Severely altered eating/swallowing; tube feeding, TPN or hospitalization 
indicated.   
 
Grade 4:  Life-threatening consequences; urgent operative intervention indicated. 
 
On day of chemotherapy administration during any treatment week, omit 
paclitaxel and carboplatin until toxicity resolves to Grade ≤ 2 as detailed in the 
table above that refers to Concurrent therapy.  
 
Radiotherapy should be interrupted for any Grade 4 toxicity or Grade 3 
pulmonary toxicity and resumed according to the table above.  If  treatment is 
interrupted for > 3 weeks, the patient should be removed from study treatment.   
 
RT should continue to be delivered for ≤ Grade 3 non-hematologic toxicities in or 
outside the radiation treatment field (with the exceptions noted in Section 8.3d for 
in-field non-hematologic toxicities).  RT should be held for Grade 4 non-
hematologic toxicities in or outside the treatment field and resumed only when 
non-hematologic toxicity is ≤ Grade 2. RT should be held for Grade 4 
hematologic toxicity, except for Grade 4 lymphopenia (at the discretion of the 
treating physician).  RT should be resumed when hematologic toxicity is ≤ Grade 
3. 
 
Radiation therapy will be continued without interruption even if 
chemotherapy and/or ABT-888/placebo are held for toxicity or any other 
reason. However, if radiation therapy is held for toxicity, chemotherapy 
and/or ABT-888 will be held as well. 
 
8.4 
Dose Modifications During Consolidation Therapy 
 
• 
Patients should meet the laboratory parameters and the performance status outlined 
in eligibility before initiation of each cycle of consolidation therapy.  
 

 
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• 
All toxicities (except alopecia and lymphopenia, hyperglycemia, hypoalbuminemia, 
elevated serum alkaline phosphatase) should have resolved to Grade 1 or lesser 
severity before initiation of the first or second cycle of consolidation therapy. 
Treatment should be delayed until recovery of blood counts to the following levels: 
absolute neutrophil count ≥ 1,500/ mcl; platelets ≥ 100,000/mcl; hemoglobin ≥ 9.0 
g/dl.   
 
• 
Only patients without disease progression based on repeat tumor 
measurements using RECIST will receive consolidation therapy. 
 
• 
If the patient is found to be eligible to continue on to consolidation therapy (4 
weeks, +/- 3 days), additional ABT-888 or ABT-888/placebo supplies should be 
ordered.   
 
Dose adjustments are to be made according to the organ system showing the greatest 
degree of toxicity. Treatment delay of > 3 weeks due to toxicity will lead to removal of the 
patient from the study. 
 
Since fatigue can be a symptom of cancer progression, dose reduction will only be done 
if it is deemed to be drug-related in the opinion of the investigator.  
 
The prophylactic use of granulocyte-colony growth stimulating factors on Cycle 1 of 
consolidation is allowed at the discretion of the treating physician. 
 
Dose levels of ABT-888 during Consolidation Treatment: 
 
ABT-888 
80 mg BID (starting dose level) for Days 1-7 and Days 22-28 
 
ABT-888 
40 mg BID (-1 dose level) for Days 1-7 and Days 22-28 
 
Carboplatin AUC 6, Paclitaxel 200 mg/m2 (starting dose level) 
 
Carboplatin AUC 5, Paclitaxel 175 mg/m2 (-1 dose level) 
 
a. 
Paclitaxel/Carboplatin Dose Modifications During Consolidation Therapy for 
Hematologic Toxicity (same for both Phase I and Phase II parts of the study) 
 
Toxicity 
NCI CTCAE Grade 
(CTCAE v4.0) 
On day of treatment 
 
Paclitaxel Dose 
At Start of 
Second Cycle 
Of Therapya,c 
Carboplatin Dose at 
Start of Second 
Cycle Of Therapya,c 
ABT-888 
versus Placebo 
Neutropenia 
1 (1500-1999/mm3) 
Maintain dose level 
Maintain dose level 
No change 
2 (1000-1499/mm3 
Hold therapyb 
Maintain dose level, if 
fully recovered in 1 
week. If not, decrease 
by 1 dose level when 
≥ 1500 mm3 
Hold therapyb 
Maintain dose level, if 
fully recovered in 1 
week. If not, decrease 
by 1 dose level when 
≥ 1500 mm3 
Hold therapy; 
resume when 
chemotherapy is 
resumed 
3 (500-999/mm3) 
Hold therapyb 
Maintain dose level, if 
fully recovered in 
1 week and add 
growth factor. If not, 
decrease by 1 dose 
level when ≥ 1500 
mm3 and add growth 
factor 
Hold therapyb 
Maintain dose level, if 
fully recovered in 1 
week and add growth 
factor. If not, 
decrease by 1 dose 
level when ≥ 1500 
mm3 and add growth 
factor 
Hold therapy; 
resume when 
chemotherapy is 
resumed and 
decrease ABT-
888/placebo by 1 
dose level 

 
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Version Date 6/12/17 
 
 
 
Toxicity 
NCI CTCAE Grade 
(CTCAE v4.0) 
On day of treatment 
 
Paclitaxel Dose 
At Start of 
Second Cycle 
Of Therapya,c 
Carboplatin Dose at 
Start of Second 
Cycle Of Therapya,c 
ABT-888 
versus Placebo 
Neutropenia (contd.) 
4 <500/mm3 
Hold therapyb 
Decrease by 1 dose 
level when ≥ 1500 
mm3 and add growth 
factor 
Hold therapyb 
Decrease by 1 dose 
level when ≥ 1500 
mm3 and add growth 
factor 
Hold therapy; 
resume when 
chemotherapy is 
resumed and 
decrease ABT-
888/placebo  by 
1 dose level 
Neutropenic fever 
Hold therapyb and  
decrease by 1 dose 
level when ≥ 1500 
mm3  Add growth 
factor 
Hold therapyb and  
decrease by 1 dose 
level when ≥ 1500 
mm3  Add growth 
factor 
Hold therapy; 
resume when 
chemotherapy is 
resumed and 
decrease ABT-
888/placebo by 1 
dose level 
Thrombocytopenia 
1 (≥75,000/mm3) 
Hold therapy until 
platelets ≥ 
100,000/mcl and 
maintain dose level 
Hold therapy until 
platelets ≥ 
100,000/mcl and 
maintain dose level 
Hold therapy; 
resume when 
chemotherapy is 
resumed and 
maintain dose 
level 
2 (50,000-
74,999/mm3) 
Hold therapyb 
Maintain dose level, if 
fully recovered in 1 
week. If not, decrease 
by 1 dose level when 
≥ 100,000 mm3 
Hold therapyb 
Maintain dose level, if 
fully recovered in 1 
week. If not, decrease 
by 1 dose level when 
≥ 100,000 mm3 
 
Hold therapy; 
resume when 
chemotherapy is 
resumed 
3 (25,000-
49,999/mm3) 
Hold therapyb 
Maintain dose level, if 
fully recovered in 1 
week. If not, decrease 
by 1 dose level when 
≥ 100,000 mm3 
Hold therapyb 
Decrease by 1 dose 
level when ≥ 100,000 
mm3 
Hold therapy; 
resume when 
chemotherapy is 
resumed and 
decrease ABT-
888/placebo by 1 
dose level 
4 (<25,000/mm3) 
Hold therapyb and 
decrease by 1 dose 
level when ≥ 100,000 
mm3 
Hold therapyb and 
decrease by 1 dose 
level when ≥ 100,000 
mm3 
Hold therapy; 
resume when 
chemotherapy is 
resumed and 
decrease ABT-
888/placebo by 1 
dose level 

 
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If During the 
Cycle (worst 
toxicity) 
Paclitaxel 
Carboplatin 
ABT-
888/placebo 
ANC < 0.5 x 109 
Add growth factor 
Add growth factor 
Decrease ABT-
888/placebo by 
1 dose level 
Fever (≥ 38ºC) with 
ANC < 0.5  
x 109 
Reduce dose by 1 
dose level for all 
subsequent cycles 
Reduce dose by 1 
dose level for all 
subsequent cycles 
Decrease ABT-
888/placebo by 
1 dose level 
Platelets < 5 0  
x 109 
No Change 
Reduce dose by 1 
dose level for all 
subsequent cycles 
Decrease ABT-
888/placebo by 
1 dose level 
a  Dose levels are relative to the worst toxicities in the previous cycle.  For con solidation  
therapy, dose reductions of paclitaxel and carboplatin below the –1 dose level will n o t 
be allowed. 
b  Repeat lab work weekly and resume chemotherapy based on this table. 
c  Dose delays greater than 3 weeks will warrant discontinuation of chemotherap y o r th e 
consolidation cycles. 
 
b. 
Paclitaxel/Carboplatin Dose Modifications During Consolidation for Non-
Hematologic Toxicity During Consolidation Therapy (same for both Phase I and 
Phase II parts of the study) 
 
Toxicity 
NCI CTCAE Grade 
(CTCAE v4.0)a 
Paclitaxel Dose 
At Start of 
Second Cycle 
Of Therapyb 
Carboplatin Dose 
at 
Start of Second 
Cycle Of Therapyb 
ABT-888/placebo 
Neuropathy 
 
 
 
≤ Grade 1 
Maintain dose level 
Maintain dose level 
No change 
Grade 2 
Hold therapy until 
Grade ≤ 1 restart at 
full dose; if 
persistent reduce 
by 1 dose level 
Hold therapy until 
Grade ≤ 1 restart at 
full dose 
Hold therapy until 
Grade ≤1 restart at full 
dose 
Grade 3 
Discontinue 
paclitaxel 
Hold therapy until 
Grade ≤ 2 and 
restart at full dose 
Hold therapy until 
Grade ≤ 2 and restart at 
full dose 
Other Non-
Hematologic 
Toxicitiesc 
Grade 2, 3 or 4 
Hold treatment until 
≤ Grade 1; reduce 
by 1 dose level 
Hold treatment until 
≤ Grade 1; reduce 
by 1 dose level 
Hold therapy. Resume 
when chemotherapy is 
resumed and decrease 
ABT-888/placebo by 1 
dose level, unless not 
possibly attributable to 
ABT-888/placebo 
a For ≤ CTCAE Grade 2 non-hematologic toxicity not described above, excluding 
neuropathy, maintain dose level of all study drugs.  For neuropathy, follow the 
guides above. 
b Dose levels are relative to the worst toxicities in the previous cycle.  For 
concurrent therapy, paclitaxel and carboplatin doses will not be adjusted. 
c With the exception of alopecia or Grade 2 nausea. For arthralgias/myalgias, 
hepatotoxicity, gastrointestinal, and allergic/hypersensitivity reactions please 
see below.   
 
 

 
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When a chemotherapy dose reduction is required during the consolidation course 
of therapy re-escalation of the chemotherapy dose will not be allowed. 
 
If chemotherapy or ABT-888/placebo doses must be withheld for greater 
than 3 consecutive weeks, the drug will be held permanently for the 
duration of consolidation therapy. 
 
c. 
Arthralgia/Myalgia  
 
The following dose adjustments are based on the worst grade experienced of 
arthralgia/myalgia of any preceding treatment course.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* If post-medication dexamethasone (4 mg orally BID for 3-5 days) was 
incorporated in regimen. If no dexamethasone was used, must add regimen to 
subsequent courses prior to dose level reductions. Hold treatment until 
resolution to ≤ Grade 1. 
 
d. 
Hepatic Toxicity (Paclitaxel dose modification only) 
 
The following dose adjustments for paclitaxel are based on ALT and bilirubin 
serum levels and should be obtained within seven days of treatment.  
ALT 
 
Bilirubin 
Paclitaxel 
ABT-888/placebo 
≤ Grade 1 
and/or 
≤ Grade 2 
No change 
No change 
≥ Grade 2 
and/or 
≥ 
 Grade 3 
HOLD* 
HOLD* 
* Hold until ALT resolution to ≤ Grade 1 and Bilirubin is ≤ Grade 2. If recovery of 
toxicity exceeds two weeks, discontinue further therapy and remove patient 
from study.  
 
If recovery of toxicity occurs within two weeks, reduce dose by 1 level above for 
both agents. No dose reduction will be done for carboplatin 
 
e. 
Gastrointestinal Toxicity  
 
Nausea and/or vomiting should be controlled with adequate antiemetic therapy. 
Prophylactic anti-emetic therapy can be used at the discretion of the treating 
physician. Patients are encouraged to take plenty of oral fluids. If  symptoms 
persist despite maximal anti-emetic therapy, ABT-888/placebo should be 
withheld until recovery to ≤ Grade 1. 
 
. 
Arthralgia/Myalgia 
Paclitaxel 
Carboplatin 
ABT-
888/placebo 
Grade 0-1 
(Normal-mild) 
No change 
 
No change 
 
No change 
 
Grade 2 
(decreased ability to 
move) 
Decrease by 1 
dose level 
No change 
No change 
Grade 3 
(disabled) 
 
Hold  treatment 
until resolution 
to 
≤ Grade 1. * 
Hold therapy 
until Grade ≤1 
restart at full 
dose 
Hold therapy until 
Grade ≤ 1 restart 
at full dose 

 
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Diarrhea should be managed with appropriate anti-diarrheal therapy. Patients 
should be encouraged to take plenty of oral fluids. If symptoms do not decrease 
to Grade 1 or less with adequate anti-diarrheal therapy, ABT-888/placebo should 
be held until recovery from symptoms to < Grade 1.  ABT-888/placebo can be re-
started at the same dose following recovery to < Grade 1 if worst grade of toxicity 
is < Grade 2). For worst Grade > 3, re-start with dose reduction by one dose 
level. 
 
If symptoms recur, the dose of ABT-888/placebo should be re-started with a 
reduction by one dose level 
 
f. 
Hypersensitivity Reactions to Paclitaxel 
 
Caution: Patients who had a mild to moderate hypersensitivity reaction have 
been successfully rechallenged, but careful attention to prophylaxis and bedside 
monitoring of vital signs is recommended.  
 
1. 
Mild symptoms (e.g., mild flushing, rash, pruritus) -Complete infusion. 
Supervise at bedside. No treatment required.  
 
2. 
Moderate symptoms (e.g., moderate rash, flushing, mild dyspnea, chest 
discomfort) -Stop infusion. Give intravenous diphenhydramine 25 mg and 
intravenous dexamethasone 10 mg. Resume infusion after recovery of 
symptoms at a low rate, 20 mg/hr. For 15 minutes, then, if no further 
symptoms, at full dose rate until infusion is complete. If symptoms recur, 
stop infusion. The patient should receive no additional paclitaxel for that 
cycle, but may be retreated after discussion with the principal 
investigator. Record toxicity on flow sheets..  
 
Severe life threatening symptoms (e.g., hypotension requiring pressor 
therapy, angioedema, respiratory distress requiring bronchodilation 
therapy, generalized urticaria)-stop infusion. Give intravenous 
diphenhydramine and dexamethasone as above. Add epinephrine or 
bronchodialtors if indicated. If wheezing is present, that is not responsive 
to administration of 0.35 cc of nebulized salbutamol solution (or 
equivalent), epinephrine is recommended. Patient should be removed 
from further protocol therapy. Report as serious adverse event.  
 
g. 
Hypersensitivity Reactions to Carboplatin: 
If the allergy develops during the consolidation part of the treatment, patients will 
have carboplatin deleted and will be evaluable, as they had completed the 9 
week DLT evaluation. 
If the allergy develops during the concurrent part of the treatment, patients will 
come off study and be replaced (if in the Phase I). 
 
h. 
Other Toxicities  
 
For any Grade 2, 3 or 4 toxicity not mentioned above, excluding hemoglobin, 
lymphocytes, alopecia or Grade 2 nausea, the treatment should be withheld until 
the patient recovers to < Grade 1.  If an abnormal laboratory value is reported, 
the toxicity should be possibly related to paclitaxel and carboplatin treatment to 
result in dose reduction. The paclitaxel and carboplatin treatment should then be 
resumed at dose level (-1) (permanent dose reduction). Dose reduction will be 
done for the drug that is most likely to have caused the toxicity. For Grade 1 
toxicities, no dose reduction should be made. 
 
 

 
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In case participants develop nausea/vomiting/diarrhea or myelosuppression, supportive 
medications will be prescribed as per Clinical Center and ASCO guidelines. 
 
8.5 
Assessment and Management of Esophageal Toxicity 
 
Esophagitis remains the major acute toxicity experienced during thoracic radiation.  With 
concurrent chemoradiation, there is an approximately 25% incidence of Grade 3/4 
esophagitis.  Esophagitis presents mainly as dysphagia and odynophagia.  
 
Management of esophagitis is initially with a soft diet and the use of topical anesthetics, 
such as lidocaine and diphenhydramine and agents that coat the irritated surfaces, such 
as sucralfate.  If symptoms progress, systemic narcotics may be used as needed.  
Severe, acute esophagitis should prompt aggressive supportive therapy including 
hydration and enteral or parenteral feeding so that lengthy treatment breaks can be 
avoided. 
 
8.6 
Colony Stimulating Factors 
 
G-CSF (Amgen) has been licensed by the Food and Drug Administration for the 
prevention of chemotherapy induced neutropenia.  In this study, G-CSF will not be 
administered to all patients to prevent neutropenia.  However, it may be used for patients 
who develop Grade 3 - 4 neutropenia.  For patients who experience Grade 3 or 4 
neutropenia or develop neutropenic fever between cycles of chemotherapy, G-CSF may 
be added to all subsequent cycles of chemotherapy.  G-CSF is commercially available 
and should be purchased through third party mechanisms.  The NCI will not provide G -
CSF for this study. 
 
If G-CSF is used, it is recommended that it be used in the following manner: 
 
If a patient develops neutropenia following chemotherapy, all dose modifications outlined 
in the protocol will be followed according to the original protocol.  However, G-CSF will be 
added to all subsequent cycles of chemotherapy, unless there is clinical suspicion that 
the neutropenia was due to an unrelated medical condition and not due to the 
chemotherapy. The use of prophylactic G-CSF with the first cycle of consolidation is at 
the discretion of the treating physician. 
 
8.7 
Dose Modification Contacts  
 
For chemotherapy-related treatment or dose modification questions, please contact Dr. 
Argiris 
at 
athanassios.argiris@gmail.com, 
Dr. 
Cristea 
at 626/256-4673 or 
mcristea@coh.org or Dr. Sands at 781/744-8400 or Jacob.M.Sands@lahey.org.  For 
radiation therapy-related treatment or dose modification questions, please contact  Dr. 
Chen at achen5@kumc.edu.  For dosing principles or questions, please consult the 
SWOG Policy #38 "Dosing Principles for Patients on Clinical Trials" at http://swog.org 
(then click on "Policies and Manuals" under the "Visitors" menu and choose Policy 38). 
 
8.8 
Adverse Event Reporting  
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 

 
S1206 
 
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Version Date 6/12/17 
 
 
 
9.0 
STUDY CALENDAR 
 
9.1 
Phase I Study Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Second Registration 
 
 
 
First Registration 
  
Consolidation PhaseΦ≠ 
F/U After 
Off Treat-
ment 
Prior to 
Pro-
gression7 
 
  
Chemoradiation 
Pre-Consolidation Phase√ 
Cycle 1 
Cycle 2 
REQUIRED STUDIES 
PRE 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
  
STUDY 
1 
2 
3 
4 
5 
6 
1 
2 
3 
4≠ 
5≠ 
6≠ 
1 
2 
3 
1 
2 
3 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History and Physical Exam* 
X* 
  
  
X 
  
  
X 
  
  
  
XΩ 
  
  
X 
  
  
X 
  
  
X 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight and Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
  
  
  
X 
  
  
X 
  
  
  
Adverse event evaluation 
  
X 
X 
X 
X 
X 
X 
  
X 
  
XΨ 
XΨ 
XΨ 
X 
  
  
X 
  
  
  
Capsule Count/patient diary 
  
X9 
X9 
X9 
X9 
X9 
X9 
  
  
  
  
  
  
X 
  
  
X 
  
  
  
Baseline Abnormailities 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
LABORATORY 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC/Differential/Platelets1 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
XΨ 
XΨ 
XΨ 
X∑ 
  
  
X 
  
  
X 
Creatinine, Electrolytes (K+, 
Na+, CI-, CO2), Mg++, Ca++ 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
XΨ 
XΨ 
XΨ 
X∑ 
  
  
X 
  
  
X 
Liver enzymes2 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
XΨ 
XΨ 
XΨ 
X∑ 
  
  
X 
  
  
X 
Pulmonary function tests¥ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X8 
Pregnancy test3 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Creatinine Clearance 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
X∑ 
  
  
X 
  
  
  
Albumin 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Brain CT or MRI 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CT of the chest, abdomen 4 
X 
  
  
  
  
  
  
  
  
  
X4 
  
  
  
  
  
  
  
X4 
X4 
Bone scan, if clinically 
indicated 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EKG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 Calendar continued on next page. Click here for Footnotes.  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

 
S1206 
 
Page 49 
 
Version Date 6/12/17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Second Registration 
 
 
 
First Registration 
  
Consolidation PhaseΦ≠ 
F/U After 
Off Treat-
ment 
Prior to 
Pro-
gression7 
 
  
Chemoradiation 
Pre-Consolidation Phase√ 
Cycle 1 
Cycle 2 
REQUIRED STUDIES 
PRE 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
  
STUDY 
1 
2 
3 
4 
5 
6 
1 
2 
3 
4≠ 
5≠ 
6≠ 
1 
2 
3 
1 
2 
3 
SPECIMEN SUBMISSION 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Paraffin-embedded tissue5 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CTC Submission6 
  
X 
  
  
X 
  
  
  
  
  
XΨ 
XΨ 
XΨ 
  
  
  
  
  
  
  
Peripheral blood 
mononuclear 
cells and 
serum/plasma/DNA/ 
RNA6 
  
X 
  
  
X 
  
  
  
  
  
XΨ 
XΨ 
XΨ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Radiation 
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
ABT-888$ 
  
X 
X 
X 
X 
X 
X∞ 
  
  
  
  
  
  
X 
  
  
X 
  
  
  
Carboplatin 
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
X 
  
  
X 
  
  
  
Paclitaxel 
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
X 
  
  
X 
  
  
  
Click here for Footnotes. 
 
 

 
S1206 
 
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Version Date 6/12/17 
 
 
 
Footnotes: 
* Baseline evaluation by Radiation Oncology and Medical Oncology. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
During chemoradiotherapy patients need a focused evaluation of toxicities on a weekly basis. However, a complete history and physical examinati on is 
only needed every 3 weeks during chemoradiotherapy, at 4 weeks (+/- 3 days) after chemoradiotherapy and prior to each cycle of consolidation 
chemotherapy. 
 
NOTE: If the patient is found to be eligible to continue on to consolidation therapy (4 Weeks, +/- 3 days), additional ABT-888 supplies should be 
ordered.  
 
1 Complete blood counts with differential and platelet count should be performed <24 h ours prior to chemotherapy administration (with the exception of 
baseline CBC which must be obtained within 28 days prior to registration and Cycle 1 which must be obtained < 72 hours prior to chemotherapy 
administration). In the event of grade 3 or 4 hematologic toxicity, follow-up CBC with differential and platelet count will be obtained every 1-3 days until 
there is evidence of hematologic recovery.  
 
2 Liver function tests should include: Bilirubin, AST (SGOT), ALT (SGPT) 
 
3 All females of childbearing potential must have a negative pregnancy test done within 3 days of initiation of treatment to rule out pregnancy. 
 
4 Tumor measurements will be made using CT scan.  CT scan MUST be of diagnostic quality. Tumor assessments will be performed at 4 Weeks  
 
(+/- 3 days) after completion of chemoradiotherapy and after completion of consolidation therapy. Subsequently, repeat imaging with CT scans  
of chest and abdomen will be performed every 4 months for up to 2 years after initial registration, then every 6 months for up to 3 years after initial registration.  
5 The following materials will be submitted: paraffin-embedded tumor specimens for immunohistochemistry and molecular studies.  
 
6 Blood samples (Peripheral Blood Mononuclear Cells, serum/plasma/DNA/RNA and Circulating Tumor Cells). See Sections 15.3b and 15.4b for the 
time points for the blood correlatives.  Blood sampling will be performed on all patients on the Phase I and Phase II.  
 
7 Patients will be followed every 4 months for the first 2 years then every 6 months until 5 years from the date of randomization. 
 
8 Pulmonary function tests (PFTs) will be performed at baseline and 6 months after completion of consolidation therapy. 
 
9 For assessment of compliance every time a new box of ABT-888 capsules is given to the patient (the patient diary is in Appendix 18.1).  
 
√ 4-6 weeks is the pre-consolidation phase; patients will not receive any drug during that phase. 
 
∞ ABT-888 to be given 1 day after completion of RT. 
 
$ Twice daily 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
¥ Within 12 weeks prior to registration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ψ To be performed only once during Weeks 4-6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ω Within +/- 3 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Φ Only patients without disease progression will receive consolidation therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
≠ Consolidation should start within 4-6 weeks of completion of RT. See Section 7.5 
 
 
 
 
 
 
 
 
 
∑ To be performed within 14 days prior to second registration. 
 
 
 
 
 
 
 
 
 
 
 
 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://swog.org/Visitors/QA/Documents/Best%20Practices%20upddate.pdf.   
 

 
S1206 
 
Page 51 
 
Version Date 6/12/17 
 
 
9.2 
Phase II Study Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Second Registration 
 
 
 
First Registration 
  
Consolidation PhaseΦ≠ 
 
 
  
Chemoradiation 
Pre-Consolidation Phase√ 
Cycle 1 
Cycle 2 
F/U After 
Off 
Treatment 
Prior to 
Progression
8 
REQUIRED STUDIES 
 
PRE 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
 
STUDY 
1 
2 
3 
4 
5 
6 
1 
2 
3 
4≠ 
5≠ 
6≠ 
1 
2 
3 
1 
2 
3 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History and Physical 
Exam* 
X* 
  
  
X 
  
  
X 
  
  
  
XΩ 
  
  
X 
  
  
X 
  
  
X 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight and Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
  
  
  
X 
  
  
X 
  
  
  
Adverse event evaluation 
  
X 
X 
X 
X 
X 
X 
  
X 
  
XΨ 
XΨ 
XΨ 
X 
  
  
X 
  
  
  
Capsule Count/patient 
diary 
  
X10 
X10 
X10 
X10 
X10 
X10 
  
  
  
  
  
  
X 
  
  
X 
  
  
  
Baseline Abnormalities 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
LABORATORY 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CBC/Differential/Platelets1 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
XΨ 
XΨ 
XΨ 
X∑ 
  
  
X 
  
  
X 
Creatinine, Electrolytes (K+, 
Na+, CI-, CO2), Mg++, Ca++ 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
XΨ 
XΨ 
XΨ 
X∑ 
  
  
X 
  
  
X 
Liver enzymes2 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
XΨ 
XΨ 
XΨ 
X∑ 
  
  
X 
  
  
X 
Pulmonary function tests¥ 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X9 
Pregnancy test3 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Creatinine Clearance 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
X∑ 
  
  
X 
  
  
  
Albumin 
 X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
LDH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Brain CT or MRI 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CT of the chest, abdomen 4 
X 
  
  
  
  
  
  
  
  
  
X4 
  
  
  
  
  
  
  
X4 
X4 
Bone scan, if clinically 
indicated 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
EKG5 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 Calendar continued on next page. Click here for Footnotes   
  
  
  
  
  
  
  
  
  
  

 
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Second Registration 
 
 
 
First Registration 
 
 
 
 
 
 
Consolidation PhaseΦ≠ 
 
 
 
Chemoradiation 
Pre-Consolidation Phase√ 
Cycle 1 
Cycle 2 
F/U After Off 
Treatment 
Prior to 
Progression 8 
REQUIRED STUDIES 
PRE 
STUDY 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
 
1 
2 
3 
4 
5 
6 
1 
2 
3 
4 
5 
6 
1 
2 
3 
1 
2 
3 
SPECIMEN SUBMISSION 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Paraffin-embedded tissue6 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CTC Submission7 
  
X 
  
  
X 
  
  
  
  
  
XΨ 
XΨ 
XΨ 
  
  
  
  
  
  
  
Peripheral blood 
mononuclear 
cells and 
serum/plasma/DNA/ 
RNA7 
  
X 
  
  
X 
  
  
  
  
  
XΨ 
XΨ 
XΨ 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Radiation 
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
ABT-888/Placebo$ 
  
X 
X 
X 
X 
X 
X∞ 
  
  
  
  
  
  
X 
  
  
X 
  
  
  
Carboplatin 
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
X 
  
  
X 
  
  
  
Paclitaxel 
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
X 
  
  
X 
  
  
  
Click here for Footnotes. 
 
 

 
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Footnotes for Calendar 9.2 
*  Baseline evaluation by Radiation Oncology and Medical Oncology. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
During chemoradiotherapy patients need a focused evaluation of toxicities on a weekly basis. However, a complete history and physical exami nation is 
only needed every 3 weeks  during chemoradiotherapy, at 4 weeks (+/- 3 days) after chemoradiotherapy and prior to each cycle of consolidation 
chemotherapy. 
 
NOTE: If the patient is found to be eligible to continue on to consolidation therapy (4 Weeks, +/- 3 days), additional ABT-888 supplies should be ordered.  
 
 1 Complete blood counts with differential and platelet count should be performed <24 hours prior to chemotherapy administration (with the exception of 
baseline CBC which must be obtained within 28 days prior to registration and Cycle 1 which must be obtained < 72 hours prior to chemotherapy 
administration). In the event of grade 3 or 4 hematologic toxicity, follow-up CBC with differential and platelet count will be obtained every 1-3 days until 
there is evidence of hematologic recovery. 
 
2  Liver function tests should include: Bilirubin, AST (SGOT), ALT (SGPT) 
 
3  All females of childbearing potential must have a negative pregnancy test done within 3 days of initiation of treatment 
 to rule out pregnancy. 
 
4  Tumor measurements will be made using CT scan.  CT scan MUST be of diagnostic quality. Tumor assessments will be performed at 4 Weeks (+/- 3 
days) after completion of chemoradiotherapy and after completion of consolidation therapy. Subsequently, repeat imaging with CT scans of chest and 
abdomen will be performed every 4 months for up to 2 years after initial registration, then every 6 months for up to 3 years after initial registration. 
 
5 EKG must be performed within 28 days prior to registration. 
6  The following materials will be submitted: paraffin-embedded tumor specimens for immunohistochemistry and molecular studies.  
 
7  Blood samples (Peripheral Blood Mononuclear Cells, serum/plasma/DNA/RNA and Circulating Tumor Cells). See Sections 15.3b and 15.4b for the 
time points for the blood correlatives.  Blood sampling will be performed on all patients on the Phase I and Phase II.  
 
8 Patients will be followed every 4 months for the first 2 years then every 6 months until 5 years from the date of randomization. 
 
9  Pulmonary function tests (PFTs) will be performed at baseline and 6 months after completion of consolidation therapy. 
 
10 For assessment of compliance every time a new box of ABT-888 capsules is given to the patient (the patient diary is in Appendix 18.1).  
 
√  4-6 weeks is the pre-consolidation phase; patients will not receive any drug during that phase. 
 
∞  ABT-888 to be given 1 day after completion of RT. 
 
$  Twice daily 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
¥  Within 12 weeks prior to registration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ψ  To be performed only once during Weeks 4-6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ω  Within +/- 3 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Φ  Only patients without disease progression will receive consolidation therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
≠  Consolidation should start within 4-6 weeks of completion of RT. See Section 7.5 
 
 
 
 
 
 
 
 
 
∑  To be performed within 14 days prior to second registration. 
 
 
 
 
 
 
 
 
 
 
NOTE:  Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for 
continuous treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined 
in https://swog.org/Visitors/QA/Documents/Best%20Practices%20upddate.pdf. 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1  
Measurability of Lesions 
 
a.  
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm  by chest x-ray, by ≥ 1.0 
cm  with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All 
tumor measurements must be recorded in decimal fractions of 
centimeters (or millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness.   
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by 
scan (CT scan slice recommended being no greater than 0.5 cm). 
 
b.    
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable as are previously 
radiated lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to 
prior scans.  Body scans should by performed with breath-hold scanning 
techniques, if possible.  
 
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
4. 
Cystic 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. 
 
5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 
 

 
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10.2  
Objective Status at Each Disease Evaluation 
 
Objective Status is to be recorded at each evaluation. All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline. All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-
measurable disease.   
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the 
“target” areas. Therefore, in these studies it is not acceptable to image only the “target” 
areas of the body in follow-up scans. For study-specific imaging requirements, see the 
Study Calendar in Section 9.0.   
 
a.  
Complete Response (CR):  Complete disappearance of all target and non-
target lesions (with the exception of lymph nodes mentioned below).  No new 
lesions.  No disease related symptoms.   Any lymph nodes (whether target or 
non-target) must have reduction in short axis to < 1.0 cm.  All disease must be 
assessed using the same technique as baseline. 
 
b. 
Partial Response (PR): Applies only to patients with at least one measurable 
lesion. Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c.  
Stable: Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
d.  
Progression: One or more of the following must occur:  20% increase in the sum 
of appropriate diameters of target measurable lesions over smallest sum 
observed (over baseline if no decrease during therapy) using the same 
techniques as baseline, as well as an absolute increase of at least 0.5 cm.  
Unequivocal progression of non-measurable disease in the opinion of the treating 
physician (an explanation must be provided).   Appearance of any new 
lesion/site.  Death due to disease without prior documentation of progression and 
without symptomatic deterioration (see Section 10.2e). 
 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm.  
 
1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is 
a sign of progression based on a new lesion. 
 
2. 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a 
confirmation by anatomical assessment (e.g. CT, MRI, x-ray) as new site 
of disease to be considered progressive disease.  In such a case, the 
date of progressive disease will be the date of the initial abnormal FDG-
PET.   
 
e.   
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 
 

 
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f.  
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment 
methods were used. 
 
g.  
Objective status notes: 
 
1.  
Non-measurable and non-target measurable disease do not affect 
Objective Status  in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR). However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician).  
 
2.   
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3.    
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression.   
 
4.  
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed.  
 
5.   
For bone disease documented on bone scan only, increased uptake 
does not constitute unequivocal progression. However, increase in the 
soft tissue component of a lesion as measured by CT or MRI would 
constitute progression. 
 
6.   
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions. 
Increase in the size of an existing effusion does not constitute 
unequivocal progression, since the fluid status of the patient could alter 
the size of the effusion.  
 
7.   
If CR determination depends on a lesion for which the status is unclear 
by the required tests, it is recommended the residual lesion be 
investigated with biopsy or fine needle aspirate.   
 
10.3  
Best Response   
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 
b.  
PR: Two or more objective statuses of PR or better a minimum of four weeks 
apart documented before progression or symptomatic deterioration, but not 
qualifying as CR. 
 
c.  
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 

 
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d.  
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e.  
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above.   
 
g. 
Symptomatic deterioration: Objective status of symptomatic deterioration within 
12 weeks of registration, not qualifying as anything else above.   
 
Inadequate assessment, response unknown:  Progression or symptomatic deterioration 
greater than 12 weeks after registration and no other response category applies. 
 
10.4 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
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 self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours.   
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours.   
 
4 
Completely disabled; cannot carry on any self -care; totally 
confined to bed or chair.   
 
10.5 
Time to Treatment Failure   
 
From date of registration to date of first documentation of progression or symptomatic 
deterioration (as defined above), early discontinuation of treatment, or death due to any 
cause.  Patients last known not to have failed treatment are censored at the date of last 
contact. 
 
10.6 
Time to Death 
 
From date of registration to date of death due to any cause.  Patients last known to be 
alive are censored at date of last contact. 
 
10.7 
Progression-Free Survival 
 
From date of registration to date of first documentation of progression or symptomatic 
deterioration (as defined above), or death due to any cause.  Patients last known to be 
alive without report of progression are censored at date of last contact. 
 
 

 
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11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Accrual 
 
This study will initially be open in limited institutions, with an expected accrual of 10-30 
patients in the Phase I portion of the trial. The estimated accrual rate for this part of the 
study is 2-3 patients/ month.  The Phase II portion of the trial will be open Group-wide. 
Based on data from previous studies in similar patient populations the estimated 
accrual rate is 8-9 patients/month for the phase II portion of the study. 
 
11.2 
Phase I Study: 
 
Section 7.3a-b provides the details of the study design for the Phase I portion of the 
study. The Phase I study will be a limited dose-escalation study with the following dose 
levels: 
 
Dose Level 
Dose 
 
 
ABT-888  
 
Carboplatin 2 AUC 
 
Paclitaxel 45 mg/ m2 
Level -1 
20 mg BID 
Weekly during RT 
Weekly during RT 
Level 0 
40 mg BID 
Weekly during RT 
Weekly during RT 
Level 1 
80 mg BID 
Weekly during RT 
Weekly during RT 
Level 2 
120 mg BID 
Weekly during RT 
Weekly during RT 
 
The primary objective of this study is to determine the maximum tolerated dose (MTD) of 
ABT-888 used in combination with carboplatin and paclitaxel (CP) in chemonaive patients 
with Stage III unresectable NSCLC. The regimen will be considered safe and the MTD 
determined if the dose-limiting toxicity rate of ABT-888 + CP is ≤ 33%. 
 
11.3 
Phase II Study 
 
The primary objective of the Phase II portion of this study is to evaluate the efficacy of 
ABT-888 in combination with carboplatin and paclitaxel in comparison with carboplatin, 
paclitaxel and placebo in chemonaive patients with unresectable Stage III NSCLC.   
 
11.4 
Sample Size and Power Justification 
 
It is assumed that the addition of ABT-888 would not be promising if the true median PFS 
were ≤ 11 months, but would be of considerable interest if the true median PFS where ≥ 
19.2 months (corresponding to a 1.75 hazard ratio).  A design with 85% power and a 
10% type I error rate would require 68 progression events to evaluate a 75% 
improvement in median PFS using a 1-sided log-rank test.  The resulting target sample 
size is 120 eligible patients accrued over 15 months and followed for a minimum of 12 
months.   Assuming a 10% ineligibility rate, the projected accrual is 132 patients. 
 
11.5 
Analyses and Timepoints 
 
Primary analyses will be performed on an intent-to-treat basis. A stratified log-rank test at 
the 10% level will be used to test the primary hypothesis. The f inal analysis will take 
place upon the observation of 68 progression events. 
 

 
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An interim analysis is planned upon the observation of 50% of the expected progression 
events (34 events at 15 months after study activation, the time of expected completion of 
accrual).  This analysis will evaluate futility alone.  Specifically, the planned analysis is a 
test of the alternative hypothesis of a hazard ratio equal to 1.75 with consideration for 
early stopping if the alternative hypothesis is rejected at the 0.05 level. 
 
Secondary analyses include the comparison of overall survival, response, and toxicity 
between study arms. A stratified log-rank test will be used to compare overall survival; a 
stratified chi-square test will be used to compare response and toxicity between the two 
arms. This design has 81% power to detect a 100% improvement in median survival time 
from 22 to 44 months using a 0.10 level test.  Additionally, this design has at least 85% 
power to detect > 20% difference in toxicity, for any given toxicity (also using a 1-sided 
0.10 level test). Within each arm, any toxicity occurring with at least a 5% probability is 
likely to be seen at least once (94% chance).  
 
Sixty patients/arm will be sufficient to estimate the 6-month overall survival probability 
and individual toxicity proportions to within at least 13% (95% confidence interval). 
 
Assuming 80% of participants will have measurable disease (as defined by RECIST); 
then approximately 48 patients/arm will be evaluable for response and disease control 
rates. This design, with 96 patients with measurable disease has at least 84% power to 
detect at least a 25% increase in rates with ABT-888 using a 1-sided 0.10 level test. 48 
patients/arm will be sufficient to estimate the response rate (confirmed and unconfirmed 
complete and partial responses) and DCR to within at least 14% (95% confidence 
interval). 
 
11.6 
Adverse Event Monitoring 
 
The Phase I portion of the trial will employ careful adverse event monitoring as previously 
established for regimens where there are limited or no pre-existing data for the specific 
combination under study, but where combination data for the targeted agent plus other 
chemotherapy regimens suggest that full doses of the study combination can be safely 
administered. Adverse event monitoring will performed by the Study Chair, Study 
Statistician and the Disease Committee Chair and include weekly toxicity reports and 
biweekly conference calls. A temporary closure will occur prior to opening this study for 
the Phase II portion in order to assess dose and to evaluate the safety profile more fully 
prior to implementation of the Phase II trial. 
 
11.7 
Data and Safety Monitoring  
 
A Data and Safety Monitoring Committee will oversee the conduct of the randomized 
Phase II portion of the study. The Committee consists of four members from outside of 
SWOG, 3 SWOG members, 3 non-voting representatives from the National Cancer 
Institute (NCI), and the Group Statistician (nonvoting).  The members of this Committee 
will receive confidential reports every 6 months from the SWOG Statistical Center, and 
will meet at the Group's biannual meetings as necessary. The Committee will be 
responsible for decisions regarding possible termination and/or early reporting of the 
study. 
 
 
12.0 
DISCIPLINE REVIEW 
 
12.1 
Radiation Therapy Review 
 
All patients registered to this study will undergo radiation therapy review by the Quality 
Assurance Review Center (QARC). Materials must be submitted within 3 days after 
initiation of radiotherapy. The purpose of this rapid review is to verify that the  

 
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radiotherapy will be given according to the protocol and to allow for enough time to make 
modifications if necessary. In addition, the Radiation Therapy Study Chair will assess the 
adherence to the protocol by reviewing the complete documentation of the administration 
after completion of all radiotherapy. Any changes in patient status (i.e., discontinuation of 
protocol treatment, delay, or break in treatment) should be communicated in writing to 
QARC by fax (401/753-7601) or email at swog@qarc.org. 
 
12.2 
Required Benchmarks 
 
Centers participating in this protocol using 3D-CRT are required to complete the 3D 
benchmark; those using IMRT must complete the IMRT questionnaire and benchmark or 
irradiate the RPC head and neck phantom.  Benchmark materials and questionnaires 
may be obtained from the Quality Assurance Review Center (www.qarc.org) and must be 
submitted before patients on this protocol can be evaluated. For information regarding 
the IMRT phantoms, please contact the RPC (http://rpc.mdanderson.org/rpc). 
 
If techniques are used to compensate for or limit respiratory motion, the QARC Motion 
Management Questionnaire must also be submitted. If patients are treated with IMRT 
and gating or tracking methods are used to compensate for respiratory motion, the RPC’s 
Thorax-Lung Phantom must be irradiated with its accompanying reciprocating platform to 
simulate motion. 
 
12.3 
Quality Assurance Documentation 
 
Required Benchmarks: See Section 12.2 for required benchmarks. 
 
Digital Submission: Submission of treatment plans in digital format (either DICOM RT 
or RTOG format) is required. Digital data must include CT scans, structures, plan and 
dose files. Submission may be either by SFTP or CD. Instructions for data submission 
are on the QARC Web site at www.qarc.org. Any items on the list below that are not part 
of the digital submission may be submitted as screen captures along with the digital data. 
 
Within 3 days from start of radiotherapy, the following data should be submitted for 
pre-treatment review: 
 
Treatment Planning System Output 
 
• 
RT treatment plan including CT, structures, dose, and plan files.  These items are 
included in the digital plan. 
• 
Dose volume histograms (DVH) of the GTV, spinal cord, right and left lungs, heart, 
esophagus, and liver.  When using IMRT, a DVH shall be submitted for a category of 
tissue called “unspecified tissue.”  This is defined as tissue contained within the skin, 
but which is not otherwise identified by containment within any other structure.  DVHs 
are included in the digital plan. 
• 
Digitally reconstructed radiographs (DRR) for each treatment field if 3D conformal 
planning is used.  DRRs should show field outlines but not target volumes or organs 
at risk.  Please include two sets, one with and one without overlays of the target 
volumes and organs at risk. 
• 
Treatment planning system summary report that includes the monitor unit 
calculations, beam parameters, calculation algorithm, and volume of interest dose 
statistics. 
 
Supportive Data 
 
• 
Copies and reports of CT scans, PET scans, and other diagnostic materials used for 
planning target volumes. 
• 
Prescription Sheet for Entire Treatment  
• 
Documentation of an independent check of the calculated dose when IMRT is used. 

 
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• 
If the recommended doses to the organs at risk are exceeded, an explanation should 
be included for review by QARC and the radiation oncology reviewers. 
 
Forms 
 
• 
RT-1 Dosimetry Summary Form 
• 
Motion Management Reporting Form 
 
Within one week of the completion of radiotherapy the following data shall be 
submitted.   
 
• 
The RT-2 Radiotherapy Total Dose Record form. 
 
• 
A copy of the patient’s radiotherapy record including prescription, and the daily and 
cumulative doses to all required areas, critical organ and reference points 
 
• 
Documentation listed above showing any modifications from original submission. 
 
Supportive Data and Forms may be included with the transmission of the digital RT data 
via sFTP or submitted separately via e-mail (swog@QARC.org) or mailed to: 
 
Quality Assurance Review Center 
640 George Washington Highway 
Building A, Suite 201 
Lincoln, RI 02865 
Tel: (401) 753-7600 
Fax: (401) 753-7601 
 
Questions regarding the dose calculations or documentation should be directed to: 
SWOG Protocol Dosimetrist 
 
Quality Assurance Review Center 
640 George Washington Highway 
Building A, Suite 201 
Lincoln, RI 02865 
Tel: (401) 753-7600 
Fax: (401) 753-7601 
 
Questions regarding the radiotherapy section of this protocol, including treatment 
interruptions, should be directed to: 
 
Allen M. Chen, M.D. (Radiation Oncology) 
Department of Radiation Oncology 
University Rainbow Boulevard, MS 4033 
Kansas City, KS  66106 
Phone: 913/588-3612 
FAX: 913/588-3663 
E-mail: achen5@kumc.edu 
 
12.4 
Definitions of Deviations in Protocol Performance 
 
Prescription Dose 
 
• 
Minor Deviation: The dose to the prescription isodose surface differs from that in the 
protocol by between 6% and 10%. 
• 
Major Deviation: The dose to the prescription isodose surface differs from that in the 
protocol by more than 10%. 

 
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Dose Uniformity 
 
• 
Minor Deviation: The prescribed dose covers between 90% and 95% of the PTV or 
the minimum dose to 1 cc of the PTV is between 90% and 95% of the prescribed 
dose or the maximum dose to 1 cc of the PTV exceeds 130% of the prescribed dose 
• 
Major Deviation: The prescribed dose covers less than 90% of the PTV or the 
minimum dose to 1 cc of the PTV is less than 90% of the prescribed dose or the 
maximum dose to 1 cc of tissue outside the PTV exceeds 120% of the prescribed 
dose. 
 
Volume 
 
• 
Minor Deviation: Margins less than specified, or field(s) excessively large as 
deemed by the study chair. 
• 
Major Deviation: GTV incorrectly defined resulting in fields that transect tumor. 
 
Critical Organ 
 
• 
Minor Deviation: The lung V20 exceeds 37% but is less than 40%. 
• 
Major Deviation: The maximum dose to the spinal cord exceeds 5,000 cGy or the 
lung V20 exceeds 40% but is less than 50%. 
  
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than ten working days 
prior to planned start of treatment). NOTE: No open label OR blinded starter supplies 
will be available for this study. Initial patient-specific clinical supplies of ABT-888 
(Phase I) or ABT-888/placebo (Phase II) will be shipped from the Pharmaceutical 
Management Branch (PMB) to the registering investigator at the time of patient 
registration and should arrive within 7 to 10 days (see Section 3.3d). 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered 
members of a Cooperative Group.  Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet to CTEP. 
 
a. 
CTEP Investigator Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all investigators participating in any NCI-sponsored clinical 
trial to register and to renew their registration annually. 
 
Registration requires the submission of: 
 
• 
a completed Statement of Investigator Form (FDA Form 1572) with an 
original signature 
• 
a current Curriculum Vitae (CV) 
• 
a completed and signed Supplemental Investigator Data Form (IDF) 
• 
a completed Financial Disclosure Form (FDF) with an original 
signature 
 
Fillable PDF forms and additional information can be found on the CTEP website 
at <http://ctep.cancer.gov/investigatorResources/investigator_registration.htm>.   

 
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For questions, please contact the CTEP Investigator Registration Help Desk 
by email at <pmbregpend@ctep.nci.nih.gov>. 
 
b. 
CTEP Associate Registration Procedures 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended for use by 
both Investigators (i.e., all physicians involved in the conduct of NCI-sponsored 
clinical trials) and Associates (i.e., all staff involved in the conduct of NCI-
sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration 
and annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. 
(See CTEP Investigator Registration Procedures above for information on 
registering with CTEP as an Investigator, which must be completed before a 
CTEP-IAM account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU 
members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
<http://ctep.cancer.gov/branches/pmb/associate_registration.htm>.  
For 
questions, please contact the CTEP Associate Registration Help Desk by 
email at <ctepreghelp@ctep.nci.nih.gov>. 
 
c. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
1. 
IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria 
including but not limited to: an active Federal Wide Assurance (FWA) 
number, an active roster affiliation with the Lead Network or a 
participating organization, a valid IRB approval, and compliance with all 
protocol specific requirements. 
 
2. 
Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the #8811 protocol page 
located on the CTSU members’ website.   
▪ 
Go to https://www.ctsu.org and log in to the members’ area using 
your CTEP-IAM username and password 
▪ 
Click on the Protocols tab in the upper left of your screen 
▪ 
Either enter the protocol # in the search field at the top of the 
protocol tree, or 
▪ 
Click on the By Lead Organization folder to expand 
▪ 
Click on the SWOG link to expand, then select trial protocol #[NCI 
Protocol #8811] 

 
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▪ 
Click on LPO Documents, select the Site Registration documents 
link, and download and complete the forms provided.   
 
3. 
Requirements For S1206 (NCI Protocol #8811) Site Registration: 
 
• 
CTSU Transmittal Sheet (optional)  
• 
IRB approval; local IRB documentation, an IRB-signed CTSU IRB 
Certification Form, Protocol of Human Subjects Assurance 
Identification/IRB Certification/Declaration of Exemption Form, or 
combination is accepted ) 
• 
CTSU RT Facilities Inventory Form  
 
NOTE:  Per NCI policy all institutions that participate on protocols 
with a radiation therapy component must participate in the Image 
and Radiation Oncology Core (IROC) monitoring program.  If  this 
form has been previously submitted to CTSU it does not need to be 
resubmitted unless updates have occurred at the RT facility 
 
4. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office, 
where they will be entered and tracked in the CTSU RSS.  
 
ONLINE:  
www.ctsu.org (members’ section) → Regulatory Submission Portal 
 
EMAIL: CTSURegulatory@ctsu.coccg.org  
(for regulatory document submission only) 
 
FAX:  215/569-0206 
MAIL:  CTSU Regulatory Office 
       
1818 Market Street, Suite 1100 
      
Philadelphia, PA 19103 
 
5. 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of 
the CTSU website. 
 
▪ Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
▪ Click on the Regulatory tab at the top of your screen 
▪ Click on the Site Registration tab 
▪ Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation 
and institutional compliance with protocol-specific requirements as 
outlined by the Lead Network. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the 
enrolling investigator’s status with the NCI or their affiliated networks. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 

 
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Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 

 
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• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated 
with the CTSU Enterprise System for regulatory and roster data and, upon 
enrollment, initializes the patient in the Rave database.  OPEN can be accessed 
at https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on 
the SWOG CRA Workbench. 
 
NOTE:  S1206 is listed as NCI #8811 in the OPEN, RSS, and Specimen 
Tracking Systems). 
 
a. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes 
and the affirmation of eligibility on the Registration Worksheet has been 
signed by the registering investigator or another investigator 
designate. Site staff should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
b. 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
c. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 888/823-5923 or 
ctsucontact@westat.com. 
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirements 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility 
will generally be deemed ineligible. 

 
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14.2 
Master Forms 
 
Master forms are included on the S1206 abstract page on the SWOG web page and (with 
the exception of the sample consent form and the Registration Worksheet) must be 
submitted to the Data Operations Center in Seattle.  Data from approved SWOG 
institutions must be submitted on-line via the Web; see Section 14.3a for details.  
Exceptions to online data submission are patient-completed (e.g. Quality of Life) f orms 
and source documents (e.g. pathology/operative/lab reports). 
 
14.3 
Data Submission Procedures  
 
a. 
SWOG institutions must submit data electronically via the Web by using the 
SWOG CRA Workbench.  To access the CRA Workbench, go to the SWOG Web 
site (http://swog.org) and logon to the Members Area.  After you have logged on, 
click on the CRA Workbench link to access the home page for CRA Workbench 
website.  Next, click on the Data Submission link and follow the instructions.  For 
new users, the link to a "Starter Kit" of help files may be found by clicking on the 
Starter Kit link at the Members’ logon page. 
 
To submit data via the web the following must be done (in order): 
 
1.  
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2.  
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, and 
3.  
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to submit data for that 
institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/ 614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page).  For 
other 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.   
 
Institutions participating through the CTSU have access to data submission tools 
available on the SWOG workbench.  Access this by using your active CTEP-IAM 
userid 
and 
password 
at 
the 
following 
url:  
https://crawb.crab.org/TXWB/CTSU/logon.aspx.  
 
b. 
If you need to submit data that are not available for online data submission, the 
only alternative is via facsimile.  Should the need for this occur, institutions may 
submit data via facsimile to 800/892-4007 or 206/342-1680 locally.  Please do 
not use cover sheet for faxed data.  Please make sure that each page of all faxed 
data include the SWOG patient number, study ID and patient initials. 
 
14.4 
Data Submission Overview and Timepoints 
 
a. 
WITHIN 7 DAYS OF INITIAL REGISTRATION SUBMIT:   
 
S1206 Prestudy Form  
 
S1206 Baseline Abnormalities Form  
 
Baseline Tumor Assessment Form (RECIST 1.1)  

 
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Submit radiology reports from all scans performed to assess disease at 
baseline.* 
 
Pathology report* 
 
Tissue submission (see Section 15.2) 
 
* NOTE: These must be faxed (see Section 14.3b) 
 
b. 
IF PATIENT CONSENTS, SUBMIT BLOOD SPECIMENS FOR RESEARCH 
SUBMIT: 
 
Blood specimens as specified in Section 15.3  
 
c. 
THREE DAYS WITHIN THE START OF RADIOTHERAPY SUBMIT: 
 
Materials for radiation therapy review as described in Section 12.3 
 
d. 
DURING CONCURRENT CHEMORADIATION TREATMENT SUBMIT: 
 
1.  
During Phase I portion ONLY 
 
AFTER EVERY 7 DAYS, SUBMIT: 
 
a. 
S1206 Adverse Event Form  
 
b. 
S1206 Concurrent Chemotherapy Treatment Form 
 
2. 
During Phase II portion ONLY 
 
AFTER COMPLETION OF EVERY CYCLE (1 CYCLE = 21 DAYS), 
SUBMIT: 
 
a. 
S1206 Adverse Event Form  
 
b.  
S1206 Concurrent Chemotherapy Treatment Form  
 
e.   
AFTER COMPLETION OF CHEMORADIATION TREATMENT: 
 
1. 
During Phase I portion ONLY 
 
AFTER EVERY 7 DAYS FOR 3 WEEKS, THEN ONCE MORE AT 6 
WEEKS POST CHEMORADIATION, SUBMIT: 
 
S1206 Adverse Event Form 
 
2. 
During Phase II portion ONLY 
 
AT 3 WEEKS AND AGAIN AT 6 WEEKS POST CHEMORADIATION, 
SUBMIT: 
 
S1206 Adverse Event Form 
 
f. 
WITHIN 7 DAYS AFTER COMPLETION OF RADIATION THERAPY, SUBMIT: 
 
Lung Carcinoma Radiation Therapy Form  
 

 
Revision #7 (contd.) 
 
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Materials as specified in Section 12.3 directly to QARC at the address in Section 
12.3 

 
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S1206 Checklist for Submission of Radiation Oncology Quality Assurance 
Materials. This is available on the QARC website at www.qarc.org 
 
g.  
WITHIN 
7 
DAYS 
OF 
SECOND 
REGISTRATION 
(CONSOLIDATION 
CHEMOTHERAPY) SUBMIT: 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) documenting Step 1 
restaging. 
 
Radiology reports from restaging 
 
Off Treatment Notice for Registration Step 1 
 
S1206 Consolidation Therapy Eligibility Form 
 
h.  
AFTER EVERY CYCLE OF CONSOLIDATION CHEMOTHERAPY (1 CYCLE=21 
DAYS) SUBMIT: 
 
S1206 Consolidation Chemotherapy Treatment Form  
 
S1206 Adverse Event Form 
 
i.  
AFTER EVERY DISEASE ASSESSMENT (SEE Sections 9.1-9.2), UNTIL 
PROGRESSION SUBMIT: 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) 
 
Radiology report(s) 
 
j.    
WITHIN 7 DAYS OF DISCONTINUATION OF ALL TREATMENT SUBMIT: 
 
Off Treatment Notice documenting reasons for off treatment 
 
S1206 Concurrent Chemotherapy Treatment Form or the S1206 Consolidation 
Chemotherapy Form  
 
S1206 Adverse Event Form  
 
k.  
ONCE OFF PROTOCOL TREATMENT SUBMIT EVERY 4 MONTHS FOR THE 
FIRST 2 YEARS, THEN EVERY 6 MONTHS UNTIL 5 YEARS FROM THE DATE 
OF RANDOMIZATION: 
   
Lung Carcinoma Follow Up Form  
 
l.  
WITHIN 14 DAYS OF PROGRESSION/RELAPSE SUBMIT: 
 
Lung Carcinoma First Site(s) of Progression or Relapse Form  
 
Follow-Up Tumor Assessment Form (RECIST 1.1)  
 
Radiology report(s) 
 
If the patient was still on protocol treatment submit material specified in Section 
14.4h if patient was off protocol treatment, submit the Lung Carcinoma Follow Up 
Form. 

 
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m. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH:  
 
Submit the Notice of Death documenting death information. In addition, if the 
patient was still on protocol treatment, submit materials specified in Section 
14.4h or if patient was no longer on treatment, submit a f inal Lung Carcinoma 
Follow Up Form. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Rapid Reporting  
 
RAPID REPORTING OF TREATMENT-RELATED DOSE-LIMITING TOXICITIES FOR 
PHASE I PORTION OF TRIAL 
 
Participation in the Phase I portion of the trial requires weekly reporting of Adverse 
Events and Treatment information on patients who have initiated treatment.  
 
Institutional participation in the Phase I portion of the trial requires the identification of a 
contact CRA and back-up CRA. Prior to registration of the first patient, each 
institution must provide the contact and back-up CRA names, e-mail addresses, 
and phone numbers to the SWOG Data Operations Center. Institutions will be 
responsible for keeping this information up-to-date and must notify the study Data 
Coordinator (Larry Kaye, LarryK@crab.org, 206/652-2267) of any changes. 
 
The contact CRA and back-up CRA will receive weekly e-mails including a list of the 
Adverse Event and Treatment forms that are overdue, currently due, or due in the next 
week. These e-mails will include a reply-to address and phone number to contact the 
Data Operations Center when questions arise. 
 
Upon activation of the Phase I portion of the study, participating institutions will receive 
an e-mail with information on current dose level, as well as specifications for e-mail and 
conference call communication among investigators participating in the Phase I portion. 
 
Participation in bi- weekly conference calls is mandatory.  
 
15.2 
Paraffin Embedded Tissue Specimens (Required Submission) for correlative studies and 
banking 
 
a. 
1-2 paraffin embedded tissue blocks containing pathologically confirmed tumor 
from time of diagnosis (or subsequent, but prior to therapy) must be submitted. If  
blocks are unavailable, 16 unstained slides are an acceptable alternative. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
b. 
Specimens must be submitted within 7 days after initial registration. 
 
c. 
Tissue specimens are to be submitted to the SWOG Specimen Repository – 
Solid Tissue, Myeloma and Lymphoma Division, Lab #201 
 
d. 
Collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage  
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp), or via 
the link on the S1206 protocol abstract page on the SWOG website 
(www.swog.org). 

 
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15.3 
Peripheral Blood (Optional Submission) for Circulating Tumor Cells for γH2Ax 
determination. 
 
a. 
Collect at least 7.5 mL of peripheral blood using a CellSave Preservation Tube 
(Veridex #7900005). Gently invert tube 8 times to prevent clotting. Label tube 
with the SWOG study number S1206 (8811), patient study ID, date of collection, 
and time of collection. Sample should be kept at ambient temperature and 
shipped on the day of collection following the directions provided in the CTC 
collection kits. 
 
b. 
With patient’s consent, peripheral blood must be obtained and submitted at the 
following timepoints:  
 
1. 
Cycle 1, Day 1 prior to the morning’s dose of ABT-888 dose 
2. 
Cycle 1, Day 2 (24 hours after the first ABT-888 dose and before 
receiving the second morning dose of ABT-888) 
3. 
Week 1, Friday after XRT (4 to 6 hours after ABT-888 morning’s dose) 
4. 
Week 4 Monday before RT 
5. 
4-6 weeks after RT completion and before starting consolidation 
chemotherapy 
 
c. 
Prior to enrolling patients to this protocol, see the following website for 
sample collection and shipping information:  
http://dctd.cancer.gov/ResearchResources/biomarkers/docs/ctc/LHTP00 
3.08.03_CellSave_Collection_Subm.pdf. 
 
d. 
Kits must be ordered at least 2 weeks in advance of enrolling your first 
patient. To order CTC collection kits, contact:  
NCI_PD_Support_CellSearch@mail.nih.gov. 
 
e. 
Peripheral Blood for Circulating Tumor Cells Specimens are to be submitted to 
Lab #217: NCI-F/FNLCR.  Contact: Dan Danner Phone: 301/846-5748. 
 
15.4 
Peripheral blood samples (serum/plasma/buffy coat) (Optional Submission) will be used 
to analyze host genomic DNA for DNA repair SNPs including ERCC1 and ERCC2. 
 
a. 
Collect at least one 1x 8 mL EDTA (purple-top) and one 1x 8 mL tube with no 
additives (red-top) at the times noted. Allow red-top tube to clot at room 
temperature for 30-60 minutes. Place purple-top tube on ice until processing.  
 
Within 1 hour of collection, centrifuge purple-top tube at 800 x g for 15 minutes. 
Immediately after centrifuging, transfer plasma in 1 mL aliquots to labeled 2 mL 
cryovials. Pipette slowly to avoid disturbing the buffy coat (the off -white layer 
between the red blood cells and the plasma) and leave a small amount of plasma 
(about 0.5 cm) to avoid contamination. Next, pipetting in a circular motion, collect 
the buffy coat and transfer to a labeled 2 mL cryovials. Cryovials should be 
labeled with SWOG study number (S1206 [8811]), Patient study ID, date and 
time of collection, and specimen type (serum/plasma/buffy). Snap freeze 
cryovials in liquid nitrogen (if available) and store at -70° until shipment. 
 
Centrifuge the red-top tube at 2500 x g for 15 minutes. Immediately after 
centrifuging, transfer the serum in 1 mL aliquots to labeled 2 mL cryovials. Store 
cryovials at -70° until shipment.  

 
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b. 
With patient’s consent, peripheral blood must be obtained and submitted at the 
following timepoints: (see Section(s) 9.1-9.2): 
 
1. 
Cycle 1, Day 1 prior to the morning’s dose of ABT-888 dose 
 
2. 
Cycle 1, Day 1, 3 hours after the morning’s dose of ABT-888 dose 
 
3. 
Week 4 before RT 
 
4. 
4-6 weeks after RT completion and before starting consolidation 
Chemotherapy 
 
c. 
Sites will use institutional supplies for the collection of serum/plasma/buffy coat. 
 
d. 
Serum/plasma/buffy coat specimens are to be submitted to the SWOG Specimen 
Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab #201 
 
e. 
Collection and submission instructions can be accessed on the SWOG Specimen 
Submission webpage  
(http://swog.org/members/clinicaltrials/specimens/stspecimens.asp), or via the 
specimen submission link on the Biospecimen Resources (Collaborative Use of 
Specimens for Translational Medicine Research) page on the SWOG website 
(www.swog.org). 
 
15.5.  Shipping of Specimens 
 
a. 
SWOG Specimen Tracking System (STS)   
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE NO 
EXCEPTIONS. 
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. SWOG members may log on the 
online system via the CRA Workbench. To access the CRA Workbench, go to 
the SWOG Web site (http://swog.org) and logon to the Members Area. After you 
have logged on using your SWOG roster ID number and password, click on the 
CRA Workbench link to access the home page for CRA Workbench website. 
First time non- SWOG users must refer to start-up instructions located at 
https://spectrack.crab.org. 
 
A copy of the Shipment Packing List produced by the online SpecimenTracking 
system should be printed and placed in the pocket of the specimen bag if it has 
one, or in a separate resealable bag. The Specimen Submission Form is NOT 
required when the online system is used. To report technical problems with 
Specimen Tracking, such as database errors or connectivity issues, please send 
an email to technicalquestion@crab.org. For procedural help with logging and 
shipping specimens, there is an introduction to the system on the Specimen 
Tracking main page (https://spectrack.crab.org/Instructions); or contact the Data 
Operations Center at  206/652-2267 to be routed to the Data Coordinator for 
further assistance. 
 
b. 
Federal guidelines for the shipment of blood products: 
 
1. 
The tube must be wrapped in an absorbent material. 
 
2. 
The tube must then be placed in an AIRTIGHT container (like a 
resealable bag). 
 

 
Revision #7 (contd.) 
 
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3. 
Pack the resealable bag and tube in a Styrofoam shipping container. 

 
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4. 
Pack the Styrofoam shipping container in a cardboard box. 
 
5. 
Mark the box "Biohazard". 
 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Publication and Industry Contact 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company(ies) 
(hereinafter referred to as "Collaborator(s)") and the NCI Division of Cancer Treatment and 
Diagnosis.  Therefore, the following obligations/guidelines in addition to the provisions in the 
"Intellectual Property Option to Collaborator"  
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) cont ained within the 
terms of award apply to the use of the Agent in this study: 
 
1. 
Agent(s) may not be used outside the scope of this protocol, nor can Agent(s) be 
transferred or licensed to any party not participating in the clinical study.  Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be 
maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without 
the permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s 
family member participating on the study, the individual should sign a confide ntiality 
agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different Co llaborative 
Agreements, the access to and use of data by each Collaborator shall be as follows (data 
pertaining to such combination use shall hereinafter be referred to as "Multi-Party Data"): 

 
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a. 
NCI will provide all Collaborators with written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of 
the proposed combination protocol, and the existence of any obligations which 
would tend to restrict NCI's participation in the proposed combination protocol. 
 
b. 
Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow said 
other Collaborator to develop, obtain regulatory approval or commercialize its 
own investigational Agent. 
 
c. 
Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use the 
Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
2. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA, 
as appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to the Collaborator(s) for Phase III studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if there 
is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator's 
confidential and proprietary data, in addition to the Collaborator(s)'s intellectual property 
rights, are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must also 
be forwarded to CTEP prior to release.  Copies of any manuscript, abstract and/or press 
release/media presentation should be sent to: 
 
E-mail:  ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to the Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
Monitoring 
 

 
Revision #7 (contd.) 
 
Page 77 
 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  
Reports are due January 31, April 30, July 31 and October 31. 

 
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Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and 
should not be used or shared beyond the purposes of completing protocol requirements 
until or unless additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements 
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of 
every clinical trial, are done to ensure the safety of patients enrolled in the 
studies as well as those who will enroll in future studies using similar agents. 
Adverse events are reported in a routine manner at scheduled times during a 
trial. (Directions for routine reporting are provided in Section 14.0.) 
Additionally, certain adverse events must be reported in an expedited manner 
to allow for more timely monitoring of patient safety and care. The f ollowing 
guidelines describe expedited adverse event reporting for this protocol. 
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP -AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically via the CTEP-AERS Web-based application located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_
events.htm. 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.   
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301/897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection. 
 
When the adverse event requires expedited reporting, submit the report within 
the number of calendar days of learning of the event, as specified in Table 16.1, 
as applicable.  
 
Any supporting documentation should be submitted to CTEP per NCI guidelines 
for AE reporting located at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguide
lines.pdf.  
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local 
policy and procedures. 

 
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e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent as part of the trial. Reporting requirements are provided in 
Table 16.1.  The investigational agent used in this study is ABT-888/placebo.  If 
there is any question about the reportability of an adverse event or if on-line 
CTEP-AERS cannot be used, please telephone or email the SAE Specialist at 
the Operations Office, 210-614-8808 or adr@swog.org, before preparing the 
report. 

 
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Table 16.1: 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1 ABT-888 in the Phase I portion and ABT-888/placebo in the 
Phase II portion. 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:    Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
 
Expedited AE reporting timelines are defined as: 
 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
May 5, 2011 
 

 
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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent 
under a Non-CTEP IND: 
 
1) 
Group-specific instructions. 
 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements. In 
addition, you may be asked to submit supporting clinical data to the 
SWOG Operations Offices in order to complete the evaluation of the 
event.  If requested, the supporting data should be sent within 5 
calendar days by fax to 210-614-0006.  Supporting clinical data 
submitted should include: 
• 
Printed copy of the first page of the CTEP-AERS Report. 
• 
Copies of clinical sourced documentation of the event. 
• 
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center copies of Off Treatment 
Notice and/or Notice of Death. 
 
g. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment 
with an agent under an NCI IND to be reported via AdEERS.  Three 
options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
• 
Myelodysplastic syndrome (MDS) 
• 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting mechanisms 
outlined in each protocol. 
 
Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the initial 
malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf  
 
2. 
Any supporting documentation should be submitted to CTEP per NCI 
guidelines 
for 
AE 
reporting 
located 
at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf.  A copy of the report and the following supporting 
documentation must also be submitted to SWOG Operations Office 
within 30 days by fax to 210/614-0006 or mail to the address below: 
 
• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   

 
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SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
 
h.  
Reporting Pregnancy, Fetal Death, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – 
Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show evidence 
of respiration, heartbeat, or definite movement of a voluntary muscle 
after expulsion from the uterus, without possibility of resuscitation” 
should be reported expeditiously as Grade 4 “pregnancy, puerperium 
and perinatal conditions – Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC.   
 
3. 
Death Neonatal  Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” 
that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.   
 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the 
General disorders and administration SOC. 
 
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed 
and faxed with any additional medical information to 301-230-0159.  The 
potential risk of exposure of the fetus to the investigational agent(s) o r 
chemotherapy agent(s) should be documented in the “Description of Event” 
section of the CTEP-AERS report. 
 
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm   
 

 
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17.0 
BIBLIOGRAPHY 
 
1. 
Curran W, Scott C, Langer CJ, et al. Phase III comparision of sequential vs. concurrent 
chemoradiation for patients (pts) witn unresected stage III non-small cell lung cancer (NSCLC): 
Initial report of Radiaton Therapy Oncology Group (RTOG) 9410. Proc Am Soc Clin Oncol 19, 
2000. 
 
2. 
Furuse K, Fukuoka M, Kawahara M, et al. Phase III study of concurrent versus sequential 
thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable 
stage III non-small-cell lung cancer. J Clin Oncol 17:2692-9, 1999. 
 
3. 
Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and 
carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally 
advanced multi-modality protocol. J Clin Oncol 23:5883-91, 2005. 
 
4. 
Vokes EE, Herndon JE, 2nd, Crawford J, et al. Randomized phase II study of cisplatin with 
gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant 
chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 
9431. J Clin Oncol 20:4191-8, 2002. 
 
5. 
Vokes EE, Herndon JE, 2nd, Kelley MJ, et al. Induction chemotherapy followed by 
chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced 
unresectable stage III Non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 
25:1698-704, 2007. 
 
6. 
Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent 
chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group 
Study S9504. J Clin Oncol 21:2004-10, 2003. 
 
7. 
Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and 
concurrent chest radiation with or without consolidation docetaxel in patients with inope rable 
stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin 
Oncol 26:5755-60, 2008. 
 
8. 
Albert JM, Cao C, Kim KW, et al. Inhibition of poly(ADP-ribose) polymerase enhances cell death 
and improves tumor growth delay in irradiated lung cancer models. Clin Cancer Res 13:3033-42, 
2007. 
 
9. 
Kummar S, Kinders R, Gutierrez ME, et al. Phase 0 Clinical Trial of the Poly (ADP-Ribose) 
Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies. J Clin Oncol, 2009. 
 
10. 
Kinders RJ, Hollingshead M, Khin S, et al. Preclinical modeling of a phase 0 clinical trial: 
qualification of a pharmacodynamic assay of poly (ADP-ribose) polymerase in tumor biopsies of 
mouse xenografts. Clin Cancer Res 14:6877-85, 2008. 
 
11. 
Gandara DR, Kawaguchi T, Crowley J, et al. Japanese-US common-arm analysis of paclitaxel 
plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related 
pharmacogenomics. J Clin Oncol 27:3540-6, 2009 
 
 
12. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in 
the controlled clinical trial. Biometrics 31: 103-115, 1975. 
 
 
 
 
 

 
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18.0 
APPENDIX 
 
18.1 
Intake Form 
 
18.2 
Correlative/Special Studies 
 
18.3 
Carboplatin Dosing Worksheet 
 
18.4 
Emergency Unblinding Guidelines 
 
18.5 
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4 

 
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18.1  
Intake Form 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature: 
 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________
 
 
 
Institution/Affiliate _______________________  Physician _____________________________ 
Instructions for the participant: 
 
This is a monthly calendar on which you are to record the number of tablets/pills/capsules you 
take each day.  Be sure you have enough calendars to last until your next appointment.  If you 
develop any side effects from the tablets/pills/capsules, mark this on the calendar on the day 
you note the effect.  Bring your calendars with you each time you have an appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
 
Your next appointment is: _______________________ 
Special instructions: 
 
Month:
Year:

 
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18.2 
Correlative/Special Studies 
 
a. 
Samples for correlative studies 
 
 
Patients are expected to start on a Monday.  The protocol will allow a +/- 24 hour 
window for chemotherapy and correlatives, except for week 1. 
 
 
1. 
Tumor tissue samples 
 
 
Tumor tissue samples will include: 
 
a. 
Archived tumor biopsy obtained prior to treatment, which will be 
used for gene expression of ERCC1 and XRCC1. (Required) 
 
2. 
Peripheral blood samples (Circulating Tumor Cells) 
 
Circulating Tumor Cells (CTC) will be collected at the following time 
points: 
 
a.  
Cycle 1, day 1 prior to the morning’s dose of ABT-888 dose 
 
b. 
Cycle 1, day 2 (24 hours after the first ABT-888 dose and before 
 
 
receiving the second morning dose of ABT-888) 
 
c.  
Week 1 Friday after XRT (4 to 6 hours after ABT-888 morning’s 
dose) 
 
d.  
Week 4 Monday before RT  
 
 
 
e.  
4-6 weeks after RT completion and before starting consolidation 
chemotherapy 
 
CTC will be used for γH2Ax determination. 
 
3.  
Peripheral blood samples (Peripheral blood mononuclear cells and 
 
 
serum/plasma/DNA/RNA) 
 
Peripheral 
blood 
mononuclear 
cells 
(PBMC) 
and 
serum/plasma/DNA/RNA will be collected at the following time points: 
 
a. 
Cycle 1, day 1 prior to the morning’s dose of ABT-888 dose 
 
b. 
Cycle 1, day 1, 3 hours after the morning’s dose of ABT-888 
dose 
 
c. 
Week 4 Monday before RT  
 
d. 
4-6 weeks after RT completion and before starting consolidation 
chemotherapy 
 
PBMC will be used to analyze host genomic DNA for DNA repair SNPs 
including ERCC1, ERCC2 and to determine PAR concentration. 
 
 

 
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b. 
Special Studies 
 
1. 
Analysis of DNA repair capacity in tumor and host 
 
 
Our hypothesis is that efficacy will be related to underlying DNA 
repair capacity.  
 
 
In archival baseline tumor tissue, we will evaluate gene expression 
of ERCC1 and XRCC1. Also, we will test host genomic DNA from 
PBMC/plasma for DNA repair SNPs, including ERCC1 and ERCC2. 
(11). Selected genotypic variants related to platinum-related DNA 
repair enzymes ERCC1 (118C
T, silent) and ERCC2 (XPD, K751Q) 
previously reported to be of functional consequence were analyzed 
by polymerase chain reaction (PCR) or pyrosequencing, as 
previously described. Briefly, PCR will be conducted by using 
Amplitaq Gold PCR master mix (ABI, Foster City, CA), 5 pmol of 
each primer, and 5 to 10 ng of DNA. Pharmacogenetic analysis will 
be conducted by using the Pyrosequencing hsAPSQ96 instrument 
and software (Biotage, Uppsala, Sweden). The genotype will be 
considered variant if it differed from the Reference Sequence 
consensus sequence for the single-nucleotide polymorphism (SNP) 
position 
(http://www.ncbi.nlm.nih.gov/RefSeq/). 
The 
ERCC1 
polymorphism will be analyzed by PCR restriction fragment  length 
polymorphism, as previously described. 
 
a. 
Paraffin-embedded tissue blocks or slides from the time of 
diagnosis (or subsequent, but prior to therapy) should be 
submitted for assessment as described above.  It is strongly 
requested that 1-2 paraffin-embedded tissue blocks containing 
pathologically confirmed tumor be submitted.  If blocks are 
unavailable, 16 unstained slides are an acceptable alternative. 
 
2.  
γ-H2AX Determination in Tumor Biopsies and Peripheral Blood Samples  
(Circulating Tumor Cells) 
 
 
 
γ-H2AX determination will be performed in tumor tissue obtained at 
baseline and after 2 weeks on treatment and circulating tumor cells 
(CTCs) at baseline as well as at various timepoints during treatment.  
 
 
Methodology 
for 
preparing 
tissue 
biopsies 
suitable 
for 
immunocytochemical analysis of γ-H2AX foci has been developed using 
normal rodent tissues by Kinders et al. (Development and Validation of a 
Quantitative Assay for γ-H2AX in Needle Biopsies, using Topoisomerase 
I Inhibitors; AACR-EORTC Conference, Molecular Targets and Cancer 
Therapeutics, 2007).  The method for collection and stabilization of the 
biopsy has been successfully employed in the Phase 0 trial of ABT-888 
and the Phase I trial of ABT-888 and topotecan. (9)   
 
The biopsies are transported to the Pathology and Histology Laboratory 
at SAIC-Frederick and upon removal from storage, slides are allowed 
processed as follows:  The biopsies are first fixed for 16-24 hours in 10% 
NBF, followed by immersion in graded ethanols, then xylene, and finally 
paraffin embedding. Five consecutive 5-micron sections are cut to 
prepare slides, and staining for γ-H2Ax is performed on a Vision 
Biosystems automated processor.  The third section is processed for 
H&E staining.  The first and the fifth sections are processed for γ-H2AX, 
and the remaining two sections are processed according to need: either 
additional γ-H2AX or CD31.  The remainder of the block is catalogued 
and stored for follow up studies for this clinical protocol.  

 
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Phosphorylated (i.e., γ-) H2AX is detected by immunostaining with MAb 
JBW301 (biotin conjugated, Upstate Biotechnology, then Alexafluor 488 
Streptavidin labeling) of formalin-fixed, paraffin embedded biopsies.  
DAPI counterstaining is performed.  The staining protocol is performed 
on a Vision Biosystems Bondmax instrument, and slides are read on a 
Nikon microscope with an automated stage and Retiga 2000R CCD 
camera.  Data is collected and analyzed in ImagePro as percent of 
nuclear area (in the entire field of view) that is positive for γ-H2AX 
staining.  At least 3 fields are imaged per slide, and at least 2 slides per 
biopsy (from non-overlapping sections of the biopsy) are analyzed.  H&E 
sections are also obtained.  Statistical analysis is performed in PADIS, 
with Excel. Specimen processing, imaging, and quantitation are all 
controlled by SOPs.  Permanent photographic records of the biopsy are 
maintained, and all specimen identification data are coded.  
 
 
The γ-H2AX nuclear marker is expressed in response to drug-induced 
DNA damage, but does not signify a cell’s commitment either to cell 
death or to DNA repair and potentially cell recovery. Recent in vitro 
discoveries about TRAIL-induced apoptosis (Yves Pommier, internal 
communication) indicate that commitment to cell death is associated with 
co-localization of γ-H2AX and additional nuclear phosphoproteins along 
the inner face of the nuclear membrane.  When using quantitative 
immunofluorescence (qIFA) analysis and different colors for γ-H2AX and 
the second marker (e.g., red and green), this co-localization pattern 
results in a “halo” shaped staining pattern of the mixed color signal (e.g., 
yellow) when the images of each marker are overlaid.  PADIS/LHTP and 
NCTVL are validating a qIFA for nuclear γ-H2AX in tumor needle 
biopsies and cytospin preparations, which is amenable to this multi-color 
analysis of co-localized markers and the potential quantitation of pro -
apoptotic cells resulting from drug exposure.  This protocol will permit 
quantitation not only of the γ-H2AX marker using the validated readout of 
the assay (% nuclear area positive for γ-H2AX signal), but also of co-
localization markers that can achieve halo staining of pro-apoptotic cells.  
The co-localized markers will include phospho forms of ataxia 
telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), 
ATR and/or Chk2, as well as other nuclear markers co-localizing with γ-
H2AX during apoptosis that may be discovered during the time period of 
this clinical trial.  Both the PADIS and NCTVL will conduct this 
quantitative immunofluorescence assay, and some specimens may be 
assayed in both laboratories to check assay performance.  In addition, 
PADIS and NCTVL may use the Pathology/Histotechnology Laboratory 
(PHL) of the NCI-Frederick to process, stain, and analyze the staining of 
sections from the clinical trial participants.  
 
c. 
Peripheral Blood Samples to collect CTCs 
 
We will perform γ-H2AX assay in CTCs per SOP on the DCTD website 
http://dctd.cancer.gov/ResearchResources/biomarkers/docs/ctc/LHTP003.0
8.03_CellSave_Collection_Subm.pdf. 
 
Briefly, collect at least 7.5 mL of peripheral blood using a CellSave Preservation 
Tube (Veridex #7900005).  Gently invert tube 8 times to preventing clotting.  
Label tube with S1206 (8811) patient study ID, date of collection, and time of 
collection.  Sample should be kept at ambient temperature and shipped on the 
day of collection. Please see CTC collection SOP provided with the CTC 
collection kits for instructions regarding the labeling and packaging of specimens. 
 
 

 
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d.  
Collection and processing of serum/plasma/DNA/RNA 
 
Blood will be collected in 1x 8 mL EDTA (purple-top) and 1x 8 mL tube with no 
additives (red-top) at the times noted in Section 15.3a.2.  
 
Allow red-top tube to clot at room temperature for 30-60 minutes.  Place purple-
top tube on ice until processing.  Cryovials should be labeled with SWOG study 
number (S1206 [8811]), Patient study ID, date and time of collection, and 
specimen type (serum/plasma/buffy). 
 
 
 
Within 1 hour of collection, centrifuge purple-top tube at 800 x g for 15 minutes.  
Immediately after centrifuging, transfer plasma in 1 mL aliquots to labeled 2 mL 
cryovials.  Pipette slowly to avoid disturbing the buffy coat (the off-white layer 
between the red blood cells and the plasma) and leave a small amount of plasma 
(about 0.5 cm) to avoid contamination.   
 
Next, pipetting in a circular motion, collect the buffy coat and transfer to a labeled 
2 mL cryovials.  Snap freeze cryovials in liquid nitrogen (if available) and store at 
-70° until shipment. 
 
 
Centrifuge the red-top tube at 2500 x g for 15 minutes.  Immediately after 
centrifuging, transfer the serum in 1 mL aliquots to labeled 2 mL cryovials. Store 
cryovials at -70° until shipment. 
 
 
 

 
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18.3 
Carboplatin Dosing Worksheet 
 
 
PATIENT'S INITIALS  
 MEDICAL RECORD #  
 
 
 
 SWOG PATIENT #  
 
 
 
TO CALCULATE Creatinine Clearance (CrCl) from SERUM CREATININE: 
 
 
CrCl =  
(140 - age)      X     wt. in kg.* 
X 
0.85 (if female)  
 
72 X serum creatinine ** 
 
 
CrCl =  
(140 -       )      X      (            )  
X 
0.85 (if female) 
 
72 X  
 
 
 
TO CALCULATE CARBOPLATIN DOSE WITH CALVERT FORMULA: 
 
 
USE CALCULATED CREATININE CLEARANCE (AS ABOVE) TO SUBSTITUTE FOR GFR. 
 
(AUC) (GFR + 25) = CARBOPLATIN DOSE PER CYCLE IN mg 
 
(X) ( 
 +25) =   
 
 mg of carboplatin 
 
 
This is the TOTAL DOSE of carboplatin (not mg/m2). 
 
Please note that: GFR should NOT exceed 125 ml/min. Hence, the maximum total  
carboplatin dose should NOT exceed 300 mg when AUC = 2 or 900 mg when AUC = 6 for this 
study. 
 
* 
Use current (actual) weight. This should be actual weight but not exceed 140% of IBW.  
** 
Carboplatin dose should be calculated using a serum creatinine value obtained within 3 
days prior to each course therapy.  In patients whose serum creatinine is < 0.8 mg/dl, 0.8 
mg/dl must be substituted in the Cockroft-Gault formula to calculate the estimated creatinine 
clearance for carboplatin dosing. 
 
NOTE:  PLEASE RETAIN ORIGINAL WORK SHEET as part of patient's PERMANENT 
RECORD.  COPIES MAY BE MADE FOR PHARMACY and/or NURSING RECORDS. 
 

 
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18.4 
Emergency Unblinding Guidelines 
 
a.  
General Considerations 
 
The randomized regimen for this study includes a blinded drug, which is either 
veliparib or placebo. During the course of this study it may become necessary to 
identify (or unblind) a patient's treatment assignment. The circumstances that will 
warrant emergency unblinding and the procedure for emergency unblinding are 
described in this Appendix. 
 
b.  
Criteria for Emergency Unblinding 
In general, treatment assignments will not be emergency unblinded unless there 
is a compelling medical or ethical reason that the treatment should be identified. 
In most circumstances it will be appropriate to treat the patient or person who 
received blinded drug as though he or she received veliparib, irrespective of the 
drug actually received. Therefore, emergency unblinding should seldom be 
necessary. 
 
The following events MAY require emergency unblinding of treatment 
assignments in this study: 
 
1. 
A compelling medical need as determined by a physician, e.g., existence 
of a condition for which knowledge of the patient's treatment assignment 
is necessary for the selection of appropriate care. 
 
2.  
Administration of blinded drug to a person other than the patient. 
 
c.  
Procedure for Emergency Unblinding 
 
Emergency unblinding of treatment assignments for patients on this study will be 
performed by the Washington Poison Center (WPC), upon approval from a 
designated physician (either one of the WPC's resource physicians or Dr. 
Athanassios Argiris). The procedure for emergency unblinding the treatment 
assignment for a patient on this study is as follows: 
 
1.  
All requests for emergency unblinding must be made by the registering 
physician or his/her designee. 
 
2.  
Call the WPC collect at 206/526-2121 from outside Washington State or 
toll free at 800/222-1222 from within Washington State. The WPC is 
accessible 24 hours per day, 365 days per year. 
 
3.  
The person calling the WPC must be prepared to provide the following 
information: 
 
Study number (S1206) 
 
SWOG Patient Number (e.g., "999999") 
 
Patient Initials 
 
Name and telephone number of the caller 
 
Reason emergency unblinding is thought to be required 
 
 

 
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4. 
The WPC will contact one of its resource physicians and provide the   
information received from the caller. If none of the WPC's resource 
physicians can be contacted, then the WPC will contact Dr. Athanassios 
Argiris. The contacted physician will evaluate the need for emergency 
unblinding and provide the WPC either approval to unblind or a 
recommendation for treatment, if any, while maintaining blinding. The 
WPC will then call the person who initiated the unblinding request and 
tell him/her either the treatment assignment or the resource physician's 
treatment recommendation. 
 
5. 
If the WPC is unable to contact any of its resource physicians or Dr. 
Argiris within three hours after receiving the request for emergency 
unblinding, then the WPC will notify the person who initiated the 
unblinding request that treatment assignment will not be unblinded at 
that time and treatment of the patient or person who received blinded 
drug should proceed as if the blinded drug is veliparib. In such cases, the 
WPC will continue to attempt to contact the resource physicians, and 
when one of them is contacted, will proceed as in #4 above. 
 
6. 
Any patient whose treatment assignment is emergency unblinded will 
receive no further blinded drug, but should continue all ot her protocol 
treatment if his/her medical condition permits. 
 
7.  
Unblinding of treatment assignments for any reason must be 
documented on the Off Treatment Notice. 
 
Questions regarding the unblinding may be directed to any of the 
following resource physicians: 
 
Athanassios Argiris, M.D. 
Medical Oncologist, Hygeia Hospital 
5 Erythrou Stavrou 
 
6th Floor, Office 6.12 
Marousi 15123 Athens, Greece 
Phone: 011 30 210 6867692 
FAX: 011 30 210 6845089 
E-mail: athanassios.argiris@gmail.com 
 
Anne Schott, M.D. 
SWOG 
24 Frank Lloyd Wright Drive 
P.O. Box 483 
Ann Arbor, MI 48106 
Phone: 734/998- 7172 
E-mail: aschott@umich.edu 
 
Washington Poison Center 
Phone: 206/526-2121 
 

 
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18.5 
Drugs Known to be Metabolized by CYP450 Isoenzymes 2D6 and 3A4  
 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; 
medical reference texts such as the Physicians’ Desk Reference may also provide this 
information. 
 
CYP2D6 
SUBSTRATES 
Amitriptyline (hydroxylation) 
Amphetamine 
Betaxolol 
Bisoprolol 
Brofaromine 
Buturolol 
Bupropion 
Captopril 
Carvedilol 
Cevimeline 
Chlorpheniramine 
Chlorpromazine 
Cinnarizine 
 
Clomipramine (hydroxylation) 
Clozapine (minor pathway) 
Codeine (hydroxylation, o-demelhylation) 
Cyclobenzaprine (hydroxylation) 
Cyclophosphamide 
Debrisoquin 
Delavirdine 
Desipramine 
Dexfenfluramine 
Dextromethorphan (o-demethylation) 
Dihydrocodeine 
Diphenhydramine 
Dolasetron 
Donepezil 
Doxepin 
Encainide 
Fenlluramine 
Flecainide 
Fluosetine (minor pathway) 
Fluphenazine 
Haiofantrine 
Haioperidol (minor pathway) 
Hydrocodone 
Hydrocortisone 
Hydroxyamphetamine 
lmipramine (hydroxylation) 
Labetalol 
Loratadine 
Maprotiline 
m-Chlorophenylpiperazine (m-CPP) 
Meperidine 
Methadone 
 
Methamphetamine 
Metoclopramide 
Metoprolol 
Mexitetine 
Mianserin 
Mirtazapine (hydroxylation) 
Molindone 
Morphine 
Nortriptyline (hydroxylation) 
Olanzapine (minor, hydroxymethylation) 
Ondansetron 
Orphenadrine 
Oxycodone 
Papaverine 
Paroxetine (minor pathway) 
Penbutolol 
Pentazocine 
Perhexiline 
Perphenazine 
Phenformin 
Pindolol 
Promethazine 
Propafenone 
Propranolol 
Quetiapine 
Remoxipride 
Risperidone 
Ritonavir (minor) 
Ropivacaine 
Selegiline 
Sertindole 
Sertratine (minor pathway) 
Sparteine 
Tamoxifen 
Thioridazine 
Tiagabine 
Timolol 
Tolterodine 
Tramadol 
Trazodone 
Trimipramine 
Tropisetron 
Venlafaxine (o-desmethylation) 
Yohimbine 
 

 
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INHIBITORS 
Amiodarone 
Celecoxib 
Chloroquine 
Chlorpromazine 
Cimelidine 
Citalopram 
Clomipramine 
Codeine 
Deiavirdine 
Desipramine 
Dextropropoxyphene 
Diitiazem 
Doxorubicin 
Entacapone (high dose) 
Fluoxetine 
Fluphenazine 
Fluvoxamine 
Haloperidol 
Labetalol 
Lobeline 
Lomustine 
 
Methadone 
Mibefradil 
Moclobemide 
Nortluoxeline 
Paroxetine 
Perphenazine 
Propafenone 
Quinacrine 
Quinidine 
Ranitidine 
Risperidone (weak) 
Ritonavir 
Sertindole 
Sertraline (weak) 
Thioridazine 
Vaiprolc acid 
Venlafaxine (weak) 
Vinblastine 
Vincristine 
Vinorelbine 
Yohimbine 
 
CYP3A3/4 
Substrates 
Acetaminophen 
Aifentanil 
Alosetron 
Alprazolam 
Amiodarone 
Amitriptyline (minor) 
Amlodipine 
Anastrozole 
Androsterone 
Antipyrine 
Astemizole 
Atorvastatin 
Benzphetamine 
Bepridil 
Bexarotene 
Bromazepam 
Bromocriptine 
Budesonide 
Bupropion (minor) 
Buspirone 
Busutfan 
Caffeine 
Cannabinoids 
Carbamazepine 
Cevimeline 
Cerivastatin 
Digitoxin 
Diltiazem 
Disopyramide 
Docetaxel 
 
Chlorpromazine 
Cimetidine 
Cisapride 
Citałopram 
Clarithromycin 
Clindamycin 
Clomipramine 
Clonazepam 
Clozapine 
Cocaine 
Codeine (demethylation) 
Cortisol 
Cortisone 
Cyclobenzaprine (demethylation) 
Cyclophosphamide 
Cyclosporine 
Dapsone 
Dehydroepiandrostendione 
Delavirdine 
Desmethyldiazepam 
Dexamethasone 
Dextromethorphan (minor, N-
demethylation)  
Diazepam (minor; hydroxylation, N-
demethylation) 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
 

 
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Substrates 
Dolasetron 
Donepezil 
Doxorubicin 
Doxycycline 
Dronabinol 
Enalapril 
Erylhromycin 
Estradiol 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestene 
Dofetilide (minor) 
Felodipine 
Fentanyl 
Fexotenadine 
Finaxteride 
Fluoxetine 
Niludipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Omeprazole (sulfonation) 
Ondansetron 
Oral contraceptives 
Orphenadrine 
Paclitaxel 
Pantoprazole 
Pimozide 
Pioglitazone 
Pravastatin 
Prednisone 
Progesterone 
Proguanil 
Propafenone 
Quercetin 
FLUTAMIDE 
Substrates 
Glyburide 
Granisetron 
Halofantrine 
Hydrocortixone 
Hydroxyarginine 
lfosfamide 
lmipramine 
lndinavir 
lsradipine 
ltraconazole 
Ketoconazole 
Lansoprazole (minor) 
Letrozole 
Levobupivicaine 
Lidocaine 
Loratadine 
Losartan 
Lovastatin 
Methadone 
Mibefradil 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine (N-demethylation) 
Montelukast 
Navelbine 
Toremifene 
Trazodone 
Tretinoin 
Triazolam 
Troglitazone 
Troleandomycin 
Venlafaxine (N-demethylation) 
Verapamil 
Vinblastine 
 
Quetiapine 
Quinidine 
Quinine 
Repaglinide 
Retinoic acid 
Rifampin 
Risperidone 
Ritonavir 
Salmeterol 
Saquinavir 
Sertindole 
Sertraline 
Sibutramine 
Sildenafil citrate 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Temazepam 
Teniposide 
Terfenadine 
Testosterone 
Tetrahydrocannabinol 
Theophylline 
Tiagabine 
Tolterodine 
Vincristine 
Warfarin (R-warfarin) 
Yohimbine 
Zaleplon (minor pathway) 
Zatoestron 
Zileuton 
Ziprasidone 
Zolpidem 
Zonisamide 

 
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INDUCERS 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
INHIBITORS 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazem 
Dirithromycin 
Disulfiram 
Entacapone (high dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
lndinavir 
lsoniazid 
ltraconazole  
 
Ketoconazole 
Metronidazole 
Mibefradil 
Miconazole (moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 
 
 
(Adapted from Cytochrome P-450 Enzymes and Drug metabolism. In : Lacy CF, Armstrong LL, 
Goldman MP, Lance LL eds. Drug Information Handbook 8th ed. Hudson, OH; LexiComp Inc. 
2000: 1364-1371