Phase II Randomized Placebo-Controlled Trial of Cisplatin With or Without ABT-888 (Veliparib) in Metastatic Triple-Negative Breast Cancer and/or BRCA Mutation-Associated Breast Cancer, With or Without Brain Metastases
Phase: PHASE2
Conditions: Metastatic BRCA Hereditary Breast Carcinoma, Metastatic Breast Carcinoma, Metastatic Malignant Neoplasm in the Brain, Metastatic Triple-Negative Breast Carcinoma, Recurrent Breast Carcinoma, Stage IV Breast Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)

 
 
 
Version Date: 
August 07, 2024 
 
TO: 
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS 
 
FROM: 
SWOG Operations Office (E-mail: protocols@swog.org) 
 
RE: 
S1416: “Phase II Randomized Placebo-Controlled Trial of Cisplatin with or Without ABT- 
888 (Veliparib) in Metastatic Triple-Negative Breast Cancer and/or BRCA Mutation- 
Associated Breast Cancer, with or Without Brain Metastases” Study Chairs: Drs. E. Rodler, 
P. Sharma, J.R. Gralow, J.B. Hicks and P. Kuhn. 
 
REVISION #8 
 
Study Chair: Eve Rodler, M.D.  
Phone number: 916/734-3772 
E-mail: S1416question@swog.org 
 
Action Codes 
()  Expedited review allowed  
()  Patients Must be Informed*  
()  Verbal notification allowed 
*   See “Patient Notification” and “Regulatory Considerations” instructions below. 
 
Key Updates 
()  Treatment / Study Calendar changes 
 
Sites using the CIRB as their IRB of record: The protocol and/or informed consent 
form changes have been approved by the CIRB and must be activated within 30 days of 
the CIRB posting of this notice. 
 
Sites not using the NCI CIRB:  Per CTMB Guidelines, the protocol updates and/or 
informed consent changes must be approved by local IRBs within 90 days of distribution 
of this notice.  
 
 
REVISION #8 
 
The above-referenced protocol has been revised to accommodate the discontinuation of the ABT-888 
(veliparib) development program and the associated study drug supply. This amendment is in response 
to Dr. Ivy’s April 26, 2023, request for amendment. 
 
All participating sites, where patients are currently receiving ABT-888 (veliparib) treatment, will receive 
this information through both the "Investigator Letter" and the "Participant Information Letter." 
 
Protocol Changes 
 
The above-referenced protocol has been updated as follows: 
 
1. 
Formatting, typographical errors, and section links were updated throughout the protocol. 
 
2. 
The version date and table of contents has been updated. 
 
3. 
Section 3.0: A note has been included specifying the expiration dates for the existing unblinded 
ABT-888 (veliparib) supplies and the end of treatment date. 
 
4. 
Section 3.1d and 7.2: A note has been included to provide the rationale for unblinding the last 

S1416 
Revision #8 (contd.) 
Page 2 
 
patient on treatment and to provide additional guidance. 
 
5. 
Section 7.4c: A subsection has been inserted to provide additional guidance for the remaining 
patient on treatment. 
 
6. 
Section 9.0: Footnote “**” has been updated to reflect patient visits and scans after the five (5) 
year follow-up time frame is at the discretion of the physician. 
 
Model Consent Form Changes 
 
The Model Consent Form has been updated as follows: 
 
1. 
The version date has been updated. 
 
2. 
“How long will I be in this study?”: A note has been inserted regarding the discontinuation of the 
ABT-888 (veliparib) development program. 
 
Investigator and Patient Letter 
 
The Investigator and Patient Letter has been included due to the following: 
 
1. 
The letters have been provided to explain the rationale for unblinding the last patient on treatment 
and to provide additional guidance.        
 
Patient Notification: 
 
Please note that the information provided below regarding patient notification and amendments to local 
consent forms reflects SWOG’s minimum requirements. Sites should refer to the policies/procedures of 
the IRB of record to determine whether they have any more stringent requirements. 
 
SWOG has determined that the changes above may affect a patient’s willingness to participate in the 
study; therefore, SWOG requires that patients be notified of these changes. 
 
Who must be informed? 
• 
All patients currently on study treatment with ABT-888 (veliparib). 
 
How must patients be notified? 
• 
For patients currently receiving ABT-888 (veliparib): Notification must take place via distribution of 
the patient letter or verbally by the next study visit. 
 
What is the notification deadline and process? 
• 
For patients currently receiving treatment with ABT-888 (veliparib): It is recommended that the 
patient be notified as soon as possible to make the determination of whether to continue 
treatment. 
 
Regulatory Considerations: 
 
Do local consent forms need to be updated? 
• 
It depends. If your site will utilize the updated consent form for notification and formal reconsent 
then local consent forms must be updated. If your site will not utilize updated consent form for 
notification and formal reconsent then local consent forms need not be updated. 
 

S1416 
Revision #8 (contd.) 
Page 3 
 
The updated protocol, model informed consent form, and patient letter can be accessed from the CTSU 
website (www.ctsu.org). Please discard any previous versions of the documents and replace with the 
updated versions. 
 
This study has been reviewed and approved by the NCI’s Central Institutional Review Board (CIRB). 
This memorandum serves to notify the NCI, and SWOG Statistics and Data Management Center. 
 
cc:        PROTOCOL & INFORMATION OFFICE 
Elizabeth Swisher, M.D. – King/Swisher Laboratory 
Ruu Hsu – Kuhn-Hicks Laboratory 
Katie Von Derau – WPC

 
S1416 
 
Page 1 
 
Version Date 08/07/2024 
 
 
 
PRIVILEGED COMMUNICATION 
Activation Date July 7, 2016 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG CANCER RESEARCH NETWORK 
TITLE PAGE 
PHASE II RANDOMIZED PLACEBO-CONTROLLED TRIAL OF CISPLATIN WITH OR WITHOUT ABT-
888 (VELIPARIB) IN METASTATIC TRIPLE-NEGATIVE BREAST CANCER AND/OR BRCA 
MUTATION-ASSOCIATED BREAST CANCER, WITH OR WITHOUT BRAIN METASTASES 
 
NCT #02595905 
 
STUDY CHAIRS: 
AGENTS: 
 
Eve Rodler, M.D. (Medical Oncology) 
NCI Supplied Investigational Agent: 
UC Davis Comprehensive Cancer Center 
ABT-888 (veliparib)/placebo (NSC 737664; 
4501 X Street, Ste. 3016 
) 
Sacramento, CA 95817 
IND-Exempt Agent: 
Phone: 916/734-3772 
Cisplatin (CDDP) (Platinol®, Platinol-AQ)  
FAX: 916/734-7946 
(NSC-119875) 
E-mail: S1416question@swog.org 
 
 
 
BIOSTATISTICIANS: 
Priyanka Sharma, M.D. (Translational Medicine) 
 
University of Kansas CC & Med Pavilion 
William E. Barlow, Ph.D. 
2330 Shawnee Mission Parkway 
Cancer Research and Biostatistics 
Mail Stop 5003 
1050 Westlake Ave N, Suite 750 
Westwood, KS 66205 
Seattle, WA 98109 
Phone: 913/588-6029 
Phone: 206/652-2267 
FAX: 913/588-4085 
FAX: 206/652-4612 
E-mail: S1416question@swog.org 
E-mail: williamb@crab.org  
 
 
Julie R. Gralow, M.D. (Medical Oncology) 
Danika Lew, M.A. 
University of Washington School of Medicine 
Jieling Miao, M.S. 
Seattle Cancer Care Alliance 
SWOG Statistics and Data Management Center 
825 Eastlake Ave E 
Fred Hutchinson Cancer Center 
MS G4-830 
1100 Fairview Avenue North, M3-C102 
Seattle, WA 98109-1023 
P.O. Box 19024 
Phone: 206/288-7722 
Seattle, WA 98109-1024 
FAX: 206/288-2054 
Phone: 206/667-4623 
E-mail: S1416question@swog.org  
FAX: 206/667-4408 
 
E-mail: dlew@fredhutch.org  
James B. Hicks, Ph.D. (Translational Medicine) 
E-mail:  jmiao@fredhutch.org  
Research Professor of Biological Sciences 
 
University of Southern California 
STUDY CHAIRS (contd.): 
3430 S. Vermont Avenue, Suite 114 
 
Los Angeles, CA  90089-3301 
Peter Kuhn, Ph.D. (Translational Medicine) 
Phone:  213/821-3980 
Dean’s Professor of Biological Sciences 
E-mail:  jameshic@usc.edu  
Professor of Medicine and Engineering 
 
University of Southern California 
 
3430 S. Vermont Avenue, Suite 114 
 
Los Angeles, CA  90089-3301 
 
Phone:  213/821-3980 
 
E-mail:  pkuhn@usc.edu  
 

S1416 
 
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ALLIANCE STUDY CHAIR: 
 
Carey K. Anders, M.D. 
University of North Carolina 
170 Manning Drive, CB #7305 
Chapel Hill, NC  27599 
Phone:  919/966-1997 
FAX:  919/966-6735 
E-mail:  carey-anders@med.unc.edu  
 
ECOG-ACRIN STUDY CHAMPION: 
 
Lori Goldstein, M.D. 
Fox Chase Cancer Center 
 
NRG STUDY CHAMPION: 
 
Shannon Puhalla, M.D. 
University of Pittsburgh School of Medicine 
 
 
 
 
 
 
 
 
 
 
 
 
 
PARTICIPANTS 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG Cancer Research Network 
 
 
 
 

 
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TABLE OF CONTENTS 
 
TITLE PAGE ................................................................................................................................................. 1 
PARTICIPANTS ............................................................................................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 3 
S1416  PROTOCOL CONTACT INFORMATION ........................................................................................ 5 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 6 
SCHEMA ....................................................................................................................................................... 7 
1.0 
OBJECTIVES .................................................................................................................................. 8 
1.1 
Primary Objectives ........................................................................................................................... 8 
1.2 
Secondary Objectives ...................................................................................................................... 8 
1.3 
Translational Objectives (see Appendix 18.5) ................................................................................. 8 
2.0 
BACKGROUND ............................................................................................................................... 9 
2.1 
General............................................................................................................................................. 9 
2.2 
BRCA deficiency as a therapeutic target in triple-negative breast cancer .............................. 9 
2.3 
Poly (ADP-ribose) polymerase (PARP) inhibitors in TNBC and BRCA-deficient breast 
cancer ............................................................................................................................................ 10 
2.4 
Efficacy of ABT-888 ..................................................................................................................... 10 
2.5 
Platinum agents in TNBC and BRCA-deficient breast cancer ................................................ 11 
2.6 
Rationale for combination of Cisplatin and a PARP inhibitor: ................................................ 12 
2.7 
Phase I study using Cisplatin and Vinorelbine with Veliparib: in Metastatic Triple-Negative 
Breast Cancer and BRCA Mutation-Associated Breast Cancer. ............................................. 13 
2.8 
Incorporation of BRCAness phenotype as an integral biomarker: ........................................ 15 
2.9 
Rationale for Brain Metastases Cohort:..................................................................................... 18 
2.10 
Inclusion of Women and Minorities ........................................................................................... 20 
3.0 
DRUG INFORMATION .................................................................................................................. 20 
3.1 
ABT-888 (Veliparib) (NSC 737664) (CTEP IND #77840) .............................................................. 20 
3.2 
Cisplatin (CDDP) (Platinol®, Platinol-AQ) (NSC-119875) .............................................................. 27 
4.0 
STAGING CRITERIA ..................................................................................................................... 29 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 29 
5.1 
Disease Related Criteria ................................................................................................................ 29 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 30 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 30 
5.4 
Regulatory Criteria ......................................................................................................................... 32 
5.5 
Progressive Brain Metastases Cohort ........................................................................................... 32 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 32 
7.0 
TREATMENT PLAN ...................................................................................................................... 33 
7.1 
BRCA1/2 testing ............................................................................................................................. 33 
7.2 
Treatment ....................................................................................................................................... 34 
7.3 
Drug Compliance Documentation .................................................................................................. 35 
7.4 
Unblinding Procedures ................................................................................................................... 35 
7.5 
Full CDUS Reporting Requirement ................................................................................................ 36 
7.6 
Criteria for Removal from Protocol Treatment ............................................................................... 36 
7.7 
Discontinuation of Treatment ......................................................................................................... 36 
7.8 
Follow-Up Period ............................................................................................................................ 36 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 36 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 36 
8.2 
General Considerations ................................................................................................................. 37 
8.3 
Dose Levels for ABT-888/placebo (as combined therapy) ............................................................ 38 
8.4 
Dose Levels for ABT-888/placebo (as monotherapy) .................................................................... 38 
8.5 
Dose Levels for Cisplatin ............................................................................................................... 38 
8.6 
Dose Modifications for ABT-888/Placebo ...................................................................................... 38 
8.7 
Dose Modifications for Cisplatin ..................................................................................................... 42 
8.8 
Dose Modifications Contacts ......................................................................................................... 43 
8.9 
Adverse Event Reporting ............................................................................................................... 43 
9.0 
STUDY CALENDAR ...................................................................................................................... 44 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 47 

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10.1 
Measurability of lesions .................................................................................................................. 47 
10.2 
Objective status at each disease evaluation .................................................................................. 48 
10.3 
Best Response ............................................................................................................................... 50 
10.4 
Assessment Criteria for Brain Metastases Cohort ................................................................... 50 
10.5 
Performance Status: ...................................................................................................................... 52 
10.6 
Time to Treatment Failure .............................................................................................................. 53 
10.7 
Time to Death ................................................................................................................................. 53 
10.8 
Progression-Free Survival.............................................................................................................. 53 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 53 
11.1 
Endpoints ....................................................................................................................................... 53 
11.2 
Accrual Goal ................................................................................................................................... 54 
11.3 
Primary Analyses ........................................................................................................................... 54 
11.4 
Exploratory analyses of PFS .......................................................................................................... 55 
11.5 
Overall Survival (OS) ..................................................................................................................... 56 
11.6 
Response rate and clinical benefit rate .......................................................................................... 57 
11.7 
Interim analysis and timing of final analysis ................................................................................... 57 
11.8 
Toxicity ........................................................................................................................................... 57 
11.9 
Data and Safety Monitoring Committee (DSMC) ........................................................................... 57 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 57 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 58 
13.1 
Registration Timing ........................................................................................................................ 58 
13.2 
Investigator/Site Registration ......................................................................................................... 58 
13.3 
CTEP Registration Procedures ...................................................................................................... 58 
13.4 
CTSU Registration Procedures ...................................................................................................... 59 
13.5 
Oncology Patient Enrollment Network (OPEN)Registration Requirements ................................... 61 
13.6 
Exceptions to SWOG registration policies will not be permitted. ................................................... 62 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 62 
14.1 
Data Submission Requirement ...................................................................................................... 62 
14.2 
Master Forms ................................................................................................................................. 62 
14.3 
Data Submission Procedures ........................................................................................................ 62 
14.4 
Data Submission Overview and Timepoints .................................................................................. 63 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 66 
15.1 
Primary Tumor Specimens (REQUIRED) ...................................................................................... 66 
15.2 
Specimens from Metastatic Tissue ................................................................................................ 67 
15.3 
BRCA 1 and BRCA 2 Testing (REQUIRED) .................................................................................. 68 
15.4 
Specimens for Circulating Tumor Cell-Next Generation Sequencing (CTC-by HD-CTC followed by 
CTC-NGS) (REQUIRED): .............................................................................................................. 69 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 73 
16.1 
Adverse Event Reporting Requirements........................................................................................ 75 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 80 
18.0 
APPENDIX ..................................................................................................................................... 90 
18.1 
ABT-888/Placebo Intake Calendar ................................................................................................ 91 
18.2 
Emergency Unblinding Guidelines ................................................................................................. 92 
18.3 
New York Heart Association Criteria .............................................................................................. 94 
18.4 
Patient Drug Information Handout and Wallet Card ...................................................................... 95 
18.5 
Translational Medicine ................................................................................................................... 97 
18.6 
Modified Breast Graded Prognostic Assessment Index .............................................................. 150 
18.7 
SWOG Biospecimen Bank (BB) Instructions ............................................................................... 151 
 

 
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S1416  PROTOCOL CONTACT INFORMATION 
 
Patient Advocate 
Ginny Mason, R.N., B.S.N. via  
Email: masonvirginia@msn.com  
 
Elda Railey via 
Email: erailey@researchadvocacy.org  
Eligibility, RAVE, Data Submission: 
SWOG Statistics and Data Management Center  
E-mail: breastquestion@crab.org  or  
Phone: 206/652-2267 
Medical Queries (treatment or toxicity related 
questions): 
Email: S1416question@swog.org 
 
Translational Medicine questions:  
Email: S1416question@swog.org 
Investigational Drug questions: 
See Protocol Section 3.0 or 
PMBAfterHours@mail.nih.gov 
Requests for Investigator’s Brochures: 
See Protocol Section 3.0 or 
http://ctep.cancer.gov/branches/pmb/agent_order_proc
essing.htm 
Access issues for the PMB Online Agent 
Ordering Processing (OAOP) application: 
IBCoordinator@mail.nih.gov 
Specimen Tracking System (STS) 
Amendments, Errors, Connectivity Issues 
and Technical issues with the SWOG CRA 
Workbench: 
technicalquestion@crab.org 
Cancer Therapy and Evaluation Program - 
Identity and Access Management (CTEP-
IAM): 
To review CTEP-IAM account (new requests, reset 
passwords): 
https://ctepcore.nci.nih.gov/iam/index.jsp 
Access to iMedidata Rave:  
See Protocol Section 14.3 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or Email: 
ctsucontact@westat.com 
Questions related to: 
Oncology Patient Enrollment Network 
(OPEN) 
See Protocol Section 13.3 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or Email: 
ctsucontact@westat.com 
Participant Transfers: 
patienttransfer@crab.org 
Serious Adverse Event Reporting questions:  
See Protocol Section 16.1  
Email: adr@swog.org  
Regulatory, Protocol, Informed Consent: 
SWOG Operations Office 
E-mail: protocols@swog.org or Phone: 210/614-8808 
 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
(Sign in at www.ctsu.org, and 
select the Regulatory > 
Regulatory Submission.)  
 
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 866-651-
2878 to receive further information 
and support.   
 
Contact the CTSU Regulatory 
Help Desk at 866-651-2878 for 
regulatory assistance. 
 
Refer to the patient enrollment 
section of the protocol for 
instructions on using the 
Oncology Patient Enrollment 
Network (OPEN). OPEN is 
accessed at 
https://www.ctsu.org/OPEN_SY
STEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN related 
questions by phone or email : 1-
888-823-5923, or 
ctsucontact@westat.com. 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave. Refer to the data 
submission section of the 
protocol for further instructions.  
 
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page located on the CTSU members’ website (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 log in with a CTEP-IAM 
username and password.  
 
For clinical questions (i.e. patient eligibility or treatment-related)  
contact the SWOG Statistics and Data Management Center by phone or email: 
 
206-652-2267 
breastquestion@crab.org  
 
For treatment or toxicity related questions contact the Study PI of the Coordinating Group at 
S1416question@swog.org.  
 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email:  
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 Web site is located at https://www.ctsu.org  
 
 

 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* 
All patients will have specimens submitted for germline BRCA testing (BROCA-HR) after 
randomization and before beginning protocol treatment.  Patients will be assigned to the 
appropriate groups for analysis based on germline BRCA status. 
o BRCA testing results provided to the enrolling site via Rave® in 4-8 weeks. 
o Genetic counseling services available for sites if needed (provided by Dr. Swisher, 
Appendix 18.5)  
 
Treatment assignment at randomization is not affected by this classification. Treatment may 
begin before results are received. 
* TNBC or BRCA 1/2 mutation associated metastatic breast cancer 
Standard Cohort and Brain Metastasis Cohort 
Registration/Randomization 
Cisplatin IV Day 1  
Placebo (ABT-888) BID Days 1-14, 
every 21 days 
Progression 
Cisplatin IV Day 1  
ABT-888 BID Days 1-14, every 21 days 
*BRCA testing 

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1.0 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
a. 
To compare the efficacy of cisplatin with or without ABT-888 (veliparib) on 
progression-free survival (PFS) in each of the following groups: 
 
1. 
Patients with germline BRCA (gBRCA) mutation-associated breast cancer 
 
2. 
Patients with germline BRCA wild-type breast cancer who have evidence 
of BRCAness phenotype 
 
3. 
Patients with germline BRCA wild-type breast cancer who do not have 
evidence of BRCAness phenotype. 
 
b. 
Brain Metastases Cohort:  To compare the efficacy of cisplatin with or without ABT-
888 on PFS in patients with triple negative and/or gBRCA mutation-associated 
breast cancer and brain metastases. 
 
1.2 
Secondary Objectives 
 
a. 
For patients with gBRCA mutation associated breast cancer (group “i” above) or 
TNBC with (group “ii”) or without (group “iii”) BRCAness phenotype, to compare 
the efficacy of cisplatin with or without ABT-888 on overall survival (OS), response 
rate, and clinical benefit rate. 
 
b. 
To compare the differential benefit of ABT-888 across the three groups using both 
PFS and OS as outcomes. 
 
c. 
For patients in the brain metastases cohort, to compare the efficacy of cisplatin 
with or without ABT-888 on OS. 
 
d. 
For patients in the brain metastases cohort, to compare the efficacy of cisplatin 
with or without ABT-888 on intracranial and extracranial response rates 
(intracranial by RANO and extracranial by RECIST 1.1). 
 
e. 
To compare toxicities of ABT-888 to placebo in each of the four groups separately. 
 
1.3 
Translational Objectives (see Appendix 18.5) 
 
a. 
To evaluate the impact of Homologous Recombination Deficiency score 
(independent of other BRCAness markers) on response rate (RR) and PFS in 
patients treated with chemotherapy versus chemotherapy plus ABT-888. 
 
b. 
To evaluate the overlap among various markers utilized to define the BRCAness 
phenotype. 
 
c. 
To evaluate the combined impact of PAM50 basal subtype and BRCAness 
phenotype on RR and PFS in patients treated with chemotherapy versus 
chemotherapy plus ABT-888. 
 
d. 
To evaluate the impact of BRCA1 mRNA expression (independent of other 
BRCAness markers) on response rate (RR) and PFS in patients treated with 
chemotherapy versus chemotherapy plus ABT-888. 
 
e. 
Application of somatic BRCAness phenotype markers on metastatic tumor tissue 
to identify patients likely to benefit from platinum-based therapy and ABT-888. 
 

 
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f. 
To determine the overlap of BRCA phenotype (germline BRCA, BRCA-like, Non-
BRCA-like) with tissue PD-L1 status and to determine if ABT-888 (veliparib) benefit 
in BRCA-like patients is maintained when adjusting for PD-L1 status. 
 
g. 
To evaluate CTC-HRD status as a predictive biomarker of response to treatment 
with cisplatin plus ABT-888 (veliparib) versus cisplatin plus placebo. 
 
h. 
To evaluate ctDNA HRR (Homologous recombination repair) mutation status as a 
predictive marker of response to treatment with cisplatin plus ABT-888 (veliparib) 
versus cisplatin plus placebo. 
 
2.0 
BACKGROUND 
 
2.1 
General 
 
Triple-negative breast cancer (TNBC) refers to a subgroup of breast carcinomas that do 
not express the estrogen receptor (ER), progesterone receptor (PR), and exhibit normal 
expression of the human epidermal growth factor receptor type (HER) 2. Due to a lack of 
well-defined molecular targets, chemotherapy is the standard of care treatment for TNBC. 
The triple-negative phenotype is found in approximately 10-17% of all breast cancers, and 
is associated with a poor prognosis, characterized by early relapse and a significantly 
shorter survival following recurrence compared with non-triple-negative cancers. 
(1,2,3,4,5,6) Data suggest that the triple-negative phenotype is an independent predictor 
of distant metastasis and cause-specific survival. (7) In the metastatic setting, patients with 
TNBC have a median survival of approximately 13 months, and short duration of response 
to treatment (median duration of response equals 12 weeks for first-line treatment; 9 weeks 
for second-line; and 4 weeks for third-line). (8) Thus, there is an unmet clinical need for 
more effective treatments in this group of patients.  
 
2.2 
BRCA deficiency as a therapeutic target in triple-negative breast cancer  
 
Triple-negative breast cancers and BRCA1 germline mutation-associated breast cancers 
share many histopathologic and molecular features. The phenotypic and molecular 
similarities between BRCA1 mutation-associated and sporadic TNBC have led many to 
surmise that a significant proportion of gBRCA wild-type TNBCs may involve BRCA1 
pathway dysfunction through non-germline mutational means and BRCA1-directed 
therapeutic approaches (such as platinum agents and poly(ADP-ribose) polymerase 
(PARP) inhibitors) are being explored for TNBC. Approximately 10-20% of TNBCs harbor 
detectable germline BRCA1 mutations and have an underlying defect in homologous 
recombination (HR) DNA repair. (9,10,11,12,13) However, DNA repair may be altered 
through other mechanisms, such as somatic or germline mutation in other genes, DNA 
methylation or attenuated mRNA expression. It is estimated that if these factors beyond 
germline BRCA mutations are comprehensively evaluated, 50-60% of TNBC will 
demonstrate HR deficiency or BRCAness making it an attractive therapeutic target for this 
subtype. (14,15,16) The combination of platinum therapy and PARP inhibition may be most 
active in tumors with gBRCA mutations and in gBRCA wild-type tumors that harbor the 
BRCAness phenotype. 
 
 

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2.3 
Poly (ADP-ribose) polymerase (PARP) inhibitors in TNBC and BRCA-deficient breast 
cancer  
 
PARP enzymes recognize DNA damage and facilitate DNA repair to maintain genomic 
stability. Preclinical studies demonstrate that PARP inhibition in the presence of BRCA 
deficiency leads to synthetic lethality. PARP inhibitors have shown preclinical and clinical 
activity in targeting tumors with pre-existing DNA repair defects, in particular BRCA1 and 
BRCA2-deficient tumors. (17,18,19,20,21,22,23,24,25) A PARP inhibitor olaparib has 
recently been approved as monotherapy by the FDA as a first-in-class drug to treat 
germline 
BRCA 
mutation-associated 
advanced 
refractory 
ovarian 
cancers 
(http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427554.htm). As 
a significant proportion of TNBC are thought to harbor DNA repair defects, it might be 
possible to extend the observation of PARP inhibitor sensitivity of gBRCA mutation-
associated tumors to gBRCA wild-type TNBC that harbor BRCAness. Preclinical studies 
also demonstrate that basal-like cell lines exhibit increased sensitivity to PARP inhibition. 
(26) Accordingly, PARP inhibitors are being explored in the general population of patients 
with TNBC (www.clinicaltrials.gov.Identifier NCT02032277). (27) 
 
As monotherapy PARP inhibitors have demonstrated limited activity in non-BRCA 
mutation-associated breast cancer. However, this information is only inferred from small 
Phase I studies and there could be several reasons for the lack of activity observed. These 
studies included a small number of unselected TNBC patients, whereas PARP inhibitors 
are expected to work only in the 40-50% of gBRCA wild-type TNBC with a BRCAness 
phenotype and not in all gBRCA wild-type TNBC. A recent Phase I study of ABT-888 
monotherapy reported modest clinical benefit rate of 19% (4/24) in BRCA mutation-
negative TNBC. (28) Furthermore, gBRCA wild-type TNBC with a BRCAness phenotype 
likely harbor only partial homologous recombination defects and PARP inhibitor 
monotherapy may lead to “synthetic sickness” rather than synthetic lethality, necessitating 
the presence of robust DNA damaging chemotherapy to achieve cell death. To date, most 
studies reporting lack of significant activity in sporadic TNBC utilized PARP inhibitor 
monotherapy. (29,30)  
 
2.4 
Efficacy of ABT-888 
 
ABT-888 is an oral small molecule inhibitor of PARP-1 and PARP-2 and inhibits PARP 
activity in xenograft models and human tumor tissue. (31,32,33) ABT-888 monotherapy 
has shown clinical activity in BRCA mutation positive breast, ovarian and prostate cancer 
patients in a Phase I dose escalation study, and in BRCA mutation-positive breast and 
ovarian cancer patients in Phase II studies. (34,35) Ongoing studies are evaluating ABT-
888 as a single agent or in combination with chemotherapeutic agents such as 
temozolomide, platinum compounds and platinum-taxane doublets, in germline BRCA 
mutation-associated breast cancers (ClinicalTrials.gov Identifier NCT01506609, NCT 
02158507). Although preclinical studies demonstrate that talazoparib (BMN673) has the 
strongest PARP trapping activity, clinically there is no evidence of superiority of one PARP 
inhibitor over others. Furthermore, preclinical studies demonstrate that trapping potency is 
directly correlated with hematopoietic progenitor cell toxicity and PARP trapping is not 
detectable nor required for activity when PARP inhibitors are combined with cisplatin. (36) 
ABT-888 traps PARP1 onto damaged DNA at clinically relevant concentrations as 
monotherapy and is capable of catalytic inhibition at concentrations where trapping is 
undetectable with regimens in which trapping is not required for activity.  
 

 
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Information on activity of ABT-888 in combination with chemotherapy in germline 
BRCA wild-type TNBC is available from three Phase I studies. (37,38,39) No 
responses were noted in sporadic TNBC with the combination of ABT-888 (low dose) 
and temozolomide. (40) In the second Phase I study, the combination of carboplatin, 
paclitaxel and ABT-888 did show promising activity with objective responses noted in 10 
out of 17 (59%) BRCA wild-type TNBC patients. (41) The third Phase I trial which used 
cisplatin, vinorelbine and ABT-888 showed objective responses in 10 out of 26 (38%) 
confirmed BRCA wild-type TNBC patients. (42) 
 
In the BRCAness population, data from other trials suggests it will be necessary to combine 
PARP inhibition with chemotherapy to be effective. To date, ABT-888 is the only PARP 
inhibitor able to combine with standard doses of platinum-based therapy. Olaparib has 
been difficult to combine with cisplatin/gemcitabine and with carboplatin at full doses and 
we have no data on how well the other PARP inhibitors will combine with chemotherapy. 
Based on a recently completed Phase I study discussed below, we have a safety profile 
for cisplatin and ABT-888, and evidence that adequate doses of cisplatin can be delivered 
in combination with a near maximal single agent dose of ABT-888.  
 
ABT-888 has also shown activity in lung cancer patients, none of whom are expected to 
harbor a BRCA mutation. A recent study in squamous cell lung cancer reported a two 
month improvement in PFS with the addition of ABT-888 to carboplatin/paclitaxel 
chemotherapy. (43)  
 
When comparing across different studies various PARP inhibitors (ABT-888, olaparib, 
rucaparib, BMN 673) have typically shown a 26-40% response rate in germline BRCA 
mutation-positive patients. (44,45,46,47,48) The variability in responses seen in the 
ovarian cancer studies is highly influenced by the number of platinum sensitive vs. resistant 
patients in each study. A recent ABT-888 monotherapy study demonstrates a RR of 35% 
in platinum sensitive and 20% in platinum resistant ovarian cancer (which is in line with 
observations with other PARP inhibitors). (49) In germline BRCA mutation-positive breast 
cancer a recently completed Phase I study evaluated 9 dose levels of ABT-888 and 
demonstrated an overall RR (at all dose levels combined) of 29% and a much higher RR 
of 60% at the RP2D. (50) This suggests a dose response relationship of ABT-888 and 
emphasizes the importance of being able to combine chemotherapy with the highest dose 
possible of ABT-888 to test for BRCAness in sporadic TNBC. All ongoing major trials of 
PARP inhibitors in metastatic breast cancer are focusing on the germline BRCA mutation-
positive breast cancer population. S1416 is the only trial that proposes to use a 
combination of robust doses of both the PARP inhibitor and cisplatin to test for activity in 
the BRCAness phenotype in TNBC. 
 
2.5 
Platinum agents in TNBC and BRCA-deficient breast cancer  
 
Platinum agents are not new to the treatment of breast cancer. In the 1980’s, cisplatin 
was evaluated in advanced breast cancer in two Phase II studies and demonstrated 
significant single-agent frontline activity with response rates in the range of 50-
54%. (51,52) Cisplatin was subsequently replaced by other agents in breast cancer 
with more favorable toxicity profiles until more recently, when there has been 
renewed interest in platinum agents in BRCA mutation-associated breast cancer 
and TNBC. Repair of platinum-induced interstrand crosslinks invokes BRCA1-
mediated homologous recombination, and there is abundant clinical and in vitro 
evidence that BRCA1-deficient cells are hypersensitive to platinum agents. 
(53,54,55,56,57) Observational studies, small neoadjuvant and metastatic 
studies have demonstrated that BRCA 1/2 mutation-associated breast cancers are 
very sensitive to platinum agents. (58,59,60,61,62,63) In a Phase II study, single 
agent cisplatin yielded an impressive 80% response rate in BRCA1 mutation-
associated MBC. (64) A recent randomized Phase III trial (TNT study, Tutt A, et al. S3-
01 2014 San Antonio Breast Cancer Symposium) demonstrated that in unselected 

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metastatic TNBC, carboplatin was equal in efficacy to docetaxel in the first-line metastatic 
setting. However, in gBRCA mutation-associated TNBC, carboplatin yielded a superior 
response rate and progression-free survival compared to docetaxel. This data from the 
TNT study strongly supports investigating the use of platinum (and not taxane)-based 
chemotherapy backbone combined with a PARPi in gBRCA mutation-associated 
metastatic TNBC and also provides reassurance regarding the activity of platinum-based 
chemotherapy in unselected metastatic TNBC. For treatment of solid tumors, cisplatin and 
carboplatin are the two commonly used platinum agents. Superiority of cisplatin over 
carboplatin has been shown in multiple solid tumors in the early stage curative setting, 
including germ cell, bladder, esophageal, and head and neck tumors, though this concept 
has never been tested in breast cancer. (65) A non-randomized Phase II study reported 
efficacy of single-agent cisplatin (75 mg/m2 every 3 weeks) or carboplatin (AUC 6 every 3 
weeks) as fırst or second-line therapy in metastatic TNBC. In this study an encouraging 
ORR of 55% was noted in patients with BRCA1 or BRCA2 germline mutations (compared 
to 26% in BRCA wild-type patients) and interestingly cisplatin demonstrated a numerically 
higher ORR (37%) compared to carboplatin (23%). (66,67) This was a non-randomized 
study so these results must be interpreted with caution. In a recent single institution 
retrospective study of 144 TNBC patients treated with platinum based neoadjuvant 
chemotherapy, superior progression-free and overall survival was noted for those receiving 
cisplatin-based regimens compared to those receiving carboplatin-based regimens. (68)  
 
Recent data from the ovarian cancer literature demonstrates that patients with a 
deleterious BRCA1/2 mutation have increased susceptibility and shortened time to 
carboplatin hypersensitivity reactions, independent of other risk factors for hypersensitivity 
reactions. (69) BRCA1 mutation carriers have an increased therapeutic susceptibility to 
platinum agents and are more likely to receive multiple cycles of platinum-based therapy. 
Thus, cisplatin (compared to carboplatin) may improve the tolerability and durability of the 
platinum-based combination regimens in BRCA mutation carriers and may be a better 
platinum partner to PARP inhibitors. Furthermore, given the recent data from randomized 
trials on the efficacy of neoadjuvant carboplatin in TNBC, several patients might already 
have been exposed to carboplatin in the neoadjuvant setting which also makes cisplatin a 
more attractive choice for a metastatic regimen. Based on the above rationale and the 
below described Phase I data the current proposal includes a cisplatin-based 
chemotherapy backbone. 
 
2.6 
Rationale for combination of Cisplatin and a PARP inhibitor: 
 
Although platinum agents and taxanes are generally considered synergistic for breast 
cancer, this may not hold true for BRCA mutation-associated breast cancer. Several in vitro 
studies have demonstrated that BRCA1- deficient cells are resistant to taxanes. (70,71,72) 
Cisplatin has demonstrated synergy with the PARP inhibitor, ABT-888, in breast cancer 
xenograft models. (73) Based on these rationales a Phase I study utilizing ABT-888 in 
combination with cisplatin and vinorelbine for patients with advanced TNBC and/or BRCA 
mutation-associated breast cancer was initiated. This study demonstrated safety, 
tolerability and a suggestion of significant efficacy in a heavily pretreated population 
(results described in detail in the section below). A Phase II trial is needed to further 
elucidate the relative contribution of PARPi in this setting. Thus, the clinical results from 
this Phase I study, in addition to the preclinical rationale, provide the basis for the S1416 
Phase II randomized trial. 
 
 

 
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2.7 
Phase I study using Cisplatin and Vinorelbine with Veliparib: in Metastatic Triple-
Negative Breast Cancer and BRCA Mutation-Associated Breast Cancer. 
 
Preclinically, cisplatin is synergistic with vinorelbine and the poly (ADP-ribose) inhibitor, 
ABT-888 and has anti-neoplastic activity in TNBC and BRCA1-deficient breast cancer.  A 
Phase I study was conducted to define the tolerability of ABT-888 with cisplatin/vinorelbine. 
In the dose escalation study ABT-888 was administered BID for 14 days with cisplatin (75 
mg/m2 Day 1) and vinorelbine (25 mg/m2 Days 1, 8) for a minimum of 6 cycles as tolerated, 
and up to 10 cycles followed by ABT-888 monotherapy. (74)  
 
A total of 50 eligible patients with advanced triple-negative and/or BRCA mutation-
associated breast cancer were enrolled in the trial between July 2010 and February 2014. 
Forty-five patients were enrolled in 9 dose levels and 5 patients in a safety expansion 
cohort. Fourteen patients (28%) were confirmed BRCA1 or BRCA2 mutation carriers. Most 
patients entered the trial with a heavy disease burden; 3 or more sites of disease. The most 
common sites were the lymph nodes, lungs, and liver. Seven patients started the trial with 
treated brain metastases. The majority of patients had received prior chemotherapy for 
metastatic disease, with a median of 1 prior regimen (range 0 to 13). Seventeen patients 
(34%) received prior platinum chemotherapy. Ten patients (20%) received vinorelbine 
before the study regimen, with 8 having prior exposure to both platinum and vinorelbine.  
 
The study regimen was reasonably well tolerated. For the 50 patients receiving study 
therapy, a median of 6 cycles of combined chemotherapy plus ABT-888 was delivered 
(range 0-9 cycles).  Compared to the intended combination therapy (full dose for 6 cycles) 
the median delivery for cisplatin was 90%, vinorelbine was 73%, and ABT-888 was 93%. 
Thirty-one patients (62%) completed at least 6 cycles of combined chemotherapy and ABT-
888, and 23 patients proceeded to monotherapy with ABT-888. The most common 
treatment-related adverse events (AEs) of all grades were nausea, fatigue, 
thrombocytopenia, anemia, and neutropenia. A majority of patients experienced these 
AEs, mainly Grade 1/2. Grade 3/4 AEs included neutropenia (36%, 3/18 febrile), anemia 
(30%), and thrombocytopenia (12%). No Grade 3/4 AEs of neuropathy, creatinine elevation 
or hearing loss were observed in the trial. 
 
Six of 23 patients reported AEs while on monotherapy, including one with Grade 3 anemia. 
The most common AEs of any grade on monotherapy were dyspepsia, nausea and 
vomiting (each 17%). 
 
There was no increase in short-term or long-term nephrotoxicity in the Phase I trial despite 
the common renal elimination of ABT-888 and cisplatin. There were no Grade 3 or 4 
platinum-related toxicities including elevated creatinine, peripheral sensory or motor 
neuropathy, or ototoxicity, which is in line with prior cisplatin/vinorelbine use in metastatic 
breast cancer. (75) In-vivo data from animal models suggest that PARP inhibitors can 
protect against the nephrotoxicity and peripheral neuropathy of cisplatin, though only a 
larger randomized trial could support this hypothesis. (76,77,78,79) 
 
The maximum tolerated dose (MTD) of ABT-888 was not reached in this Phase I trial. 
Single dose limiting toxicity (DLT) events were rare and occurred in 3 dose cohorts. A 
patient at dose level 3 (40 mg) with Grade 4 thrombocytopenia was subsequently found to 
have bone marrow involvement of breast cancer. A patient in dose level 4 (60 mg), with 10 
prior lines of therapy in the metastatic setting, had a DLT of Grade 4 neutropenic fever. 
The patient had a pericardial effusion at the time and died of disease progression before 
completing one cycle of treatment. A patient at dose level 8 (200 mg) experienced Grade 
3 neutropenic fevers in the setting of a breast abscess.  This patient recovered from the 
acute infection and was able to remain on study for 10 months.  
 
As monotherapy, the current recommended Phase II dose for ABT-888 is 400 mg BID 
throughout a 28-day cycle. At this dose, the most notable toxicities have been 

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gastrointestinal. (80) Since nausea and vomiting could compromise the dose-intensity of 
the chemotherapy backbone, doses of ABT-888 exceeding 300 mg BID were not pursued 
in combination chemotherapy. Unlike other PARP inhibitor combination chemotherapy 
regimens in which myelotoxicity has significantly limited dose delivery of the agents, this 
platinum doublet/PARP inhibitor regimen offered high dose-intensity of cisplatin and ABT-
888, though more frequent dose reductions and delays occurred with vinorelbine. (81,82) 
 
Seven serious adverse events during combination therapy were likely related to treatment: 
five episodes of Grade 3/4 neutropenia; one of Grade 4 thrombocytopenia, and one of 
Grade 3 dehydration. Five patients (2 at 20 mg, 1 at 40 mg, 1 at 60 mg, and 1 at 120 mg 
of ABT-888) died within 30 days of stopping study therapy. These deaths were attributed 
to rapid disease progression soon after enrollment (within the first cycle in 3 patients).  
 
Of 50 patients evaluable for safety, two were not evaluated for response due to withdrawal 
before the first radiographic response for reasons other than disease or toxicity; one of 
these died within 6 months and is assessable for progression-free survival. Best overall 
response was a complete response for 4/48 patients (8%) and partial response for 17 
patients (35%), for an overall response rate of 44% (95% CI 31%-58%). Seventeen 
patients (35%) had stable disease, and 10 (21%) had progressive disease as best 
response or were not assessed due to disease or toxicity. BRCA mutation presence versus 
absence appears to be associated with both response (CR+PR, 64% vs 39%, mid-p=0.15) 
and progression-free survival at 6 months (PFS6) (71% vs 30%, mid-p=0.01).  
 
Median PFS was 5.5 months (95% CI 4.1 -6.7), and the median OS was 9.6 months (95% 
CI 8.1 – 20.7).  PFS and OS were greater for patients with a germline BRCA mutation 
(median 9.2 months PFS, 22.6 months OS) than for germline BRCA wild-type (4.2 months, 
8.7 months) or unknown mutational status (4.0 months, 6.2 months) (log-rank test, p<0.001 
for PFS, p=0.003 for OS).  
  
Two patients who achieved a CR are long-term responders. A patient in the 60 mg dose 
cohort with a BRCA1 mutation (exon 13 insert 6kb rearrangement) received 6 cycles of 
combination therapy. Complete radiographic response of liver and distant lymph node 
lesions occurred at 36 weeks, and she has been maintained through 57 cycles of 
monotherapy (40 months since starting study therapy) and remains on trial.  The second 
long-term responder with radiographic CR (120 mg dose cohort) tested negative for a 
BRCA1/2 mutation. She received 6 cycles of combination therapy. Radiographic complete 
response was achieved at 54 weeks. She remains on ABT-888 monotherapy 37 cycles 
after starting study therapy.  
 
This Phase I trial demonstrated that the combination of cisplatin, vinorelbine and ABT-888 
is generally well tolerated in patients with advanced TNBC and/or BRCA mutation-
associated breast cancer. The 300 mg BID dose of ABT-888 that can be combined with 
this cytotoxic regimen is close to the maximal PARP inhibitor dose and is a clinically active 
single agent dose.  Anti-neoplastic activity was observed in both BRCA mutation carriers 
and in germline BRCA 1/2 wild-type patients. 
 
The Phase I study results show better response rate and median PFS than other trials of 
platinum monotherapy. In our study, the ORR and median PFS (44% and 5.5 months 
respectively) is higher compared to that observed in the TBCRC0009 Phase II non-
randomized trial in metastatic TNBC patients (25% and 2.9 months respectively) and in the 
Phase III TNT trial (31% and 3.1 months respectively), despite a more heavily pretreated 
population. (83,84)  The suggestion of greater clinical activity warrants further investigation 
of this combination in metastatic TNBC patients and provided a rationale for the SWOG 
Phase II study. 
 
The recommended randomized Phase II dose (RPTD) of ABT-888 in combination with 
cisplatin and vinorelbine is 300 mg BID, the highest dose of ABT-888 reached to date in 
combination chemotherapy trials for breast cancer. This is significant because there is 

 
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evidence for a dose response relationship with ABT-888, and single-agent activity is 
observed beginning at 300 mg BID. (85) In BRCA mutation-positive cancer, a recently 
completed Phase I study evaluated 9 dose levels of ABT-888 and demonstrated an ORR 
(at all dose levels combined) of 29% and a much higher response rate of 60% at the 
recommended Phase II dose. (86) Tutt and colleagues also observed a dose response 
relationship with the oral PARP inhibitor olaparib in BRCA mutation-associated breast 
cancer. (87) The finding of higher clinical response rates with higher doses of ABT-888, 
despite achieving 90% PARP inhibition at lower doses by PAR assay, suggests that 
combinations which allow for higher PARP inhibitor dosing are preferred in order to achieve 
the best therapeutic response. (88,89)  
 
In this Phase I study, it was not possible to determine the relative contribution of the 
chemotherapy backbone and the PARP inhibitor. The patient who has remained on trial for 
the longest duration (over 40 months), BRCA1 mutation-positive, converted from a partial 
to a complete response while on ABT-888 monotherapy (300 mg BID), providing evidence 
of the antineoplastic activity of single-agent ABT-888 at a high dose. Prolonged response 
to PARP inhibitor monotherapy was also observed in a patient with confirmed BRCA 
mutation-negative TNBC, supporting the hypothesis that a BRCAness phenotype exists 
which will respond to PARP inhibition. The SWOG Phase II study has selected biomarkers 
to identify TNBC tumors with BRCAness. Since several mechanisms can result in a HR 
deficiency, a single biomarker is unlikely to detect all patients with the BRCAness 
phenotype. Thus a multipronged approach is being utilized. 
 
Although less commonly used in breast cancer, cisplatin may be a better platinum partner 
than carboplatin for ABT-888 in TNBC and BRCA mutation-positive breast cancer. In 
contrast to the high dose of ABT-888 attained with cisplatin-based therapy in this Phase I 
study, myelosupression has limited the dose of ABT-888 that can be combined with 
carboplatin as a single agent or with a carboplatin and paclitaxel doublet. (90,91)  
 
The Phase I study noted a higher response rate in BRCA mutation carriers compared to 
BRCA wild-type TNBC patients (64% versus 39%) and a higher 6-month PFS (71% versus 
30%). This is congruent with results from other studies. In the TBCRC trial, the ORR was 
higher in patients with BRCA1 or BRCA2 germline mutations (55%) compared to BRCA 
wild-type TNBC patients (26%), again demonstrating the heterogeneity of response in this 
population. Similarly, in the Phase III TNT trial, single-agent carboplatin offered superior 
response for BRCA mutation-positive TNBC patients compared to docetaxel but this was 
not the case in BRCA wild-type TNBC patients. (92) A significant number of BRCA wild-
type patients in the Phase I study did respond to treatment, indicating a need for further 
development and validation of correlative studies to identify which patients have tumors 
with a HR defect, BRCAness phenotype that will render them sensitive to platinum plus 
PARP inhibition.  
 
The clinical results from this Phase I study, in addition to the preclinical rationale, provide 
the basis for the proposed SWOG Phase II randomized trial. The Phase II trial will 
determine the relative contribution of the PARP inhibitor to cisplatin chemotherapy. 
 
The Phase II trial will utilize a multipronged biomarker approach to define a BRCAness 
phenotype and will test the hypothesis that the combination of platinum therapy and ABT-
888 will be most active in breast cancers associated with germline BRCA mutations and in 
BRCA wild-type breast cancers harboring the BRCAness phenotype, but less active in the 
non-BRCA-like phenotype. 
 
2.8 
Incorporation of BRCAness phenotype as an integral biomarker:  
 
In patients with wild-type gBRCA, and perhaps even in patients with gBRCA mutations, 
several mechanisms can result in a HR deficiency that leads to the BRCAness phenotype. 
A single test is unlikely to detect all patients with the BRCAness phenotype. It is speculated 

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that if other factors beyond germline BRCA mutations are comprehensively evaluated, 50-
60% of TNBC will demonstrate HR deficiency or BRCAness. (93,94,95) Thus a 
multipronged approach which utilizes various assays for identification of a BRCAness 
phenotype is incorporated in this proposal. These BRCAness phenotype markers have 
been incorporated as integral biomarkers in this Phase II study. The combination of 
platinum therapy and ABT-888 may be most active in tumors with a germline BRCA1 
deficiency and in tumors that harbor the BRCAness phenotype. The primary analysis 
assumes that all patients with a BRCAness phenotype can be identified so the analysis 
cannot be performed in the absence of these integral biomarkers.  
 
There is a clear need to improve outcomes in patients with metastatic TNBC. Homologous 
deficiency (which leads to BRCAness phenotype) may serve as a potential therapeutic 
target for a large fraction of TNBC patients. Both platinum agents and PARP inhibitors can 
potentially target the BRCAness phenotype. Single arm studies have demonstrated the 
preliminary activity of single-agent platinum compounds, PARP inhibitors and 
platinum/PARPi combinations in BRCA mutation-associated breast cancer and in 
unselected TNBC. (96,97,98,99,100,101,102) A recent Phase I study (discussed above) 
demonstrated very promising response rates in advanced BRCA mutation-associated 
breast cancer and TNBC utilizing a combination of platinum-based cytotoxic chemotherapy 
and the PARP inhibitor ABT-888. Several ongoing randomized studies are evaluating the 
efficacy of PARP inhibitors in the presence of platinum-based chemotherapy in germline 
BRCA mutation carriers but randomized studies evaluating PARP inhibitors in the general 
population of advanced TNBC patients are lacking. An ongoing Phase II/III AbbVie-
sponsored trial is evaluating temozolomide plus ABT-888 or carboplatin and paclitaxel with 
or without ABT-888 in patients with BRCA mutation-associated advanced breast cancer. 
(ClinicalTrials.gov Identifier NCT01506609) This trial will be informative about the 
contribution of a PARP inhibitor to a carboplatin-based regimen in BRCA-associated breast 
cancer, but it does not include sporadic TNBC patients, is using carboplatin (instead of 
cisplatin) and is using a lower, intermittent dose of ABT-888 that is not anticipated to have 
single-agent activity. S1416 uses a cisplatin-based cytotoxic chemotherapy regimen and 
is designed to determine if the addition of a PARP inhibitor (ABT-888) improves patient 
outcomes in advanced BRCA mutation-associated breast cancer and TNBC with an 
underlying BRCAness phenotype. It is now becoming increasingly clear that upfront 
incorporation of biomarkers indicative of BRCAness is needed in trial designs for 
successful evaluation of BRCA-directed therapies (platinum agents and PARPi) in the 
clinical setting. 
 
S1416 trial design is unique as it plans to use an a priori determined multi-pronged integral 
biomarker approach to assess the effectiveness of a PARP inhibitor in TNBC 
subpopulations with and without BRCAness phenotype. It is anticipated that S1416 will 
provide data on the efficacy of a new class of targeted therapy (PARP inhibitors) in the 
BRCAness phenotype TNBC patients and serve to validate the activity of PARP inhibitors 
in BRCA mutation-associated breast cancer. Clinical and biomarker Information learned 
from this trial will be utilized to design a larger Phase III study with chemotherapy with or 
without ABT-888 in TNBC patients with a BRCAness phenotype. This trial design includes 
a platinum-based regimen which is devoid of anthracycline/cyclophosphamide. Cisplatin 
has 
potential 
advantages 
over 
the 
conventional 
regimens. 
Anthracycline/cyclophosphamide, although effective in early stage breast cancer, does 
have rare long-term serious cardiac and hematological side effects. Recent in vitro and 
animal data demonstrate that BRCA1 is an essential response molecule that shields 
cardiomyocytes from DNA damage, apoptosis and heart dysfunction and the presence of 
a germline BRCA2 mutation is associated with increased anthracycline-associated cardiac 
toxicity. (103,104,105) Several in vitro studies have demonstrated that BRCA1-deficient 
cells are resistant to taxanes and a recent retrospective analysis demonstrated that BRCA1 
mutation-associated advanced TNBCs are less sensitive to single-agent taxanes than 
sporadic TNBCs. (106,107,108,109) Thus a platinum plus PARPi regimen which is devoid 
of anthracyclines and taxanes may be attractive for early stage TNBC especially if it is 
BRCA mutation-associated and has the potential of being valuable in the neoadjuvant 

 
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setting in selected patients. The knowledge gained from the biomarkers will be valuable for 
future clinical research involving DNA damaging agents in TNBC. Specifically, one of the 
exploratory objectives is to evaluate the germline BRCA mutation status and BRCAness 
phenotype markers as platinum response biomarkers. This information will be helpful for 
the future interpretation of the ongoing and planned studies involving platinum agents. See 
Appendix 18.5 for information regarding the Translational Medicine studies. 
 
A brief summary of the integral markers is described below.   
 
• 
Germline BRCA1/2 testing: Germline BROCA-HR utilizes a targeted capture and 
massively parallel sequencing approach and detects germline mutations in 
BRCA1/2 (and additional genes known to be involved in the homologous 
recombination pathway). (110)  BROCA-HR will be performed by Dr. Elizabeth 
Swisher's CLIA certified lab at the University of Washington on all patients, 
prioritizing patients who enter the trial with unknown BRCA mutation status.  A 
CLIA certified report for all confirmed deleterious mutations will be provided to the 
sites within 6 weeks. Germline testing will not delay treatment randomization. Upon 
enrollment, patients will be randomly assigned to ABT-888 or not. Assignment to 
the gBRCA confirmed positive or negative groups will occur after the BROCA-HR 
testing results are available.   
 
 
 
• 
BRCAness phenotype assessment: The following set of markers will be utilized 
to designate BRCAness phenotype in gBRCA wild type subjects (Table 1), which 
also describes the prioritization order of the tests in case of insufficient material). 
A positive result on >1 of the below described markers will place the subject in the 
BRCAness group. Extrapolating from prior studies, the estimation is that 
approximately 50% of gBRCA negative TNBC patients will have a BRCAness 
phenotype, i.e. will be positive on at least one of the measures below. 
(111,112,113) A brief description of the markers is provided below.  A detailed 
description of all the BRCAness phenotype markers (a-d) is provided in Section 
18.5 Translational Medicine. 
 
Table 1: BRCAness phenotype assignment markers (description and priority list)  
Marker  
Material needed 
BRCAness 
phenotype *  
Priority 
order  
HRD score  
Tumor gDNA  
(500 ng) 
High HRD score  
1 
Somatic BRCA 
1/2  mutations 
Tumor gDNA  
(1 ugm) 
Mutation/s present 
2 
BRCA1 Promoter 
methylation (PM) 
Tumor gDNA  
(100 ng) 
PM present  
3 
Non-BRCA 
germline HR 
mutations 
Germline DNA 
Mutation/s present 
4 
* A positive result on ≥ 1 of the markers will place the subject in the BRCAness  
 
a) Homologous Recombination Deficiency (HRD) assay: HRD assay (Myriad Inc) 
combines genomic patterns of loss of heterozygosity (LOH) “footprint”, 
telomeric allelic imbalance (TAI) and large-scale state transitions (LST) scores 
to generate an HRD score (using a custom Agilent SureSelect XT capture 
followed by sequencing on Illumina HiSeq250). (114) The HRD score has 
shown a robust correlation with HR insufficiency and allows for the detection 
of HR deficiency regardless of its etiology or mechanism. Preliminary studies 
demonstrate that a high HRD score is noted in 40-60% of TNBC and 
significantly correlates with response to platinum therapy in early stage TNBC 

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and response to a PAPRi in ovarian cancer. The assay is compatible with 
FFPE tumor tissue, requires 500 ng of tumor DNA and has high sensitivity for 
identification of BRCA-deficient tumors. (115,116) Tumor HRD assay will be 
performed for the entire study population; Results for gBRCA1/2 mutation 
negative patients will be utilized for determination of BRCAness and results for 
gBRCA mutation positive patients will be utilized to evaluate the impact of HRD 
score on outcomes for this group as an exploratory objective. HRD score will 
be evaluated using pre-specified cut point of 42. 
b) Somatic mutations in BRCA 1/2 genes: In addition to providing a score, the 
HRD 
assay 
also 
detects 
somatic 
mutations 
(point 
mutations, 
insertions/deletions, gene rearrangements) in BRCA1 and BRCA2.  Patients 
with somatic BRCA 1/2 mutations will be assigned to the BRCAness group. 
c) BRCA1 promoter methylation (PM): Hypermethylation of the BRCA1 promoter 
has been proposed as one of the mechanisms for functionally inactivating the 
BRCA1 gene in sporadic breast cancers and is associated with a gene 
expression profile similar to that of inherited BRCA1 mutation-associated 
breast cancer.  BRCA1 promoter methylation (PM) is observed in 20-40% of 
sporadic TNBC and in vitro data suggests that epigenetic silencing of BRCA1 
via promoter methylation confers the same degree of sensitivity to PARP 
inhibitors as does a deleterious BRCA1 mutation. (117.118,119,120,121) One 
hundred micrograms of tumor DNA Methylation-specific PCR will be utilized to 
detect hypermethylation of the areas of interest in the CpG islands of the 
BRCA1 promoter for patients who are confirmed gBRCA 1/2 mutation 
negative.   
d) Germline mutations in non-BRCA Fanconi Anemia/HR pathway genes: All 
study participants will undergo germline BROCA-HR testing for gBRCA status 
determination. This test also detects germline mutations in 37 additional genes 
(involved in the FA/HR pathway, e.g. PALB2, RAD51C, RAD51D). Patients 
identified to have deleterious germline mutations in these additional genes will 
be assigned to the BRCAness group. (122 
 
2.9 
Rationale for Brain Metastases Cohort: 
 
Recent studies illustrate high rates of brain metastases (BM) in TNBC (as high as 50%), 
with survival following CNS recurrence often less than 6 months, and a median PFS of ~ 
2–3 months. (123, 124, 125, 126, 127) The mainstay of treatment of CNS disease in breast 
cancer remains local therapies, including radiation (whole brain radiation treatment 
(WBRT)), stereotactic radiosurgery (SRS), gamma knife (GK)), and/or surgical resection. 
While no systemic therapies are approved for treatment of BM, chemotherapy is frequently 
used in an attempt to control systemic disease, as despite its poor prognosis, TNBC is 
quite sensitive to cytotoxics. In particular, TNBC can respond well to anthracyclines as 
monotherapy or in combination with taxanes, or to taxanes or platinums as monotherapy. 
(128, 129, 130) Despite this sensitivity, the risk of relapse/recurrence remains quite high, 
and treatment of intracranial disease with systemic agents is limited by the ability of drugs 
to achieve sufficient concentration in the CNS. Novel approaches are clearly needed. 
 
In the past two decades, both clinicians and laboratory scientists have increasingly 
recognized that breast cancer is a clinically and biologically heterogeneous disease, well 
beyond the traditional clinical classifications based on hormone and HER2 status. Five 
major and one rare molecular subtype of breast tumors have been identified and validated, 
including basal-like, HER2 enriched, normal breast tissue-like, luminal-like (including 
luminal A and B), and more recently claudin-low. (131, 132) The subtype basal-like breast 
cancer (BBC; ~10-25% of all breast cancer) comprises 50-75% of TNBC, with the 
remaining TNBC falling within the other subtypes. (133) Common features of BBC include 
unique expression of cytokeratins 5, 6 or 17, an aggressive rate of proliferation (likely due 
to deficient RB and p53, very common in this subtype), and association with BRCA1 
mutations. In fact, the majority of BRCA1 mutant patients who develop breast cancer 
develop the basal-like subtype. (89) Paradoxically, this defect can render these cancers 

 
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more sensitive to DNA damaging agents such as doxorubicin and the platinum agents, and 
also increases their dependence on alternative (i.e., non-defective) DNA repair 
mechanisms, such as those mediated via the nuclear enzyme poly(ADP-ribose)-
polymerase (PARP). (134) PARP recognizes DNA damage, and expedites its repair. In-
vitro studies have demonstrated the striking sensitivity of tumor cells deficient in BRCA to 
PARP inhibition. (135) Further, preclinical tumor models exposed to PARP inhibitors 
become sensitized to a variety of DNA-damaging agents, including cisplatin, leading to 
higher rates of cell death. (136)  
 
S1416 is evaluating the efficacy of enhancing the cytotoxic effect of cisplatin with PARP 
inhibition in germline BRCA mutation positive and germline BRCA wild type patients with 
BRCAness phenotype. This strategy may also be effective in TNBC patients with similar 
molecular phenotypes who have developed BM since several PARP inhibitors in clinical 
development are able to cross the blood brain barrier and; platinum agents, such as 
cisplatin and carboplatin have been shown to cross the blood brain barrier, albeit with 
comparable but limited penetration of the CNS in preclinical models. (137,138,139) 
Interestingly, a recent report showed that histone deacetylase inhibitor treatment induced 
BRCAness and synergistic lethality with ABT-888 and cisplatin against human TNBC cells. 
(140) Further, an investigation of carboplatin and ABT-888 in mouse models of TNBC BM, 
both BRCA mutant and WT, demonstrated that both agents reached CNS tumors, as 
evidenced by evaluation of dynamic changes in gene expression and intracranial tumor 
PARP levels. (141) The combination yielded improved OS in BRCA-mutant but not WT 
models of TNBC as compared to controls. Based on these data, DNA damage response 
via GH2AX and apoptosis via CC3 was measured in one BRCA mutant and one BRCA 
wild type model; increased DNA damage and apoptosis in response to carboplatin and 
carboplatin/ABT-888 was observed in the BRCA mutant model only. 
 
Further support for enrolling a cohort of patients with BM in S1416 is based on the 
successful treatment of breast cancer patients with BM with platinum agents in the clinic. 
A recent study of carboplatin in combination with bevacizumab in breast cancer patients 
with BM reported reductions in the volume of CNS disease, including the subgroup with 
TNBC. (142) Importantly, the safety of the combination of ABT-888 with carboplatin has 
been established in breast cancer (I-SPY2). (143) Collectively, preclinical and clinical data 
strongly support the conduct of a clinical trial evaluating platinum-based DNA damaging 
chemotherapy with ABT-888 in patients with TNBC who have BM. Given that 
approximately half of the patients with TNBC will develop CNS metastases, it is important 
to identify novel combinations that successfully treat intracranial as well as extracranial 
disease with the goal of improving survival for patients facing this challenging disease. 
 
 

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2.10 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to 
measure differences of intervention effects.  Males can be enrolled, though only 1-2 are 
expected to be enrolled. The anticipated accrual in the ethnicity/race and sex categories is 
shown in the table below. The numbers below are for the total number of patients. 
 
Enter actual estimates, whole numbers only (percentages, fractions, or decimals 
are not acceptable). 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial 
Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
American Indian/ 
Alaska Native 
1 
0 
0 
0 
1 
Asian 
2 
0 
0 
0 
2 
Native Hawaiian 
or Other Pacific 
Islander 
0 
0 
0 
0 
0 
Black or African 
American 
30 
0 
0 
0 
30 
White 
281 
1 
17 
0 
299 
More Than One 
Race 
1 
0 
0 
0 
1 
Total 
315 
1 
17 
0 
333 
 
 
3.0 
DRUG INFORMATION 
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, cisplatin is commercially available; therefore, Investigator Brochures are not 
applicable to this drug.  Information about commercial drugs is publicly available in the prescribing 
information and other resources. 
 
For this study, ABT-888 and matching placebo are investigational and are being provided under an 
IND held by the National Cancer Institute.  The current version of the Investigator Brochure for the 
agent will be accessible to site and investigators and research staff through the PMB Online Agent 
Ordering Process (OAOP) application 
(http://ctep.cancer.gov/branches/pmb/agent_order_processing.htm). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the maintenance of 
an “active” status and a “current” password.  Questions about IB access may be directed to the 
PMB IB Coordinator via e-mail (ibcoordinator@mail.nih.gov).  
 
NOTE: AbbVie has notified NCI CTEP of their intent to discontinue development of ABT-888 
(veliparib).  As a result, ABT-888 (veliparib) will not be available for treatment of patients after 
December 31, 2024.  Please discuss this with any patients currently receiving ABT-888 (veliparib) 
to make alternate treatment arrangements, if appropriate. 
 
  
3.1 
ABT-888 (Veliparib) (NSC 737664) (CTEP IND #77840) 
 
a. 
DESCRIPTION 
 
Chemical Name: 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide 
 

 
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Other Names: A-861695.0, Veliparib 
 
Classification: Poly (ADP-ribosome) polymerase (PARP) Inhibitor 
 
Molecular Formula: C13H16N4O  
 
Molecular Weight: 244.29 
 
Description: White opaque capsule 
 
b. 
TOXICOLOGY 
 
Comprehensive Adverse Events and Potential Risks List (CAEPR) for ABT-888 
(NSC 737664) 
 
The Comprehensive Adverse Event 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 via CTEP-AERS (except as noted 
below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm 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. 
 
 
Version 2.4, May 13, 20181 
 
 
 Adverse Events with Possible  
 Relationship to ABT-888 (Veliparib) 
 (CTCAE 5.0 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) 

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 Adverse Events with Possible  
 Relationship to ABT-888 (Veliparib) 
 (CTCAE 5.0 Term) 
[n= 2310] 
 
 Specific Protocol 
Exceptions to 
Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<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) 
 
Hypophosphatemia  
Hypophosphatemia 
(Gr 3) 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED 
(INCL CYSTS AND POLYPS) 
 
 
 
Leukemia 
secondary to 
oncology 
chemotherapy 
 
 
 
Myelodysplastic 
syndrome 
 
 
 
Treatment 
related 
secondary 
malignancy 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
 
 
Dysgeusia 
 
Dysgeusia (Gr 2) 
 
Headache 
 
Headache (Gr 3) 
 
 
Seizure 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Rash maculo-papular  
 
VASCULAR DISORDERS 
 
 
 
Thromboemboli
c event2 
 
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. 

 
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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 - Bone marrow hypocellular; 
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); Lung infection; Lymph 
gland infection; Mucosal infection; Sepsis; Shingles; Skin infection; Upper 
respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising; 
Dermatitis radiation; Radiation recall reaction (dermatologic) 
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; Muscle cramp; 
Myalgia; Neck pain; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) -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 
RENAL AND URINARY DISORDERS - Dysuria; Hematuria; Proteinuria  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Cough; 
Dyspnea; Epistaxis; Hypoxia; Nasal congestion; Pharyngolaryngeal pain; Pleural 
effusion; Pneumonitis; Respiratory failure 

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SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; Nail changes; Palmar-plantar erythrodysesthesia syndrome; 
Pruritus; Purpura; Rash acneiform 
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 
 
Clinical Supplies: ABT-888 (NSC 737664/IND 77840) and matching Placebo will 
be provided free of charge by AbbVie Inc. and distributed by the Pharmaceutical 
Management Branch (PMB), Cancer Therapy Evaluation Program (CTEP), 
Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute 
(NCI).  
 
Veliparib 100 mg and 0 mg matching placebo will be supplied as immediate 
release capsules. The veliparib capsule contains veliparib, 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. Lime green with two black bars. 
 
ABT-888 and matching Placebo will be supplied in bottles containing 64 capsules 
with a child-resistant cap and a tamper-evident seal.  
 
Each blinded, patient-specific bottle will be labeled with …  
• 
the protocol number (i.e., “S1416”)  
• 
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.,"S1416-XXX", which represents the 
unique patient identifier assigned at registration)  
• 
the patient initials (i.e., Last initial, First initial, Middle initial [e.g., 
"LFM"])  
• 
the agent identification (i.e., “ABT-888 100 mg or Placebo”)  
• 
a blank line for the pharmacist to enter the patient’s name  
• 
administration instructions (i.e., “Take __ capsules two times daily for 
14 out of 21 days 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., 2014 = 14, 2015 = 15) 

 
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and a day count (e.g., January 1 = 001, December 31 = 365). For example, a bottle 
labeled and shipped on January 1, 2014 would have a Julian date of ‘14001’ and 
a bottle labeled and shipped on December 31, 2014 would have a Julian date of 
‘14365’. 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 14 breaking the blind. The Julian Date – Order number (e.g., 
2014352-0003) from the patient-specific label must be used as the Lot number on 
the NCI DARF.  
 
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 this study. Patient-
specific supplies will be sent to the registering investigator at the time of 
registration/randomization and should arrive within 5 business days. Patients will 
be registered/randomized by the SWOG Statistics and Data Management 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 Statistics and Data 
Management Center will electronically transmit a clinical drug request for that 
patient to the PMB. This request will be entered and transmitted by the SWOG 
Statistics and Data Management 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 Standard FedEx (generally 
two day delivery). Thus, if a patient is registered on Monday, the SWOG Statistics 
and Data Management 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 orders on Friday.  
 
The initial request will be for 6 x 64 count bottles of ABT-888/placebo, a sufficient 
amount to complete the initial 3 cycles (9 weeks) of treatment. After 7 weeks (two 
weeks before needed), sites may reorder an additional 6 x 64 count bottles (3 cycle 
supply) by submitting an agent request 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., "S1416- 
XXX") 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.  
 
Note: Initial supplies will be provided based on sites dispensing 2 full bottles per 
cycle. If a site is required by local practice to dispense an exact quantity for each 
cycle, ABT-888/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 must 
include all of the information from the original patient specific bottle sent from the 
PMB (including the Julian Date.) Expiration will be 30 days from the repackaging 
date when stored at 15°C to 25°C (59°F to 77°F).  
 
Special Ordering Procedures for Patients Transitioning to ABT-888/placebo 
Monotherapy: If the patient is switched from combination therapy to monotherapy 
(ABT-888/placebo 400 mg BID daily for 21 days), a request for additional supplies 

S1416 
 
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to accommodate the new dose and schedule must be ordered through the PMB 
Online Agent Order Processing (OAOP) application. The person ordering the 
supplies through OAOP should answer “Yes” to the question “Is a dose adjustment 
required?” The Dose Adjustment to “ABT-888/placebo 400 mg BIB QD for 21 days” 
can then be selected. This will populate the appropriate quantity to send (3 bottles) 
for the new dose and schedule. 
 
Agent Transfers: Capsules 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) or by calling the 
PMB at 240-276-6575. The patient ID number (e.g., "S1416-XXX"') 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., 
"NCI S1416"). 
 
Agent Returns: Only undispensed clinical supplies should be returned to the 
PMB. When it is necessary to return study drug (e.g., sealed or undispensed partial 
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 15 the CTEP home page 
(http://ctep.cancer.gov) or by calling the PMB at 240-276-6575. The patient ID 
number (e.g., "S1416-XXX") and the patient initials (e.g., "LFM") should be entered 
in the "Lot Number" field. Opened bottles (returned by the patient) with remaining 
capsules should be documented on the patient-specific Oral NCI Investigational 
Agent Accountability Record (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 Oral NCI Investigational Agent 
Accountability Record available on the CTEP home page (http://ctep.cancer.gov). 
A separate Oral NCI Investigational Agent Accountability Record must be 
maintained for each patient ID number (e.g., "S1416-XXX") on this protocol. 
NOTE: The Julian Date – Order number combination found in the upper right-hand 
portion of the patient-specific label must be used as the Lot Number. This number 
will be used in the event of a stock recovery or recall of the investigational agent. 
 
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 18.2).  This 
service is available 24 hours a day, 365 days a year.  The WPC will require the 
protocol number (i.e., “S1416”), the patient ID number (e.g., “S1416-XXX”), 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. 
NOTE: The remaining patient on treatment has been unblinded to reveal their 
usage and dosage of ABT-888 (veliparib). The unblinding was prompted by the 
pharmaceutical collaborator’s (AbbVie) notification of the discontinuation of the 
ABT-888 (veliparib) development program. See Section 7.4c for additional 
guidance. 
 
 

 
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3.2 
Cisplatin (CDDP) (Platinol®, Platinol-AQ) (NSC-119875) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action:  
 
Cisplatin (cis-diamminedichloroplatinum) is a heavy metal complex containing a 
central platinum atom surrounded by two chloride atoms and two ammonia 
molecules in the cis position. It is water soluble and acts as a bifunctional alkylating 
agent with cell cycle nonspecific characteristics.  The intra-strand cross-links, in 
particular with guanine and cytosine, change DNA conformation and inhibit DNA 
synthesis leading to the cytotoxic and anti-tumor effects of cisplatin. Although 
cisplatin seems to act as an alkylating agent, there are data to indicate that its 
mode and sites of action are different from those of nitrogen mustard and the 
standard alkylating agents and that cisplatin does not exhibit cross-resistance with 
other alkylating agents or nitrosoureas. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Following rapid IV injection of cisplatin over up to one hour, 
peak plasma drug and platinum concentrations occur immediately.  When 
cisplatin is administered by IV infusion over 6 or 24 hours, plasma 
concentrations of total platinum increase gradually during the infusion and 
peak immediately following the end of the infusion.  
 
2. 
Distribution: Following intravenous dosing, cisplatin distributes rapidly into 
tissues, with highest concentrations in the liver, prostate and kidney.  
Plasma levels of cisplatin decay in a biphasic mode with an initial half-life 
of 25 to 49 minutes, and a secondary phase ranging from 58 to 73 hours.  
This prolonged phase is due to protein binding, which exceeds 90%.  
Cisplatin penetrates poorly into the CNS. 
 
3. 
Metabolism: Cisplatin is non-enzymatically transformed to one or more 
metabolites that are extensively protein bound and have minimal cytotoxic 
activity.  The non-protein bound (unchanged) fraction is cytotoxic. 
 
4. 
Elimination: Urinary excretion is incomplete.  Following bolus injection or 
infusion over a dose range of 40-140 mg/m2 varying in length from 1-24 
hours, from 10 to about 40% of the administered platinum is excreted in 
the urine in 24 hours.  Renal clearance of free platinum exceeds the 
glomerular filtration rate, indicating that cisplatin or other platinum-
containing molecules are actively secreted by the kidneys.  Renal 
clearance of free platinum is nonlinear and variable, and is dependent on 
dose, urine flow rate, and individual variability in the extent of active 
secretion and possible tubular reabsorption. 
 
 

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c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of cisplatin:  
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in > 20% of subjects treated with cisplatin 
include:  nausea, vomiting, myelosuppression, anemia, leukopenia, 
thrombocytopenia, nephrotoxicity (acute renal failure and chronic renal 
insufficiency), and ototoxicity. 
 
Adverse effects reported in 4% to 20% of subjects include: alopecia, 
dysgeusia, diarrhea, hypersensitivity reaction, confusion, vestibular 
dysfunction, peripheral neuropathy, and blurred vision or altered color 
perception. 
 
Serious adverse effects reported in ≤ 3% of subjects include: secondary 
malignancy, and seizure. 
 
2. 
Pregnancy and Lactation: Category D. Cisplatin can cause fetal harm 
when administered to a pregnant woman. In mice, cisplatin is teratogenic 
and embryotoxic.  This drug has been found to be excreted in human milk 
and because of the potential for serious adverse reactions in nursing 
infants, patients receiving cisplatin should not breast feed. 
 
3. 
Drug 
Interactions: 
During 
cisplatin 
therapy, 
plasma 
levels 
of 
anticonvulsant agents (valproic acid, phenytoin, and carbamazepine) may 
become sub-therapeutic and should be monitored. Concomitant use with 
aminoglycosides and amphotericin B increase risk of nephrotoxicity. 
Concomitant use with loop diuretics and aminoglycosides increase risk of 
ototoxicity. Concurrent use with lithium may result in reduced lithium 
plasma concentration. Concurrent use with warfarin may result in 
increased INR. Concurrent use with thioctic acid may result in decreased 
cisplatin effectiveness and should be avoided.  
 
Due to potential drug interactions, a complete patient medication list, 
including cisplatin, should be screened prior to initiation of and during 
treatment with cisplatin. See Section 8.0 Toxicities to be Monitored and 
Dosage Modifications. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan  
 
e. 
HOW SUPPLIED  
 
Cisplatin is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert for the most comprehensive and up to date 
information. 
 
 
 

 
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4.0 
STAGING CRITERIA 
 
 
Note:  All staging will be based on the American Joint Committee on Cancer 2010 Staging System, 
7th Edition. 
 
M1 
Distant detectable metastases as determined by classical clinical and radiographic means 
and/or histologically proven larger than 0.2 mm. 
 
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 Onstudy Form and submit via Medidata Rave® 
(see Section 14.0).  Any potential eligibility issues should be addressed to the SWOG Statistics and Data 
Management Center in Seattle at 206/652-2267 or breastquestion@crab.org prior to registration. NCI policy 
does not allow for waiver of any eligibility criterion  
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
 
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 3 weeks later would be considered Day 21.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 21, 42 or 56 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
5.1 
Disease Related Criteria 
 
a. 
Patients must have metastatic and/or recurrent (distant or locoregionally 
recurrent*) breast cancer and be HER2 non-over expressing per 2013 ASCO-CAP 
HER testing guidelines (0 or 1+ by IHC; and/or HER2 ratio < 2.0 and HER2 copy 
number < 4 signals/cell by ISH). 
 
* 
Local Regional Recurrence 
• 
In the breast (after preserving therapy) 
• 
In the chest wall (after mastectomy) 
• 
In the ipsilateral/parasternal/infra-or supraclavicular lymph nodes 
• 
In the skin of the chest wall (not breast) 
• 
In the reconstructed breast 
 
b. 
Patients must also meet at least one of the following criteria: 
 
1)  
Triple Negative: Histologically confirmed primary and/or metastatic site 
that is ER-negative (≤ 1%), PR-negative (≤ 1%), and HER2–negative. 
 
2)  
BRCA mutation: Previously confirmed deleterious BRCA1 or BRCA2 
germline mutation or suspected deleterious BRCA1 or BRCA2 germline 
mutation if the classification being used is the 5-tier classification. 
Documentation of germline test results are required. (Note that submission 
of specimens as outlined in Section 5.1e is still required.) 
 
c. 
Patients must have measurable or non-measurable disease (see Section 10.1). 
Patients must have a chest/abdominal/pelvis CT scan (or PET/CT of diagnostic 
quality, conventional or spiral) prior to registration. If the patient is unable to 
undergo CT with IV contrast due to allergy or renal insufficiency, a non-contrast 
CT may be performed. All scans needed for assessment of measurable disease 

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must be performed within 28 days prior to registration. 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. 
 
d. 
Patients must be women or men ≥ 18 years of age. 
 
e. 
Patients must have adequate tissue available and must agree to have specimens 
submitted for germline BRCA DNA sequencing and other correlative studies per 
Sections 15.1, 15.2, 15.3 and 15.4. 
 
NOTE: Blood for BRCA mutation testing is to be collected and submitted after 
registration but before treatment. 
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Patients must have had ≤ 1 prior cytotoxic regimen for metastatic disease (unless 
enrolling in the Progressive Brain Metastases Cohort; see Section 5.5). Note that 
endocrine and immunotherapies do not count as cytotoxic regimens. 
 
b. 
Patients must have completed any prior radiation therapy and hormonal therapy 
at least 14 days prior to registration.  
 
c. 
Patients must not have received prior cisplatin or PARP inhibitors. Prior carboplatin 
in the adjuvant/neoadjuvant setting is allowed, if completed more than 12 months 
prior to study entry. 
 
d. 
Patients must not have received any chemotherapy within 14 days prior to 
registration. 
 
e. 
Patients must not have received any immunotherapy, biologic or any 
investigational drug within 28 days prior to registration. Patients must not have 
received bevacizumab within 42 days prior to registration. 
 
f. 
Patients may receive bisphosphonates or denosumab concurrently with study 
treatment.  If started prior to registration, it must be started at least 7 days prior to 
registration.  See Section 7.2 for information regarding starting bisphosphonates 
or denosumab after registration. 
 
g. 
Patients must have recovered to ≤ Grade 2 following a significant adverse event 
or toxicity attributed to previous anti-cancer treatment except neurotoxicity which 
must be ≤ Grade 1. 
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have a performance status of 0-2 by Zubrod criteria (see Section 
10.4). 
 
b. 
Patients must have adequate bone marrow function, as defined by Absolute 
Neutrophil Count (ANC) of >/= 1,500/mcL, hemoglobin >/= 10 g/dL and a platelet 
count >/= 100,000/ mcL within 21 days prior to registration.  Patients must not have 
had a blood transfusion within 28 days prior to registration. 
 
c. 
Patients must have adequate hepatic function obtained within 21 days prior to 
registration and documented by all of the following: 
 
• 
Bilirubin ≤ 1.5 mg/dL (or ≤ 3.0 mg/dL if due to Gilbert's Syndrome or if liver 
metastases are present) 

 
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• 
ALT and AST ≤ 2.5 x Institutional Upper Limit of Normal (IULN) (or ≤ 5 x 
IULN if liver metastases are present) 
 
d. 
Patients must have adequate renal function with serum creatinine level ≤ IULN 
within 21 days prior to registration. 
 
e. 
Patients must have serum chemistries (including potassium and magnesium) done 
within 21 days prior to registration to obtain baseline values. 
 
f. 
Patients must not have a clinically relevant hearing impairment ≥ Grade 2. 
 
g. 
Patients must be able to swallow whole capsules. 
 
h. 
Patients with a history of uncontrolled seizure disorder; including focal or 
generalized seizure may not have had a seizure within one year prior to 
registration. 
 
i. 
Patients with known brain metastases must either meet the additional criteria in 
Section 5.5 and enroll as part of the Progressive Brain Metastases Cohort, or have 
clinically controlled neurologic symptoms, defined as surgical excision and/or 
radiation therapy followed by 14 days of stable neurologic function prior to 
registration. Patients with incidentally discovered or asymptomatic brain 
metastasis(es) must receive surgical excision and/or radiation therapy prior to 
registration. Patients with progressive brain metastases following prior treatment 
are not eligible for the Standard Cohort, but may be considered for the Progressive 
Brain Metastases Cohort (see Section 5.5). 
 
j. 
Patients must not have treatment-related AML (t-AML)/MDS or features 
suggestive of AML/MDS. 
 
k. 
Patients must not have had prior allogeneic bone marrow transplant or double 
umbilical cord blood transplantation. 
 
l. 
Patients must not have any incidence of or uncontrolled medical illness (e.g. active 
cardiac symptoms, active systemic infection, etc.) that would limit the patient’s 
ability to participate in the protocol. 
 
m. 
Patients must not have baseline peripheral neuropathy that exceeds Grade 1. 
 
n. 
Patients must have a complete history and physical examination within 28 days 
prior to registration. 
 
o. 
Patients of childbearing potential must not be pregnant (negative pregnancy test) 
or nursing due to the possibility of harm to a fetus or nursing infant from this 
treatment regimen. Men and women of reproductive potential must have agreed 
to use an effective contraceptive method for 6 months after completion of study 
treatment. 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. 
 

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p. 
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. 
 
5.4 
Regulatory Criteria 
 
a. 
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. 
 
b. 
As a part of the OPEN registration process (see Section 13.3 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. 
 
5.5 
Progressive Brain Metastases Cohort 
 
S1416 is one study with two cohorts.  Patients who have progressive brain metastases 
after surgical excision and/or intracranial radiation will be in the Progressive Brain 
Metastases Cohort and will require a baseline MRI. Patients with previously treated brain 
metastases, stable disease and stable neurologic function for 14 days prior to trial 
registration will be in the Standard Cohort and may obtain MRI of the brain at the 
physician’s discretion. Randomization and treatment is the same for both cohorts. 
 
In addition to all of the previous eligibility criteria, patients with progressive brain 
metastases who do not satisfy the conditions in Section 5.3i to enroll in the Standard Cohort 
(neurologic stability for 14 days following surgery and/or radiation therapy) must also meet 
the following criteria to enroll as part of the Progressive Brain Metastases Cohort: 
 
a. 
Patients with progressive brain metastases must have a baseline brain MRI within 
28 days prior to registration.  Brain metastases must be progressive and ≥ 10 mm 
in longest dimension on radiographic imaging AFTER prior intracranial radiation 
(IR) therapy (i.e., WBRT, SRS, GK or local equivalent). Patients must not have 
evidence of diffuse leptomeningeal disease on brain MRI or by previously 
documented CSF cytology. Discrete dural metastases are permitted.  There must 
be no evidence of hemorrhage or impending herniation on baseline brain imaging.  
Patients with contraindication to gadolinium-enhanced MRI imaging are not 
eligible. 
 
b. 
Patients must be on a stable or decreasing dose of steroids for ≥ 7 days prior to 
registration. 
 
c. 
If patient has had an open brain biopsy, at least 28 days must have elapsed 
between biopsy and registration. 
 
d. 
Patients enrolling in the Progressive Brain Metastases Cohort can have received 
up to 3 prior lines of cytotoxic chemotherapy for metastatic disease.  Note that for 
enrollment in the standard cohort, patients must have had ≤ 1 prior cytotoxic 
regimen for metastatic disease. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Patients will be stratified at registration by cohort: Progressive Brain Metastases Cohort vs 
Standard (no progressive brain metastases) Cohort. 
 

 
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Patient randomization will be stratified by number of prior cytotoxic regimens for metastatic disease: 
0 prior regimens vs. ≥1 prior regimens.   
 
Additionally, patients within the brain metastases cohort will be stratified by Modified Breast Graded 
Prognostic Assessment Index (modified breast-GPA) (144): ≤ 1 vs >1. (See Appendix 18.6) 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Eve Rodler at 916/734-3772 
(S1416question@swog.org) 
or 
Dr. 
Priyanka 
Sharma 
at 
913/588-6029 
(S1416question@swog.org).  For dosing principles or questions, please consult the SWOG Policy 
#38 
"Dosing 
Principles 
for 
Patients 
on 
Clinical 
Trials" 
at 
https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf.  
 
7.1 
BRCA1/2 testing 
 
All patients will have BRCA1/2 testing completed as outlined in Section 15.3 and Appendix 
18.5. 
 
Results of BRCA1, BRCA2 and other ten actionable genes in the BROCA-HR panel (ATM, 
BARD1, BRIP1, CHEK2, NBN, PALB2, PTEN, RAD51C, RAD51D, TP53) will be provided 
to the treating physician within 4-8 weeks. Only deleterious mutations will be reported, and 
variants of uncertain significance will not be reported. Mutations in other FA-HR pathway 
genes included in this BROCA-HR panel which are not known to have clear evidence of 
increased cancer risk will not be provided to the treating physicians since this part of the 
test is “research use” only and not considered to be of clinical significance. 
 
The genetic testing results for all trial patients will be provided back to the enrolling site via 
Rave® as a report uploaded in the Genetic Testing Results folder and will include both 
“positive” and “negative” results for 12 genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, 
CHEK2, NBN, PALB2, PTEN, RAD51C, RAD51D, TP53). As stated above a positive result 
will only include “deleterious mutation”. Mutations of uncertain significance will not be 
reported. 
 
Providers will also have access to phone genetic counseling and advice regarding 
management guidelines for patients with deleterious mutations. This may specifically be 
needed for mutations in non BRCA genes. If a site/provider wishes to make use of this 
resource please contact Dr. Swisher at swishere@uw.edu.  Do not contact Dr. Swisher’s 
lab for genetic counseling if the patient has not consented. For further questions you can 
also contact Dr. Sharma at S1416question@swog.org.  Please note that genetic 
counseling services are available to sites, not individual patients. 
 

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7.2 
Treatment 
 
Patients will be randomized to one of the following arms: 
 
•  Arm 1: cisplatin + placebo (ABT-888) 
•  Arm 2: cisplatin + ABT-888 
 
Agent 
Dose 
Route 
Day 
Schedule* 
Cisplatin 
75 mg/m2 
IV (over 1 hour) a 
Day 1 
 
ABT-888/ 
300 mg per dose 
PO 
Days 1-14 
Twice daily 
Placebo 
(600 mg per day) 
 
 
 
*  Note:  One cycle = 21 days 
a Sites may use institutional guidelines for duration of cisplatin administration. Appropriate 
pre- and post-hydration for the cisplatin chemotherapy and electrolyte replacement 
including at least 1 liter of pre-hydration solution are recommended according to 
institutional guidelines.  Furosemide, mannitol, and electrolyte supplementation may be 
included according to local practices as well. With the inclusion of high-dose cisplatin, 
anti-emetic prophylaxis should also be administered according to institutional guidelines 
and must follow NCCN guidelines including a corticosteroid, 5-HT3, and NK1 receptor 
antagonist. 
 
NOTE:  Patients may begin bisphosphonates, denosumab, or myeloid growth factor 
support after completion of Cycle 1 of protocol therapy. 
 
Patients with stable disease/PR/CR may continue both drugs until disease progression. 
However, if after 4 cycles of combination therapy a patient experiences an unacceptable 
toxicity, cisplatin can be discontinued at the discretion of the treating physician and patients 
may continue ABT-888/placebo until progression. If patients have intolerable toxicity to 
cisplatin after three cycles, despite dose reductions, then they should discontinue therapy 
and be removed from protocol treatment. If monotherapy is selected after at least 4 cycles 
of cisplatin, the dose will be 400 mg BID of ABT-888/placebo to be taken continuously for 
21 days of each 21-day cycle.  An optional “run-in” period of at least two weeks will be 
allowed during which the patient can start with an ABT-888/placebo monotherapy dose of 
300 mg po BID and if tolerated, the patient may transition to the higher 400 mg BID dose 
to be taken continuously for 21 days of each 21-day cycle. 
 
For patients who continue on ABT-888/placebo, the investigator should notify PMB so that 
the ABT-888/placebo supplies can be adjusted to accommodate the extended dosing. 
 
In order for patients to receive the potential benefits of cisplatin plus ABT-888/placebo 
followed by the option of ABT-888/placebo monotherapy and not exclude those patients 
who may have difficulty tolerating 6 cycles of cisplatin, 4 cycles are required before a switch 
to monotherapy.  Rationale for at least 4 cycles of cisplatin:  Patients may enter this trial 
with baseline peripheral neuropathy Grade 1 due to prior taxane treatment in the (neo) 
adjuvant or metastatic setting which could progress to Grade 2 or greater with multiple 
cycles of cisplatin. We would like patients to receive the potential benefits of cisplatin plus 
ABT-888/placebo followed by the option of ABT-888/placebo monotherapy and not exclude 
those patients who may have difficulty tolerating 6 cycles of cisplatin.  Therefore, we require 
4 cycles before a switch to monotherapy (6 should be encouraged), and if patients cannot 
tolerate at least 3 cycles despite dose reductions, then the patient should be removed from 
protocol treatment due to toxicity. 
 
 
 
NOTE: The remaining patient on treatment has been unblinded to reveal their usage and 
dosage of ABT-888 (veliparib). The unblinding was prompted by the pharmaceutical 

 
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collaborator’s (AbbVie) notification of the discontinuation of the ABT-888 (veliparib) 
development program. See Section 7.4c for additional guidance. 
 
 
7.3 
Drug Compliance Documentation 
 
Drug compliance will be recorded by patients on the ABT-888/Placebo 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.  
 
7.4 
Unblinding Procedures 
 
Patients who have progression of disease as defined in Section 10.2 have the option to be 
unblinded in planned fashion, as described in this section. Any request for unblinding other 
than for progression of disease will follow the procedures for emergency unblinding as 
outlined in Appendix 18.2. There will be no crossover to ABT-888 for patients who were on 
the placebo arm. 
 
a. 
Criteria for Planned Unblinding: 
 
Planned unblinding procedure applies to patients who experience progression as 
defined in Section 10.2. It is vital to properly apply the protocol specified definition 
of progression. If any questions arise with regard to progression for a patient, 
please contact the Breast Data Coordinator in Seattle by telephone at 206/652-
2267, 6:30 a.m. to 4:00 p.m. Pacific Time, Monday through Friday, excluding 
holidays, or the S1416 Study Chair, Dr. Rodler or in her absence, Dr. Sharma. 
 
Prior to planned unblinding, the tumor assessment forms must be submitted and 
processed by the S1416 Study Chair Dr. Rodler (or Dr. Sharma in her absence). 
To request a planned unblinding, submit the Baseline Tumor Assessment Form 
and all appropriate Follow Up Tumor Assessment forms for the patient in Rave, 
then email breastquestion@crab.org with the subject line “S1416 Patient 
#XXXXXX, Requesting Planned Unblinding” to notify the S1416 Data Coordinator 
who will review the documentation for completeness in Rave before contacting the 
Study Chairs. Please allow a minimum of 2 working days for review of forms. Dr. 
Rodler (or Sharma) will provide a written confirmation to the site that the patient 
has an adequately documented progression. This documentation must be 
uploaded to the Planned Unblinding Form in Rave®. 
 
b. 
Planned Unblinding Procedures 
 
Patients may be unblinded at time of disease progression using the Planned 
Unblinding Form in Rave®.  The Planned Unblinding Form is available in the “Add 
Event” dropdown box on the “Subject” tab in Rave®.  Complete both questions 
and click the “Save” button to see the unblinded treatment assignment displayed 
on the form. 
 
c. 
Discontinuation of Blinded Supplies for ABT-888 (Veliparib) (NSC # 737664) 
 
Due to the discontinuation of the ABT-888 (veliparib) development program, the 
blinded supplies of ABT-888 (veliparib) expired in October 2023 and additional 
blinded treatment is not available. Upon notification of the plan to discontinue the 
ABT-888 (veliparib) development program, any investigators with patients 
currently on treatment with ABT-888 or placebo must unblind their patients to 
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is found to be receiving ABT-888 (veliparib), the treating investigator should 
discuss alternative treatment options, as well as a suitable transition date prior to 
the expiration of the blinded supplies. Treating investigators may request that the 
patient be allowed to continue open-label ABT- 888 (veliparib), noting the agent 
will no longer be available after December 31, 2024. 
 
Sites are expected to continue the protocol-specified data submission 
requirements in Section 14.0 for all patients.  
 
7.5 
Full CDUS Reporting Requirement 
 
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 14.4c, the S1416 Treatment Form, and 
the S1416 Adverse Event Form).  A cycle is defined as 21 days. 
 
7.6 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease or symptomatic deterioration (as defined in Section 10.2). 
 
b. 
Unacceptable toxicity and discontinuation of ABT-888/placebo. (NOTE:  Patients 
who continue on ABT-888/placebo monotherapy after discontinuation of cisplatin 
due to toxicity are still on protocol treatment.) 
 
c. 
Treatment delay > 4 weeks for events that are clearly not related to the study drug 
treatment (i.e. planned surgical procedures or acute viral illnesses).  Treatment 
delay > 3 weeks for any other reason. 
 
d. 
Start of alternative anti-cancer agent during the study period.  Use of palliative 
radiotherapy and surgery related to the goal of rendering or maintaining a complete 
remission is acceptable. 
 
e. 
Patient becomes pregnant or begins breastfeeding during the treatment portion of 
the study. 
 
f. 
The patient may withdraw from the study at any time for any reason. 
 
7.7 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.8 
Follow-Up Period 
 
 
All patients will be followed until death or 5 years after registration, whichever occurs first. 
 
 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
Two different versions of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be used on this study. 
 
a. 
Serious Adverse Event (SAE) reporting 
 
The CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 
will be utilized for SAE reporting only. The CTCAE Version 5.0 can be 

 
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downloaded from the CTEP home page (https://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0. 
 
b. 
Routine toxicity reporting 
 
This study will utilize the CTCAE Version 4.0 for routine toxicity reporting.  A copy 
of the CTCAE Version 4.0 can be downloaded from the CTEP home page 
(https://ctep.cancer.gov).  All appropriate treatment areas should have access to a 
copy of the CTCAE Version 4.0. 
 
8.2 
General Considerations 
 
c. 
Missed doses are to be omitted rather than made up. If the patient misses a 
scheduled dose of ABT-888/placebo and less than 6 hours have passed since the 
scheduled dosing time, the dose should be taken immediately.  Otherwise, the 
dose should be considered missed.  If the patient vomits, the dose should be 
omitted. 
 
d. 
If multiple toxicities are experienced, dose modifications will be based on the 
toxicity requiring the largest dose reduction. 
 
e. 
Reductions are based on the dose given in the preceding reporting period and are 
based on toxicities observed since the prior toxicity evaluation. 
 
f. 
Once dose is reduced on combined therapy, patients will continue at new dose. 
No dose re-escalations are allowed while on combined therapy. 
 
g. 
If a patient is on monotherapy he/she may have at least a trial 2 week period (“run-
in”) of taking ABT-888/placebo 300 mg BID, prior to taking the 400 mg BID 
monotherapy dose.  If the monotherapy dose is reduced, patients will continue at 
new dose.  No dose re-escalations are allowed. 
 
h. 
The dose modifications are for events that are possibly, probably or definitely 
related to the study drug.  
 
i. 
Gastrointestinal toxicities, predominantly nausea and vomiting, have been 
observed with ABT-888 as single-agent therapy and most frequently at higher 
doses (300-400 mg BID). These toxicities most commonly occurred within the first 
few days or weeks of ABT-888 treatment and were most often Grade 2 or lesser 
severity.  However 5% of subjects experienced Grade 3 nausea during the first 4 
weeks of ABT-888 treatment at 400 mg BID.  To optimize dose intensity and 
maintain patient quality of life, early initiation of scheduled anti-emetic therapy 
(5HT-3 antagonists, metoclopramide, prochlorperazine) and/or lorazepam should 
be considered.  In addition, management should include counseling regarding 
these toxicities and may include interruption of dosing, dose modification or ABT-
888 discontinuation.  In addition to the use of anti-emetic medications, 
investigators should rely on standard clinical practice for nausea management. 
 
 

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8.3 
Dose Levels for ABT-888/placebo (as combined therapy) 
 
Dose Levels 
Dose 
 
 
Full 
3 capsules BID (100 mg x 3 for a total dose of 300 mg/dose – 
600 mg/day) 
 
-1 Level 
2 capsules BID (100 mg x 2 for a total dose of 200 mg/dose – 
400 mg/day) 
 
-2 Level 
1 capsule BID (100 mg/dose – 200 mg/day) 
 
-3 Level 
Discontinue ABT-888 
 
 
8.4 
Dose Levels for ABT-888/placebo (as monotherapy) 
 
Dose Levels 
Dose 
 
 
Full 
4 capsules BID (100 mg x 4 for a total dose of 400 mg/dose – 
800 mg/day) 
 
-1 Level 
3 capsules BID (100 mg x 3 for a total dose of 300 mg/dose – 
600 mg/day) 
 
-2 Level 
2 capsules BID (100 mg x 2 for a total dose of 200 mg/dose – 
400 mg/day) 
 
-3 Level 
Discontinue ABT-888 
 
 
8.5 
Dose Levels for Cisplatin 
 
Dose Levels 
Dose 
 
 
Full 
75 mg/m2 
 
-1 Level 
60 mg/m2 
 
-2 Level 
50 mg/m2 
 
-3 Level 
Discontinue cisplatin 
 
 
8.6 
Dose Modifications for ABT-888/Placebo  
 
The dose levels and the general approach to dose modification of ABT-888 therapy is 
shown in Sections 8.3 and 8.4. Specific dose modification information for some AEs are 
provided in other sections.  AEs should be treated with the appropriate maximum 
supportive care, and dose reductions should be clearly documented in the electronic case 
report form (eCRF). 
 
The time the study drug is held should not exceed 3 weeks.  Once the dose of the study 
drug has been reduced, no dose re-escalation is permitted. 
 
AEs requiring ABT-888 to be discontinued: 
• 
Bone marrow findings consistent with AML/MDS  
• 
Severe persistent anemia 
 

 
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Patients should not be allowed to remain in the study if they are taking ABT-888 as 
monotherapy and one of the toxicities above occurs.   
 
Hematologic toxicity 
 
Management of neutropenia and thrombocytopenia 
 
Neutropenia and thrombocytopenia are recognized common adverse drug reactions 
reported for ABT-888.  Treatment should be managed according to the following table: 
 
CTCAE Grade 
Definition 
ABT-888 Dose 
1-2> 
ANC > 1.0 G/L or 
Platelet count  
> 50 G/L 
Investigator judgement to continue treatment 
or allow dose interruption; dose interruptions 
should be for a maximum of 3 weeks; 
appropriate supportive treatment and causality 
investigation. 
3-4 
ANC <1.0 G/L or 
Platelet count  
< 50 G/L 
Dose interruption until recovered to CTCAE 
Grade ≤1 for a maximum of 3 weeks.  Upon 
recovery, ABT-888 dose should be reduced by 
one dose level.  If repeat CTCAE Grade 3-4 
occurrence, further dose reduce one ABT-888 
dose level. 
ANC = absolute neutrophil count; CTCAE = Common Terminology Criteria for Adverse 
Events 
Use of hematopoietic agents 
 
Use erythropoietin-stimulating agents per standard of care National Comprehensive 
Cancer Network (NCCN) and/or institutional guidelines, iron supplements, and/or 
transfusions as clinically indicated for management of anemia.   Prescribing information 
for the erythropoiesis stimulating agents (including Aranesp, Epogen and Procrit) highlight 
that there is a potential risk of shortening the time to tumor progression or disease-free 
survival.   Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is not 
recommended.  Aranesp, Epogen and Procrit may not alleviate fatigue or increase energy, 
and should not be used in patients with uncontrolled hypertension.  The package inserts 
for these agents should be consulted. 
 
If a patient develops febrile neutropenia, ABT-888 should be stopped and appropriate 
management including G-CSF should be given according to local hospital 
guidelines.   Please note that G-CSF should not be used within at least 24 hours of the 
last dose of ABT-888 unless absolutely necessary. Thus, G-CSF may be started Cycle 
2, Day 15. 
 
Platelet transfusions, if indicated, should be done according to local hospital guidelines. 
 
Dose modifications for hematologic toxicity 
 
Patients who have ABT-888/placebo held for hematologic toxicities should have blood 
counts and differentials checked at least weekly until recovery; these data should be 
recorded in eCRF as extra laboratory examinations.   If counts do not improve to CTCAE 
Grade 1 or better despite drug cessation for 3 weeks, patients should be referred to a 
hematological oncologist for further assessment.   A bone marrow analysis should be 
considered. 
 

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For AEs that are unrelated to the study drug, study drug may be withheld for up to 3 weeks 
at the discretion of the treating Investigator. 
 
If the patient is receiving combination cisplatin plus ABT-888/placebo, then both drugs 
must be started at the same time for a new cycle to commence, when hematologic 
toxicities have improved to Grade 1 or better. 
 
Management of anemia 
 
Anemia is a common adverse drug reaction related to ABT-888.   Management of anemia 
is in accordance with the following table: 
 
CTCAE Grade 
Definition 
ABT-888 Dose 
2 
Hb <10 but ≥ 8 
g/dL 
Give appropriate supportive treatment and 
investigate causality.  Investigator judgement 
to continue ABT-888 or interrupt dose for a 
maximum of 3 weeks.  If repeat Hb < 10 but ≥ 
8 g/dL, dose interrupt until Hb ≥ 10 g/dL for 
maximum of 3 weeks and upon recovery dose 
reduce by one dose level as a first step and 
then reduce by a second dose level as a 
second step upon recurrence of Grade 2 AE. 
 
3 
 
Hb <8  g/dL 
 
Give appropriate supportive treatment and 
investigate causality.  Interrupt ABT-888 until 
improved to Hb ≥ 10 g/dL.  Upon recovery 
dose reduce ABT-888 by one dose level. If 
repeat Hgb < 8 g/dL, after one dose reduction, 
then discontinue ABT-888/placebo. 
. 
BID = twice daily; Hb = hemoglobin 
 
Common treatable causes of anemia (e.g., iron, vitamin B12 or folate deficiencies and 
hypothyroidism) should be investigated and appropriately managed.  In some cases 
management of anemia may require blood transfusions.  Any subsequently required dose 
interruptions related to development of anemia, or coexistent with newly developed 
neutropenia, and/or thrombocytopenia, will require ABT-888 dose reductions by one dose 
level as a first step and then reduce by a second dose level as a second step upon 
recurrence of Grade 2 AE. 
 
If Hb drops to < 8 g/dL despite the dose reduction or more than one blood transfusion is 
required to recover Hb levels with no alternative explanation for the anemia, ABT-888 
should be permanently discontinued. 
 

 
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Management of prolonged hematological toxicities while on study treatment 
 
If a patient develops prolonged hematological toxicity such as: 
 
• 
≥ 2 week interruption/delay in velaparib due to CTCAE Grade ≥ 3 anemia (Hb <8 
g/dL) and/or development of blood transfusion dependence 
 
• 
≥ 2 week interruption/delay in ABT-888 due to CTCAE Grade ≥3 neutropenia (ANC 
<1 x 109/L) 
 
• 
≥ 2 week interruption/delay in ABT-888 due to CTCAE Grade ≥ 3 
thrombocytopenia and/or development of platelet transfusion dependence 
(Platelets <50 x 109/L) 
 
Check weekly differential blood counts including reticulocytes and peripheral blood 
smear.   If any blood parameters remain clinically abnormal after 3 weeks of dose 
interruption, the patient should be referred to a hematological oncologist for further 
investigations.   Bone marrow for evaluation and cytogenetics should be considered at this 
stage according to standard hematological oncology practice.   ABT-888 should be 
discontinued if blood counts do not recover to CTCAE Grade ≤1 within 3 weeks of dose 
interruption. 
 
Management of MDS/AML 
 
Patients who develop MDS/AML on treatment should discontinue ABT-888 treatment and 
be managed appropriately. 
 
Management of seizures 
 
Any event of seizure, regardless of grade or attribution, requires interruption of ABT-
888/placebo and discussion with the Study Chair regarding the decision to resume 
treatment. 
 
Management of other non-hematological toxicities 
 
If ≥ Grade 3 non-hematological toxicity occurs, then interrupt ABT-888/placebo until 
recovery to Grade ≤ 1. Then resume ABT-888/placebo at same dose. If event returns to 
Grade ≥ 3, then interrupt ABT-888/placebo until recovery to Grade ≤ 1. Then reintroduce 
ABT-888/placebo at one lower dose level.  If the event returns to Grade ≥ 3 then 
discontinue the ABT-888/placebo. 
 
 
 

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8.7 
Dose Modifications for Cisplatin 
 
Hematological 
toxicity 
Actions 
 
Grade 2 
Thrombocytopenia 
 
 
 
 
 
Grade > 3 
Thrombocytopenia 
 
 
Hold cisplatin until recovery to Grade ≤ 1. Then resume cisplatin 
at same dose. If thrombocytopenia again returns to Grade 2, 
interrupt cisplatin until recovery to Grade ≤ 1. Then reintroduce 
cisplatin at one lower dose level. One further dose reduction is 
allowed for Grade 2 thrombocytopenia.  If the event returns to 
Grade 2 then discontinue the cisplatin. 
 
Hold cisplatin until recovery to Grade ≤ 1. Then resume cisplatin 
at same dose level. If thrombocytopenia again returns to Grade 
≥ 3, interrupt cisplatin until recovery to Grade ≤ 1. Then 
reintroduce cisplatin at one lower dose level. One further dose 
reduction is allowed for Grade > 3 thrombocytopenia. If the 
event returns to Grade ≥ 3 then discontinue the cisplatin. 
 
Grade 3 
Neutropenia  
 
 
 
 
 
Grade 4 
Neutropenia 
 
 
 
 
Grade ≥ 3 Febrile 
Neutropenia 
 
 
Interrupt cisplatin until recovery to Grade ≤ 1. Then resume 
cisplatin at same dose level.  If ANC again returns to Grade 3, 
hold cisplatin until recovery to Grade ≤ 1 and then resume 
cisplatin at one lower dose level. One further dose reduction is 
allowed for Grade 3 neutropenia. If the event returns to Grade 3 
then discontinue cisplatin. 
 
Interrupt cisplatin until recovery to Grade ≤ 1. Then resume 
cisplatin at one lower dose level. One further dose reduction is 
allowed for Grade 4 neutropenia. If the event returns to Grade 4 
then discontinue cisplatin. 
 
 
Interrupt cisplatin until recovery to Grade ≤ 1. Then resume 
Cisplatin at one lower dose level.  If again returns to Grade ≥ 3, 
discontinue patient from cisplatin. 
 
Non-hematological 
toxicity 
Actions 
 
Grade ≥ 2 
Ototoxicity or 
Nephrotoxicity  
 
Grade 2 Peripheral 
Neuropathy 
 
Grade 3 Peripheral 
Neuropathy 
 
 
Grade 4 Peripheral 
Neuropathy 
 
Interrupt cisplatin until recovery to Grade ≤ 1. Then resume 
cisplatin at one lower dose level.  If the event returns to Grade ≥ 
2, then discontinue the cisplatin. Decrease the cisplatin to one 
lower dose level. 
 
Decrease the cisplatin to one lower dose level. 
 
 
Interrupt cisplatin until recovery to Grade < 2. Then resume 
cisplatin at one lower dose level. If the event returns to Grade 3, 
then discontinue the cisplatin. 
 
Discontinue cisplatin 
 
Other Grade 3 non-
hematological 
toxicity 
 
 
 
Interrupt cisplatin until recovery to Grade ≤ 1. Then resume 
cisplatin at same dose. If event returns to Grade 3, then 
interrupt cisplatin until recovery to Grade ≤ 1. Then reintroduce 

 
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Hematological 
toxicity 
Actions 
Other Grade 4 non-
hematological 
toxicity 
cisplatin at one lower dose level.  If the event returns to Grade 
3, then discontinue the cisplatin. 
 
Interrupt cisplatin until recovery to Grade ≤ 1. Then reintroduce 
cisplatin at one lower dose level.  If the event returns to Grade 
4, then discontinue the cisplatin. 
 
 
8.8 
Dose Modifications Contacts 
 
For treatment or dose modification questions, please contact Dr. Eve Rodler at 916/734-
3772 (S1416question@swog.org) or Dr. Priyanka Sharma at 913/588-6029 
(S1416question@swog.org) 
 
8.9 
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. 

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9.0 
STUDY CALENDAR 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3  
Cycle 4   
Cycle 5 
Cycle 6 @ 
Off Treat 
F/U Prior 
to Prog £ 
Off Treat 
F/U  After 
Prog √ 
REQUIRED STUDIES 
PRE 
STUDY 
W 
W W W W W W W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
W 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
PHYSICAL 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
History & Physical Exam   
X 
X
Я 
  
  
X 
 
  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Weight and Performance 
Status   
X 
X
Я 
  
  
X 
 
  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
  
  
Clinical Disease Assessment 
** 
  
 
  
  
 
X 
 
  
X 
  
 
X 
 
 
X 
 
 
X 
 
 
X 
  
Toxicity Notation      
  
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Review  Intake Calendar & 
Pill Count 
  
 
  
  
X 
 
  
X 
 
 
X 
 
 
X 
 
 
X 
 
 
  
  
LABORATORY $ 
  
 
  
  
  
 
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
CBC, differential, platelets 
X 
X# 
  
  
X 
 
  
X 
  
 
X 
  
  
X 
  
  
X 
  
  
  
  
Serum Chemistry (including 
Potassium, Magnesium)  
X 
X# 
  
  
X 
 
  
X 
  
 
X 
  
  
X 
  
  
X 
  
  
  
  
Serum Creatinine 
X 
X# 
  
  
X 
 
  
X 
  
 
X 
  
  
X 
  
  
X 
  
  
  
  
Bilirubin 
X 
X# 
  
  
X 
 
  
X 
  
 
X 
  
  
X 
  
  
X 
  
  
  
  
ALT/AST 
X 
X# 
  
  
X 
 
  
X 
  
 
X 
  
  
X 
  
  
X 
  
  
  
  
Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCANS $ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT scan chest/abd/pelvis for 
tumor measurement  ** 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Brain MRI (only for patients in 
brain metastases cohort) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
MANDATORY SPECIMEN 
SUBMISSION 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Tissue for Correlative Studies 
(see Sections 15.1 and 15.2) 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Blood  for BRCA testing (see 
Section 15.3) 
X Ƃ 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood  for CTC testing (see 
Section 15.4) ¥ 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X¥ 
 
(CORRESPONDING FOOTNOTES ARE CONTINUED ON THE NEXT PAGE.)  
 
 

 
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Cycle 1 
Cycle 
2 
Cycle 3  
Cycle 4   
Cycle 5 
Cycle 6 
@ 
Off 
Tre
at 
F/U 
Prio
r to 
Pro
g £ 
Off 
Tre
at 
F/U  
Afte
r 
Pro
g √ 
REQUIRED 
STUDIES 
PR
E 
ST
UD
Y 
W W W W W W W W W W W W W W W W W W 
 
1 2 3 4 5 6 7 8 9 
1
0 
1
1 
1
2 
1
3 
1
4 
1
5 
1
6 
1
7 
1
8 
TREATMEN
T (see 
Section 7.0 
for details) 
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
ABT-
888/Placebo  
† 
  
X X 
 
X X  
X X 
 
X 
X 
  
X 
X 
  
X 
X 
  
  
  
Cisplatin   
 
X 
 
 
X  
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
NOTE:  Forms are found on the protocol abstract page of the SWOG website 
(www.swog.org).  Forms submission guidelines are found in Section 14.0. 
 
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://www.swog.org/sites/default/files/docs/2017-
10/Best%20Practices%20upddate.pdf. 
 
Footnotes: 
√  
After progression, follow-up will occur (with lab tests and scans performed at the discretion of the 
treating physician) every 6 months until 5 years after registration or until death, whichever occurs 
first.  
Я  If prestudy history and physical exam, weight and performance status are obtained within 21 Days 
prior to treatment, they do not need to be repeated for Cycle 1, Day 1. 
# 
Labs should be redrawn within 7 days prior to Cycle 1, Day 1. 
†   ABT-888/placebo is taken twice a day on Days 1-14 for all cycles with drug supply dispensed as 
per Section 3.1d. Patients with stable disease/PR/CR will continue both drugs until disease 
progression. If after 4 cycles of combination therapy a patient experiences an unacceptable toxicity, 
cisplatin can be discontinued and ABT-888/placebo will continue until progression taken twice a 
day on Days 1-21 continuously for 21 days of each 21 day cycle. 
@ Protocol treatment and parameters will continue at these intervals until patient has met any of the 
criteria outlined in Section 7.6. 
** 
Disease will be assessed clinically at each visit.  Scans must be completed every 9 weeks for 54 weeks from registration and then every 18 weeks until 
progression, or more often as clinically indicated, using the same method used at baseline. If a scan is performed earlier than the next scheduled 9 week 

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scan, the next scan should occur 9 weeks from the actual date of the scan, not from the scheduled date.  All sites of disease that existed at baseline must 
be evaluated at each assessment.  Measurements must be provided for target measurable lesions, while presence or absence must be noted for non-
target measurable and non-measurable disease. For all patients after the 5-year follow-up mark, patient visits and scans are at the physician’s discretion. 
£ 
If patient is taken off protocol treatment for any reason other than progression, he/she must continue to be followed every 9 weeks for progression for 54 
weeks from registration, then every 18 weeks until progression. 
¥ 
Circulatory Tumor Cell (CTC) specimens should be submitted at baseline, Cycle 2 Day 1 and at Progression (see Section 15.4). 
$ 
The window for CT scans is +/- 3 days. Labs for toxicity assessment must be obtained within 3 days prior to the treatment cycle initiation. 
Ƃ 
Blood for BRCA testing is to be submitted after registration and before beginning protocol treatment, to be collected and shipped in the same day.  See 
Section 15.3. 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
Evaluation of disease will be done using two separate criteria in this study, RECIST 1.1 (Sections 
10.1-10.3) and the assessment criteria from the RANO-BM group for intracranial disease for 
patients in the Brain Metastases Cohort (see Section 10.4). 
 
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 be 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 

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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. 
 
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.   

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10.3 
Best Response 
 
a. 
CR:  At least one objective status of CR documented before progression or 
symptomatic deterioration. 
 
b. 
PR: At least one objective status of PR or better 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. 
 
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 
Assessment Criteria for Brain Metastases Cohort 
 
a. 
Measurable disease: Measurable disease is defined as contrast enhancing 
lesions that can be accurately measured in at least one dimension (longest 
diameter to be recorded) with a minimum size of 1.0 cm, visible on two or more 
axial slices that are preferably ≤ 0.5 cm apart with 0-mm skip (and ideally ≤ 1.5 mm 
apart with 0-mm skip). In addition, although the longest diameter in the plane of 
measurement is to be recorded, the diameter perpendicular to the longest diameter 
in the plane of measurement should be at least 0.5 cm for the lesion to be 
considered measurable. If the MRI is performed with thicker slices, the size of the 
measurable lesion at baseline should be at least double the slice thickness. 
 
b. 
Non-measurable disease: All other lesions, including lesions with longest 
dimension (LD) < 1.0 cm, lesions with borders that cannot be reproducibly 
measured, dural metastases, bony skull metastases, and leptomeningeal disease. 
 
c. 
Baseline Documentation of Target and Non-Target Lesions in the CNS: When 
more than one measurable lesion in the CNS is present at baseline, all lesions up 
to a maximum of five CNS lesions should be identified as target lesions and will be 
recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesion[s] with the longest diameter), but in addition, should be 
those that lend themselves to reproducible repeated measurements. 
 

 
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d. 
Objective Status and Best Response: Patients in the brain metastases cohort 
will have non-CNS disease assessed and objective status determined according 
to RECIST 1.1 criteria, and CNS disease assessed and objective status 
determined per the RANO-BM criteria below for intracranial response.  A 
determination of progression for PFS is defined as either an objective status of PD 
by RANO-BM for CNS or an objective status of progression by RECIST 1.1 for 
non-CNS, or both. 
 
Evaluation of Target Lesions: 
 
Complete response (CR): Disappearance of all CNS target lesions sustained for 
at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. 
 
Partial response (PR): At least a 30% decrease in the sum LD of CNS target 
lesions, taking as reference the baseline sum LD sustained for at least 4 weeks; 
no new lesions; stable to decreased corticosteroid dose; stable or improved 
clinically.  
 
Progressive disease (PD): At least a 20% increase in the sum LD of CNS target 
lesions, taking as reference the smallest sum on study (this includes the baseline 
sum if that is the smallest on study).  In addition to the relative increase of 20%, at 
least one lesion must increase by an absolute value of ≥ 0.5 cm to be considered 
progression.  
 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum LD while on study. 
 
Evaluation of Non-Target Lesions: 
Non-target lesions should be assessed qualitatively at each of the time points 
specified in the protocol. 
CR: Requires all of the following: disappearance of all enhancing CNS non-target 
lesions, no new CNS lesions. 
 
e. 
Non-CR/Non-PD: Persistence of one or more non-target CNS lesion(s)  
PD: Any of the following: unequivocal progression of existing enhancing non-target 
CNS lesions, new lesion(s) (except while on immunotherapy-based treatment), or 
unequivocal progression of existing tumor-related non-enhancing (T2/FLAIR) CNS 
lesions. In the case of immunotherapy-based treatment, new lesions alone may 
not constitute progressive disease 
 

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Summary of Criteria for Assessment of CNS Metastases 
Criterion 
CR 
PR 
SD 
PD 
Target 
lesions 
None 
≥ 30% decrease 
in sum LD 
relative to 
baseline 
< 30% decrease 
relative to baseline but 
< 20% increase in sum 
LD relative to nadir 
≥ 20% increase 
in sum LD 
relative to nadir* 
Non-
target 
lesions 
None 
Stable or 
improved 
Stable or improved 
Unequivocal PD* 
New 
lesion(s)*
* 
None 
None 
None 
Present* 
Corticost
eroids 
None 
Stable or 
decreased 
Stable or decreased 
NA+ 
Clinical 
status 
Stable or 
improved 
Stable or 
improved 
Stable or improved 
Worse* 
Requirem
ent for 
response 
All 
All 
All 
Any+ 
Abbreviations: CNS, central nervous system; RANO, Response Assessment in 
Neuro-Oncology; CR, complete response; PR, partial response; SD, stable 
disease; PD, progressive disease; NA, not applicable; LD, longest dimension. 
* Progression occurs when this criterion is met.  
** New lesion = new lesion not present on prior scans and visible in at least 2 
projections.  If a new lesion is equivocal, for example because of its small size, 
continued therapy may be considered, and follow up evaluation will clarify if it 
represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan 
showing the new lesion.  
+ Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioration. 
 
10.5 
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.   
 

 
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10.6 
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. 
 
10.7 
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. 
 
10.8 
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. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Endpoints 
 
The primary endpoint is progression-free survival (PFS) defined as time from registration 
(randomization) to progression or death due to any cause. Progression is defined as 
radiologic progression of disease by RECIST criteria or unequivocal progression of non-
measurable disease in the opinion of the treating physician (an explanation must be 
provided). Progression in the brain metastases cohort is defined as the first detection of 
radiologic progression of intracranial, extracranial or both intracranial and extracranial 
disease. 
 
Secondary endpoints include response rate (measurable disease only), clinical benefit 
rate, and overall survival. Overall survival is defined as time from registration to death due 
to any cause.  Patients without the event are censored at the last contact.  Patients will be 
followed for a minimum of 5 years after registration to determine overall survival results. 
 
Patients who meet eligibility criteria for the trial will be enrolled and randomized to Arm 1 
or Arm 2 for treatment.  Patients will be stratified at time of randomization by line of therapy.  
At the start of the trial patients are not randomized by BRCA status but will be analyzed 
within their BRCA group after it is determined. Patients who enter the trial will undergo 
centralized BRCA1/2 mutation testing and ultimately be assigned to the appropriate group 
(germline mutation confirmed positive or germline mutation confirmed negative). Because 
the testing takes several weeks, it is not possible to delay randomization until the test result 
is known.  Interim assessments will be performed to assess the balance of the groups 
which incorporates information gained from BRCA1/2 mutation testing. 
 
Classification of patients as germline BRCA or BRCA-like or non BRCA-like will be 
determined within a few weeks after randomization. We will monitor the number of patients 
in each of the three groups. If the observed accruals deviate strongly from the expected 
distribution across the three groups, it may be necessary to move to upfront testing of 
patients and to close groups that have fulfilled their accrual totals. Minor deviations from 
the expected numbers will be allowed since little impact on power would occur. 
 

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11.2 
Accrual Goal 
 
Cohort 1: The original expectation was that we would accrue 7 patients per month so that 
it would have taken 33 months to accrue 235 patients.  It actually took 20 months to accrue 
the 235 patients.  However, because there are smaller numbers in the two subgroups of 
greatest scientific interest than predicted, we are extending the sample size to 324.  For 
the amended sample size of 324 we estimate 12 patients per month after re-opening 
accrual.  The total duration of the accrual period would be 30 months allowing for the 
temporary suspension. Follow-up after the last patient enrolled is 15 additional months 
before the PFS analysis is performed, but all patients are followed for survival for a 
minimum of five years in order to assess OS. A total of 324 patients will be randomized 1:1 
between the two arms with stratification on line of therapy. Originally the expected 
distribution was 63 BRCA-mutation patients, 86 BRCA-like non-carriers, and 86 non-
carriers without BRCA characteristics. Using the data available from the interim analysis 
the final projection for the 324 patients is 44 BRCA-mutation patients, 99 BRCA-like non-
carriers, and 142 non-carriers without BRCA characteristics. An additional 39 patients will 
not be able to be classified due to limited tumor tissue available, assay failure, or an 
inconclusive result from the assays. Extrapolating from prior studies, approximately 50% 
of primary sporadic TNBC patients are expected to have a BRCAness phenotype, but it 
could vary between 40-60%.  Note that based on data available from interim analysis 
approximately 40% of the BRCA mutation negative patients are being classified as BRCA-
like.  We have four possible methods for classifying as BRCA-like. 
 
After approximately 50% of the expected accruals, we will reassess the proportions 
allocated to each of the categories and determine if upfront stratification will be needed to 
prevent large discrepancies from the projected accruals in each category. 
 
Progressive Brain Metastases Cohort (Cohort 2):  In the cohort of patients with progressive 
brain metastases, the expectation is to accrue 2-3 patients per month so it will take about 
24 months to accrue 98 patients.  Follow-up after the last patient enrolled is 6 additional 
months before the PFS analysis is performed, but all patients are followed for survival for 
a minimum of 5 years in order to assess OS.  A total of 98 patients will be randomized 1:1 
between the two arms. 
 
At the time of this sample size revision there are only three patients in the progressive brain 
metastases cohort.  Therefore, we retain the overall accrual maximum of 333 patients even 
though the main cohort will accrue 324 patients.  The brain metastases cohort will be closed 
when the main cohort completes accrual. 
 
11.3 
Primary Analyses 
 
In the first cohort we will perform three separate analyses, followed by tests of interaction. 
Since this is a Phase II study, we do not adjust for multiple comparisons in order not to 
miss a significant signal. With the new sample sizes for the subgroups we recalculate 
power under the original assumptions.  Note that we have determined that upfront testing 
for the various assays used for BRCA like classification is not practical due to the assay 
turn-around times and therefore it is not possible to close one or more subgroups and keep 
others open. 
 
Primary analysis 1: Compare ABT-888 to no ABT-888 in the BRCA mutation-carriers 
(n=44) 
 

 
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A median PFS of 4 months is assumed for Arm 1 (cisplatin + placebo) that improves to 7 
months for Arm 2 (cisplatin + ABT-888). Outcome data is expected to be available from 42 
of the 44 registered patients.  Assuming a hazard ratio (HR) of 1.75 for standard versus 
experimental, the study will have 69% power (1-sided α = 0.10) to detect if the experimental 
arm (2) is superior to the standard arm (1). A larger α is used due to the difficulty of enrolling 
patients with BRCA mutations as well as the likelihood of success with the experimental 
therapy.  A stratified log-rank test will be used to compare PFS between the two arms in 
an ITT analysis where stratification is by line of therapy. Power drops from 80% to 69% 
under the new design considerations, but unfortunately a full increase in the sample size 
to restore 80% power is not possible. 
 
Primary analysis 2: Compare ABT-888 to no ABT-888 in the BRCA mutation-negative 
BRCAness-like group (n=99). 
 
A median PFS of 4 months is assumed for Arm 1 (cisplatin+ placebo) that improves to 7 
months for Arm 2 (cisplatin + ABT-888). Outcome data is expected to be available from 95 
of the 99 registered patients. Assuming a hazard ratio (HR) of 1.75 for standard versus 
experimental, the study will have 85% power (1-sided α = 0.05) to detect if the experimental 
arm (2) is superior to the standard arm (1). A stratified log-rank test will be used to compare 
PFS between the two arms in an ITT analysis. 
 
Secondary analysis 1: Compare ABT-888 to no ABT-888 in the BRCA mutation-negative 
non-BRCA-like group (n=142)  
 
Theoretically we would expect no difference by treatment (median PFS of 4 months in both 
arms). However, it is possible that the classification of BRCA-like status has error or that 
ABT-888 is efficacious anyway in this group.  Outcome data is expected to be available 
from 136 of the 142 registered patients. A test of efficacy will be conducted at 1-sided α = 
0.10 even though little or no effect is expected.  A stratified log-rank test will be used to 
compare PFS between the two arms in an ITT analysis. Note:  The CIRB requested this 
be labeled as a secondary analysis, rather than the third primary analysis as approved in 
the protocol reviewed by CTEP. 
 
Progressive Brain Metastases Cohort 
 
Primary analysis:  Compare ABT-888 to no ABT-888 in patients with active brain 
metastases that are progressive after prior intracranial therapy (N=98). 
 
A median PFS of 2 months is assumed for Arm 1 (cisplatin + placebo) that improves to 3.5 
months for Arm 2 (cisplatin + ABT-888).  Assuming a hazard ratio (HR) of 1.75 for standard 
versus experimental, the study will have 84% power (1-sided α=0.05) to detect if the 
experimental arm (2) is superior to the standard arm (1) with 89 PFS events.  Outcome 
data is expected to be available from 93 of the 98 registered patients. A stratified log-rank 
test will be used to compare PFS between the two arms in an ITT analysis where 
stratification is by modified breast-GPA and prior systemic therapies. 
 
11.4 
Exploratory analyses of PFS 
 
Interactions of group and treatment using PFS: 
 
Exploratory interaction analysis 1: Test for an interaction of BRCA-like status by 
treatment. Treatment in the BRCA-like group (n=99) is expected to be effective (7 months 
to 4 months), but no effect is expected in the non-BRCA-like group (n=142). The study will 
have 78% power (1-sided α = 0.10) to detect this interaction.  
 

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Exploratory interaction analysis 2: Test for an interaction of a BRCA mutation versus 
BRCA-like status by treatment. Treatment in both the BRCA-like group (n=99) and the 
BRCA mutation group (n=44) is expected to be effective (7 months to 4 months), so no 
interaction is expected.   
 
The patients who cannot be classified into subgroups will be included in a separate analysis 
comparing treatment.  It is likely that these results will be intermediate to those for the three 
separate subgroups since they are likely comprised of all three groups, but just could not 
be categorized. 
 
At the conclusion of these analyses, it should be clear if there is a positive signal for ABT-
888 in both BRCA-mutated and BRCA-like patients, failing to reject the null of no ABT-888 
effect in the non-BRCA-like cohort does not imply that ABT-888 has no effect in this 
subgroup.  It is possible that a smaller effect exists but this trial is not sized sufficiently to 
detect such a difference. Progression will be determined by clinical symptoms and 
radiologic assessments, per RECIST.  A stratified log-rank test will be used to compare 
PFS for Arm 1 (cisplatin + placebo) versus Arm 2 (cisplatin plus ABT-888), with additional 
analyses using Cox regression.  It is assumed that the benefit of ABT-888 will be the same 
(on the log hazard rate scale) for gBRCA mutation-positive and for BRCA-like TNBC, but 
have no effect for non-BRCA like TNBC. These assumptions will be tested in appropriate 
tests of interaction. This secondary analysis will examine treatment effects for groups 
defined as gBRCA mutation-positive and BRCAness combined versus non-BRCAness, 
and will test the treatment by phenotype interaction. 
 
Brain Metastases Cohort 
 
Exploratory Analysis:  Compare ABT-888 to no ABT-888 in the patients with progressive 
brain metastases with or without either a BRCA-mutation or BRCA-like phenotype. 
 
For patients with BRCA-mutation or BRCA-like phenotype, it is assumed that a greater 
improvement in PFS would occur with the combination therapy that would result in an 
increase from a median PFS of 2 months for Arm 1 (cisplatin + placebo) to at least 4 months 
for Arm 2 (cisplatin + ABT-888), and corresponding HR ≥ 2.0.  Because markers will be 
exploratory, analysis will only be conducted under a hypothesis testing framework if at least 
half of the patients enrolled (n ≥ 49) have evaluable specimen which indicate a BRCA-
mutation or BRCA-like phenotype, and at least 80% power using a log-rank that with a 1-
sided α = 0.10.  A larger α is used for the exploratory analysis due to the uncertainty of 
enrolling patients with evaluable specimen for BRCA status.  A stratified log-rank test will 
be used to compare PFS between the two arms in an ITT analysis where stratification is 
by modified breast-GPA.  If fewer than 49 brain metastases patients are enrolled with an 
identified BRCA-mutation or BRCA-like phenotype, the subgroup analysis will be 
estimation-only in order to explore the treatment effects in the biomarker—defined 
subgroup, reporting the observed HR and 95% confidence interval from a stratified Cox 
proportional hazard model. 
 
Theoretically, we would expect no difference by treatment in BRCA mutation-negative non-
BRCA-like subgroup.  Analysis plans will be estimation-only for patients confirmed to be in 
this biomarker-defined subgroup, reporting the observed HR and 95% confidence interval 
from a stratified Cox proportional hazards model. 
 
11.5 
Overall Survival (OS) 
 
The same analyses as in Sections 11.3 and 11.4 will be repeated using OS instead of PFS.   
 

 
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11.6 
Response rate and clinical benefit rate 
 
Response rate will be analyzed for patients with measurable disease. Patients who achieve 
complete or partial response will be classified as having a response. Clinical benefit will be 
assessed in all patients and will include those with complete or partial response and those 
with stable disease for 6 months. The primary analyses will be conducted using these 
binary responses using Fisher’s exact test and logistic regression. 
 
11.7 
Interim analysis and timing of final analysis 
 
Parent/Primary Cohort: Under the alternative hypothesis, about 207 events are expected 
overall in the three subgroups. Therefore, final analyses will be conducted at the expected 
total number of events or 2 years after the last randomized patient, whichever comes first. 
 
Original protocol: We will monitor the three groups separately with respect to the 
percentage of expected failures.  Ideally there will be a single time point for interim 
analyses where 50% of the expected total events have occurred.  However, if any group 
has not yet reached 35% of the expected events or if one group has already reached 65% 
of the events, then separate interim analysis time points will be used.  There are no planned 
interim efficacy analyses.  If the groups are randomized as expected then 109 events would 
be reached after 2 years of accrual at about 67% of accrual.  If the hazard ratio for ABT-
888 versus no ABT-888 exceeds 1.0 (i.e. is in the wrong direction) in any one of the three 
groups, then we will recommend that no further patients will be randomized to that 
group.  This recommendation will be made to the DSMC who will make the final 
recommendation about the trial.  This would require an amendment since up-front testing 
would then be required before randomizing a patient. Currently, classification is done after 
a patient is enrolled and randomized.  
 
Revised protocol: Due to the speed of accrual and delay in classification of patients into 
subgroups, a single interim analysis was performed after 235 patients were accrued.  The 
DSMC recommended continuing the study as planned incorporating the new sample size 
into the protocol. 
 
Original protocol:  A similar futility analysis will be performed in the brain metastasis cohort 
when 50% of the expected 89 events have occurred, and will recommend closure if the 
hazard ratio for ABT-888 versus no ABT-888 exceeds 1.0. 
 
Revised protocol: The DSMC recommended closure of this cohort at the same time as the 
main cohort completes accrual regardless of the total number of accrued patients. 
 
11.8 
Toxicity 
 
Toxicity is assessed using criteria based on CTCAE Version 4. The two arms will be 
compared using Fisher’s exact test for dichotomous classifications (e.g. Grades 3-5 versus 
Grades 0-2) for each toxicity. No adjustment for multiplicity is done since an important 
toxicity signal could be missed. 
 
11.9 
Data and Safety Monitoring Committee (DSMC) 
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistics and Data Management Center, and will meet at 
the Group's bi-annual meetings as necessary.  The Committee will be responsible for 
decisions regarding possible termination and/or early reporting of the study. 
 
12.0 
DISCIPLINE REVIEW 

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There will be no discipline review for this study. 
 
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 blinded starter supplies will be available 
for this study. Initial patient-specific clinical supplies of ABT-888/placebo 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 3.1d). 
 
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. 
 
13.3 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials to register and to renew their 
registration annually.  To register, all individuals must obtain a Cancer Therapy Evaluation 
Program 
(CTEP) 
Identity 
and 
Access 
Management 
(IAM) 
account 
at 
https://ctepcore.nci.nih.gov/iam.  In addition, persons with a registration type of Investigator 
(IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository 
(RCR) at https://ctepcore.nci.nih.gov/rcr. 
 
RCR utilizes five-person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System (RUMS), OPEN, 
Rave, acting as a primary site contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, training, 
employment, license, and 
certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following: 

 
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• 
Addition to a site roster 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol Principle (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
 
Additional 
information 
is 
located 
on 
the 
CTEP 
website 
at 
https://ctep.cancer.gov/investigatorResources/default.htm.  For questions, please contact 
the RCR Help Desk by email at RCRHelpDesk@nih.gov.  
 
13.4 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
a. 
IRB Approval:   
 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research Program 
(NCORP) Research Bases after March 1, 2019, all U.S.-based sites must be 
members of the NCI Central Institutional Review Board (NCI CIRB). In addition, 
U.S.-based sites must accept the NCI CIRB review to activate new studies at the 
site after March 1, 2019. Local IRB review will continue to be accepted for studies 
that are not reviewed by the CIRB, or if the study was previously open at the site 
under the local IRB. International sites should continue to submit Research Ethics 
Board (REB) approval to the CTSU Regulatory Office following country-specific 
regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
for Local Context (SSW) to the CIRB using IRBManager to indicate their intent to 
open the study locally. In order for the SSW approval to be processed, the 
Signatory Institution must inform the CTSU which CIRB-approved institutions 
aligned with the Signatory Institution are participating in the study. The NCI CIRB’s 
approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 
network or protocol level. Questions about establishing site preferences can be 
addressed to the CTSU Regulatory Office by emailing the email address above or 
calling 1-888-651-CTSU (2878). 
 
Sites using their local IRB or REB, must submit their approval to the CTSU 
Regulatory Office using the Regulatory Submission Portal located in the 
Regulatory section of the CTSU website. Acceptable documentation of local 
IRB/REB approval includes: 
• 
Local IRB documentation; 
• 
IRB-signed CTSU IRB Certification Form; and/or 
• 
Protocol of Human Subjects Assurance Identification/IRB  
 
Certification/Declaration of Exemption Form. In addition, the Site-Protocol 
Principal Investigator (PI) (i.e. the investigator on the IRB/REB approval) must 
meet the following criteria to complete processing of the IRB/REB approval record: 
• 
Holds an Active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian 
sites only) and on at least one participating roster; 

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• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 
1572 in the RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
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 the following: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 
b. 
Protocol-Specific Requirements For S1416 Site Registration:   
 
• 
IRB approval (For sites not participating via the NCI CIRB; 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) 
• 
For applicable NCTN studies with a radiation and/or imaging (RTI) component, 
the enrolling site must be aligned to a RTI provider.  To manage provider 
associations, access the Provider Association tab on the CTSU website at 
https://www.ctsu.org/RSS/RTFProviderAssociation, 
to 
add 
or 
remove 
associated providers.  Sites must be linked to at least one IROC credentialed 
provider to participate on trials with an RT component. Enrolling sites are 
responsible for ensuring that the appropriate agreements are in place with their 
RTI provider, and that appropriate IRB approvals are in place.   
 
c. 
Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. 
To participate, the institution and its associated investigators and staff must be 
associated with the LPO or a Protocol Organization (PO) on the protocol. One way 
to search for a protocol is listed below. 
• 
Log on to the CTSU members’ website (https://www.ctsu.org) using your 
CTEP-IAM username and password; 
• 
Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top of the 
protocol tree, or 
o Click on the By Lead Organization folder to expand, then select 
SWOG, and protocol number S1416; 
• 
Click on Documents, select Site Registration, and download and complete 
the forms provided. (Note: For sites under the CIRB, IRB data will load 
automatically to the CTSU.)  

 
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d. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal on the CTSU website. 
 
To access the Regulatory Submission Portal log in to the CTSU members’ website, 
go to the Regulatory section and select Regulatory Submission. 
 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in 
order to receive further instruction and support. 
 
e. 
Checking Your Site’s Registration Status: 
 
You can verify your site’s registration status on the members’ side of the CTSU 
website. Site registration status may be verified on the CTSU members’ website.  
• 
Click on Regulatory at the top of the screen; 
• 
Click on Site Registration; and 
• 
Enter the sites 5-character CTEP Institution Code and click on Go. 
o Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with NCI or their affiliated networks. 
 
13.5 
Oncology Patient Enrollment Network (OPEN)Registration Requirements 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management system, 
Medidata Rave. 
 
Requirements for OPEN access:   
 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Must be on an LPO roster, ETCTN 
corresponding roster, or participating organization roster with the role of Registrar. 
Registrars must hold a minimum of an Associate Plus (AP) registration type; 
• 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• 
Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and  
• 
All patients have signed an appropriate consent form and HIPAA authorization form (if 
applicable). 
 

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Note:  The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. You may print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
13.6 
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 
 
Data submission schedule will be created by the stat center using the format below. 
 
14.1 
Data Submission Requirement 
 
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. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the CTSU website 
(www.ctsu.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details. 
 
14.3 
Data Submission Procedures 
a. 
Medidata Rave is a clinical data management system being used for data 
collection for this trial/study. Access to the trial in Rave is controlled through the 
CTEP-IAM system and role assignments.  
 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave 
CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator.  
 
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an 
Associate Plus (AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator 
(NPIVR) or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration 
type. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
 
Upon initial site registration approval for the study in Regulatory Support System 
(RSS), all persons with Rave roles assigned on the appropriate roster will be sent 
a study invitation e-mail from iMedidata. To accept the invitation, site staff must log 

 
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in to the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-
IAM username and password and click on the accept link in the upper right-corner 
of the iMedidata page. Site staff will not be able to access the study in Rave until 
all required Medidata and study specific trainings are completed. Trainings will be 
in the form of electronic learnings (eLearnings) and can be accessed by clicking 
on the link in the upper right pane of the iMedidata screen. If an eLearning is 
required and has not yet been taken, the link to the eLearning will appear under 
the study name in iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will 
be granted, and a Rave EDC link will display under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in RSS will receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website in the Data Management section under the Rave 
resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ 
website 
in 
the 
Data 
Management 
> 
Rave 
section 
at 
www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-823-5923 or 
by e-mail at ctsucontact@westat.com.   
 
b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG 
website (www.swog.org).  
 
For 
difficulties 
with 
the 
CRA 
Workbench, 
please 
email 
technicalquestion@crab.org.  
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 
 
d. 
Data Quality Portal 
 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
 
The DQP is located on the CTSU members’ website under Data Management. The 
Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
 
Note: Some Rave protocols may not have delinquent form details or reports 
specified on the DQP. A protocol must have the Calendar functionality 
implemented in Rave by the Lead Protocol Organization (LPO) for delinquent form 
details and reports to be available on the DQP. Site staff should contact the LPO 
Data Manager for their protocol regarding questions about Rave Calendar 
functionality. 
 
14.4 
Data Submission Overview and Timepoints  

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a. 
WITHIN 7 DAYS OF REGISTRATION:  
 
Submit the following: 
 
S1416 Onstudy Form 
 
S1416 Baseline Abnormalities Form 
 
S1416 Baseline Tumor Assessment Form 
 
Documentation of previously confirmed deleterious BRCA1 or BRCA2 germline 
mutation 
 
Pathology Report 
 
Submit radiology reports from all scans performed to assess disease at baseline. 
 
b. 
WITHIN 14 DAYS AFTER REGISTRATION: 
 
Submit the following: 
 
Tissue and blood specimens as outlined in Section 15.0. 
 
c. 
WITHIN 7 DAYS AFTER EACH CYCLE OF TREATMENT: 
 
Submit the following: 
 
S1416 Treatment Form 
 
S1416 Adverse Event Summary Form 
 
d. 
WITHIN 14 DAYS AFTER EACH SCAN FOR DISEASE ASSESSMENT (EVERY 
9 WEEKS UP UNTIL 54 WEEKS FROM REGISTRATION, THEN EVERY 18 
WEEKS UNTIL PROGRESSION OR AS CLINICALLY INDICATED): 
 
Submit the following: 
 
Follow Up Tumor Assessment Form 
 
Scan reports 
 
e. 
WITHIN 14 DAYS OF DISCONTINUATION OF BLINDED TREATMENT: 
 
Submit the following: 
 
Off Treatment Notice 
 
Final S1416 Treatment Form 
 
S1416 Adverse Event Form 
 
f. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit the following: 
 
Follow Up Tumor Assessment Form 
 
Scan reports 
 

 
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Off Treatment Notice, final S1416 Treatment Form and S1416 Adverse Event 
Form and (if the patient was still on protocol treatment) or  
 
Follow-Up Form (if the patient was off protocol treatment) documenting date, site 
and method for determining progression/relapse. 
 
 

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g. 
AFTER OFF TREATMENT EVERY 9 WEEKS UP UNTIL 54 WEEKS FROM 
REGISTRATION, THEN EVERY 18 WEEKS UNTIL PROGRESSION, THEN 
EVERY 6 MONTHS UNTIL 5 YEARS AFTER REGISTRATION: 
 
Submit the following: 
 
Follow Up Form 
 
Late Effects Form (if prior treatment for progression or relapse or a second primary, 
and prior to non-protocol treatment, the patient experiences any severe [Grade ≥ 
3] long term toxicity that has not been previously reported). 
 
h. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death and a final S1416 Treatment Form and S1416 Adverse 
Event Form (if the patient was still on protocol treatment) or Follow-Up Form (if the 
patient was off protocol treatment) documenting death information. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Primary Tumor Specimens (REQUIRED) 
 
Primary tumor specimens (submitted to the SWOG Specimen Bank – Solid Tissue, 
Myeloma and Lymphoma Division, Lab #201) required for patient: 
 
a. 
Specimens must be submitted at the following times: 
 
1. 
Baseline Submission - Formalin Fixed Paraffin Embedded (FFPE) Block 
or 20 unstained slides (eighteen (18) ten-micron uncharged slides and two 
(2) five-micron charged slides) from primary tumor. If unstained slides are 
being submitted, the following sequence for slide preparation should be 
followed: First, cut one (1) five-micron slide, followed by nine (9) ten-
micron slides, followed by one (1) five-micron slide, followed by nine (9) 
ten-micron slides. NOTE: If archived primary tumor is not available, please 
contact Dr. Sharma (S1416question@swog.org).  
 
b. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage   
https://www.swog.org/member-resources/biospecimen-resources), or via the link 
on the S1416 protocol abstract page on the SWOG website (www.swog.org). 
 
c. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
d. 
Any leftover tissue not consumed by testing will be banked for future use according 
to the patient’s selection on the “Optional Biobanking for Possible Future Studies” 
section of the consent form. 
 
 

 
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15.2 
Specimens from Metastatic Tissue 
 
Specimens from metastatic tissue (or recurrence) (submitted to the SWOG Specimen Bank 
– Solid Tissue, Myeloma and Lymphoma Division, Lab #201): 
 
a. 
Specimens must be submitted at the following times: 
 
Baseline Submission – Formalin Fixed Paraffin Embedded (FFPE) Block or 10 
unstained slides (8-ten micron uncharged slides and 2- five micron charged slides) 
from archived metastatic tissue. 
 
If archival metastatic tumor tissue is exhausted, then a new fresh tumor biopsy that 
is formalin-fixed and paraffin-embedded (FFPE) is highly recommended with 
patient’s consent.  Submission of the metastatic tissue is not required if no archival 
specimen is available and a new biopsy is not feasible. 
 
b. 
Metastatic Tissue Biopsy Instructions: 
 
If a pre-treatment metastatic tumor biopsy is performed, a local standard surgical 
consent form must be obtained.  The biopsy can be image-guided or excisional 
and can be obtained as per local institutional guidelines. The use of imaging to 
facilitate biopsies will be decided by members of the Interventional Radiology team 
at the clinical site and may include ultrasound, CT scan, or MRI. Brain biopsies will 
be permitted if the patient has medical necessity for craniotomy for clinical care. 
Mediastinal, laparoscopic, gastrointestinal, or bronchial endoscopic biopsies can 
be obtained incidentally to a clinically necessary procedure and not for the sole 
purpose of the clinical trial. Sites are requested to follow the below standard 
instructions for metastatic tumor biopsy and preparation of paraffin embedded 
tissue block: 
 
-Obtain four 16-gauge or 18-gauge core needle biopsy specimens. 
-Place the fresh tissue in formalin.  Do not exceed 24 hours fixation time. 
-Fixed tissue must be paraffin embedded within 24 hours. 
-Cut one H&E (hematoxylin and Eosin) stained section from the representative 
paraffin-embedded tissue block. 
 
c. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
d. 
Specimen submission instructions can be accessed on the SWOG  
Specimen Submission webpage 
(https://www.swog.org/member-resources/biospecimen-resources), or via the link 
on the S1416 protocol abstract page on the SWOG website (www.swog.org).  
 
e. 
Any leftover tissue not consumed by testing will be banked for future use according 
to the patient’s selection on the “Optional Biobanking for Possible Future Studies” 
section of the consent form. 
 
 

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15.3 
BRCA 1 and BRCA 2 Testing (REQUIRED) 
 
Specimens for Germline BRCA1 and BRCA2 testing (submitted to the University of 
Washington – King/Swisher Laboratory, Lab #223) required for all patients: 
 
a. 
Specimens must be submitted at the timepoints listed below.  Collection 
instructions are outlined in Section 15.3c and submission instructions are outlined 
in Section 15.3e. The genetic testing results for the patient will be provided back 
to the enrolling site in Rave® as a report uploaded in the Genetic Testing Results 
folder, and will include both “positive” and “negative” results for 12 genes (BRCA, 
BRCA2, ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, PTEN, RAD51C, RAD51D, 
TP53).  A positive result will only include “deleterious mutation”.  Mutations of 
uncertain significance will not be reported. 
 
Note that treatment may begin prior to receiving results. 
 
b. 
Specimens must be submitted at the following times (see Section 9.0): 
 
1. 
Baseline Submission (after registration, collected and submitted on the 
same day) – 7mL whole blood in yellow top (ACD solution A) tube.  
 
c. 
COLLECTION INSTRUCTIONS 
 
ONLY 
COLLECT 
AND 
SHIP 
SAMPLES 
TO 
THE 
KING/SWISHER 
LABORATORY MONDAY THROUGH THURSDAY. DO NOT DRAW SAMPLES 
ON A FRIDAY OR THE DAY BEFORE A HOLIDAY. SAMPLES MUST BE 
SHIPPED ON THE SAME DAY OF COLLECTION. 
 
1. 
No processing necessary. The filled tube must be maintained at ambient 
(15–30°C) temperature, avoiding extremes of heat and cold, at all times. 
 
d. 
Specimen collection kits are not being provided for this submission; sites will use 
institutional supplies. 
 
e. 
SHIPPING SAMPLES 
 
1. 
SWOG Specimen Tracking System (STS) 
 
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. Non- SWOG users may log into SpecTrack using their 
CTSU UserID and password on the SpecTrack login page located at: 
https://spectrack.crab.org (select the option “SWOG – SWOG – CTSU”).  
SpecTrack start-up instructions (both written and demo) are available after 
signing in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 

 
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(NOTE: If a specimen had an incomplete submission, this must be 
documented in the Specimen Tracking System under “Comments.”  If no 
specimen was available, this must be documented in the Specimen 
Tracking System by choosing “Notify that Specimen Cannot be 
Submitted”). 
 
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 SWOG Statistics and Data Management Center at 206/652-
2267 to be routed to the Data Coordinator for further assistance. 
 
In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of blood samples for SWOG Biospecimen Bank 
Submission and BRCA1 and BRCA2 testing is identified as follows: 
 
Lab #223:  
King/Swisher Laboratory 
Phone: 206/616-4296 
Contact:  Dr. Elizabeth Swisher 
 
2. 
Federal guidelines for the shipment of blood products: 
 
a. 
The tube must be wrapped in an absorbent material. 
 
b. 
The tube must then be placed in an AIRTIGHT container (like a 
resealable bag). 
 
c. 
Pack the resealable bag and tube in a Styrofoam shipping 
container. 
 
d. 
Pack the Styrofoam shipping container in a cardboard box. 
 
e. 
Mark the box "Biohazard". 
 
 
15.4 
Specimens for Circulating Tumor Cell-Next Generation Sequencing (CTC-by HD-CTC 
followed by CTC-NGS) (REQUIRED): 
 
a. 
Specimens must be submitted at the timepoints listed below.  Collection 
instructions are outlined in Section 15.4c and submission instructions are outlined 
in Section 15.4e. 
 
b. 
Specimens must be submitted at the following times (see Section 9.0): 
 
1. 
1 tube of whole blood in a Streck Cell-Free DNA tube after registration 
(prior to treatment), Cycle 2 Day 1 and progression. The specimens must 
be shipped on the same day as collection. 
 
 

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c. 
Specimen Collection Instructions for CTC-NGS 
 
ONLY COLLECT AND SHIP SAMPLES TO THE LABORATORY MONDAY 
THROUGH THURSDAY. DO NOT DRAW SAMPLES ON A FRIDAY OR THE DAY 
BEFORE A HOLIDAY.  SAMPLES MUST BE SHIPPED ON THE SAME DAY OF 
COLLECTION. 
 
• 
Materials required for blood collections are one (1) Streck Cell-Free DNA tube, 
Vacutainer brand adapter, and needles. 
• 
Blood samples can be obtained by venipucture using a Vacutainer brand 
adapter and needle, or from a port or other central venous catheter using 
appropriate access needles and techniques. 
• 
If multiple tubes are being drawn, the Streck Cell-Free DNA tube must be last. 
• 
If no other tubes are needed, then the first 2 mL of blood must be drawn into 
another tube (not Streck Cell-free DNA) and discarded. Then, proceed to draw 
blood into the Streck Cell-free DNA tube. 
• 
Fill the Streck Cell-free DNA tube. Minimum blood volume is 8-9 mL.   
• 
Invert Streck Cell-free DNA tube a minimum of eight (8) times to ensure proper 
mixing of the additives contained in the tube.   
• 
Write the SWOG patient number, visit designation (i.e. baseline, C2D1, 
progression) and the date of collection on the tube.   
• 
The filled tube must be maintained at ambient (15–30°C) temperature, 
avoiding extremes of heat and cold, at all times.   
 
d. 
Specimen Collection Kits for CTC-NGS (sent to Kuhn Laboratory) 
 
Supplies can be obtained by sending an e-mail to kuhnlab@usc.edu.  Please 
indicate the part number and quantities. To facilitate the ordering process, the 
subject line of the e-mail should be “S1416 [NCI site code]”. Please provide full 
shipping address. 
 
Part Number 
Product Description 
Quantity 
42107 
CTC-NGS shipping kit 
1 
 
CTC-NGS Shipping kit includes Standard71 shipping system, Streck Cell-
free DNA tube and shipping instructions.  
 
The hours of operation for the Kuhn Lab are Monday-Friday, 8:00 AM – 5:00PM 
PST. Although the lab will attempt to ship supplies out as quickly as 
possible, orders should be placed approximately 10 days before supplies are 
needed. 
 
e. 
Shipping Instructions 
 
ONLY COLLECT AND SHIP SAMPLES TO THE DESIGNATED STUDY 
LABORATORY MONDAY THROUGH THURSDAY, DO NOT DRAW SAMPLES 
ON A FRIDAY OR THE DAY BEFORE A HOLIDAY.  SAMPLES MUST BE 
SHIPPED ON THE SAME DAY OF COLLECTION. 
 
 

 
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1. 
SWOG Specimen Tracking System (STS) 
 
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. Non- SWOG users may log into SpecTrack using their 
CTSU UserID and password on the SpecTrack login page located at 
https://spectrack.crab.org (select the option “SWOG – SWOG – CTSU”).  
SpecTrack start-up instructions (both written and demo) are available after 
signing in to SpecTrack. 
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag.  
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database 
errors 
or 
connectivity 
issues, 
please 
send 
an 
e-mail 
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 SWOG Statistics and Data Management Center at 206/667-
2267 to be routed to the Data Coordinator for further assistance. 
 
In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of blood samples CTC-NGS testing (1 Streck Cell-Free 
DNA tube) is identified as follows: 
 
Lab #209:     
Kuhn-Hicks Laboratory 
Phone: 213/740-9945 
Contact:  Xiomara Villasenor  
E-mail:  kuhnlab@usc.edu     
 
NOTE:  SpecTrack will prompt you to enter the CBC results for each of the 
CTC-NGS collection timepoints. 
 
2. 
Guidelines for the shipment of CTC-NGS (sent to the Kuhn laboratory) 
 
a. 
Instructions 
are 
available 
at: 
http://kuhn.usc.edu/SWOG1416shipping/   
Ship on collection day (Monday to Thursday) and select 
appropriate courier overnight service for delivery by 10:30 am of 
the day after collection day 
• 
If FedEx: select Priority Overnight service 
• 
If UPS: select Next Day Air service 
 
b. 
The filled Streck Cell-Free DNA blood collection tube must be 
inserted into the inner primary container along with a sachet of 
absorbent material. Place cap on securely to close. 
 
c. 
The primary container must be placed into a secondary container. 
Place cap on securely to close. 
 

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d. 
Place the secondary container containing the primary container 
and the Streck Cell-Free DNA blood collection tube into one half 
of the white cassette. 
 
e. 
Place the second half of the white cassette onto the other half 
fitting the plugs into the holes to close the cassette. 
 
f. 
Place the white cassette into the protective silver shipping air bag. 
Place the Shipment Packing List (generated by SpecTrack) inside 
and close the bag. 
 
g. 
Place the shipping air bag into the blue standard71.com 
cardboard box and close. 
 
h. 
Generate the courier shipping label as instructed in (a). Insert 
label in the pouch attached to the outside of the blue cardboard 
box. Contact your local courier representative for pick-up. 
i. 
Notify the receiving laboratory of the pending shipment by e-mail 
(kuhnlab@usc.edu) on collection day. The subject line should be 
“S1416 [NCI site code].” Include the following information:  
• 
Patient ID (6 digits) and Specimen # (7 digits, as 
provided by SpecTrack) 
• 
Visit designation (Baseline, C2D1 or Progression)  
• 
Date and time of blood collection  
• 
Shipment tracking number 
 
 
 

 
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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 supplied by CTEP, DCTD, NCI used in this protocol is provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company (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) contained within the 
terms of award apply to the use of the Agent in this study: 
 
1. 
Agent may not be used outside the scope of this protocol, nor can Agent be transferred or 
licensed to any party not participating in the clinical study.  Collaborator data for Agent is 
confidential and proprietary to Collaborator and shall be maintained as such by the 
investigators.  The protocol documents for studies utilizing Agent 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 confidentiality 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 Collaborative 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"): 
 
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 

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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. 
 
3. 
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 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
protocol and patient-specific CDUS data will be submitted quarterly to CTEP by electronic means, 
either by FTP burst of data or via the CDS web application.  Reports are due January 31, April 30, 
July 31 and October 31. The SWOG Statistics and Data Management Center will submit data using 
the CDUS that can be found on the CTEP web site (http://ctep.cancer.gov/reporting/cdus.html)  
 
 
 

 
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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 following guidelines prescribe 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_eve
nts.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.  
 
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.  
 
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. 
 
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system. 
 
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 reportable 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. 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: 
Late Phase 2 and Phase 3 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/placebo. 
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 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar 
Days 
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. or 
Section 16.1f.   
  
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 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
 
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 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 
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 Statistics and Data Management Center copies of Off 
Treatment Notice and/or Notice of Death. 
 
2) 
The adverse events listed below also require expedited monitoring for this 
trial: 
• 
Seizures – report all occurrences regardless of Grade attribution  
 
3) 
The adverse events listed below do not require expedited reporting via 
CTEP-AERS: 
• 
Neutropenia ≤ Grade 4 
 
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 CTEP-AERS.  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.  
 
 

 
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2. 
Supporting documentation should be submitted to CTEP in accordance 
with instructions provided by the CTEP-AERS system.  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   
 
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) or 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 
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46  
Sandhu SK, Schelman WR, Wilding G, et al. The poly (ADP-ribose) polymerase inhibitor niraparib 
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47  
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48  
Coleman R, Sill M, Thaker P, et al.  A phase II evaluation of selumetinib (AZD6244, ARRY-142886), 
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63  
Sharma P, SABCS Abstract PD09-02, 2012. 
 
64  
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65  
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68  
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69  
Moon D, et al. Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin 
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72  
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ovarian cancer, or basal-like breast cancer (BRCA-wt), J Clin Oncol 30 (suppl; abstr 3054), 2012. 
 
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Somlo G, Frankel P, Luu T, et al. Phase II trial of single agent PARP inhibitor ABT-888 (ABT-888 
[vel]) followed by postprogression therapy of vel with carboplatin (carb) in patients (pts) with stage 
BRCA-associated metastatic breast cancer (MBC): California Cancer Consortium trial, J Clin Oncol 
32:5s (suppl; abstr 1021), 2014. 
 
 

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Appleman L, Beumer J, Puhalla S, et al. A phase 1 study of ABT-888 (ABT-888) in combination 
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of Clinical Oncology (Supplement to Journal of Clinical Oncology); 30: 185s, 2012. 
 
92  
Tutt A, Ellis P, Kilbum L, et al.  TNT: a randomized phase III trial of carboplatin compared with 
docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA 1/2 
breast cancer.  SABCS Abstract, 2014. 
 
93  
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Supplement, PD09-02, 2012. 
 
94  
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96  
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97  
Tutt A, et al. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 
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98  
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First efficacy results from the I-SPY 2 TRIAL. Cancer Res 73(24): Supplement, S5-02, 2013. 
 
99  
Rodler ET, GJ, Kurland BF, et al. Phase I: ABT-888 with cisplatin (CP) and vinorelbine (VNR) in 
advanced triple-negative breast cancer (TNBC) and/or BRCA mutation-associated breast cancer. 
J Clin Oncol (suppl; abstr 1004), 32(5s): abstr 2569, 2014. 
 
100  
Byrski T, et al. Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in 
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101  
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102  
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104  
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105  
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107  
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microtubule-interfering agents. Int J Oncol 26(5): 1257-63, 2005. [PMID: 15809716] 
 
108  
Lafarge S, et al. Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering 
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109  
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110  
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carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A, 2011. [PMID: 
22006311] 
 
111  
Sharma P, et al. BRCA1 insufficiency is predictive of superior survival in patients with triple negative 
breast cancer treated with platinum based chemotherapy. Cancer Res 72(24): Supplement, PD09-
02, 2012. 
 
112  
Lips EH, et al. Triple-negative breast cancer: BRCAness and concordance of clinical features with 
BRCA1-mutation carriers. Br J Cancer 108(10): 2172-7, 2013. [PMID: 23558900] 
 
113  
Telli, ML. PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and 
carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and 
BRCA1/2 mutation-associated breast cancer. J Clin Oncol (31s), 2013. 
 
114  
Rodler ET, GJ, Kurland BF, et al. Phase I: ABT-888 with cisplatin (CP) and vinorelbine (VNR) in 
advanced triple-negative breast cancer (TNBC) and/or BRCA mutation-associated breast cancer. 
J Clin Oncol (suppl; abstr 1004), 32(5s): abstr 2569, 2014. 
 
115  
Abkevich V, et al. Patterns of genomic loss of heterozygosity predict homologous recombination 
repair defects in epithelial ovarian cancer. Br J Cancer 107(10): 1776-82, 2012. [PMID: 23047548] 
 
116  
Telli ML, JK, Abkevich V, Hartman A-R, et al. Homologous Recombination Deficiency (HRD) score 
predicts pathologic response following neoadjuvant platinum-based therapy in triple-negative and 
BRCA1/2 mutation-associated breast cancer (BC). Cancer Research 72: 141s, 2012. 
 
117  
Arun B, et al. Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation 
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21900106] 
 
118  
Garber JE, et al. Neo-adjuvant cisplatin (CDDP) in "triple-negative" breast cancer (BC). Breast 
Cancer Research and Treatment 100:S149, 2006, abstract 3074. 
 
119  
Kolaric K, et al. Phase II clinical trial of cis dichlorodiammine platinum (Cis DDP) in metastatic brain 
tumors. J Cancer Res Clin Oncol 104(3): 287-93, 1982. [PMID: 6761344] 
 
120  
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1811-4, 1988. [PMID: 3199166] 
 
121  
Silver DP, et al. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. Journal of Clinical 
Oncology 28(7): 1145-53, 2010. [PMID: 20100965] 
 
 

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Pennington KP, et al. Germline and somatic mutations in homologous recombination genes predict 
platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer 
Res 20(3): 764-75, 2014. [PMID: 24240112] 
 
123  
Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A. Winer EP. Sites of distant recurrence and clinical 
outcomes in patients with metastatic triple-negative breast cancer: high incidence of central 
nervous system metastases. Cancer 113, 2638-2645, 2008. 
 
124  
Niwinska A, Murawska M, Pogoda K. Breast cancer brain metastases: differences in survival 
depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-
brain radiotherapy (WBRT). Ann Oncol 21, 942-948, 2010. 
 
125  
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A.  Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier 
occurrence of cerebral metastases. European journal of cancer 45, 2792-2798, 2009. 
 
126  
Lin JU GR, Younger WJ, et al. Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients 
(pts) with breast cancer brain metastases (BCBM). J Clin Oncol 31, 2013. 
 
127  
Anders C DA, Abramson V, et al.  TBCRC 018: phase II study of iniparib in combination with 
irinotecan to treat progressive triple negative breast cancer brain metastases. Breast Cancer Res 
Treat, 2014. 
 
128  
Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, 
Perou CM.  The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. 
Clin Cancer Res 13, 2329-2334, 2007. 
 
129  
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M, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L.  Response to neoadjuvant 
therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26, 1275-
1281, 2008. 
 
130  
Tutt A EP, Kilbum L, et al.  TNT: A randomized phase III trial of carboplatin compared with docetaxel 
for patients with metastatic or recurrent locally advanced triple negative or BRCA 1/2 breast cancer. 
in San Antonio Breast Cancer Symposium, San Antonio, TX, 2014. 
 
131  
Niwinska A, Murawska M, Pogoda K. Breast cancer brain metastases: differences in survival 
depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-
brain radiotherapy (WBRT). Ann Oncol 21, 942-948, 2010. 
 
132  
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Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D.  Repeated 
observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad 
Sci U S A 100, 8418-8423, 2003. 
 
133  
Perou CM.  Molecular stratification of triple-negative breast cancers. The oncologist 16 Suppl 1, 
61-70, 2011. 
 
134  
Shaheen M, Allen C, Nickoloff JA, Hromas R.  Synthetic lethality: exploiting the addiction of cancer 
to DNA repair. Blood 117, 6074-6082, 2011. 
 
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Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ, Bontcheva-Diaz VD, Cox BF, 
DeWeese TL, Dillehay LE, Ferguson DC, Ghoreishi-Haack NS, Grimm DR, Guan R, Han EK, 
Holley-Shanks RR, Hristov B, Idler KB, Jarvis K, Johnson EF, Kleinberg LR, Klinghofer V, Lasko 
LM, Liu X, Marsh KC, McGonigal TP, Meulbroek JA, Olson AM, Palma JP, Rodriguez LE, Shi Y, 
Stavropoulos JA, Tsurutani AC, Zhu GD, Rosenberg SH, Giranda VL, Frost DJ.  ABT-888, an orally 
active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical 
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137  
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DeWeese TL, Dillehay LE, Ferguson DC, Ghoreishi-Haack NS, Grimm DR, Guan R, Han EK, 
Holley-Shanks RR, Hristov B, Idler KB, Jarvis K, Johnson EF, Kleinberg LR, Klinghofer V, Lasko 
LM, Liu X, Marsh KC, McGonigal TP, Meulbroek JA, Olson AM, Palma JP, Rodriguez LE, Shi Y, 
Stavropoulos JA, Tsurutani AC, Zhu GD, Rosenberg SH, Giranda VL, Frost DJ.  ABT-888, an orally 
active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical 
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138  
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in nonhuman primates. Cancer Chemother Pharmacol 65, 817-824, 2010. 
 
139  
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Cancer Res 11, 1669-1674, 2005. 
 
 
140  
Ha K, Fiskus W, Choi DS, Bhaskara S, Cerchietti L, Devaraj SG, Shah B, Sharma S, Chang JC, 
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and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast 
cancer cells. Oncotarget 5, 5637-5650, 2014. 
 
141  
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Nikolaishvili-Feinberg N, Bash R, O'Neal S, Sandison K, Parker JS, Santos C, Darr D, Zamboni W, 
Lee YZ, Miller CR, Anders CK.  Efficacy of Carboplatin Alone and in Combination with ABT888 in 
Intracranial Murine Models of BRCA-Mutated and BRCA-Wild-Type Triple-Negative Breast Cancer. 
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142  
Lin JU GR, Younger WJ, et al. Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients 
(pts) with breast cancer brain metastases (BCBM). J Clin Oncol 31, 2013. 
 
143  
Rugo HS OO, DeMichele A et al.  Veliparib/carboplatin plus standard neoadjuvant therapy for high-
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Symposium, San Antonio TX, 2013. 
 
144  
Subbiah I, Lei X, Weinberg J, et al.  Validation and development of a modified breast graded 
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J Clin Oncol 33:2239-45, 2014. 
 
 
 
 

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18.0 
APPENDIX 
 
18.1  
ABT-888/Placebo Intake Calendar 
 
18.2 
Emergency Unblinding Guidelines 
 
18.3  
New York Heart Association Criteria 
 
18.4 
Patient Drug Information Handout and Wallet Card  
 
18.5 
Translational Medicine Studies  
 
18.6 
Modified Breast Graded Prognostic Assessment Index 
 
18.7 
SWOG Biospecimen Bank (BB) Instructions 
 
 
 

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18.1 
ABT-888/Placebo Intake Calendar 
 
Cycle: ________    Start Date: ____________  Start Day (circle one): Sun  M  Tu  W Th  Fr  Sat   
 
Instructions for the participant: 
This is a 21 day cycle calendar on which you are to record the number of ABT-888/Placebo capsules 
you take each day.  ABT-888/Placebo should be taken twice daily at the same time of day for 14 days 
out of 21 days if taken with chemotherapy, or for 21 days continuously if taken after completing 
chemotherapy as monotherapy.  You may take the medication with or without food.  If you miss your 
scheduled dose of ABT-888/Placebo and less than 6 hours have passed since the scheduled dosing 
time, the dose may be taken.  
• 
Missed doses are to be omitted rather than made up. 
• 
If you vomit a dose, the dose should not be retaken. 
• 
If you develop any side effects from the capsule, mark this on the calendar on the day you note 
the effect.  Contact site personnel listed below. 
 
Put the date in the box on the calendar and note the time of each dose for each day.  Take medication 
as directed by study doctor. Line through the days medication is not taken. 
 
Storage: 
ABT-888/Placebo capsules should be stored at room temperature (not to exceed 25ºC) in their original 
container.  Keep the medication in the bottles provided and do not transfer it to any other container. 
If you have questions contact: ____________________ Telephone: _____________________ 
Special instructions: 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
 
AM: 
_______ 
PM: 
_______ 
 
Compliance confirmed by________________________________________ 
Research Staff Signature and Date 

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18.2 
Emergency Unblinding Guidelines 
 
a. 
General Considerations 
 
The randomized regimen for this study includes ABT-888 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 ABT-888/placebo as though he or she received ABT-888, 
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 ABT-888/placebo 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, Dr. Eve 
Rodler, or Dr. Priyanka Sharma).  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. 
 
The person calling the WPC must be prepared to provide the following 
information: 
 
Study number (S1416) 
SWOG Patient Number (e.g., "S1416-XXX") 
Patient Initials (LFM) 
Name and telephone number of the caller 
Reason emergency unblinding is thought to be required 
 

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3. 
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. Eve Rodler or 
Dr. Priyanka Sharma.  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. 
 
4. 
If the WPC is unable to contact any of its resource physicians or Drs. 
Rodler or Sharma 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 ABT-
888/placebo should proceed as if the ABT-888/placebo is ABT-888.  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 #3 
above. 
 
5. 
Any patient whose treatment assignment is emergency unblinded will 
receive no further ABT-888, but should continue all other protocol 
treatment if his/her medical condition permits. 
 
6. 
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: 
 
Eve Rodler, M.D. (Medical Oncology) 
UC Davis Comprehensive Cancer Center 
 
4501 X Street, Ste. 3016 
 
Sacramento, CA 95817  
Phone: 916/734-5959 
 
Fax: 916/734-7946 
 
E-mail: erodler@ucdavis.edu  
 
 
Priyanka Sharma, M.D. (Translational Medicine) 
University of Kansas CC & Med Pavilion  
2330 Shawnee Mission Parkway 
 
Mail Stop 5003  
Westwood, KS 66205 
 
Phone: 913/588-6029 
 
FAX: 913/588-4085 
 
E-mail: psharma2@kumc.edu   
 
Julie R. Gralow, MD 
Seattle Cancer Care Alliance 
825 Eastlake Ave E 
MS G3-630 
Seattle, WA  98109-1023 
Phone:  206/288-7722  
E-mail:  pink@u.washington.edu  
 
Washington Poison Center 
Phone:  206/526-2121 
 

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18.3 
New York Heart Association Criteria 
 
 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
* To control or relieve symptoms, as determined by the patient, rather than as advised by the physician. 
** At accustomed occupation or usual tasks. 
 

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18.4 
Patient Drug Information Handout and Wallet Card 
 
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements  
 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to the patient 
at the time of enrollment.  Use or modify the text as appropriate for the study agent, so that the 
patient is aware of the risks and can communicate with their regular prescriber(s) and pharmacist.  
A convenient wallet-sized information card is also included for the patient to clip out and retain at 
all times.  If you choose to use them, please note that the information sheet and wallet card will 
require IRB approval before distribution to patients.] 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
study drug ABT-888 (veliparib)/placebo.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for others who 
care for this patient.  
 
These are the things that you as a prescriber need to know: 
 
ABT-888 (veliparib)/placebo interacts with certain specific enzymes in the liver. 
• 
The enzymes in question are CYP 1A1, 2D6, 2C19, and 3A4.  ABT-888 (veliparib) is 
metabolized by these enzymes and may be affected by other drugs that inhibit or induce 
these enzymes. 
 
To the patient: Take this paper with you to your medical appointments and keep the attached 
information card in your wallet.   
 
ABT-888 (veliparib)/placebo may interact with other drugs which can cause side effects.  For this 
reason, it is very important to tell your study doctors of any medicines you are taking before you 
enroll onto this clinical trial.  It is also very important to tell your doctors if you stop taking any regular 
medicines, or if you start taking a new medicine while you take part in this study.  When you talk 
about your current medications with your doctors, include medicine you buy without a prescription 
(over-the-counter remedy), or herbal supplements such as St. John’s Wort.  It is helpful to bring 
your medication bottles or an updated medication list with you. 
 
Many health care providers can write prescriptions.  You must tell all of your health care providers 
(doctors, physician assistants, nurse practitioners, or pharmacists) you are taking part in a clinical 
trial.  
 
These are the things that you and they need to know:  
 
ABT-888 (veliparib)/placebo must be used very carefully with other medicines that need certain 
liver enzymes to be effective or to be cleared from your system.  Before you enroll onto the 
clinical trial, your study doctor will work with your regular health care providers to review any 
medicines and herbal supplements that are considered “strong inducers/inhibitors of CYP 1A1, 
2D6, 2C19, and 3A4.” 
• 
Please be very careful!  Over-the-counter drugs (including herbal supplements) may 
contain ingredients that could interact with your study drug.  Speak to your doctors or 
pharmacist to determine if there could be any side effects.  
• 
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.  
Your study doctor’s name is  
 
_____________________________________ and he or she can be contacted at  
 
_____________________________________. 
May 2015 
 

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STUDY DRUG INFORMATION WALLET CARD   
 
You are enrolled on a clinical trial using the experimental 
study drug ABT-888 (veliparib)/placebo.  This clinical trial is 
sponsored by the NCI.      ABT-888 (veliparib)/placebo may 
interact with drugs that are processed by your liver.  Because 
of this, it is very important to: 
 Tell your doctors if you stop taking any medicines or if you 
start taking any new medicines. 
 Tell all of your health care providers (doctors, physician 
assistants, nurse practitioners, or pharmacists) that you are 
taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need 
to use an over-the-counter medicine or herbal supplement. 
 
 
 
ABT-888 (veliparib)/placebo interacts with CYP 1A1, 
2D6, 2C19, and 3A4, and must be used very 
carefully with other medicines that interact with 
these enzymes and proteins. 
 Before you enroll onto the clinical trial, your study 
doctor will work with your regular health care 
providers to review any medicines and herbal 
supplements that are considered “strong 
inducers/inhibitors of CYP 1A1, 2D6, 2C19, and 
3A4” 
 Before prescribing new medicines, your regular 
prescribers should go to a frequently-updated 
medical reference for a list of drugs to avoid, or 
contact your study doctor.   
 Your study doctor’s name is 
________________________  
and can be contacted at _________________________.  

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18.5 
Translational Medicine 
 
a. 
Introduction: 
 
The overarching hypothesis of the study is that the combination of platinum therapy 
and ABT-888 will be most active in breast cancers (BC) associated with germline 
(g) BRCA mutations and in BRCA wild-type triple negative breast cancer (TNBC) 
that express the BRCAness phenotype, but less active in the non-BRCA 
phenotype TNBC.  Thus, the gBRCA testing and BRCAness phenotype 
assessment (which will be done using a multipronged biomarker approach) are 
integral biomarkers for this Phase II study (since the primary analysis depends on 
these assessments). The primary hypothesis tests whether ABT-888 is beneficial 
in the two populations, gBRCA mutation associated BC and in BRCA wild-type 
TNBC that express the BRCAness phenotype excluding those TNBC without the 
BRCAness phenotype. The secondary hypothesis then tests whether there is an 
interaction of ABT-888 and the BRCA phenotype (gBRCA positive and BRCAness 
type versus non-BRCA phenotype).  
 
The following hypotheses will be addressed in the primary and secondary 
objectives of this trial: 
• 
That cisplatin chemotherapy plus ABT-888 will be more effective than 
cisplatin chemotherapy alone in patients with gBRCA mutations and in 
patients with gBRCA wild-type metastatic TNBC that exhibit “BRCAness” 
phenotype (as assessed by predetermined BRCAness phenotype 
markers) but will not be effective in patients with gBRCA wild-type TNBC 
that lack BRCAness phenotype. 
• 
Up to 50% of gBRCA wild-type metastatic TNBC will exhibit “BRCAness” 
phenotype (as assessed by pre-determined BRCAness markers). 
• 
Pre-treatment metastatic tumor tissue may be a better tumor source than 
primary tumor to detect “real time” BRCAness phenotype in metastatic 
TNBC and that TM studies on pre-treatment tumor tissue may improve the 
performance of the already incorporated integral biomarkers in identifying 
TNBC patients likely to benefit from platinum-based therapy and ABT-
888/placebo. 
 
In 
order 
to 
address 
these 
hypotheses, 
we 
will 
perform 
several 
translational/correlative science investigations (Figure 1, Figure 2 and Table 1). 
These will include germline markers of homologous recombination repair 
deficiency and somatic markers of “BRCAness.” The latter is a term coined by 
Ashworth and colleagues to describe cancers (mostly triple negative) that arise in 
patients with known wild-type germline BRCA1 and 2, yet behave as if they harbor 
defects in homologous recombination and DNA repair. (1) Therefore, we will 
collect both germline and somatic tumor tissue. The germline DNA will be used to 
determine germline BRCA1/2 status and germline mutations in other genes 
involved in homologous recombination-Fanconi Anemia pathway. 
 
Somatic tissue will be collected from both gBRCA1/2 mutated and wild-type 
patients to determine “BRCAness” phenotype. We will mandate submission of at 
least archived, formalin-fixed, paraffin embedded (FFPE) primary cancer and/or 
metastatic tissue. Table 1 and Figure 1 list the integral BRCAness phenotype 
assays, with each assay described in detail later in this section.   
 

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b. 
Objectives:  
 
Primary objective:  
 
1. 
For patients with gBRCA mutation associated breast cancer or TNBC with 
a BRCAness phenotype, to compare the efficacy of cisplatin with or 
without ABT-888 on progression-free survival (PFS) (gBRCA mutation 
status and predetermined BRCAness phenotype markers are integral to 
the study). 
 
Secondary objectives:  
 
1. 
For patients with gBRCA mutation associated breast cancer or TNBC with 
a BRCAness phenotype, to compare the efficacy of cisplatin with or 
without ABT-888 on overall survival (OS) and overall response rate (ORR) 
(gBRCA mutation status and predetermined BRCAness phenotype 
markers are integral to the study) 
  
2. 
To test the following molecular determinants (in metastatic and/or primary 
tumor tissue) of response to ABT-888 and cisplatin-based chemotherapy 
(Integrated markers): 
 
a. 
Basal and Claudin low molecular breast cancer subtypes as 
assessed by PAM 50 assay  
b. 
Quantitative BRCA1mRNA expression  
c. 
Independent 
assessment 
of 
each 
individual 
BRCAness 
phenotype marker  
d. 
Novel BRCAness assays: if during the course of the study other 
novel and robust BRCAness assays become available we hope to 
evaluate the impact of the newer assay/s (independent of the pre-
specified BRCAness markers). Before being incorporated into the 
protocol, a new marker will require approval by SWOG Leadership 
and the NCI in accordance with policies for use of biospecimens 
from NCTN clinical trials. 
 
 
3. 
To determine the overlap of BRCAness phenotype (germline BRCA, 
BRCA-like, Non-BRCA-like) integral biomarkers with tissue PD-L1 status 
and to determine if veliparib benefit in patients with BRCA-like phenotype 
is maintained when adjusting for PD-L1 status. 
 
4. 
To evaluate CTC-HRD status as a predictive biomarker of response to 
treatment with cisplatin plus ABT-888 (veliparib) versus cisplatin plus 
placebo. 
 
5. 
To evaluate ctDNA HRR mutation status as a predictive marker of 
response to treatment with cisplatin plus ABT-888 (veliparib) versus 
cisplatin plus placebo. 
 

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Exploratory objectives:  
 
1. 
Evaluation of markers of PARPi resistance (e.g.: tissue 53BP1 and BRCA 
reversion mutations).  
 
2. 
To evaluate overlap among the various BRCAness markers.  
 
3. 
To collect and bank the following specimens for future research: 
 
a. 
Germline DNA  
b. 
Cancer Tissue  
c. 
Cell-free DNA 

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c. 
Figures and tables 
 
Figure 1: Trial schema with integral/integrated TM components 
 
 
 
 
Post hoc integrated and exploratory biomarker Analysis  

BRCA1 mRNA expression, Basal subtype 

PD-L1 IHC 

PAM50 BRCAness analysis of metastatic tumor tissue 

CTC NGS and circulating cell-free DNA analyses 
TNBC or BRCA 1/2 mutation associated breast cancer 
0 to 1 prior lines of cytotoxic chemotherapy in metastatic setting (N = 324) 
Randomize
Cisplatin 75 mg/m2 IV Day 1  
Placebo BID Days 1-14 
Cisplatin 75 mg/m2 IV Day 1 
ABT-888 300 mg po BID Days 1 - 14 
All patients will have germline BRCA testing (BROCA-HR, Swisher Lab, UW) 
after randomization and then will be assigned to the appropriate groups based 
on germline BRCA testing which is integral to the study 

Germline BRCA testing results provided to enrolling MD in 4 – 8 weeks  
Germline BRCA mutation confirmed positive 
(N = 44) 
Germline BRCA mutation confirmed negative 
(N = 241) 
BRCAness Group   (N = 99 estimate) 
Non-BRCAnessGroup  (N = 142 estimate) 
Post Randomization  
BRCAness Biomarker Analysis 
(Integral biomarkers) 

HRD mean score  

Somatic mutations in BRCA 
1/2  

Non-BRCA germline HR 
mutations  

BRCA1 promoter methylation 
 
Archived FFPE primary and/or 
metastatic tissue (if previously 
obtained)  
Optional: Pre-treatment 
metastatic tumor biopsy. 
1 Yellow top tube for germline 
testing 
One Streck tube for CTC and 
ctDNA 
 

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Table 1: Priority table for BRCAness phenotype markers  
Marker  
Material needed 
BRCAness phenotype *  
Priority order  
HRD score  
Tumor gDNA  
High HRD score  
1 
BRCA1 Promoter 
methylation(PM) 
Tumor gDNA 
PM present  
3 
Somatic BRCA 1/2  mutations 
Tumor gDNA 
Mutation/s present 
2 
Non-BRCA germline HR 
mutations 
Germline DNA 
Mutation/s present 
4 
*A positive result on >1 of the markers will place the subject in the BRCAness phenotype group 
 
Figure 2: Specimen workflow figure for TM studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
d. 
GERMLINE MARKERS OF HOMOLOGOUS RECOMBINATION DEFICIENCY  
Accruing site 
Specimen: One yellow top ACD 
solution A tube 
Laboratory/institution: Swisher 
Lab, University of Washington 
Address:  
University of Washington 
1959 NE Pacific St 
Seattle, WA 98195 
Contacts: Elizabeth Swisher, MD 
Shipment instructions: 
overnight ambient temperature 
Assay to be performed: 
BROCA-HR (Integral marker) 
All tumor specimens to be 
submitted to SWOG 
Biospecimen Bank 
1) Primary and metastatic 
FFPE specimens. 2) Pre-
treatment metastatic biopsy 
material. 
Store at SWOG 
Biospecimen Bank for 
post hoc integrated 
and 
exploratory assays  
1. Metastatic tissue 
2. Remaining Primary 
FFPE specimens  
Primary FFPE specimens to be distributed every quarter 
Laboratory/institution: Myriad Laboratories 
Inc.  
Address: Myriad Laboratory Inc  
320 Wakara Way, Salt Lake City, UT 84108  
 
Contacts: Anne-Rene Hartman, M.D. and 
Kirsten Timms, Ph.D. 
Amount: Three 10 micron uncharged slides 
plus one 5 micron charged slide for H&E 
staining (or H&E slide if already made by 
nationwide). 
Shipment instructions:  FedEx overnight 
on ice packs 
Assay to be performed: HRD score and 
somatic BRCA1/2 mutations (Integral 
markers) 
Laboratory/Institution: Univ. of Kansas 
Medical Center, CMOL 
Address: University of Kansas Medical 
Center CMOL, Mail Stop: 3040 
3901 Rainbow Boulevard 
Kansas City, KS  66160 
Contacts:  Priyanka Sharma, MD and 
Andrew Godwin, PhD 
Amount: Eight 10 micron uncharged 
slides plus one 5 micron charged slide 
for H&E staining (or H&E slide if already 
made by nationwide) 
Shipment instructions: FedEx 
overnight on ice packs 
Assays to be performed: BRCA1 
promoter methylation, BRCA1 
expression, PAM 50 basal subtyping 
(Integral and Integrated markers) 

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1. 
Germline BRCA1 and BRCA2 testing (BROCA-HR). 
 
Germline BRCA testing will be used as a stratification variable for this 
Phase II study. Germline (g) BRCA1/2 status is essential for assigning 
patients to germline BRCA mutation-positive and negative groups. 
BROCA-HR test will be done for gBRCA 1/2 testing. The patient will be 
entered into the trial and randomly assigned to ABT-888 or not. Upon 
availability of BROCA-HR result (which will be within 6-8 weeks of the 
patient’s entry into the trial) patient will be assigned to gBRCA mutation 
confirmed positive or negative group. Thus, gBRCA testing will not delay 
randomization to treatment or initiation of treatment. 
 
BRCA1 and BRCA2 (BRCA1/2) are tumor suppressor genes, in which 
inherited loss-of-function mutations confer a high lifetime risk of breast and 
ovarian carcinoma. (2) BRCA1/2 are key components of the BRCA-
Fanconi anemia (FA) pathway, which is critical to homologous 
recombination (HR)-mediated DNA repair. Repair of platinum-induced 
interstrand 
crosslinks 
invokes 
BRCA1-mediated 
homologous 
recombination, and there is abundant clinical and in vitro evidence that 
BRCA1-deficient cells are hypersensitive to platinum agents. (3,4,5,6,7,8)  
 
Randomized neoadjuvant and metastatic studies suggest that BRCA1/2 
mutation-associated breast cancers are very sensitive to platinum agents. 
(9,10,11,12,13,14) PARP enzymes recognize DNA damage and facilitate 
DNA repair to maintain genomic stability. Preclinical studies demonstrate 
that PARP inhibition in the presence of BRCA deficiency leads to synthetic 
lethality. (15) PARP inhibitors (i) have shown preclinical and clinical 
activity in targeting tumors with pre-existing DNA repair defects, in 
particular BRCA1 and BRCA2 deficient advanced breast and ovarian 
tumors. (16,17,18,19,20,21,22,23,24) A PARP inhibitor olaparib has 
recently been approved as monotherapy by the FDA as a first-in class drug 
to treat germline BRCA mutation associated advanced refractory ovarian 
cancers 
(https://www.fda.gov/drugs/resources-information-approved-drugs/fda-
approves-olaparib-germline-brca-mutated-metastatic-breast-cancer). 
 
The above data provide a strong rationale for evaluation of platinum- 
based chemotherapy with or without a PARPi in breast cancer patients 
with gBRCA1/2 mutations. Triple-negative breast cancers and BRCA1 
germline mutation-associated breast cancers share many histopathologic 
and molecular features. However, many additional genes involved in 
homologous recombination may be altered by mutation, rearrangement, 
DNA methylation or attenuated mRNA expression and can result in 
impairment of the HR pathway in TNBC. It is speculated that if other factors 
beyond germline BRCA mutations are comprehensively evaluated, 50-
60% of TNBC will demonstrate HR deficiency or BRCAness. (25,26,27) 
The combination of platinum therapy and PARP inhibition may be most 
active in tumors with germline BRCA1 deficiency and in BRCA wild-type 
tumors that harbor the BRCAness phenotype. 
 
The main aim of this randomized Phase II study is to investigate whether 
the addition of a PARP inhibitor (ABT-888) to platinum-based therapy will 
improve progression free survival (PFS) for patients with germline BRCA 
mutation-associated breast cancers and sporadic triple negative breast 
cancers that express a BRCAness phenotype. Thus, gBRCA1/2 testing for 
the entire study cohort is essential (integral biomarker) for identification of 
the gBRCA mutation positive and negative cohorts. Further delineation of 

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the BRCAness phenotype in the gBRCA mutation negative (sporadic) 
TNBC will be done utilizing a priori defined markers (as described above 
in Table 1 and later in the document). 
 
2. 
Laboratory conducting BROCA-HR assay: 
 
Elizabeth Swisher, MD 
Professor, Dept Ob/Gyn 
University of Washington 
1959 NE Pacific St 
Seattle, WA 98195 
(206)543-3669 
 
Laboratory: King/Swisher Lab 
University of Washington 
1959 NE Pacific St, 
Health Science Building, K154 
Seattle, WA 98195 
(206)616-4296 
CLIA ID No: 50D0631935 
Expiration: 9/27/2019 
 
3. 
Description of the BROCA-HR assay: 
 
A targeted capture and massively parallel sequencing approach called 
BROCA will be applied to samples. For the proposed study, a more recent 
version of BROCA-HR with 40 genes (includes BRCA1/2 as well as genes 
selected based on known involvement hereditary breast/ovarian cancer or 
Homologous recombination/ genomic stability) will be utilized. Library 
preparation has been fully automated to increase sample turnaround and 
lower cost. Paired-end libraries with 350bp inserts will be prepared from 
1ug of constitutional DNA and hybridize to a custom pool of 
oligonucleotides targeting genomic regions as previously described using 
the SureSelectXT enrichment system on a Bravo liquid-handling 
instrument (Agilent). (28) Following capture, samples will be barcoded with 
48 different indexed primers. The pooled samples are sequenced on a 
single lane of a HiSeq flowcell (Illumina) with 2x101bp paired end reads 
and a 7bp index read to allow for de-multiplexing and binning of individual 
samples. Single nucleotide variants and insertions and deletions will be 
detected as previously described with some updates in the bioinformatics 
pipeline. (29,30) Deletions and duplications of exons will be detected by a 
combination of depth of coverage and split read analysis as previously 
described, supplemented with additional alignments generated by 
SLOPE. (31,32) All germline loss of function mutations in cancer 
susceptibility genes will be confirmed with PCR amplification and Sanger 
sequencing. 
 
 

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4. 
Description of the specimens, and anticipated methods for specimen 
acquisition and processing: 
 
Preferred Specimen: 7ml whole blood 
Minimum Volume: 3.5 mL 
Instructions: Collect in yellow top (ACD solution A) tube. Specimen to be 
shipped at ambient temperature for overnight delivery. 
Specimen Stability: Room temperature: 3 days; Refrigerated: N/A; Frozen: 
N/A 
Specimen processing: DNA will be extracted from peripheral blood 
mononuclear cells (PBMCs) 
The results will be reported as deleterious germline BRCA mutation 
“present” or absent. Variants of uncertain significance will not be reported. 
 
5. 
The expected distribution of the biomarker in the study population: 
 
It is estimated that 20% of the study population will demonstrate 
deleterious germline BRCA1/2 mutation. (33,34) Cutpoints will not be 
used for germline BRCA testing. Test results will be described as 
deleterious germline mutation “present” or “absent”. In gBRCA mutation-
positive patients median PFS of 4 months is assumed for Arm 1 (cisplatin) 
that improves to 7 months for Arm 2 (cisplatin + ABT-888). 
 
6. 
The accessibility of the biomarker assay results: 
 
Clinical BRCA testing report will be provided to the enrolling site for all 
patients.  The genetic testing results for each patient will be provided via 
Rave® as a report uploaded in the Genetic Testing Results folder. 
 
Genetic counseling services for sites with patients with positive results will 
be provided when needed (via telephone). Sites/providers in need of such 
service should contact Dr. Elizabeth Swisher at swishere@uw.edu. Note 
that counseling services are provided to sites to assist with how to manage 
patients in need of genetic counseling.  The counseling provided is not 
intended to be provided directly to patients, and is not required of the site.  
Sites may refer patients to their preferred genetic counseling service. 
 
7. 
Data on the analytical performance of the assay: 
 
Accuracy and precision BROCA HR captures > 99% of known deleterious 
BRCA1 and 2 Mutations. (24) Deleterious BRCA1 and BRCA2 mutations 
will be defined in the standard fashion to include protein truncating 
mutations (with the exception on the benign variant BRCA2 K3326*), and 
missense mutations demonstrated experimentally to be damaging. Both 
“BIC”, and “HGVS” nomenclatures will be used to report the deleterious 
mutations. Variants of uncertain significance will not be reported. 
Turn-around time: 4-8 weeks 
Failure rate: <1%.  (35) 
 
 

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8. 
Discrepancy between prior germline BRCA testing and trial testing:  
 
Although germline BRCA testing is recommended for a significant number 
of TNBC patients (all patients < 60 years of age) we expect that only 40-
50% of patients will have had prior testing.  We expect to find a deleterious 
BRCA mutation via the BROCA test in small percentage (< 2%) of patients 
who have had a prior negative BRCA test. This will be typically due to 
missed gene-disrupting large rearrangements. With the BROCA test, the 
chances of not detecting a previously known deleterious BRCA mutation 
are virtually nil (centralized BRCA testing has been done by BROCA-HR 
on >3000 cancer patients on clinical trials, and all previously known BRCA 
mutations were detected, personal communication Dr. Swisher). 
 
e. 
Germline testing for Non-BRCA genes (BROCA-HR) 
 
1. 
Background 
 
Germline BRCA1/2 mutations are the prototype molecular alterations that 
confer homologous recombination deficiency and sensitivity to PARPi. 
(36,37) PARPi also selectively kill cells in vitro that are deficient in other 
homologous recombination (HR) genes including RAD51D, NBN, ATM, 
and CHEK2. (38,39) Germline and somatic mutations in BRCA1/2 and 
other BRCA-FA genes in ovarian carcinomas are associated with 
improved response to primary platinum therapy and longer overall 
survival. (40)  Germline loss-of-function mutations in 12 such genes in 
ovarian cancer were evaluated using the BROCA test. Germline mutations 
were noted in >90% of the genes in the Fanconi anemia pathway with a 
prevalence of 23% in this series of ovarian cancer patients. (41) Utilizing 
the similar targeted genomic capture and next-generation sequencing 
platform a recent study evaluated inherited mutations in FA-HR genes in 
high risk African-American breast cancer patients. In this series of African-
American patients 22% of harbored a damaging mutation in one of the FA-
HR pathway genes. (42)  In a large unselected TNBC population a recent 
study has reported a non-BRCA germline mutation prevalence rate of 4%. 
(43) Thus, 4-22% of TNBC patients may carry germline mutations in non-
BRCA FA pathway gene and presence of these mutations has high 
likelihood of impacting response to PARPi therapy.  
 
Accordingly, a panel of FA-HR pathway gene is incorporated in the 
BROCA-HR test. The following genes are included in the BROCA-HR test: 
   
BROCA HR pathway: ATM, ATR, BABAM1, BAP1, BARD1, BLM, BRCA1, 
BRCA2 (FANCD1), BRIP1 (FANCJ), BRCC3, BRE, CHEK1, CHEK2, 
ERCC1, ERCC4 (FANCQ), FAM175A (abraxas), FANCA, FANCB, 
FANCC, FANCD2, FANCE, FANCF, FANCG (XRCCC9), FANCI, FANCL, 
FAMCM, GEN1, MRE11A, NBN, PALB2 (FANCO), RAD50, RAD51C 
(FANCO), RAD51D, RBBP8 (CtIP), SLX4 (FANCP), UIMC1 (RAP80), 
XRCC2,TP53 PI3K pathway: PTEN, PI3KCA 
 

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Non-BRCA Germline mutations in FA-HR genes will be used as a 
stratification variable for this phase II study. BROCA-HR testing which 
includes BRCA1/2 and other FA-HR pathway genes will be done post 
randomization for all patients. Patients with non-BRCA deleterious 
mutations in FA-HR genes will be stratified to the BRCAness group.  We 
estimate that 4-7% of the study population with WT gBRCA1/2 will harbor 
deleterious germline mutations in non BRCA FA-HR genes. (44,45) 
Cutpoints will not be used for germline testing. Test results will be 
described as deleterious germline mutation “present” or “absent”.  
Presence of germline BRCA1/2 mutation will supersede the finding of 
germline mutation in non BRCA genes for group assignment (for example 
if a patient is found to have both a deleterious BRCA mutation and 
deleterious mutation in an additional FA-HR pathway gene, that patient 
will be placed in the gBRCA mutation positive group). 
 
Laboratory conducting the BROCA-HR assay:  
 
Elizabeth Swisher, MD 
Professor, Dept Ob/Gyn 
University of Washington 
1959 NE Pacific St 
Seattle, WA 98195 
(206)543-3669 
 
Laboratory: King/Swisher Lab 
University of Washington 
1959 NE Pacific St,  
Health Science Building, K154 
Seattle, WA 98195 
(206)616-4296 
CLIA ID No: 50D0631935 
Expiration: 9/27/2019 
 
2. 
Description of the BROCA-HR assay:  
 
A targeted capture and massively parallel sequencing approach called 
BROCA-HR will be applied to samples. For the proposed study, a more 
recent version of BROCA-HR with 40 genes (includes BRCA1/2 as well as 
genes selected based on known involvement hereditary breast/ovarian 
cancer or Homologous recombination/ genomic stability) will be utilized. 
Library preparation has been fully automated to increase sample 
turnaround and lower cost. Paired-end libraries with 350bp inserts will be 
prepared from 1ug of constitutional DNA and hybridize to a custom pool 
of oligonucleotides targeting genomic regions as previously described 
using the SureSelectXT enrichment system on a Bravo liquid-handling 
instrument (Agilent). (46) Following capture, samples will be barcoded with 
48 different indexed primers. The pooled samples are sequenced on a 
single lane of a HiSeq flowcell (Illumina) with 2x101bp paired end reads 
and a 7bp index read to allow for de-multiplexing and binning of individual 
samples. Single nucleotide variants and insertions and deletions will be 
detected as previously described with some updates in the bioinformatics 
pipeline. (47,48) Deletions and duplications of exons will be detected by a 
combination of depth of coverage and split read analysis as previously 
described, supplemented with additional alignments generated by 
SLOPE. (49,50) All germline loss of function mutations in cancer 
susceptibility genes will be confirmed with PCR amplification and Sanger 
sequencing. 
 

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3. 
Description of the specimens and methods for specimen acquisition 
and processing:  
 
Specimen collected for germline BRCA testing will be utilized for testing of 
the non BRCA HR pathway genes and added specimen will not be 
needed.  
 
4. 
The accessibility of the biomarker assay results: 
 
Germline mutations for these additional genes involved in FA-HR pathway 
may impact response to DNA damaging therapy (like PARPi) in an 
affected individual with known breast cancer. Results of BRCA1, BRCA2 
and other ten actionable genes in the BROCA-HR panel (ATM, BARD1, 
BRIP1, CHEK2, NBN, PALB2, PTEN, RAD51C, RAD51D, TP53) will be 
provided to the treating physician. Only deleterious mutations will be 
reported, and variants of uncertain significance will not be reported. 
Mutations in other FA-HR pathway genes included in this BROCA-HR 
panel which are not known to have clear evidence of increased cancer risk 
will not be provided to the treating physicians since this part of the test is 
“research use” only and not considered to be of clinical significance. 
 
The genetic test result for all trial patients will be provided back to the 
ordering physician and will include both “positive” and “negative” results 
for 12 genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBN, 
PALB2, PTEN, RAD51C, RAD51D, TP53). As stated above a positive 
result will only include “deleterious mutation”. Mutations of uncertain 
significance will not be reported.  
 
Providers will also have access to phone genetic counseling and advice 
regarding management guidelines for sites/providers with patients with 
deleterious mutations. This may specifically be needed for mutations in 
non BRCA genes. If a site/provider wishes to make use of this resource 
please contact Dr Swisher at swishere@uw.edu. For further questions you 
can also contact Dr. Sharma at: S1416question@swog.org. Please note 
that genetic counseling services are available to sites, not individual 
patients. The counseling provided is not intended to be provided directly 
to patients, and is not required of the site.  Sites may refer patients to their 
preferred genetic counseling service. 
 
5. 
Data on the analytical performance of the assay:  
 
Accuracy and precision BROCA HR captures > 99% of known deleterious 
germline mutations in FA-HR pathway.  (51) 
Reportable range, reference ranges/intervals (normal values): Deleterious 
mutations will be defined in the standard fashion to include protein 
truncating 
mutations, 
and 
missense 
mutations 
demonstrated 
experimentally to be damaging. Both “BIC” and “HGVS” nomenclatures 
will be used to report the deleterious mutations. Variants of uncertain 
significance will not be reported. 
Turn-around time: 12 weeks 
Failure rate: < 1% (52)  
 
 

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f. 
SOMATIC BRCAness PHENOTYPE MARKERS 
 
Formalin Fixed paraffin embedded primary tumor tissue (collected for routine 
clinical care) will be used for somatic BRCAness phenotype markers. If the 
primary tumor tissue is not available FFPE metastatic tumor tissue will be used 
for these assays.  
 
1. 
Homologous Recombination Deficiency (HRD) assay and somatic 
BRCA1/2 mutations  
 
Tumor Homologous Recombination Deficiency assay and somatic BRCA 
mutation testing will be used as a stratification variable for this Phase II 
study.  Tumor HRD and somatic BRCA mutation testing will be done post 
randomization for all patients. In the germline BRCA mutation negative 
group (see Figure 1) patients with high HRD score or somatic BRCA 
mutations will be stratified to the BRCAness group. Tumor HRD and 
somatic BRCA mutation testing is done simultaneously as part of one 
single test.  
  
In addition to BRCA1 and BRCA2, there are many additional homologous 
recombination-related genes that may be altered by mutation, 
rearrangement, DNA methylation or mRNA expression that are 
hypothesized to result in impairment of the homologous recombination 
pathway.  A Homologous Recombination Deficiency (HRD) assay has 
been developed by Myriad Inc., which evaluates genomic patterns of loss 
of heterozygosity (LOH) “footprint” as an indicator of HR deficiency and 
thus allows for the detection of homologous recombination deficiency 
regardless of its etiology or mechanism. The assay is compatible with 
FFPE tumor tissue, requires 200-500 ng of tumor DNA and has high 
sensitivity for identification of BRCA-deficient tumors. (53,54,55)  
 
The HRD assay has recently been evaluated in several TNBC clinical 
studies. (56,57,58) In a cohort of 77 TNBC/BRCA mutation carriers 
enrolled on a neoadjuvant study of gemcitabine, carboplatin and iniparib 
(a drug which was initially investigated as a PARP inhibitor however 
oxidative damage is now thought to be the mechanism of cytotoxicity), 
74% of TNBC tumors had a high HRD score. The mean HRD score was 
higher for responders vs. non responders and there was no difference in 
the HRD scores between the BRCA-intact and mutant responders. The 
HRD score significantly correlated with pathologic response to platinum-
based chemotherapy in this study (RCB 0/1 rate of 70% in patients with a 
high score vs. 20% in patients with a low score, p=0.0001). (59) High HRD 
score also predicted pathological complete response to neoadjuvant 
platinum-based chemotherapy in another neoadjuvant study. (60) 
 
Correlative work from a Phase II metastatic platinum trial (TBCRC-009) 
has also recently demonstrated that high tumor HRD predicts response to 
treatment. (61)  
 

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A recent randomized Phase III trial (TNT) demonstrated that in unselected 
metastatic TNBC patients carboplatin was equal in efficacy to docetaxel in 
metastatic setting. (62) However, in gBRCA mutation associated TNBC 
carboplatin yielded a superior response rate and progression-free survival 
compared to docetaxel.  In the TNT study high HRD score (done on 
primary tumor specimens) in gBRCA negative patients did not select for 
sensitivity to carboplatin over docetaxel. Further, correlative work from the 
TNT study where other BRCAness markers like BRCA1 promoter 
methylation (PM) and HRD will be evaluated simultaneously are awaited 
and may explain the lack of association of response between high HRD 
score and platinum therapy. Our proposal does not rely on just HRD and 
utilizes four different markers to designate BRCAness in gBRCA negative 
patients (HRD score, somatic BRCA mutations, BRCA1 PM and germline 
BRCA mutations in other FA-HR pathway genes). It is possible that the 
Myriad HRD assay does not identify all tumors with HR deficiency (and 
thus response to platinum and or/PARP inhibitors) in metastatic setting 
and thus may lead to inaccurate predictive results when used as an only 
test of BRCAness phenotype.  
 
Tumor HR deficiency assays have not been evaluated as predictive 
biomarkers of response to PARPi in breast cancer yet, but recent 
encouraging data has come forth from the ovarian cancer literature. 
Correlative biomarker work from the ARIEL2 ovarian cancer study (Phase 
II study of single agent PARPi, Rucaparib) was recently presented. This 
trial recruited a significant proportion of BRCA wild-type tumors in order to 
identify biomarkers of response to PARPi in this population. 42% of the 
BRCA wild-type study population had tumor genomic LOH and presence 
of tumor genomic LOH was associated with response to single agent 
rucaparib in BRCA wild-type patients. (63) This data highly supports the 
concept of utilizing tumor LOH/genomic instability assay to select for 
PARPi therapy in the context of a clinical trial.  
 
BRCA1 and BRCA2 somatic mutations occur in approximately 4% of 
TNBC. (64,65) Ovarian cancer literature suggests that somatic BRCA 
mutation also confer sensitivity to PARPi. (66) Somatic BRCA mutations 
are identified in the process of Myriad HRD test, thus a separate test (or 
tumor material) will not be needed for BRCA1/2 somatic mutation testing.  
 
Results of the HRD assay and somatic BRCA mutation testing will not be 
provided to the treating physicians or the patients.  
 
2. 
Laboratory conducting the assay:  
 
Myriad Laboratory Inc  
320 Wakara Way, Salt Lake City, UT 84108  
Attention: Anne-Rene Hartman M.D and Kirsten Timms PhD 
CLIA ID No: 8/14/15 
Expiration: 8/14/15 
 
 

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3. 
Description of the assay:  
 
Extraction of DNA from FFPE tumors: A 5 micron H&E slide will be 
reviewed by a pathologist to facilitate enrichment of tumor derived DNA. 
Ten micron sections will be cut and regions of highest tumor cell density 
will be scraped from the slide. For DNA extraction, the Promega Maxwell 
16 FFPE Plus LEV DNA purification kit (Promega, Madison, WI) will be 
used. Tissue will be incubated overnight at 56 degrees Celsius with 
proteinase K in a shaking heat block.  After the overnight incubation 
undigested material is spun out and the Maxwell cartridges are loaded. 
gDNA will be eluted in 60 ul of low TE. 
 
Hybridization capture and sequencing: A custom capture panel will be 
used targeting 54,091 SNPs. 50 – 200 ng of genomic DNA will be sheared 
to an average size of 150 base pairs on a Covaris E220 focused 
ultrasonicator. Sheared DNA end repair, A-base tailing, and adapter 
ligation reactions and indexed library amplification will be performed 
according to manufactures recommendations (Kapa Biosystems, cat. # 
KK8200).  Kapa HiFi PCR will be performed for 6 cycles with the following 
cycling parameters: 98°C for 45 seconds; 8 cycles of 98°C for 15 seconds, 
60°C for 30 seconds, 72°C for 30 seconds; 72°C for 1 minute.  Genomic 
libraries will then pooled at an equal molar ratio and hybridized with the 
SureSelectxt2 
capture 
library 
according 
to 
manufactures 
recommendations (Agilent Technologies, cat. # 5190-4867).  Post 
hybridization amplification will then performed on pooled indexed libraries 
using Kapa HiFi PCR for 8 cycles with the following parameters: 98°C for 
45 seconds; 8 cycles of 98°C for 15 seconds, 60°C for 30 seconds, 72°C 
for 30 seconds; 72°C for 1 minute.  Libraries will be quantified on an Agilent 
2200 Tape, normalized to 2nM, and denatured using 0.1 NaOH prior to 
sequencing.  Sequencing will be performed on an Illumina HiSeq 2500 
according to manufacturer’s protocols (Illumina). 
 
Tumor BRCA1 and BRCA2 mutation screening: Sequence reads 
generated on the HiSeq2500 are trimmed at both the start and end to 
remove low quality bases that could generate spurious variant calls. To 
call variants each read is aligned with the expected wild-type sequence of 
the exon. This alignment is a pairwise alignment performed by JAligner 
(http://jaligner.sourceforge.net/). Any differences represent variants. 
Variant calls from all reads for a sample are compiled in order to calculate 
the frequencies of all identified variants. Mutation Sequencing does not 
differentiate between germline and somatic mutations.  Specifically, we 
are not assessing for inherited BRCA1 and 2 mutations 
 
SNP Analysis: A SNP sequence database for mapping sequence reads 
will be created by cutting from the whole genome (version 19) sequences 
of the SNPs with 400 bp flanks around the SNP positions. Each sequence 
read will be considered mapped if it matched to the database sequence 
with 7 or less mismatches. Sequence reads overlapping a SNP position 
will be used to count the SNP alleles. The resulting read counts will used 
to reconstruct allele specific copy number (ASCN) at each SNP location 
using an algorithm. (67)  
 
 

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4. 
Quality of ASCN reconstruction: To evaluate the quality of ASCN 
reconstruction, a quality metric, KS quality, was introduced. The specific 
definition of KS quality is based on Kolmogorov-Smirnov statistic. High 
quality ASCN reconstruction is expected to produce high KS quality. 
Through visual inspection of about hundred samples, a cutoff value 12.7 
for KS quality has been established. ASCN reconstructions with KS quality 
below this cutoff are considered as failed. There are two major reasons for 
failures: (1) high noise level in the sequence data and (2) low tumor 
content in a sample. 
 
5. 
Calculation of HRD-LOH, HRD-TAI, HRD-LST, and HRD-Sum scores:  
 
HRD-LOH score is defined as the number of LOH regions longer than 15 
Mb but shorter than the whole chromosome. (68,69) HRD-TAI score is 
defined as the number of regions with allelic imbalance longer than 11 Mb 
that extend to one of the subtelomeres but do not cross the centromere. 
(70) A region will be counted only if it encompassed a certain minimum 
number of SNPs (on average approximately 1.8 Mb).  
 
HRD-LST score is the number of break points between regions longer than 
10 Mb after filtering out regions shorter than 3 Mb. (71) HRD-LST score 
increases with ploidy both within BRCA1/2 intact and deficient samples. 
Instead of using ploidy-specific cutoffs, the HRD-LST score was modified 
by adjusting it by ploidy: LSTm = LST – kP where P is ploidy and k is a 
constant. Based on multivariate logistic regression analysis with deficiency 
as an outcome and HRD-LST and P as predictors, k = 15.5 provided the 
best separation between intact and deficient samples.  
 
6. 
Scoring procedures and type of data to be acquired:  
 
Type of data will be quantitative/ continuously distributed.  HRD-Sum 
score is the sum of the HRD-LOH, HRD-TAI and HRD-LST scores (the 
number of LOH regions longer than 15 Mb but shorter than the length of a 
whole chromosome). (72,73) TAI Score (the number of telomeric regions 
imbalance which extend to the subtelomere but do not cross the 
centromere) and LST Score (the number of chromosomal breaks between 
adjacent regions longer than 10 Mb after filtering out regions shorter than 
3 Mb). The HRD score ranges from 0-100. A high HRD score is defined 
as 42 or greater based on data generated by the manufacturer (Myriad). 
Patients with a high tumor HRD score (i.e., >42) will be stratified to the 
BRCAness group regardless of the tumor BRCA mutation results.  
Patients with tumor/somatic BRCA mutation will be stratified to BRCAness 
group regardless of the HRD score.  Within the germline BRCA mutation-
negative section of the study population it is estimated that 40% patients 
will demonstrate a high HRD score and 4% will demonstrate somatic 
BRCA mutations. (74,75,76) 
 
7. 
Description of the specimens and methods for specimen acquisition 
and processing:  
 
Formalin fixed paraffin-embedded primary tumor tissue block. 
 
Minimum Volume: Three 10-micron uncharged slides for DNA isolation 
and, one 5-micron charged/uncharged slide for H&E staining  
 
Instructions: Specimens to be shipped on ice via overnight Fedex to the 
SWOG Biospecimen Bank.  
 

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Specimen processing: Specimens (slides or FFPE blocks) will be stored 
at the SWOG Biospecimen Bank at 4˚C till ready to be shipped to Myriad 
Inc for HRD analysis.  
 
8. 
Data on the analytical performance of the assay:  
 
Reportable range:  
The reportable range of HRD assay is between 0-100.  
Somatic (tumor) BRCA mutations will be reported as “present” or “absent”.  
Turn-around time: 8-12 weeks 
Failure rate: 10% 
 
g. 
BRCA1 PROMOTER METHYLATION.  
 
1. 
Introduction:  
 
Tumor BRCA1 promoter methylation (PM) testing will be used as a 
stratification variable for this Phase II study.  Tumor BRCA1 PM testing 
will be done post randomization for all patients in the germline BRCA 
mutation-negative group (see trial Schema) and patients with tumor 
BRCA1 PM will be stratified to the BRCAness group. 
 
Hypermethylation of the BRCA1 promoter has been proposed as one of 
the mechanisms for functionally inactivating the BRCA1 gene in sporadic 
breast cancers and this epigenetic inactivation of BRCA1 is associated 
with a gene expression profile similar to that of inherited BRCA1 mutation-
associated breast cancer. (77,78,79) BRCA1 PM is observed in 20-40% 
of sporadic TNBC and may be an important mechanism contributing to the 
loss of BRCA1 function in sporadic TNBC. (80,81,82,83,84) 
 
Methylation-specific PCR (MSPCR) has been utilized to detect 
hypermethylation of the areas of interest in the CpG islands of the BRCA1 
promoter by many investigators. (85,86,87) MSPCR is relatively 
inexpensive and can be performed on genomic DNA derived from 
formalin-fixed paraffin-embedded (FFPE) tissue, and can be being easily 
applied to clinical settings.  We recently completed two pilot studies to 
examine the feasibility of detecting BRCA1 PM and mRNA expression on 
FFPE tissue and to investigate the prognostic significance of BRCA1 PM 
and expression in patients treated with chemotherapy for early stage 
TNBC. (88,89) 
 
In the first study of 39 patients, BRCA1 PM was detected in 30% of the 
specimens, was associated with lower BRCA1 transcript levels 
(suggesting epigenetic silencing of BRCA1 gene) and was associated with 
significantly worse DFS and OS in this cohort of anthracycline-based 
chemotherapy treated patients (Figure 2A and B). (90) 
 

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Figure 2: Kaplan-Meier Recurrence-free survival (A) and Overall Survival 
(B) curves from the anthracycline cohort and overall survival curve (C) 
from platinum cohort. Presence of BRCA1 PM was designated as 
“BRCAness present” in the anthracycline cohort.  
 
In a second pilot study, tissue BRCA1 PM and BRCA1 expression and 
germline BRCA mutations were evaluated in 30 patients who received 
neoadjuvant platinum-based chemotherapy. BRCAness (defined by the 
presence of a germline BRCA1/2 mutation or BRCA1 PM or low BRCA1 
mRNA expression) was present in 53% of patients and was associated 
with significantly better OS survival in this platinum-treated cohort (Figure 
2C). (91)  
 
In both of these studies we were able to successfully determine BRCA1 
promoter methylation status in 95% of the FFPE specimens using 
methylation-specific PCR assay.  An ongoing correlative science study 
lead by SWOG (S9313C, Evaluation of BRCAness as Prognostic Marker 
in Triple-Negative Breast Cancer Patients Treated with Adjuvant 
Anthracycline-Based Chemotherapy, PI: Sharma) is also further 
evaluating prognostic value of tissue BRCA1 PM (and other BRCAness 
markers) in 455 early stage TNBC patients. The results of this large study 
are expected in early 2016 and will also inform the analysis of the present 
proposal.  Embedded within this study, the CMOL is validating a promoter 
methylation assay using next generation sequencing techniques in a 
subset of specimens. If proven more sensitive than the current approach 
then future analyses may incorporate this NGS assay.  Bisulphite-treated 
DNA for the gel-based assays will be used for this validation. 
 
In summary, BRCA1 PM could serve as a clinically useful biomarker that 
could identify a significant proportion of early stage TNBC patients who 
likely would experience enhanced benefit from BRCA1-directed 
therapeutic approaches such as platinum compounds and/or PARP-
inhibitors.  Indeed, in vitro data suggests that epigenetic silencing of 
BRCA1 via promoter methylation confers the same degree of sensitivity to 
PARP inhibitors as does BRCA1 mutation. (92) 
 
A 
B 
C 
BRCA1 PM (BRCAness) present 
BRCA1 PM (BRCAness) present 
BRCAness present 
BRCAness absent 
BRCA1 PM (BRCAness) absent 
BRCA1 PM (BRCAness) absent 

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2. 
Laboratory conducting the BRCA1 PM assay:  
 
Andrew K Godwin, PhD 
Professor, Department of Pathology & Laboratory Medicine, University of 
Kansas Medical Center 
Director, Molecular Oncology, University of Kansas Medical Center 
University of Kansas Medical Center 
Kansas City, KS 66160 
   
Laboratory: 
Clinical Molecular Oncology Laboratory (CMOL) 
University of Kansas Medical Center 
2601 Olathe Boulevard 
Bldg 020, Room 4005 
Kansas City, KS  66160 
 
Mailing address: 
University of Kansas Medical Center 
CMOL, Mail Stop: 3040 
3901 Rainbow Boulevard 
Kansas City, KS  66160 
Director Office: 913-945-6373 
Assistant Director Office: 913-945-6388 
Laboratory: 913-945-6391 
CLIA ID No: 17D2042936 
Expiration: 06/17/2016 
 
3. 
Description of the assay:  
 
Methylation Specific PCR (MSP) 
Genomic DNA (gDNA) will be isolated using commercially available kits 
(EpiTect Plus FFPE Bisulfite Kit, Qiagen).  Purified converted DNA (100 
ng) will be subjected to methylation-specific PCR (MSPCR) using the 
EpiTect® MSP Kit (Qiagen).  The unmethylated template primers will be 
(forward) 
TTGGTTTTTGTGGTAATGGAAAAGTGT 
and 
(reverse) 
CAAAAAATCTCAACAAACTCACACCA, resulting in an 86 base pair PCR 
product.  The methylated template primers will be (forward) 
TCGTGGTAACGGAAAAGCGC and (reverse) 
AAATCTCAACGAACTCACGCCG, resulting in a 75 base pair PCR 
product.  These primers have been extensively characterized by previous 
groups. (43-49) PCR conditions will be as follows:  95°C for10 minutes, 
then 35 cycles of 94°C for 15 seconds, 55°C for 30 seconds, 72°C for 30 
seconds, and a final extension at 72°C for 10 minutes.  PCR products will 
be electrophoresed on a 2.5% agarose gel stained with ethidium bromide 
and visualized on a UVP Bioimaging system.  Specificity of the reactions 
will be confirmed using the EpiTect® Control DNA set (Qiagen) with the 
same primers and PCR conditions.  Gels images (e.g., Figure 1) will be 
visualized with UV light in a MultiImage Light Cabinet (Alpha Innotech 
Corp).  The intensity of each band will be measured and analyzed using 
the AlphaView SA software (Cell Biosciences, Inc).  These relative band 
intensities will be used to establish the quantitative ratio of the two 
products by comparing the unmethylated and methylated bands. 
 
 

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Figure 1: (B) Specificity controls for the MSP reaction.  Unconverted 
genomic DNA (CC), universally unmethylated bisulfite-converted genomic 
DNA (CU) and universally methylated bisulfite-converted (CM) will be 
amplified with primers specific for bisulfite-converted unmethylated (U) or 
methylated (M) BRCA1 promoter. 
 
4. 
Description of the specimens and methods for specimen acquisition 
and processing:  
 
Formalin fixed paraffin-embedded primary tumor tissue block. 
Minimum Sample Requirement: Three 10 micron uncharged slides for 
DNA isolation and one 5 micron charged slide for H&E staining. 
 
Instructions: Specimens to be shipped by overnight FedEx delivery to 
SWOG Biospecimen Bank Specimen processing: Specimens (slides or 
FFPE blocks) will be stored at the SWOG Biospecimen Bank at 4 ˚C until 
shipped to the University of Kansas Medical Center for the correlative 
studies. 
 
5. 
Scoring procedures and type of date to be acquired:  
 
Type of data will be Qualitative/non-ordered categorical.  The results will 
be reported as BRCA1 promoter methylation “present” or “absent”. 
 
6. 
Expected distribution and cut points: It is estimated that 30% of the 
germline BRCA mutation negative study population will demonstrate 
BRCA1 PM. (93,94,95,96,97) We do not expect any patients with 
germline BRCA mutations to have tissue BRCA1 PM as several prior 
studies have previously demonstrated that germline BRCA mutations and 
BRCA1 PM are mutually exclusive. (98,99,100) 
 
Cutpoints will not be used for reporting BRCA1 PM.  Test results will be 
recorded as BRCA1 PM “present” or “absent”.  We will use band intensity 
ratios between unmethylated and methylated to determine the promoter 
methylation status.  Commercially available positive and negative controls 
(EpiTect Control DNA set by Qiagen) will be used with each run as well as 
run-to-run clinical positive and negative samples.  The band intensity ratio 
of clinical samples will be compared to commercial positive and negative 
controls to define the methylation status. 
 
BRCA1 promoter methylation results will not be relayed back to the 
patients or the providers 
 

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7. 
Data on the analytical performance of the assay: 
 
Accuracy 
and 
precision: 
The 
Clinical 
Laboratory 
Improvement 
Amendments (CLIA) to the code of federal regulations (42 CFR part 493) 
govern quality standards for laboratory testing of human specimens for the 
purpose of diagnosis, prevention, treatment of disease, or assessment of 
health.  CLIA regulations require that each laboratory that introduces a lab-
developed-test system must do the following before reporting patient test 
results: demonstrate that it can obtain performance specifications 
comparable to those established by the manufacturer for the following 
performance characteristics: a. accuracy; b. precision; c. reportable range 
of test results for the test system.  The accuracy or overall concordance is 
defined as: (# of True positives + # of True negatives) / (# of True positives 
+ # of False positives + # of False negatives + # of True negatives).  The 
inner-laboratory comparison of tests results will be used to estimate assay 
accuracy.  If the observed result agreed with the expected result the result 
is assumed to be “true” for the purposes of determining “true positives” 
and “true negatives”. If the observed result disagreed with the expected 
result the result is assumed to be “false” for the purposes of determining 
“false positives” and “false negatives”.  The precision which includes 
repeatability (within-run imprecision) and reproducibility (run-to-run, day-
to-day imprecision) will be achieved by consistent and expected test 
results from the tests on multiple runs throughout the validation period.   
 
Turn-around time: 6-8 weeks 
Failure rate: <5% 
 
h. 
Liquid 
Biopsy 
Integrated 
Markers: 
Circulating 
tumor 
cells 
(CTC) 
homologous recombination deficient (HRD) status and HR repair (HRR) gene 
mutation status.  
 
1. 
Background: 
 
a. 
CTC-HRD 
 
Various studies have correlated the homologous repair deficiency 
(HRD)  phenotype with chromosome instability (CIN) measured 
by aggregate copy number alterations (CNA) in the genome (101). 
Large-scale transitions (LST), is a form of CNA defined as 
chromosomal breakages that generate chromosomal gains or 
losses of 10 Mb or more. LST (also known as ‘genome scarring’) 
correlates HRD associated with the presence of BRCA1/2 
mutations in breast and ovarian cancer (102,103). Using the High 
Definition-Single Cell Analysis (HD-SCA) methodology (EPIC 
sciences, CTC platform) the tissue-based LST measure has been 
adopted for single circulating tumor cells (CTC) and the technical 
feasibility of determining LST number in single CTCs by next-
generation sequencing (NGS) has been demonstrated (104, 105).    
 

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Evaluation of LST along with morphometric parameters in prostate 
cancer CTCs using the commercial version of the HD-SCA (Epic 
Sciences) has recently been published (106). In this study 10,240 
CTCs in 367 pre-treatment blood samples obtained from 294 
patients with metastatic castration-resistant prostate cancer were 
studied and a CTC with 9 or more LSTs was scored as a LST-high 
CTC. It was demonstrated that high LST in CTC was a marker of 
HRD/ CIN.  At a cutoff of 3 or more LST-high CTCs per mL of 
blood, the sensitivity was 83%, specificity 100%, and PPV of 
100%. Thus, an LST score of 9 or greater in >3 CTC cell/ml blood 
was deemed to be the appropriate threshold for denoting CTC 
HRD/CIN positive status.  In this large study morphological 
analysis of CTC was also used to ‘predict’ which single CTCs (and 
thereby, which cases) are likely to exhibit CIN (or genomic 
evidence of HRD), followed by single cell NGS analysis to score 
LST. Using a clinical validation sets it was also demonstrated the 
above defined threshold for CIN in pretreatment CTCs strongly 
associated with poor overall survival in patients treated with 
androgen receptor signaling inhibitors and taxanes. In this study 
overall frequency of patients with  ≥3 LST-high CTCs per mL of 
blood exceeded 40%.  This threshold of CTC LST coupled with 
cell morphology metrics has also been assessed in a phase II 
prostate cancer study that compared aboraterone to abiraterone 
+ veliparib. In this study, CTC- HRD/CIN positive status was noted 
in 48% of patients and correlated with better PSA responses with 
abiraterone + veliparib compared to abiraterone in patients with 
metastatic prostate cancer (107).  
 
For the analysis on the S1416 samples, the technology and 
thresholds described above will be used to denote CTC-HRD 
status for the primary analysis.  Alternative thresholds for CTC-
HRD will be explored in secondary analyses. 
 
Somatic HRR mutations and PARPi efficacy: 
  
Emerging studies are now starting to demonstrate efficacy of 
PARPi in setting of somatic HRR gene mutations in ovarian and 
prostate cancer. TOPARP-B trial in prostate cancer and ARIEL 2 
study in ovarian cancer demonstrated preliminary efficacy of 
PARPi in patient population beyond germline or somatic BRCA 
mutations (108, 109). In breast cancer, a small Phase II study also 
suggested benefit of PARP inhibitor Talazolarib in breast cancer 
patients with non-BRCA somatic HRR genes mutations (110). 
Lack of availability of adequate amount of tissue samples and 
assay failure pose challenges for HRD profiling when using tissue 
sample thus underscoring the need for a non-invasive, ctDNA 
alternative. For example, in S1416 even in setting of mandatory 
tumor tissue submission, for 22% of patient population tissue 
based HRD could not be determined. Furthermore, CTC HRD 
assessment is also dependent on presence of CTC and is 
uninformative for patients who do not have any CTC. Thus, 
assessment of ctDNA based HRD is a valuable addition to the 
GuardantOMNITM, is a 500-gene liquid biopsy panel that 
annotates 
pathogenic 
SNV/Indels, 
identify 
structural 
rearrangements, gene-level homozygous deletions, loss-of-
heterozygosity (LOH) and genome-wide LOH, CNV and de-novo 
fusions. GuardantOMNITM ctDNA tests performance has recently 
been studies in >620 prostate cancer patients and showed that 

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relative prevalence of ctDNA detected HRR alterations was 
consistent with those in tissue (111). We plan to use 
GuardantOMNITM for assessment of ctDNA HRR gene 
mutations. 
 
2. 
Hypotheses:  
 
a. 
Patients 
with 
CTC-HRD+ 
status 
will 
experience 
longer 
progression-free survival (PFS) in the presence of cisplatin plus 
ABT-888 (veliparib) treatment compared to treatment with 
cisplatin plus placebo.  
 
b. 
Patients with ctDNA HRR gene mutation (pathogenic/likely 
pathogenic) will experience longer progression-free survival 
(PFS) in the presence of cisplatin plus ABT-888 (veliparib) 
treatment compared to treatment with cisplatin plus placebo. 
 
3. 
Laboratories conducting the assays:  
 
CTC-HRD:  
Convergent Science Institute in Cancer 
University of Southern California (USC) 
1002 Childs Way, MCB 350 
Los Angeles, CA 90089-3502 
 
and 
 
Epic Sciences, Inc. 
9381 Judicial Drive, Suite 200 
San Diego, CA 92121 
 
Both laboratory locations are operating equivalent experimental setups.  
 
Allocation of work is as follows: 
 
Convergent Science Institute in Cancer at USC: Custom cryostorage of 
slides as per protocol (already completed as part of previous objectives); 
QA/AC as per protocol. Data analysis of scanning and genomics data 
(lead). 
 
Epic Sciences, Inc.: Staining and scanning of slides. Single cell genomics. 
Data analysis of scanning and genomic data (will be accomplished jointly 
with USC). 
 
Although this work will be performed  in a Research Use Only (RUO) 
format, a CLIA-CAP certified version of the high definition-single cell 
analysis (HD-SCA) has been commercialized by Epic Sciences (La Jolla, 
CA) and the reimbursable test for androgen receptor variant 7 is available. 
 
ctDNA  
Guardant Health, Inc  
505 Penobscot Dr. 
Redwood City, CA 94063 
 
 

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4. 
Description of the specimens and previous methods for specimen 
acquisition and processing:  
 
CTC-HRD: In accordance with the previously approved S1416 protocol: a) 
whole blood samples were previously collected in 10 mL cfDNA Streck 
tubes, b) shipped overnight to the Kuhn/Hicks lab at USC, c) upon receipt, 
plasma was separated/aliquoted and frozen and the cellular components 
spread on prepared microscope slides (within 48 hours of blood 
collection), and then d) slides were stored at -80°C for subsequent 
analysis 
(e.g.: 
immunofluorescent 
staining, 
cell 
enumeration, 
morphometric analysis and sequencing). As of December  12, 2020, the 
Kuhn-Hicks lab at USC had received, processed, and archived slides 
representing 798 draws from 331 unique patients, with a processing failure 
rate of <2%.  
 
CTC-HRD: As indicated above, approximately 8 mL whole blood was 
previously collected in 10mL cfDNA Streck tubes, from 3 timepoints:  prior 
to treatment, Cycle 2/ Day 1, and at time of progression will be utilized. At 
least two slides corresponding to the analysis of approximately 1 mL of 
blood will be analyzed. Given that 8 mL of blood was collected for each 
patient, only a small proportion of the total sample available will be utilized 
for the CTC-HRD analysis. 
 
ctDNA:  2-4 mLs of frozen plasma (previously collected and stored) will be 
utilized. 
 
5. 
Description of the assays: 
  
a. 
CTC-HRD assessment 
 
The HD-SCA® (high definition-single cell analysis) workflow 
(Figure 1) is developed as a direct analysis approach for rare cells 
to extract the maximum information from the cellular and acellular 
components of a blood draw. The cell-based component is 
designed to identify multiple subpopulations of cells in blood 
samples and capability to subject these cells to genomics and 
targeted proteomics characterization. It is based on semi-
quantitative 
imaging 
approaches, 
including 
4-color 
immunofluorescence (IF) and digital morphometry where DAPI is 
used to identify nucleated cells, CD45 to identify white blood cells 
(WBC), a pan-cytokeratin cocktail to identify cells of epithelial 
origin, and CD31 to exclude endothelial cells. The HD-SCA 
protocol also isolation and storage of plasma that can be 
processed for ctDNA sequencing.  
 
Figure 1: HD-SCA with specifics for CTC detection, imaging, and large-scale transitions (LST) scoring. 
CTC-HRD:  

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CTC-HRD is a combination of CTC immunostaining and genomic 
assay. Semi-quantitative imaging approaches, including 4-color 
immunofluorescence (IF) and digital morphometry is utilized to 
identify CTCs (DAPI is used to identify nucleated cells, CD45 to 
identify white blood cells (WBC), a pan-cytokeratin cocktail to 
identify cells of epithelial origin, and CD31 to exclude endothelial 
cells). Identified CTCs will then be picked for low-pass 
sequencing. Previously published and widely used methodology 
will be employed for generating quantitative CNA data from single 
cells. (112, 113, 114).  Bioinformatic analysis will be as previously 
published (115, 116). (After sequencing and generation of 
genomic CNA profiles, each cell will be scored for large-scale 
transitions (LST) (CNA segments >10 Mbp). A CTC with 9 or 
more LSTs will be scored as LST-high CTC. Patient samples 
with 3 or more LST-high CTCs per mL of blood will be 
denoted as CTC-HRD positive (CTC-HRD+). 
 
CTC Q/A and feasibility data from S1416: 
 
Given the novelty of CTC-genomics for HRD assessment in breast 
cancer a feasibility pilot was desired. However, a TNBC metastatic 
1-2nd line treated patient sample set where liquid biopsy samples 
were processed on the HD-SCA platform and single CTC could 
be subjected to sequencing could not be identified. Thus, a 30 
sample Q/A endeavor utilizing random pretreatment S1416 
samples was undertaken to establish feasibility. This was 
undertaken in the blinded fashion without knowledge of either 
treatment arm assignment, patient outcome or tissue HRD 
assignment. In this Q/A study 75% of the pretreatment samples 
demonstrated >3.0 CTC/ml and of the samples with >3 CTC/ml, 
45% met the above-described CTC-HRD positive threshold.  
 
b. 
CtDNA  
 
GuardantOMNITM:  
 
ctDNA NGS analysis will be performed at Guardant Health, Inc. 
(Redwood City, CA), a CLIA-certified, College of American 
Pathologists (CAP)-accredited, New York State Department of 
Health-approved laboratory.   
 
The 2.145 Mb GuardantOMNI assay identifies single nucleotide variants (SNVs) and indels in 500 genes, 
copy number amplifications (106 genes), fusions (21 genes), MSI-High status, and tumor mutational burden 
(TMB) (117, 118). SNVs and indels are classified as somatic or germline using a statistical beta-binomial 
model (119). PlasmaTMB will be reported as mutations per Mb by the GuardantOMNI algorithm which 
includes all somatic synonymous and non-synonymous SNVs and indels excluding germline, CHIP, driver 
and resistance mutations, with statistical adjustment for sample-specific tumor shedding and molecular 
coverage. Samples with low tumor shedding (all somatic mutations <0.3% maximum somatic allele fraction) 
or low unique molecule coverage will be identified as plasmaTMB-unevaluable. Validation of plasmaTMB 
and MSI have been previously described (120,121). Assuming optimal input material the anticipated assay 
failure rate is < 2%.  
 

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 Product Features 
GuardantOMNITM 
Number of genes 
500 genes 
Total size 
2.145 Mb 
Optimal input 
material 
5-30 ng cfDNA from ≥2mL plasma 
Somatic variant 
detection 
• 
Small Nucleotide Variants 
(SNVs, 496 genes) 
• 
Short insertions/deletions 
(Indels, 496 genes) 
• 
Copy Number Amplifications 
(CNAs, 106 genes) 
• 
Fusions (21 genes) 
Tumor Mutational 
Burden (TMB) 
TMB score (mut / Mb) 
Microsatellite 
Instability (MSI) 
MSI-High status 
Homologous 
Recombination 
Repair Deficiency 
(HRD) 
24 HRR genes (list provided in a 
separate document) 
• 
SNV/Indel Deleterious and 
Reversion Annotation 
• 
Copy number deletions 
(homozygous, loh, and 
indeterminate zygosity) 
• 
Fusions and long (multi-exon) 
deletions  
• 
Biallelic mutation annotation 
 
 

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Alteration 
Type 
Reportable 
Range 
95% Limit 
of 
Detection 
(LoD) 
Specificity 
SNVs  
(496 genes) 
≥0.04% 
0.15 – 0.6%* 
>99% 
Indels  
(496 genes) 
≥0.1% 
0.4 – 0.8%* 
>99% 
Activating 
Fusions  
(21 genes) 
≥3 
molecules 
0.1 – 0.2% 
>99% 
Amplifications 
(106 genes) 
≥2.18 
copies 
2.18 – 2.9 
copies for 
90% of 
genes 
>99% 
HRR 
Deletions  
(13 genes) 
≤1.82 
copies 
8 – 30% 
tumor 
fraction** 
>99% 
HRR LoF 
Fusions  
(24 genes) 
≥3 
molecules 
0.1 – 0.2% 
>99% 
*  
Range for 95% LoD include clinically actionable and non-clinically 
actionable variants, respectively. 
**  Range for 95% LoD is for homozygous and heterozygous deletions, 
respectively.  
All metrics are based on 30 ng input using cfDNA clinical samples 
except for HRR deletions, which are based on in-silico simulations 
as described in Figure 1.  
Specificity is based on false negative variant detection across a 
large cohort of normal samples. 
 
ctDNA HRR mutation distribution:  
 
The above 24 genes will comprise ctDNA HRR mutation panel. 
Patients with known germline BRCA1/2 mutations will be excluded 
from this analysis.   
 
Based on the review of existing literature and interrogation of 
METABRIC and TCGA data sets, it is expected that 30% of patient 
samples will demonstrate ctDNA HRR mutations.  
 
Results of CTC, CTC-HRD testing and ctDNA will not be provided 
to the treating physicians or the patients. 
 

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6. 
Endpoints:  
 
a. 
Primary 
 
The primary outcome in the clinical trial, progression-free survival 
(PFS), would be the primary outcome for these TM analyses.  
 
b. 
Secondary 
 
Overall survival and response rate would be secondary endpoints. 
 
7. 
Statistical Analyses:  
 
S1416 completed accrual with 335 in the primary cohort, of whom 322 are 
eligible. The trial results were reported at the virtual ASCO meeting in June 
2020 and the primary manuscript is in preparation.  
 
The protocol specified three separate comparisons as shown in the table 
below. Classification into HRD phenotype for the primary study 
assessment is based on tissue HRD. Some patients were not able to be 
classified due to missing tissue or blood, or failure of the tissue HRD 
assay/s.  
 
The 257 patients with negative germline BRCA status will be used for 
statistical analysis. This includes 48 patients with who are germline 
negative, but have unknown tissue HRD status due to assay failure/lack 
of tumor tissue. Therefore, using pretreatment blood for HRD phenotype 
assessment provides a complementary means for assaying HRD in 
S1416. 
 
Table 2. Analysis of PFS for the primary S1416 trial subgroups  
 
Subgroup 
Eligible 
N 
Median PFS 
for placebo 
vs. ABT-888 
HR (ABT-888 vs. 
placebo),  95% CI, 
and p-value 
1: gBRCA mutation +ve 
37 
6.4 mos. vs. 
6.2 mos. 
0.66 (0.30-1.44); 
p=0.29 
2: gBRCA mutation -ve 
HRD phenotype 
present 
99 
4.2 mos. vs. 
5.9 mos. 
0.53 (0.34-0.83); 
p=0.006 
3: gBRCA mutation -ve 
HRD phenotype 
absent  
110 
3.0 mos. vs. 
4.0 mos. 
0.89 (0.60-1.32); 
p=0.89 
Unclassified 
75 
 
 
 
 

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a. Primary Objective: To assess the impact of pre-treatment CTC-
HRD status on PFS in patients treated with chemotherapy versus 
chemotherapy plus ABT-888 (veliparib) on S1416. 
 
Classification into HRD phenotype for the primary study 
assessment is based on tissue HRD. In the current proposal we 
propose basing HRD phenotype on CTC-HRD status.  
 
Of the 257 eligible patients who tested as germline BRCA 
negative, 252 (98%) contributed a baseline blood sample for CTC 
and ctDNA evaluation. We expect 75% of the patients would have 
detectable CTCs (n=189) at the threshold level of ≥3 cells/ml. Any 
value less than 3 cells/ml is considered below the level of 
detection and is called negative. 
 
Patient samples with 3 or more LST-high CTCs per mL of blood 
will be denoted as CTC-HRD+. 50% of patients with detectable 
CTC are expected to have CTC-HRD+ status, thus this assay 
would evenly divide patients as HRD+ and HRD- (n~94 in each 
group).).  In those with available blood specimens submitted, the 
overall treatment hazard ratio for veliparib versus placebo is 0.78 
(95% CI 0.60-1.01) with median PFS of 4.3 months and 3.3 
months for veliparib and placebo, respectively.  
 
For the power calculations we assume 50% in each treatment 
group and 50% for each CTC-HRD group (positive or negative).  
For medians we assume 3.3 months for placebo treatment for 
both HRD+ and HRD- while for the veliparib arm we assume 3.3 
months for HRD- and 6.1 months for HRD+ patients. This is 
consistent with the overall treatment effect ignoring HRD status 
under an exponential model.   
 
i.  gBRCA mutation negative, CTC-HRD positive patients would 
have improved PFS with ABT-888 (median 6.1 mos) than with 
placebo (3.3 mos) when combined with chemotherapy 
(HR=0.54). For the expected  95 total patients distributed 
equally by treatment arm with median follow-up of two years 
and two-sided α=0.05, there is 84% power to show a 
significant difference between treatment arms. Analysis is by 
log-rank testing and Cox regression. 
 
ii. 
gBRCA mutation negative, CTC-HRD negative patients would 
not have improved PFS with ABT-888 (median 3.3 mos) than 
with placebo (3.3 mos) when combined with chemotherapy. 
We would have n=95 patients for this comparison. We would 
not formally test with a noninferiority design due to sample 
size requirements. We would not expect any statistically 
significant differences with log-rank testing and Cox 
regression.  
 
iii. Prediction: Among gBRCA mutation negative patients, CTC-
HRD positive patients would have improved PFS with ABT-
888 (median 6.1 mos) than with placebo (3.3 mos) when 
combined with chemotherapy, while there would be no 
treatment effect for CTC-HRD negative patients with ABT-888 
(median 3.3 mos) than with placebo (3.3 mos) when combined 
with chemotherapy. There would be 95 patients in both the 

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positive and negative groups. With median follow-up of two 
years and one-sided α=0.10 (consistent with the original 
hypotheses), there is 79% power to show a significant 
interaction between subgroup and treatment. Analysis is by 
Cox regression.  
 
b. Secondary Objective: To evaluate pre-treatment ctDNA HRR 
mutations (HRRmut) as predictive marker of response to 
treatment with cisplatin plus ABT-888 (veliparib) versus cisplatin 
plus placebo. 
 
We assume that n=247 (98%) of the patients who submitted blood 
(n=252) will have availability of ctDNA HRR mutations 
GuardantOMNITM test.  We also assume that 30% will be positive 
for HRR mutations.   
 
For the placebo arm we assume no difference in median PFS by 
HRRmut status (i.e.: 3.3 months for both).   
 
For the veliparib arm we assume median PFS of 3.7 months for 
the 70% with negative HRRmut status and median PFS of 6.9 
months for the 30% with positive HRRmut status. This is 
consistent with the observed veliparib median of 4.3 months 
overall based on an exponential model. 
 
i. 
First, we show that treatment is effective in the subset positive 
for ctDNA HRRmut (n=74). Treatment with ABT-888 would 
result in improved PFS (median 6.9 mos) compared to 
placebo (3.3 mos) when both arms receive chemotherapy. 
One-half of the 74 patients are in each treatment arm. With 
median follow-up of two years and two-sided α=0.05, there is 
88% power to show a significant difference between treatment 
arms. Again, analysis is by log-rank testing and Cox 
regression. 
 
ii. 
For those without ctDNA HRRmut we expect very small 
improvement in PFS with ABT-888 (median 3.7 mos) than 
with placebo (3.3 mos) when combined with chemotherapy. 
For this comparison we would have 173 patients since 70% 
are expected to be negative. As expected this difference is not 
likely to be statistically significant (2-sided α=0.05) with a 
power of 11%.  We will test this difference using a log-rank 
test followed by Cox regression.  
 
iii. Prediction: HRRmut patients would have improved PFS with 
ABT-888 (median 6.9 mos) than with placebo (3.3 mos) when 
combined with chemotherapy, while there would be modest 
treatment effect for patients negative for HRR mutations with 
ABT-888 (median 3.7 mos) than with placebo (3.3 mos) when 
combined with chemotherapy. For the positive group there 
would be n=74 patients, while the negative group would have 
n=173. With a median follow-up of two year and one-sided 
α=0.10, there is 82% power to show a significant interaction 
between HRRmut subgroup and treatment. Analysis is by Cox 
regression.  
 
c. Exploratory objectives: 
 

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i. 
We will assess the degree of overlap between CTC-HRD 
positivity and HRRmut positivity. It is possible that HRRmut 
positivity is a subset of CTC-HRD positivity. If there is some 
discrepancy then a combined classification could be more 
powerful.  
 
ii. 
We will assess the overlap of tissue HRD status with HRD 
status of liquid biopsy components. 
 
iii.  To be called CTC-HRD positive there must be 3 or greater 
CTC cells/ml as a minimum threshold.  It is possible that a 
higher value may be optimal. After the distribution of CTC-
HRD is determined, two higher values will be selected that 
identify significant fractions of positive values to be useful.  
The survival analyses described above would be repeated 
with the two higher values to determine if either maximizes 
prediction of benefit of veliparib using the higher threshold. 
Any newly established cutpoint would need to be validated in 
another cohort of similar patients.  
 
iv.  CTC with 9 or more LSTs is to be designated as LST-high 
CTC. It is possible that a higher value may be more optimal. 
After distribution of LST is assessed we will evaluate alternate 
LST cutoffs. The survival analyses described above would be 
repeated with the alternate LST cut offs to determine if 
alternate cut offs maximizes prediction of benefit. Any newly 
established cutpoint would need to be validated in another 
cohort of similar patients. 
 
j. 
OTHER INTEGRATED BIOMARKERS 
  
1. 
PD-L1 
 
a. 
Introduction  
 
Since the initiation of S1416, immune checkpoint inhibitors have 
shown activity in treatment of patients with metastatic TNBC. In 
2020, the U.S. Food and Drug Administration granted approval to 
pembrolizumab in combination with chemotherapy for patients 
with TNBC whose tumors express PD-L1 (CPS ≥10)). FDA also 
approved the PD-L1 IHC 22C3 pharmDx (Dako North America, 
Inc.) as a companion diagnostic for selecting patients with TNBC 
for pembrolizumab. This approval was based on the IKEYNOTE-
355 trial which enrolled patients with metastatic TNBC who had 
not received prior chemotherapy for metastatic disease. (122)  In 
the KEYNOTE-355 trial, 38% of patients demonstrated tumor PD-
L1 positivity (CPS>10.  Pembrolizumab plus chemotherapy is now 
considered standard of care first line treatment for patients with 
metastatic TNBC with PD-L1 positivity.  (123)    
 
Assessment the overlap between BRCA-like phenotype and PD-
L1 positivity will be a vital component to inform the appropriate 
setting and patient population for a Phase III trial evaluating 
PARPi + cisplatin combination. The information about this overlap 
is not available from any other trials. The Impassion 130 trial 
demonstrated that that about 50% of patients with germline BRCA 
1/2 mutation have PDL-1 positivity. (124) This proportion is not 

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much different than what is noted for unselected TNBC patients 
where 40% are noted to have PD-L1 positivity.  
 
PD-L1 testing was not planned at the initiation of the trial given 
lack of information on efficacy of immune check point inhibitors in 
breast cancer at the time of development of S1416. There is some 
indirect evidence from another SWOG-led TM study (S9313C, PI: 
Priyanka Sharma) that shows that for patients with early stage 
TNBC there is some overlap between immune rich and HRD 
phenotype TNBC but that this overlap is not complete. For 
example, in S9313C there was no association between tumor 
infiltrating lymphocytes (TILs) and HRD status and only a modest 
association between an immune gene signature and HRD 
(unpublished data).    
 
The hypothesis is that PD-L1 positivity in BRCA-like phenotype 
TNBC will be similar to what is noted for unselected TNBC (i.e., 
approximately 40-50%), and, similarly, that PD-L1 status will not 
change the effect of veliparib in S1416 nor will it be prognostic. 
PD-L1 status (by immunohistochemistry) will be assessed for all 
enrolled patients for whom gBRCA status and BRCA-like status is 
available and primary tumor tissue is available in the SWOG 
Biospecimen Repository (Estimated N=246) to allow for combined 
classification of patients by PD-L1 status and BRCA phenotypes. 
 
b. 
Laboratory Conducting the Assay 
 
Laboratory: 
Biospecimen Resource Core Facility (BRCF) Histology Service/ 
Pathology Histology Resource 
University of Kansas Medical Center 
3901 Rainbow Boulevard 
Hixson Building, Room G013 
Kansas City, KS 66160 
 
Andrew K Godwin, PhD Professor & Division Director, Genomic 
Diagnostics, Director, BRCF  
Rashna Madan, MBBS, Professor, Assistant Director, BRCF &  
Department of Pathology & Laboratory Medicine 
University of Kansas Medical Center 
Kansas City, KS 66160 
 
c. 
Required BioSpecimen samples 
 
• 
Two (2) 4–5 microns thick, positively charged and unbaked 
slides plus  
 
d. 
Description of the Assay 
 
PD-L1 protein expression in TNBC is determined by using 
Combined Positive Score (CPS), which is the number of PD-L1 
staining cells (tumor cells, lymphocytes, macrophages) divided by 
the total number of viable tumor cells, multiplied by 100.The 
specimen will be considered PD-L1 positive if CPS ≥ 10 (PD-L1 
IHC 22C3 pharmDx Interpretation Manual – Triple-Negative 
Breast Cancer). Immunohistochemical staining for PD-L1 will be 
performed utilizing the PD-L1 IHC 22C3 pharmDx kit from Dako 

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Agilent, Santa Clara, CA using a standardized clinical protocol 
with appropriate positive and negative controls. 
 
e. 
Endpoints 
 
Primary endpoint: Determine the overlap of (integral) BRCA 
phenotype (germline BRCA, BRCA-like, Non-BRCA-like) with 
(integrated) PD-L1 status. 
 
Secondary endpoint: Determine if veliparib benefit in BRCA-like 
patients is maintained when adjusting for PD-L1 status.  
 
f. 
Statistical Plan 
 
The analysis will include 246 patients classified previously by the 
integral markers into three groups: 37 germline BRCA positive 
patients; 99 BRCA-like patients; and 110 non-BRCA-like patients. 
Our primary question is whether the BRCA-positive phenotypes 
which includes 136 patients (gBRCA (n=37) and BRCA-like 
(n=99)) differ from the non-BRCA- like group with respect to PD-
L1 status. Assuming that 90% can have PD-L1 determined will 
give results for 122 and 99 respectively for the two groups.  We 
do not expect there to be an association of PD-L1 with the two 
groups (1. gBRCA and BRCA-like; (2) Not BRCA-like).  A 
difference of 19% in PD-L1 positivity between the two groups can 
be detected with 80% power and 2-sided α=0.05. Chi-square 
testing is used.  We will also assess any difference within germline 
BRCA and BRCA-like patients though power is limited to find a 
significant difference. Even with no significant difference among 
the BRCA phenotypes, it will still be informative for future trial 
design. 
 
For the secondary outcome we wish to determine if PD-L1 might 
confound the effect of veliparib on PFS and OS. Separately, for 
the BRCA-like and non-BRCA-like groups we will fit a Cox model 
of randomized treatment on the survival outcomes with 
stratification for line of therapy. Then PD-L1 will be added to the 
Cox model to determine if it changes the effect of veliparib by 10% 
or more (definition of confounding).  We predict it will not change 
the effect of veliparib nor will PD-L1 be prognostic. 
 
2. 
BRCA1 EXPRESSION 
 
a. 
Introduction 
 
Tumor quantitative BRCA1mRNA expression will be evaluated for 
its association with outcome under cisplatin therapy with or 
without ABT-888. 
 
Retrospective biomarker studies in lung and ovarian cancer 
suggest that low BRCA1 expression may be associated with 
response to platinum chemotherapy. (125,126) We recently 
completed two pilot studies to examine the feasibility of detecting 
BRCA1 PM and mRNA expression on formalin-fixed paraffin-
embedded (FFPE) tissue and to investigate the prognostic 
significance of BRCA1 PM and expression in patients treated with 
chemotherapy for early stage TNBC. (127,128) The data on 
BRCA1 PM has already been described in the previous section.  

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In the first study of 39 patients, treated with anthracycline-based 
adjuvant chemotherapy low BRCA1 expression was prognostic. 
Five-year RFS was 44% for patients with BRCA1 expression in 
the lowest three quartiles compared to 89% for patients with 
BRCA1 expression in the highest quartile (p=0.034, log rank test). 
While the same trend was maintained for OS (five-year OS 67% 
lowest three quartiles; 89% highest quartile), the trend was not 
statistically significant (p=0.099, log rank test). (129) In the second 
pilot study, tissue BRCA1 PM and BRCA1 expression and 
germline BRCA mutations were evaluated in 30 patients who 
received neoadjuvant platinum-based chemotherapy. BRCAness 
(defined by the presence of a germline BRCA1/2 mutation or 
BRCA1 PM or low BRCA1 mRNA expression) was present in 53% 
of patients and was associated with significantly better OS survival 
in this platinum-treated cohort. (130) 
 
In both of these studies we were able to successfully determine 
BRCA1 mRNA expression in >90% of the FFPE specimens.  An 
ongoing correlative science study lead by SWOG (S9313C, 
Evaluation of BRCAness as Prognostic Marker in Triple-Negative 
Breast Cancer Patients Treated with Adjuvant Anthracycline-
Based Chemotherapy, PI: Sharma) is also further evaluating 
prognostic value of tissue BRCA1 mRNA in 455 early stage TNBC 
patients.  
 
b. 
Laboratory conducting the assay:  
 
Andrew K Godwin, PhD 
Professor, Department of Pathology & Laboratory Medicine, 
University of Kansas Medical Center 
Director, Molecular Oncology, University of Kansas Medical 
Center 
University of Kansas Medical Center 
Kansas City, KS 66160 
   
Laboratory: 
Clinical Molecular Oncology Laboratory (CMOL) 
University of Kansas Medical Center 
2601 Olathe Boulevard 
Building 020, Room 4005 
Kansas City, KS  66160 
 
Mailing address: 
University of Kansas Medical Center 
CMOL, Mail Stop: 3040 
3901 Rainbow Boulevard 
Kansas City, KS  66160 
Director Office: 913-945-6373 
Assistant Director Office: 913-945-6388 
Laboratory: 913-945-6391 
CLIA ID No: 17D2042936 
Expiration: 06/17/2016 
 
 

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c. 
Description of the assay 
 
RNA isolation: Tumor-dense areas of the FFPE tissue sections 
will be macrodissected.  There will not be any correction for tumor 
content in the sample.  Minimum tumor content of 20% will be 
required. RNA will be isolated using commercially available kits.  
 
BRCA1 mRNA quantitative real-time PCR (qRT-PCR): RNA will 
be reverse transcribed to cDNA which will be assayed in duplicate 
for BRCA1 transcript levels as well as reference transcripts using 
specific primer and probe sets. Cycle threshold (Ct) values will be 
calculated for each endpoint, corrected for housekeeping gene 
expression and relative gene expression will be calculated using 
the ΔΔCt method, with normal breast tissue cDNA as calibrator. 
(131)  
 
Scoring procedures: BRCA1 expression will be reported as 
multiples of the median. (132)  Expression is a continuous marker 
so it will be tested in two ways.  First, low expression (first quartile) 
will be tested against higher values (upper 75%) in a Cox 
regression, adjusting for treatment.  For the second method, log 
expression will be tested as a continuous variable in the Cox 
regression. We will be assessing BRCA1 expression both as a 
binary and continuous variable.  Low BRCA1 expression is 
expected to be associated with response to DNA damaging 
therapy.  Since the goal is to use BRCA1 expression as a 
predictive marker of response (and not resistance) to DNA 
damaging therapy, we want to compare the group with lowest 
expression to the rest of the study population. Thus, a binary split 
at 25% was chosen.  Furthermore, S9313C is also using the 
binary split at 25%. 
 
d. 
Description of the specimens and methods for specimen 
acquisition and processing: Formalin fixed paraffin-embedded 
primary tumor tissue block. 
 
Minimum Sample Requirement: Two 10 micron uncharged slides 
for RNA isolation and one 5 micron charged slide for H&E staining. 
 
Instructions: Specimens to be shipped by overnight FedEx 
delivery to SWOG Biospecimen Bank Specimen processing: 
Specimens (slides or FFPE blocks) will be stored at the SWOG 
Biospecimen Bank at 4˚C until shipped to the University of Kansas 
Medical Center for the correlative studies.  
 
e. 
Power Calculation 
 
We will be measuring BRCA1 expression in patients known to not 
have BRCA mutations.  Then, 164 patients will have available 
PFS and BRCA1 expression data.  To compare the bottom 25% 
to the upper 75%, we assume a median PFS of 4 months for the 
smaller group.  The comparison also assumes 33 months of 
enrollment with 15 additional months after the last accrual.  In the 
absence of a treatment effect, we can detect with 80% power (1-
sided α=0.05) a difference in median PFS of 2.3 months or 
greater.  If treatment is effective in the study, then the analyses 
need to test the interaction of treatment and the BRCA1 
expression status as well.  Power for dichotomized BRCA1 is 

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lower than that for continuous BRCA though the latter does not 
solve the cutpoint problem without additional work. 
 
3. 
PAM 50 BASAL SUBTYPE 
 
a. 
Introduction  
 
It is thought that the triple-negative phenotype is a surrogate for 
the gene expression based basal like category.  However, there 
is a lack of complete overlap between TNBC (defined on 
immunohistochemistry) and gene expression based basal-like 
category.  Approximately 80% of triple-negative tumors are basal-
like on gene expression and the remaining 20% consist of tumors 
of other subtypes suggesting that non-basal triple-negative 
tumors are a mixture of all other subtypes.  Thus, the basal-like 
gene expression distinction appears to identify a relatively more 
homogenous subgroup compared to the triple-negative tumors 
(as identified on IHC).  We intend to perform gene expression-
based assays to identify samples that are basal-like, which may 
prove to be more precise when looking for correlates with PFS. In 
a recent neoadjuvant study 88% of non-metastatic TNBC were 
found to be of basal subtype and the presence of basal subtype 
did not predict for differential benefit from addition of carboplatin 
to AC/T chemotherapy. (Sikov WM, et al. [S4-05] However, the 
relationship between basal subtype, BRCAness phenotype and 
response to a PARPi has also not been studied.   
 
b. 
Laboratory conducting the assay:  
 
Andrew K Godwin, PhD 
Professor, Department of Pathology & Laboratory Medicine, 
University of Kansas Medical Center 
Director, Molecular Oncology, University of Kansas Medical 
Center 
University of Kansas Medical Center 
Kansas City, KS 66160 
   
Laboratory: 
Clinical Molecular Oncology Laboratory (CMOL) 
University of Kansas Medical Center 
2601 Olathe Boulevard 
Bldg 020, Room 4005 
Kansas City, KS  66160 
 
Mailing address: 
University of Kansas Medical Center 
CMOL, Mail Stop: 3040 
3901 Rainbow Boulevard 
Kansas City, KS  66160 
Director Office: 913-945-6373 
Assistant Director Office: 913-945-6388 
Laboratory: 913-945-6391 
CLIA ID No: 17D2042936 
Expiration: 06/17/2016 
 
c. 
Description of the assay 
 

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RNA isolation: Tumor-dense areas of the FFPE tissue sections 
will be macrodissected. There will not be any correction for tumor 
content in the sample.  Minimum tumor content of 20% will be 
required. RNA will be isolated using commercially available kits. 
Amount of RNA needed:  200 – 300 ng. 
 
The PAM50 assay is an in vitro assay which is performed on the 
NanoString nCounter Dx Analysis System using RNA isolated 
from FFPE breast tumor tissue.  The algorithm uses a 50-gene 
expression profile to assign breast cancer to one of four PAM50 
molecular subtypes determined by the tumor’s molecular profile.  
Reagents (CodeSet containing the genes for the PAM50 gene 
signature and nCounter master kit) will be purchased from 
NanoString technology and assay will be run on the n-Counter 
(NanoString) system (which is housed in the clinical molecular 
oncology laboratory at the University of Kansas).  Subtype calls 
will be generated using the nSolver™ Analysis Software (a free 
data analysis program that offers nCounter users the ability to QC, 
normalize, and analyze data). Tumor intrinsic subtypes will be 
performed for all patients who are germline BRCA negative. 
 
d. 
Analysis Plan   
 
Molecular classification results are expected in 95% of the study 
population.  We expect 85% of our study population to be basal 
subtype on PAM50 subtyping.  Primary study analysis 2 and 3 
(germline BRCA negative patients) will be repeated on patients 
with basal subtype tumors.  If 95% complete the assay and, of 
those 85% are basal, we should have 66 of the 82 patients with 
PFS data available to test this question in both subsets.  This does 
assume that sharpening the criteria to include only basal disease 
does not change the distribution of BRCAness phenotype status.  
Again, we would not expect an effect of treatment in non-BRCA 
like basal patients.  We would expect a treatment effect in BRCA-
like patients, with 72% power (1-sided α=0.05) we could detect an 
increase in median PFS from 4 to 7 months due to Veliparib.  To 
have 80% power, the median PFS would need to increase to 7.5 
months. 
  
Analytically, we would use a log-rank test on each of the two non-
BRCA mutation groups who are identified as basal using the 
PAM50 test, followed by Cox regression to obtain he hazard ratio.  
The data would be then extended to the full sample.  It is expected 
that there would be a slight change in the HR toward the null due 
to the contamination from the nonbasal tumors.  The sample size 
is too small to show a significant interaction of Veliparib with 
basal/nonbasal status, but this model will be tested.   
 
PAM 50 basal subtyping: The PAM50 assay is an in vitro assay 
which is performed on the NanoString nCounter Dx Analysis 
System using FFPE breast tumor tissue previously diagnosed as 
invasive breast carcinoma. The algorithm uses a 50-gene 
expression profile to assign breast cancer to one of four PAM50 
molecular subtypes determined by the tumor’s molecular profile. 
(133) This qualitative assay utilizes gene expression data, 
weighted together with clinical variables to generate a risk 
category and numerical score, to assess a patient’s risk of distant 
recurrence of disease. (134) 

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e. 
Description of the specimens and methods for specimen 
acquisition and processing: 
 
Formalin fixed paraffin-embedded primary tumor tissue block. 
Minimum Sample Requirement: Three 10 micron uncharged 
slides for RNA isolation and one 5 micron charged slide for H&E 
staining. 
 
Instructions: Specimens to be shipped by overnight FedEx 
delivery to SWOG Repository Specimen processing: Specimens 
(slides or FFPE blocks) will be stored at the SWOG Biospecimen 
Bank at 4˚C until shipped to the University of Kansas Medical 
Center for the correlative studies. 
 
4. 
BRCANESS PHENOTYPE ASSESSMENT ON THE METASTATIC 
TUMOR  
 
a. 
Introduction  
 
Background: The Primary Translational Medicine objectives of 
S1416 are focused around germline and somatic integral and 
integrated BRCAness markers which have been previously been 
reviewed and approved by CTEP and BIQSFP.   
 
The overall design of this trial is to test whether adding ABT-888 
(PARP inhibitor) to platinum-based chemotherapy will improve 
outcomes in patients with metastatic TNBC with germline BRCA 
mutation or somatic BRCAness phenotype (somatic markers to be 
done on archived FFPE primary tumor). However an important 
secondary aim is:  
 
• 
Application of somatic BRCAness phenotype markers on 
metastatic tumor tissue (this was highly encouraged by 
CTEP) to improve the accuracy of identification of patients 
likely to benefit from platinum-based therapy and ABT-888.   
 
Hypothesis: It is now increasingly being understood that primary 
tumor may not always reflect the biology in metastatic setting. Our 
hypothesis for this specific secondary integrated aim is that 
compared to archived primary tumor, metastatic tumor tissue may 
be a better source to detect “real time” BRCAness phenotype in 
metastatic TNBC and that translational medicine studies on 
metastatic tumor tissue may improve the performance of the 
already incorporated integral biomarkers in identifying TNBC 
patients likely to benefit from platinum-based therapy and ABT-
888. 
 
b. 
Assays to be performed 
 
The integral and integrated somatic BRCAness markers which are 
already approved to be performed on the archived primary tumor 
tissue (BRCA1 Promoter methylation, BRCA1 mRNA expression, 
somatic BRCA mutation, tumor genomic instability) will be 
performed on the pre-treatment metastatic biopsies. In addition to 
the currently identified assays, if during the course of the study 
other novel and robust BRCAness assays become available we 
hope to incorporate them in the study. A new marker before being 

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incorporated will be will require approval from NCI CTEP or the 
NCI correlative science committee (depending on whether the trial 
is ongoing or closed) in accordance with policies for use of 
biospecimens from NCTN clinical trials. 
 
In addition to answering TM objective of S1416, tumor tissue 
(primary and metastatic) collected as part of this study will also 
serve as a valuable source for future correlative studies aimed at 
molecular characterization of TNBC.   
 
c. 
Pre-Treatment metastatic biopsy:  
 
Since biomarker analysis on the pre-treatment tumor tissue is not 
being utilized for treatment assignment it was felt that mandating 
a pre-treatment biopsy may hider accrual to the study and also 
considered coercion by some institutional review boards. Thus, 
the following plan is going to be implemented for collection of 
metastatic tumor. 
 
It is mandatory for investigators to attempt to obtain metastatic 
tumor tissue.  When archived metastatic tissue is not available it 
will be highly recommended that pre-treatment metastatic 
biopsies be obtained unless in the opinion of the investigator 
image-guided biopsy poses undue risk. 
 
Specifically, we request: 
 
1) Archived metastatic tumor from previous clinical biopsy OR  
 
2) If archived metastatic tumor is not available (biopsy of 
metastatic site not done, only FNA was done or previous biopsy 
material has been exhausted) pre-treatment metastatic biopsy will 
be highly recommended. If, in the opinion of the investigator, 
image guided biopsy poses undue risk to the patient (brain lesion, 
proximity to major blood vessel etc.) or may not provide adequate 
sample (pleural fluid, ascites, bone) please consult with the Study 
Chair.  Eligibility in these situations would then be handled on 
case by case basis after discussion with Study Chair.   
 
Adopting the above approach would allow patients who don’t have 
adequate archived metastatic tissue available, but have easily 
accessible skin, chest wall, lung, liver or lymph node metastatic 
sites to undergo pre-treatment biopsy and participate on the trial. 
This approach would also allow patients with inaccessible 
lung/liver mets, or where biopsy would not provide adequate 
sample (pleural fluid, ascites, bone only disease) to participate by 
only having to submit a primary block. Since this is a study of 
TNBC we expect very low percentage of patients to present with 
bone only metastatic disease.  
 
 

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d. 
Statistical considerations: 
 
End points  
The primary endpoint is progression-free survival (PFS) defined 
as time from registration (randomization) to progression or death 
due to any cause. Progression is defined as radiologic 
progression of disease by RECIST criteria or unequivocal 
progression of non-measurable disease in the opinion of the 
treating physician (an explanation must be provided).  
 
Secondary endpoints include response rate (measurable disease 
only), clinical benefit rate, and overall survival. Overall survival is 
defined as time from registration to death due to any 
cause.  Patients without the event are censored at the last 
contact.  Patients will be followed for a minimum of 5 years after 
registration to determine overall survival results. 
 
Accrual Goal 
We anticipate that metastatic archived tumor tissue will be 
submitted for 40% of patients and another 30-40% of patients will 
undergo pre-treatment metastatic biopsy.  Thus, we will expect to 
have metastatic tumor for 70-80% of the study population. 
Metastatic tumor BRCAness phenotype assessment will be done 
for all germline BRCA negative patients with available metastatic 
tumor tissue. The trial plans to accrue 172 germline BRCA 
mutation negative patients. We are assuming availability of 
metastatic tumor for 70% of germline BRCA negative study 
population  
 
Classification of patients as germline BRCA positive will take 
place during the course of the trial (real time testing). Metastatic 
tumor BRCA phenotype-like assessment will be done after 
completion of accrual to the study.   
 
Statistical Analyses 
 
Primary analysis 2: Compare ABT-888 to no ABT-888 in the 
BRCA mutation-negative BRCAness-like group (n=70% of 86).  
 
A median PFS of 4 months is assumed for Arm 1 (cisplatin+ 
placebo) that improves to 7 months for Arm 2 (cisplatin + ABT-
888). Outcome data is expected to be available from 82 of the 86 
registered patients, but only 70% will have metastatic tissue so we 
assume the overall sample size is 57.  Thus, we adjust the Type 
1 error for this analysis to 10% instead of 5% (1-sided). Assuming 
a hazard ratio (HR) of 1.75 for standard versus experimental, the 
study will have 79% power (1-sided α = 0.10) to detect if the 
experimental arm (2) is superior to the standard arm (1). A 
stratified log-rank test will be used to compare PFS between the 
two arms in an ITT analysis. 
 
Primary analysis 3: Compare ABT-888 to no ABT-888 in the 
BRCA mutation-negative non-BRCA-like group (n=XX 70% of 86)  
 
Theoretically we would expect no difference by treatment (median 
PFS of 4 months in both arms). However, it is possible that the 
classification of BRCA-like status has error or that ABT-888 is 

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efficacious anyway in this group.  Outcome data is expected to be 
available from 82 of the 86 registered patients. A test of efficacy 
will be conducted at 1-sided α = 0.10 even though little or no effect 
is expected.  A stratified log-rank test will be used to compare PFS 
between the two arms in an ITT analysis.  
 
5. 
NOVEL BRCAness ASSAYS 
 
The purpose of this trial is to determine if the assays in our multipronged 
approach will be able to define a BRCAness phenotype and clinical 
response to PARP inhibition therapy. We anticipate that technical and 
biological advances will continue to progress as this study is conducted 
and at the end of the study, it is likely that other measures of BRCAness, 
and new technologies to define it, will be available. 
 
In order for new BRCAness assays to be incorporated into the study as it 
progresses, protocol amendments will require approval from the 
NCI/CTEP in accordance with policies for use of biospecimens from NCTN 
clinical trials.  At the end of the trial, proposals for retrospective studies of 
newer assays may be submitted to the Central Correlative Sciences 
Committee for review. 
 
Circulating Tumor Cells 
The overall goal of this translational medicine project is to identify patients 
treated with the PARPi who are refractory to the treatment. This section 
describes future plans to perform genomic and proteogenomic assays on 
isolated tumor cell DNA. This research will require review and approval in 
order to proceed. A correlative science study will be submitted to the NCI 
for review and approval prior to commencing research related to CTC’s. 
One tube of blood, drawn into a Streck Cell-free DNA tube, will be sent to 
the Kuhn-Hicks lab (Los Angeles, CA) for divisions into aliquots for CTC 
identification and extraction for CNV analysis, as well as for plasma for 
circulating DNA analysis, and WBC for germ line DNA analysis 
(exploratory and when sufficient sample is available as not all blood 
samples will have the required 8 ml of blood). Thus, the Kuhn-Hicks 
laboratory will process the blood they receive for both cell analysis and 
cell-free DNA isolation. A single blood draw will be collected at baseline, 
Cycle 2 Day 1, and at progression. 
 
 

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31  
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32  
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targeted high-throughput sequence data. BMC Genomics 12:184, 2011. 
 
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34  
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a prospective triple-negative breast cancer registry: implications for 
hereditary breast and/or ovarian cancer syndrome testing. Breast Cancer 
Research and Treatment: 1-8, 2014. 
 
35  
Walsh T, Lee M, Casadei S, et al: Detection of inherited mutations for breast 
and ovarian cancer using genomic capture and massively parallel 
sequencing. Proc Natl Acad Sci U S A 107:12629-33, 2010. 
 
36  
Bryant H, Schultz N, Thomas H, et al. "Specific killing of BRCA2-deficient 
tumours with inhibitors of poly(ADP-ribose) polymerase." Nature 434(7035): 
913-917. 2005. 
 
37  
Farmer H, McCabe N, Lord C, et al. "Targeting the DNA repair defect in 
BRCA mutant cells as a therapeutic strategy." Nature 434(7035): 917-921. 
2005. 
 
38  
McCabe N, Turner N, Lord C, et al. "Deficiency in the repair of DNA damage 
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Pennington K, Walsh T, Harrell M, et al. "Germline and somatic mutations in 
homologous recombination genes predict platinum response and survival in 
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41  
Walsh T, Casadei S, Lee M, et al. "Mutations in 12 genes for inherited 
ovarian, fallopian tube, and peritoneal carcinoma identified by massively 
parallel sequencing." Proc Natl Acad Sci USA. 2011. 
 
42  
Churpek J, Zheng Y, Casadei S, et al. "Inherited mutations in breast cancer 
genes in African American breast cancer patients revealed by targeted 
genomic capture and next-generation sequencing." J Clin Oncol 31 (suppl; 
abstr CRA1501). 2013. 
 
43  
Couch F, Hart S, Sharma P, et al. "Inherited mutations in 17 breast cancer 
susceptibility genes among a large triple-negative breast cancer cohort 
unselected for family history of breast cancer." J Clin Oncol 33(4): 304-311. 
2015. 
 
44  
Couch F, Hart S, Sharma P, et al. "Inherited mutations in 17 breast cancer 
susceptibility genes among a large triple-negative breast cancer cohort 
unselected for family history of breast cancer." J Clin Oncol 33(4): 304-311. 
2015. 
 
45  
Sharma P, Klemp J, Kimler B, et al. "Germline BRCA mutation evaluation in 
a prospective triple-negative breast cancer registry: implications for 
hereditary breast and/or ovarian cancer syndrome testing." Breast Cancer 
Research and Treatment: 1-8. 2014. 
 
46  
Walsh T, Lee M, Casadei S, et al. "Detection of inherited mutations for breast 
and ovarian cancer using genomic capture and massively parallel 
sequencing." Proc Natl Acad Sci USA 107(28): 12629-12633. 2010. 
 
47  
Pritchard C, Smith C, Salipante S, et al. "ColoSeq Provides Comprehensive 
Lynch and Polyposis Syndrome Mutational Analysis Using Massively 
Parallel Sequencing." J Mol Diagn 14(4): 357-366. 2012. 
 
48  
Pritchard C, Salipante S, Koehler K, et al. "Validation and implementation of 
targeted capture and sequencing for the detection of actionable mutation, 
copy number variation, and gene rearrangement in clinical cancer 
specimens." The Journal of molecular diagnostics : JMD 16(1): 56-67. 2014. 
 
49  
Pritchard C, Smith C, Salipante S, et al. "ColoSeq Provides Comprehensive 
Lynch and Polyposis Syndrome Mutational Analysis Using Massively 
Parallel Sequencing." J Mol Diagn 14(4): 357-366. 2012. 
 
50  
Nord A, Lee M, King M, et al. “Accurate and exact CNV identification from 
targeted high-throughput sequence data." BMC Genomics 12: 184. 2011. 
 
 

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51  
Walsh T, Casadei S, Lee M, et al. "Mutations in 12 genes for inherited 
ovarian, fallopian tube, and peritoneal carcinoma identified by massively 
parallel sequencing." Proc Natl Acad Sci USA. 2011. 
 
52  
Walsh T, Casadei S, Lee M, et al. "Mutations in 12 genes for inherited 
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53  
Abkevich V, Timms K, Hennessy B, et al. "Patterns of genomic loss of 
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54  
Telli M, Abkevich J, Hartman A, et al. Homologous Recombination 
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55  
Timms K, Neff C, Morris B, et al. "Association between BRCA1/2 status and 
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56  
Isakoff S, Mayer E, He L, et al. "TBCRC009: A Multicenter Phase II Clinical 
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57  
Telli M, Jensen K, Vinayak A, et al. "Phase II Study of Gemcitabine, 
Carboplatin, and Iniparib as Neoadjuvant Therapy for Triple-Negative and 
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58  
Tutt A, E. P., Kilburn L, Gilett C, et al. "The TNT trial: A randomized phase 
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59  
Telli M, Jensen K, Vinayak A, et al. "Phase II Study of Gemcitabine, 
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60  
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61  
Isakoff S, Mayer E, He L, et al. "TBCRC009: A Multicenter Phase II Clinical 
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62  
Tutt A, E. P., Kilburn L, Gilett C, et al. "The TNT trial: A randomized phase 
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63  
Swisher E, B. J., Kaufmann S, Oza A, et al. Updated clinical and preliminary 
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Spain, European Journal of Cancer. 2014. 
 
64  
Tutt A, E. P., Kilburn L, Gilett C, et al. "The TNT trial: A randomized phase 
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65  
Network, T. C. G. A. "Comprehensive molecular portraits of human breast 
tumours." Nature 490(7418): 61-70. 2012. 
 
66  
Ledermann J, Harter P, Gourley C, et al. "Olaparib maintenance therapy in 
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67  
Abkevich V, Timms K, Hennessy B, et al. "Patterns of genomic loss of 
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68  
Abkevich V, Timms K, Hennessy B, et al. "Patterns of genomic loss of 
heterozygosity predict homologous recombination repair defects in epithelial 
ovarian cancer." Br J Cancer 107(10): 1776-1782. 2012. 
 
69  
Telli M, Abkevich J, Hartman A, et al. Homologous Recombination 
Deficiency (HRD) score predicts pathologic response following neoadjuvant 
platinum-based therapy in triple-negative and BRCA1/2 mutation-associated 
breast cancer (BC). 2012. 
 
70  
Birkbak N, Wang Z, Kim J, et al. "Telomeric allelic imbalance indicates 
defective DNA repair and sensitivity to DNA-damaging agents." Cancer 
Discov 2(4): 366-375. 2012. 
 
71  
Popova T, Manie E, Rieunier G, et al. "Ploidy and large-scale genomic 
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72  
Timms K, Neff C, Morris B, et al. "Association between BRCA1/2 status and 
DNA-based assays for homologous recombination deficiency in breast 
cancer." Cancer Res 73(24): Supplement, P6-05-10. 2013. 
 
73  
Isakoff S, Mayer E, He L, et al. "TBCRC009: A Multicenter Phase II Clinical 
Trial of Platinum Monotherapy with Biomarker Assessment in Metastatic 
Triple-Negative Breast Cancer." J Clin Oncol 33(17): 1902-1909. 2015. 
 
74  
Telli M, Jensen K, Vinayak A, et al. "Phase II Study of Gemcitabine, 
Carboplatin, and Iniparib as Neoadjuvant Therapy for Triple-Negative and 
BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-
Based Measure of Genomic Instability: PrECOG0105." J Clin Oncol 33(17): 
1895-1901. 2015. 
 
75  
Tutt A, E. P., Kilburn L, Gilett C, et al. "The TNT trial: A randomized phase 
III trial of carboplatin (C) compared with docetaxel (D) for patients with 
metastatic or recurrent locally advanced triple negative or BRCA1/2 breast 
cancer (CRUK/07/012)." San Antonio Breast Cancer Symposium: Abstract 
S3-01. 2014. 
 
76  
Network, T. C. G. A. "Comprehensive molecular portraits of human breast 
tumours." Nature 490(7418): 61-70. 2012. 
 
77  
Esteller M. "Epigenetic lesions causing genetic lesions in human cancer: 
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78  
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79  
Wei M, Grushko T, Dignam J, et al. "BRCA1 Promoter Methylation in 
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2005. 
 
80  
Network, T. C. G. A. "Comprehensive molecular portraits of human breast 
tumours." Nature 490(7418): 61-70. 2012. 
 
81  
Wei M, Grushko T, Dignam J, et al. "BRCA1 Promoter Methylation in 
Sporadic Breast Cancer Is Associated with Reduced BRCA1 Copy Number 
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82  
Esteller M, Silva J, Dominguez G, et al. "Promoter Hypermethylation and 
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83  
Xu X, Gammon M, Zhang Y, et al. "Gene promoter methylation is associated 
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84  
Sharma P, Stecklein S, Kimler B, et al. "The prognostic value of promoter 
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3(2): 1-11. 2014. 
 

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85  
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Sporadic Breast Cancer Is Associated with Reduced BRCA1 Copy Number 
and Chromosome 17 Aneusomy." Cancer Research 65(23): 10692-10699. 
2005. 
 
86  
Esteller M, Silva J, Dominguez G, et al. "Promoter Hypermethylation and 
BRCA1 Inactivation in Sporadic Breast and Ovarian Tumors." Journal of the 
National Cancer Institute 92(7): 564-569. 2000. 
 
87  
Veeck J, Ropero S, Setien F, et al. "BRCA1 CpG Island Hypermethylation 
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88  
Sharma P, Stecklein S, Kimler B, et al. "The prognostic value of promoter 
methylation in early stage triple negative breast cancer." J Cancer Ther Res 
3(2): 1-11. 2014. 
 
89  
Sharma P, Stecklein S, Kimler B, et al. "BRCA1 insufficiency is predictive of 
superior survival in patients with triple negative breast cancer treated with 
platinum based chemotherapy." Cancer Res 72(24): Supplement, PD09-02. 
2012. 
 
90  
Sharma P, Stecklein S, Kimler B, et al. "The prognostic value of promoter 
methylation in early stage triple negative breast cancer." J Cancer Ther Res 
3(2): 1-11. 2014. 
 
91  
Sharma P, Stecklein S, Kimler B, et al. "BRCA1 insufficiency is predictive of 
superior survival in patients with triple negative breast cancer treated with 
platinum based chemotherapy." Cancer Res 72(24): Supplement, PD09-02. 
2012. 
 
92  
Veeck J, Ropero S, Setien F, et al. "BRCA1 CpG Island Hypermethylation 
Predicts Sensitivity to Poly(Adenosine Diphosphate)- Ribose Polymerase 
Inhibitors." Journal of clinical oncology 28(29): e563-e564. 2010. 
93  
Network, T. C. G. A. "Comprehensive molecular portraits of human breast 
tumours." Nature 490(7418): 61-70. 2012. 
 
94  
Wei M, Grushko T, Dignam J, et al. "BRCA1 Promoter Methylation in 
Sporadic Breast Cancer Is Associated with Reduced BRCA1 Copy Number 
and Chromosome 17 Aneusomy." Cancer Research 65(23): 10692-10699. 
2005. 
 
95  
Esteller M, Silva J, Dominguez G, et al. "Promoter Hypermethylation and 
BRCA1 Inactivation in Sporadic Breast and Ovarian Tumors." Journal of the 
National Cancer Institute 92(7): 564-569. 2000. 
 
96  
Xu X, Gammon M, Zhang Y, et al. "Gene promoter methylation is associated 
with increased mortality among women with breast cancer." Breast Cancer 
Research and Treatment 121(3): 685-692. 2010. 
 
97  
Sharma P, Stecklein S, Kimler B, et al. "The prognostic value of promoter 
methylation in early stage triple negative breast cancer." J Cancer Ther Res 
3(2): 1-11. 2014. 
 

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98  
Network, T. C. G. A. "Comprehensive molecular portraits of human breast 
tumours." Nature 490(7418): 61-70. 2012. 
 
99  
Sharma P, Stecklein S, Kimler B, et al. "BRCA1 insufficiency is predictive of 
superior survival in patients with triple negative breast cancer treated with 
platinum based chemotherapy." Cancer Res 72(24): Supplement, PD09-02. 
2012. 
 
100  Lips E, Mukhtar R, Yau C, et al. "Lobular histology and response to 
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101  Popova, T., E. Manié, G. Rieunier, V. Caux-Moncoutier, C. Tirapo, T. 
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Sastre-Garau, A. Vincent-Salomon, D. Stoppa-Lyonnet and M.-H. Stern 
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Basal-like Breast Carcinomas with <em>BRCA1/2</em> Inactivation." 
Cancer Research 72(21): 5454-5462. 
 
102  Popova, T., E. Manié, G. Rieunier, V. Caux-Moncoutier, C. Tirapo, T. 
Dubois, O. Delattre, B. Sigal-Zafrani, M. Bollet, M. Longy, C. Houdayer, X. 
Sastre-Garau, A. Vincent-Salomon, D. Stoppa-Lyonnet and M.-H. Stern 
(2012). "Ploidy and Large-Scale Genomic Instability Consistently Identify 
Basal-like Breast Carcinomas with <em>BRCA1/2</em> Inactivation." 
Cancer Research 72(21): 5454-5462. 
 
103  Marquard, A. M., A. C. Eklund, T. Joshi, M. Krzystanek, F. Favero, Z. C. 
Wang, A. L. Richardson, D. P. Silver, Z. Szallasi and N. J. Birkbak (2015). 
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homologous recombination deficiency suggests novel indications for 
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104  Popova, T., E. Manié, G. Rieunier, V. Caux-Moncoutier, C. Tirapo, T. 
Dubois, O. Delattre, B. Sigal-Zafrani, M. Bollet, M. Longy, C. Houdayer, X. 
Sastre-Garau, A. Vincent-Salomon, D. Stoppa-Lyonnet and M.-H. Stern 
(2012). "Ploidy and Large-Scale Genomic Instability Consistently Identify 
Basal-like Breast Carcinomas with <em>BRCA1/2</em> Inactivation." 
Cancer Research 72(21): 5454-5462. 
 
105  Greene, S. B., A. E. Dago, L. J. Leitz, Y. Wang, J. Lee, S. L. Werner, S. 
Gendreau, P. Patel, S. Jia, L. Zhang, E. K. Tucker, M. Malchiodi, R. P. Graf, 
R. Dittamore, D. Marrinucci and M. Landers (2016). "Chromosomal 
Instability Estimation Based on Next Generation Sequencing and Single Cell 
Genome Wide Copy Number Variation Analysis." PLOS ONE 11(11): 
e0165089. 
 
106  Schonhoft, J. D., J. L. Zhao, A. Jendrisak, E. A. Carbone, E. S. Barnett, M. 
A. Hullings, A. Gill, R. Sutton, J. Lee, A. E. Dago, M. Landers, S. F. 
Bakhoum, Y. Wang, M. Gonen, R. Dittamore and H. I. Scher (2020). 
"Morphology-predicted large scale transition number in circulating tumor 
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outcome in castration-resistant prostate cancer." Cancer Research: 
canres.1216.2020. 
 
 

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107  Dittamore, R., Y. Wang, S. Daignault-Newton, W. M. Stadler, A. Jendrisak, 
F. Y. Feng, A. E. Dago, J. Lee, R. P. Graf, M. A. Landers, A. Chinnaiyan and 
M. Hussain (2018). "Phenotypic and genomic characterization of CTCs as a 
biomarker for prediction of Veliparib therapy benefit in mCRPC." Journal of 
Clinical Oncology 36(15_suppl): 5012-5012. 
 
108  Swisher, E. M., K. K. Lin, A. M. Oza, C. L. Scott, H. Giordano, J. Sun, G. E. 
Konecny, R. L. Coleman, A. V. Tinker, D. M. O'Malley, R. S. Kristeleit, L. Ma, 
K. M. Bell-McGuinn, J. D. Brenton, J. M. Cragun, A. Oaknin, I. Ray-Coquard, 
M. I. Harrell, E. Mann, S. H. Kaufmann, A. Floquet, A. Leary, T. C. Harding, 
S. Goble, L. Maloney, J. Isaacson, A. R. Allen, L. Rolfe, R. Yelensky, M. 
Raponi and I. A. McNeish (2017). "Rucaparib in relapsed, platinum-sensitive 
high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, 
open-label, phase 2 trial." The Lancet Oncology 18(1): 75-87. 
 
109  Mateo, J., N. Porta, D. Bianchini, U. McGovern, T. Elliott, R. Jones, I. 
Syndikus, C. Ralph, S. Jain, M. Varughese, O. Parikh, S. Crabb, A. 
Robinson, D. McLaren, A. Birtle, J. Tanguay, S. Miranda, I. Figueiredo, G. 
Seed, C. Bertan, P. Flohr, B. Ebbs, P. Rescigno, G. Fowler, A. Ferreira, R. 
Riisnaes, R. Pereira, A. Curcean, R. Chandler, M. Clarke, B. Gurel, M. 
Crespo, D. Nava Rodrigues, S. Sandhu, A. Espinasse, P. Chatfield, N. 
Tunariu, W. Yuan, E. Hall, S. Carreira and J. S. de Bono (2020). "Olaparib 
in patients with metastatic castration-resistant prostate cancer with DNA 
repair 
gene 
aberrations 
(TOPARP-B): 
a 
multicentre, 
open-label, 
randomised, phase 2 trial." The Lancet Oncology 21(1): 162-174. 
 
110  Gruber, J. J., A. Afghahi, A. Hatton, D. Scott, A. McMillan, J. M. Ford and M. 
L. Telli (2019). "Talazoparib beyond BRCA: A phase II trial of talazoparib 
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Oncology 37(15_suppl): 3006-3006. 
 
111  Yen, J., S. Gnerre, C. Barbacioru, E. Helman, O. Manor, A. Yablonovitch, R. 
V. Satya, L. Liu, J. Saam, S. Fairclough, B. Nagy, R. Lanman, D. Chudova 
and A. Talasaz (2020). "Abstract 729: Landscape of homologous 
recombination repair (HRR) mutations in prostate cancer profiled by ctDNA 
next-generation sequencing." Cancer Research 80(16 Supplement): 729-
729. 
 
112  Navin, N., J. Kendall, J. Troge, P. Andrews, L. Rodgers, J. McIndoo, K. 
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single-cell sequencing." Nature 472(7341): 90-94.  
 
113  Baslan, T., J. Kendall, L. Rodgers, H. Cox, M. Riggs, A. Stepansky, J. Troge, 
K. Ravi, D. Esposito, B. Lakshmi, M. Wigler, N. Navin and J. Hicks (2012). 
"Genome-wide copy number analysis of single cells." Nat Protoc 7(6): 1024-
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114  Schonhoft, J. D., J. L. Zhao, A. Jendrisak, E. A. Carbone, E. S. Barnett, M. 
A. Hullings, A. Gill, R. Sutton, J. Lee, A. E. Dago, M. Landers, S. F. 
Bakhoum, Y. Wang, M. Gonen, R. Dittamore and H. I. Scher (2020). 
"Morphology-predicted large scale transition number in circulating tumor 
cells identifies a chromosomal instability biomarker associated with poor 
 

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outcome in castration-resistant prostate cancer." Cancer Research: 
canres.1216.2020.  
 
115  Baslan, T., J. Kendall, L. Rodgers, H. Cox, M. Riggs, A. Stepansky, J. Troge, 
K. Ravi, D. Esposito, B. Lakshmi, M. Wigler, N. Navin and J. Hicks (2012). 
"Genome-wide copy number analysis of single cells." Nat Protoc 7(6): 1024-
1041.  
 
116  Schonhoft, J. D., J. L. Zhao, A. Jendrisak, E. A. Carbone, E. S. Barnett, M. 
A. Hullings, A. Gill, R. Sutton, J. Lee, A. E. Dago, M. Landers, S. F. 
Bakhoum, Y. Wang, M. Gonen, R. Dittamore and H. I. Scher (2020). 
"Morphology-predicted large scale transition number in circulating tumor 
cells identifies a chromosomal instability biomarker associated with poor 
outcome in castration-resistant prostate cancer." Cancer Research: 
canres.1216.2020.  
 
117  Helman, E., C. Artieri, J. V. Vowles, J. Yen, T. Nance, M. Sikora, J. 
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118  Odegaard, J. I., J. J. Vincent, S. Mortimer, J. V. Vowles, B. C. Ulrich, K. C. 
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J. Nagy, C. E. Lee, L. A. Kiedrowski, C. P. Paweletz, H. Eltoukhy, R. B. 
Lanman, D. I. Chudova and A. Talasaz (2018). "Validation of a Plasma-
Based Comprehensive Cancer Genotyping Assay Utilizing Orthogonal 
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119  Nance, T., E. Helman, C. Artieri, J. Yen, T. P. Slavin, D. Chudova, R. B. 
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differentiation of somatic vs. germline variants in liquid biopsies using a 
betabinomial model." Cancer Research 78(13 Supplement): 4272-4272. 
 
120  Artyomenko, A., M. Sikora, M. Lefterova, V. M. Raymond, D. Gavino, C. 
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J. A. Willis, M. Fakih, S. Kopetz and A. Talasaz (2018). "Microsatellite 
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121  Quinn, K., E. Helman, T. Nance, C. Artieri, J. Yen, J. Zhao, S. Fairclough, 
M. Sikora, D. Chudova, R. B. Lanman and A. Talasaz (2018). "Development 
and analytical validation of a plasma-based tumor mutational burden (TMB) 
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122  Cortes J, Cescon D, Rugo HS, Nowecki Z, Im SA, Yusof M, et al. 
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123  Schmid P, Adams S, Rugo HS, et al. Atezolizumab and Nab-Paclitaxel in 
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124  Emens LA, Loi S, Rugo HS, et al. IMpassion130: Efficacy in immune 
biomarker subgroups from the global, randomized, double-blind, placebo-
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treatment-naïve, locally advanced or metastatic triple-negative breast 
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Antonio, TX: December 4-8, 2018. Abstract GS1-04. 
 
125  Sun C, et al. “miR-9 regulation of BRCA1 and ovarian cancer sensitivity to 
cisplatin and PARP inhibition.” J Natl Cancer Inst. Nov 20; 105 (22): 1750-8, 
2013. 
 
126  Yangh Y, et al. “Breast cancer susceptibility gene 1 (BRCA1) predict clinical 
outcome in platinum and taxol based chemotherapy in non-small-cell lung 
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127  Sharma P, Stecklein SR, Kimler BF, et al: BRCA1 insufficiency is predictive 
of superior survival in patients with triple negative breast cancer treated with 
platinum based chemotherapy. Cancer Res 72: Supplement, PD09-02, 
2012. 
 
128  Sharma P, Stecklein S, Kimler B, et al. "The prognostic value of promoter 
methylation in early stage triple negative breast cancer." J Cancer Ther Res 
3(2): 1-11. 2014. 
 
129  Sharma P, Stecklein S, Kimler B, et al. "The prognostic value of promoter 
methylation in early stage triple negative breast cancer." J Cancer Ther Res 
3(2): 1-11. 2014. 
 
130  Sharma P, Stecklein SR, Kimler BF, et al: BRCA1 insufficiency is predictive 
of superior survival in patients with triple negative breast cancer treated with 
platinum based chemotherapy. Cancer Res 72: Supplement, PD09-02, 
2012. 
 
131  Petroff B, Phillips T, Kimler B, et al. “Detection of biomarker gene expression 
by real-time polymerase chain reaction using amplified ribonucleic acids 
from formalin-fixed random periareolar fine needle aspirates of human 
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132  Petroff B, Phillips T, Kimler B, et al. “Detection of biomarker gene expression 
by real-time polymerase chain reaction using amplified ribonucleic acids 
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133  Goldhirsch A, et al. “Strategies for subtypes-dealing with the diversity of 
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134  Parker J, Et al. “Supervised risk predictor of breast cancer based on intrinsic 
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18.6 
Modified Breast Graded Prognostic Assessment Index 
 
The Modified Breast Graded Prognostic Assessment Index (modified breast-GPA) is 
calculated as the sum of the scores for the four factors as indicated in the following table: 
 
Factor 
0 
0.5 
1.0 
1.5 
2.0 
Karnofsky PS 
≤ 50  
60 
70 to 80 
90 to 100 
-- 
Subtype 
TNBC 
HR+/HER2- 
HR-/HER2+ 
HR+/HER2+ 
-- 
Age, years 
> 50 
≤ 50 
-- 
-- 
-- 
No. of brain  
metastases 
> 3 
1 to 3 
-- 
-- 
-- 
 
 
 

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18.7 
SWOG Biospecimen Bank (BB) Instructions 
 
Formalin-fixed paraffin-embedded (FFPE) tissue will be submitted to the SWOG BB (Solid 
Tissue Division) along with the appropriate pathology report(s).  Submitting sites must label 
specimens with at least the SPID, block number, and indicate if the tissue is from a primary 
(P) or metastatic (M) site in addition to the standard labeling requirements. Sites will submit 
a FFPE block or 20 unstained slides from the primary tumor.  Sites will also submit a FFPE 
block or 10 unstained slides from the archival metastatic tumor, or – if no archival 
metastatic FFPE is available – four FFPE core needle biopsies and an H&E-stained slide 
from the metastatic tumor biopsy may be submitted. 
 
The Bank will store FFPE blocks/slides in a refrigerator (4°C) until distribution.  Questions 
regarding specimen inventory at the Bank should be sent to  
BPCSWOG@nationwidechildrens.org.   
 
After every 40 patients accrued in the Standard Cohort, the SWOG Statistics and Data 
Management Center will send a list of patients to the SWOG Biospecimen Bank so that 
specimens can be shipped to the laboratories performing the assays for classification.  The 
repository will distribute primary FFPE slides and deidentified pathology reports, to both 
Myriad Laboratories and Drs. Sharma and Godwin at University of Kansas Medical Center, 
at the addresses below.  If a block is received, the Bank will cut slides in the following 
sequence: one (5 µm) charged H&E stained slide and three (10 µm) uncharged unstained 
slides; one charged and H&E stained (5 µm) slide and eight (10 µm) uncharged unstained 
slides to distribute as indicated below: 
 
1. 
Three (10 µm) unstained uncharged slides and one (5 µm) charged slide* for H&E 
staining from the primary tumor will be shipped to: 
 
Anne-Rene Hartman, MD and Kirsten Timms, PhD  
Myriad Laboratory Inc. 
320 Wakara Way, 
Salt Lake City, UT 84108 
 
The H&E stained slide will be returned to the SWOG BB for long-term storage. 
 
2. 
Eight (10 µm) unstained uncharged slides and one (5 µm) charged slide* for H&E 
staining from the primary tumor will be shipped to: 
 
Priyanka Sharma, MD and Andrew Godwin, PhD 
University of Kansas Medical Center CMOL 
Mail Stop: 3040 
3901 Rainbow Boulevard 
Kansas City, KS 66160 
 
The H&E stained slide will be returned to the SWOG BB for long-term storage. 
 
3. 
H&E slide (previously created and shipped to Myriad) will be returned to the SWOG 
Biospecimen Bank. The H&E slide plus two (2) 4–5 microns thick, positively 
charged and unbaked slides will be shipped to Foundation Medicine, Inc. at the 
following address.  
 
Foundation Medicine, Inc.  
Attn: Accessioning 
7010 Kit Creek Road 
Morrisville, NC 27560 
Phone: 888/988.3639 
 

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*Note: If a block is received at the SWOG Biospecimen Bank, then the Bank will cut and 
stain the charged slide prior to distribution. If slides are received, then an unstained slide 
will be sent. 
 
Metastatic and all remaining primary FFPE will be stored at the SWOG BB for post hoc 
integrated/exploratory assays.