Clinical trial NCT01149083
Conditions: Anatomic Stage III Breast Cancer AJCC v8 Anatomic Stage IV Breast Cancer AJCC v8 Locally Advanced Breast Carcinoma Metastatic Breast Carcinoma Unresectable Breast Carcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2010-06-30; Completion date: 2024-09-30
Enrollment: 77 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase II trial studies how well veliparib with or without carboplatin works in treating patients with stage III or IV breast cancer. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether veliparib is more effective with or without carboplatin in treating breast cancer.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate the efficacy of single agent veliparib (ABT-888) (NSC 737664) in breast cancer (BRCA) carriers with metastatic breast cancer based on response rate (Response Evaluation Criteria In Solid Tumors \[RECIST\] criteria).

SECONDARY OBJECTIVES:

I. To conduct subset analysis on BRCA1 versus (vs.) BRCA2 and hormone receptor status.

II. To evaluate progression-free survival of patients on single-agent ABT-888. III. To further describe the safety and tolerability of ABT-888 (NSC 737664) as a single agent and in combination with carboplatin for BRCA-associated breast cancer.

IV. To evaluate the pharmacokinetics of ABT-888 (NSC 737664) alone and in combination with carboplatin.

V. To assess the relationship between the level of poly adenosine diphosphate (ADP) ribose polymerase (PARP) inhibition by ABT-888 and biomarkers of deoxyribonucleic acid (DNA) damage in peripheral blood mononuclear cell (PBMC's) and in tumor.

VI. To explore the relationship between biomarkers of drug effect and progression-free survival.

VII. To evaluate the efficacy and safety of the combination of carboplatin and ABT-888 in patients who have failed single agent ABT-888.

VIII. To conduct subset analysis on BRCA1 vs. BRCA2 and hormone receptor status.

OUTLINE: This is a dose-escalation study of veliparib. Patients are assigned to 1 of 2 phases.

SAFETY LEAD-IN PHASE: Patients receive veliparib orally (PO) twice daily (BID) on days 1-21 of each cycle and carboplatin intravenously (IV) over 30 minutes on day 1 of each cycle. Cycles repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and may optionally undergo biopsies throughout the study. Patients undergo blood sample collection during screening and on study.

PHASE II: Patients receive veliparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Upon progression, patients are taken off treatment for 1 week and may then continue to recieve veliparib along with carboplatin IV over 30 minutes on day 1 of each cycle. Cycles repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and may optionally undergo biopsies throughout the study. Patients undergo blood sample collection during screening and on study.

\* As of the November 9, 2023 amendment, the pharmaceutical collaborator has discontinued the ABT-888 development program with the National Cancer Institute Cancer Therapy Evaluation Program (CTEP). Clinical supply will no longer be available after December 31, 2024. Patients will discontinue treatment by December 31, 2024, or earlier.

After completion of study treatment, patients are followed up every 6 months.

Arms: arm 1: Patients receive veliparib PO BID on days 1-21 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Upon progression, patients are taken off treatment for 1 week and may then continue to recieve veliparib along with carboplatin IV over 30 minutes on day 1 of each cycle. Cycles repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and may optionally undergo biopsies throughout the study. Patients undergo blood sample collection during screening and on study. arm 2: Patients receive veliparib PO BID twice daily on days 1-21 of each cycle and carboplatin IV over 30 minutes on day 1 of each cycle. Cycles repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and may optionally undergo biopsies throughout the study. Patients undergo blood sample collection during screening and on study.
Interventions: intervention 1: Biopsy intervention 2: Biospecimen Collection intervention 3: Carboplatin intervention 4: Computed Tomography intervention 5: Magnetic Resonance Imaging intervention 6: Veliparib
Intervention descriptions: intervention 1: Undergo biopsy intervention 2: Undergo blood sample collection intervention 3: Given IV intervention 4: Undergo CT intervention 5: Undergo MRI intervention 6: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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SUMMARY OF CHANGES
Date:
November 9, 2023
Document:
NCI Protocol #8264, PhII-96: “Phase II Trial of Single Agent ABT-888
with Post-Progression Therapy of ABT-888 in Combination with 
Carboplatin in Patients with Stage IV BRCA-associated Breast Cancer.”
Note:
The following is a Summary of Changes between the 6.1.23 and 11.9.23
versions of protocol
#
Section
Comments
1.
Protocol 
Version
and Face page
Changed protocol version to November 9, 2023.  Dates in the footers were also changed to 
11.9.23v.
2.
5.1 and 9.1.1
Added information regarding the discontinuation of ABT-888 drug program. Patient will 
discontinue treatment by December 31, 2024 or earlier. 


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NCI Protocol #: 8264
Local Protocol #: PhII-96
Title:  
Phase II Trial of Single Agent ABT-888 with Post-Progression Therapy of ABT-888
in Combination with Carboplatin in Patients with Stage IV BRCA-associated Breast 
Cancer
Coordinating Center:
California Cancer Consortium Data Coordinating Center
City of Hope 
1500 E. Duarte Road, Duarte, California 91010
Telephone: 626-256-HOPE (4673) x 65928
Fax: 626-256-8654
Contact E-mail:  cccp@coh.org
Principal Investigator:
Joanne Mortimer, M.D.
City of Hope 
1500 East Duarte Road
Duarte, CA  91010
Phone: (626) 256-4673
Email:  jmortimer@coh.org 
Co-Investigators:
Timothy Synold, Pharm D (not a treating physician)
City of Hope 
1500 East Duarte Road
Duarte, CA  91010
Phone: (626) 256-4673 x 62110
Fax: (626) 301-8862
Email:  tsynold@coh.org
Edward M. Newman, PhD (not a treating physician)
City of Hope 
1500 East Duarte Road
Duarte, CA  91010
Phone: (626) 256-4673 x 62566
Fax: (626) 301-8862
Email:  enewman@coh.org
Timothy O’Connor, Ph.D. (not a treating physician)
City of Hope 
1500 East Duarte Road
Duarte, CA  91010
Phone:  (626) 256-4673 x 68220
Fax: (626) 358-7703
Email:  toconnor@coh.org


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Darcy Spicer, MD
USC/Norris Cancer Center
1441 Eastlake Avenue
Los Angeles, CA  90033
Phone: 323-865-3900
Fax: 323-865-0061
E-mail: dspicer@hsc.usc.edu
Chandra P. Belani, MD
Penn State Milton S. Hershey Medical Center
Penn State Cancer Institute, H072
500 University Drive, P.O. Box 850
Hershey, PA  17033-0850
Phone: 717-531-1078
Fax: 717-531-0002
E-mail: cbelani@psu.edu
Adam Brufsky, MD, Ph.D
University of Pittsburgh Cancer Institute
300 Halket Street, 4th floor
Pittsburgh, PA 15213
Phone: 412-641-6500
Fax 412-641-7678
Email: brufskyam@upmc.edu
Shannon L. Puhalla, M.D.
University of Pittsburgh Cancer Institute
Magee-Womens Hospital
300 Halket Street, Suite 3525
Pittsburgh, PA 15213
Phone: 412-641-5792
Fax: 412-641-6461
Email: puhallasl@upmc.edu
Jan Hendrik Beumer, Pharm.D., Ph.D. (not a treating physician) 
University of Pittsburgh Cancer Institute Suite G.27d
5117 Centre Avenue
Pittsburgh, PA 15213-1863
Tel.off.: +1-412-623-3216
Tel.lab.: +1-412-623-3238
Fax.: +1-412-623-1212
Email: beumerjh@upmc.edu
New York Consortium:
Tessa Cigler, MD
Weill Cornell Medical College


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425 East 61st Street, 8th Floor
New York, NY 10065
Phone: 212.821.0736
Email:  tec9002@med.cornell.edu
Franco Muggia, MD
New York University
550 1st Avenue
New York, New York  10016
Phone: 212-652-1917
Email: franco.muggia@nyumc.edu
University of Chicago Consortium:
Everett E. Vokes, M.D.
University of Chicago
5841 S. Maryland Ave. MC 2115
Chicago, IL 60637
Phone: (773) 702-9306
Email: evokes@medicine.bsd.uchicago.edu
Rita Nanda, M.D.
University of Chicago
5841 S. Maryland Ave. MC 2115
Chicago, IL 60637
Phone: (773) 834-2756
Email: rnanda@medicine.bsd.uchicago.edu
Cynthia Ma, M.D., Ph.D.
Washington University
School of Medicine
Campus Box 8056
660 South Euclid Avenue
St. Louis MO  63110
Telephone: 314-362-9383 
Fax: 314-362-7086
Email: cma@im.wustl.edu
Edith Perez, M.D.
Mayo Clinic Jacksonville
4500 San Pablo Road
Jacksonville FL 32224
Telephone: 904-953-7283
Fax: 904-953-1412
Email:  perez.edith@mayo.edu


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Matthew Goetz, M.D.
Mayo Clinic Cancer Center
200 First Street SW
Rochester MN 55905
Telephone: 507-284-2511
Fax: 507-284-5280
Email:  goetz.matthew@mayo.edu
Antonio C. Wolff, M.D.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
1650 Orleans St. 
Baltimore, MD, 21231-1000
Telephone: 410-614-4192
Fax: 410-955-0125
Email:  awolff@jhmi.edu
David Kelsen MD 
Edward S Gordon Chair in Medical Oncology 
Chief, Gastrointestinal Oncology Service 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, NY 10021 
Phone: (212) 639-8470
Fax: (646) 422-2017
Email:  kelsend@mskcc.org
Judy Garber, MD, MPH
Dana Farber Cancer Institute
1 Jimmy Fund Way, Bldg Smith 2
Boston, MA 02115-6007
Phone: (617) 632-2282
Fax: (617) 632-3161
Email:  judy_garber@dfci.harvard.edu
Nadine M. Tung, MD
Beth Israel Deaconess Medical Center
330 Brookline Avenue
Boston, MA 02215
T: 617-667-7082
F: 617-975-5665
Email:  ntung@bidmc.harvard.edu
Steven Isakoff, MD PhD
Massachusetts General Hospital
55 Fruit Street, LH306
Boston, MA 02114
P: 617-726-4920


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F: 617-643-0589
Email:  sisakoff@partners.org
Srikala Sridhar, MD
Princess Margaret Hospital
610 University Ave.
Toronto, ON
Canada
M5G 2M9
Phone: (416) 946-2249
Fax: 416-946-6546
Email: srikala.sridhar@uhn.on.ca
Banu K. Arun, MD
MD Anderson Cancer Center
1515 Holcombe Blvd.
Houston, TX 77030
Phone: (713) 792-2817
Email: barun@mdanderson.org
David R. Gandara, MD
Tianhong Li, MD
University of California Davis Cancer Center
4501 X Street
Sacramento CA  95817
Phone:  916-734-3771
Fax:  916-734-7946
E-mail: david.gandara@ucdmc.ucdavis.edu
E-mail:  tianhong.li@ucdmc.ucdavis.edu
Statistician:
Paul Frankel, Ph.D.
City of Hope 1500 East Duarte Road
Duarte, CA  91010
Phone: (626) 256-4673 x 65265
Fax: (626) 471-7106
Email:  pfrankel@coh.org
Research Nurse:
Norma Baker, RN
City of Hope 
1500 East Duarte Road
Duarte, CA  91010
Phone: (626) 471-9200
Fax: (626) 301-8850
Email:  nbaker@coh.org
City of Hope Affiliates: 


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Stephen Koehler, MD 
City of Hope Medical Group, Inc.,
209 Fair Oaks Avenue
South Pasadena, CA 91030
626/396-2900
Skoehler@cohmg.com
Participating Centers:  
University of California Davis Cancer Center and Affiliates
City of Hope Comprehensive Cancer Center and Affiliates
University of Southern California-Norris Cancer Center
University of Pittsburgh Comprehensive Cancer Center
Penn State Cancer Institute
University of Chicago Consortium
Princess Margaret Hospital
MD Anderson Cancer Center
New York Consortium
Mayo Clinic Phase 2 Consortium
Dana Farber Cancer Institute 
Beth Israel Deaconess Medical Center
Massachusetts General Hospital
NCI Supplied Agent:
ABT-888 (NSC 737664, IND# 
)
Commercially Available Agent:
Carboplatin
Protocol Version Date:
Original protocol v1 dated 11/12/09
Response to Consensus Review dated 2/5/10
Response to Follow-Up Review dated 2/26/10
Amendment dated 6/24/10
Amendment dated 10/18/10
RRA – CAEPR amendment dated 1/13/11
Amendment dated 2/25/11
Amendment dated 6/23/11
Amendment dated 9/01/11
Amendment dated 10/6/11
Amendment dated 11/21/11
Amendment dated 4/24/12 – Rejected
Amendment dated 5/11/12
Amendment dated 5/29/12
Amendment dated 7/17/12
Amendment dated 8/20/12 – Action Letter - CAEPR


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Amendment dated 7/23/13
Amendment dated 12/31/13
Amendment dated 4/20/16 – Action Letter CAEPR
Amendment dated 3/14/18 – CTCAE change
Amendment dated 6/14/18 – RRA (disapproved)
Amendment dated 7/9/18 – RRA (disapproved)
Amendment dated 7/19/18 – RRA (disapproved)
Amendment dated 8/6/18 – RRA
Amendment dated 1/5/21 – PI change
Amendment dated 6/1/23 – Drug availability and expiration 
Amendment dated 11/9/23 – Updated drug availability 


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SCHEMA
Safety lead-in: Stage IV BRCA-associated breast cancer patients will be treated with carboplatin 
on day 1 of each 21 day cycle, given at an AUC of 5. The dose of carboplatin may be fixed at a 
lower AUC if DLTs in the safety lead-in prompt adoption of any of the reduced [-] dose 
schedules, except for individual dose modifications in subsequent cycles to address toxicities.
ABT-888 will be given on days 1-21 of each cycle, starting at 50 mg po BID (and then at 100 
mg, 150 mg, and 200 mg BID) per cohort. Between 12-27 patients will be treated during the 
safety lead-in, and no patients in the safety lead-in will be included in the primary analysis of the 
Phase II study as the Phase II portion patients start treatment with single agent ABT-888. [Note:
safety lead-in was completed with 25 patients, and the MTD was established with carboplatin 
AUC 5, ABT-888 150 mg BID]
Phase II Study:
Stage IV BRCA (stratified by BRCA1 or BRCA2)-associated breast cancer patients will initiate 
treatment with ABT-888 at the single agent recommended dose 400mg BID, based on CTEP 
recommendations and toxicity experience from PHI-63 NCI #8282: A Phase I Study of 
Chronically-Dosed, Single Agent ABT-888 in Patients with Either BRCA 1/2-Mutated Cancer: 
Platinum Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer; or Basal Like 
Breast Cancer.
Following progression, patients will be off treatment for one week (see justification in statistics 
section), and then if they meet the eligibility requirements, the patients will initiate treatment 
with carboplatin AUC 5 plus ABT-888 150 mg BID (as the Maximum Tolerated Dose of the 
combination established during the safety lead-in noted above).
The two strata (BRCA1 and BRCA2-associated breast cancer) will accrue independently: 
Initially 10 patients will be accrued to a stratum. More than 1 confirmed response in the first 10
patients in a strata will result in an additional 12 patients accrued to that stratum (for a total of 
22). As a result, if 2 responses are seen in the first 10 patients with both BRCA1 and BRCA2-
associated breast cancer, a total of 44 patients will be accrued to the Phase II portion of this 
study. 


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TABLE OF CONTENTS
 
1 
OBJECTIVES ...................................................................................................... 14 
1.1 
PRIMARY OBJECTIVES.....................................................................................14 
1.2 
SECONDARY OBJECTIVES...............................................................................14 
2 
BACKGROUND .................................................................................................. 15 
2.1 
BRCA-RELATED CANCER ................................................................................15 
2.2 
ABT-888 (NSC 737664):.......................................................................................17 
2.3 
CARBOPLATIN....................................................................................................20 
2.4 
RATIONALE .........................................................................................................22 
3 
PATIENT SELECTION ..................................................................................... 23 
3.1 
ELIGIBILITY CRITERIA.....................................................................................24 
3.2 
EXCLUSION CRITERIA......................................................................................25 
3.3 
INCLUSION OF WOMEN AND MINORITIES..................................................26 
4 
REGISTRATION PROCEDURES .................................................................... 28 
4.1 
GENERAL GUIDELINES ....................................................................................28 
4.2 
REGISTRATION PROCESS.................................................................................28 
5 
TREATMENT PLAN .......................................................................................... 29 
5.1 
AGENT ADMINISTRATION ...............................................................................29 
5.2 
DEFINITION OF DOSE-LIMITING TOXICITY FOR SAFETY LEAD-IN ......30 
5.3 
RULES FOR DOSE ESCALATION DURING SAFETY LEAD-IN ...................31 
5.4 
DEFINITION OF THE MTD AND RECOMMENDED PHASE 2 DOSE ..........32 
5.5 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES..34 
5.6 
DURATION OF THERAPY..................................................................................34 
5.7 
DURATION OF FOLLOW-UP .............................................................................35 
6 
DOSING DELAYS/DOSE MODIFICATIONS ................................................ 36 
6.1 
DOSE MODIFICATIONS FOR HEMATOLOGICAL TOXICITY......................37 
6.2 
DOSE MODIFICATIONS FOR NON-HEMATOLOGICAL TOXICITY............40 
7 
ADVERSE EVENTS:  CAEPR LIST AND REPORTING 
REQUIREMENTS ............................................................................................... 44 


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7.1 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST 
(CAEPR)................................................................................................................44 
7.2 
ADVERSE EVENT CHARACTERISTICS..........................................................49 
7.3 
EXPEDITED ADVERSE EVENT REPORTING .................................................51 
7.4 
ROUTINE ADVERSE EVENT REPORTING......................................................53 
7.5 
SECONDARY AML/MDS....................................................................................53 
8 
PHARMACEUTICAL INFORMATION .......................................................... 54 
8.1 
CTEP-SUPPLIED INVESTIGATIONAL AGENTS.............................................54 
8.2 
OTHER INVESTIGATIONAL AGENTS .............................................................56 
8.3 
CARBOPLATIN....................................................................................................56 
9 
CORRELATIVE/SPECIAL STUDIES ............................................................. 58 
9.1 
OPTIONAL BLOOD SAMPLES FOR FUTURE GENETIC RESEARCH 
STUDIES ...............................................................................................................58 
9.2 
MOLECULAR CORRELATES ............................................................................58 
10 
STUDY CALENDAR .......................................................................................... 65 
11 
MEASUREMENT OF EFFECT ........................................................................ 67 
11.1 
DEFINITIONS.......................................................................................................67 
11.2 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE .................68 
11.3 
RESPONSE CRITERIA ........................................................................................71 
11.4 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE ................74 
12 
DATA REPORTING / REGULATORY CONSIDERATIONS ...................... 75 
12.1 
DATA REPORTING ..............................................................................................75 
12.2 
RESPONSIBILITY FOR SUBMISSION..............................................................75 
12.3 
CTEP MULTICENTER GUIDELINES ................................................................75 
12.4 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT 
(CRADA) / CLINICAL TRIALS AGREEMENT (CTA)......................................76 
13 
STATISTICAL CONSIDERATIONS ............................................................... 78 
13.1 
STUDY DESIGN/ENDPOINTS ...........................................................................78 
13.2 
SAMPLE SIZE/ACCRUAL RATE .......................................................................78 
13.3 
STRATIFICATION FACTORS .............................................................................79 
13.4 
ANALYSIS OF CORRELATIVE/SPECIAL STUDIES .......................................80 
14 
CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS ............. 83 
14.1 
OVERSIGHT.........................................................................................................83 


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15 
REFERENCES ..................................................................................................... 85 
APPENDICES ......................................................................................................................... 91 
APPENDIX A - PERFORMANCE STATUS CRITERIA ......................................................92 
APPENDIX B - CTEP MULTI-CENTER GUIDELINES.......................................................93 
APPENDIX C - CCCP REGISTRATION PROCEDURES ....................................................95 
APPENDIX D - CCCP SPECIMEN SUBMISSION FORM...................................................96 
APPENDIX E - PATIENT MEDICATION DIARY ..............................................................97 
APPENDIX E:  PATIENT MEDICATION DIARY................................................................98 
APPENDIX F STANDARD OPERATING PROCEDURES FOR CORRELATIVE 
STUDIES .............................................................................................................100 


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PROTOCOL SYNOPSIS AND OVERALL DESIGN
Title:
Phase II Trial of ABT-888 with Post-Progression Therapy of ABT-888 in 
Combination with Carboplatin in Patients with Stage IV BRCA-associated 
Breast Cancer
Sponsor:
National Cancer Institute
Project phase:
Phase II with a combination lead-in
Objectives:
x
To evaluate the efficacy of single agent ABT-888 (NSC 737664) in BRCA carriers 
with metastatic breast cancer based on response rate (RECIST criteria)
x
To evaluate progression-free survival of patients on single-agent ABT-888.
x
To further describe the safety and tolerability of ABT-888 (NSC 737664) as a single 
agent and in combination with carboplatin for BRCA-associated breast cancer.
x
To evaluate the pharmacokinetics of ABT-888 (NSC 737664) alone and in 
combination with carboplatin.
x
To assess the relationship between the level of PARP inhibition by ABT-888 and 
biomarkers of DNA damage in PBMC’s and tumor
x
To explore the relationship between biomarkers of drug effect and progression-free 
survival
x
To evaluate the efficacy and safety of the combination of carboplatin and ABT-888 in 
patients who have failed single agent ABT-888.
x
To conduct subset analysis on BRCA1 vs. BRCA2 and hormone receptor status
Study design:
This is a Phase II trial to establish the single agent activity with ABT-888 in BRCA1 and 
BRCA2 patients.  Following progression, patients will receive ABT-888 plus carboplatin after a 
one week delay according to the dose established in a safety lead-in.
Sample size:
20-44 patients are expected to be treated on the Phase II part of the 
trial (10-22 per BRCA1 and BRCA2 stratum).
Investigational Product(s):
ABT-888 (NSC 737664)
Carboplatin (commercially available)
Dose regimen:
ABT-888 at 400 mg BID. The post-progression dosing, following 
a 1 week delay, will be dosed according to the safety-lead in of 
this study (150 mg BID plus carboplatin AUC 5). 
Safety lead-in:
Stage IV BRCA-associated breast cancer patients will be treated with 
carboplatin on day 1 of each 21 day cycle, given at an AUC of 5 in the first dose level.  The dose 
of carboplatin may be fixed at a lower AUC if DLTs in the safety lead-in prompt adoption of any 


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of the reduced [-] dose schedules.  ABT-888 will be given on days 1-21 of each cycle, starting at 
50 mg po BID (and then at 100 mg, 150 mg, and 200 mg BID per cohort, if those doses do not 
exceed the recommended Phase II single agent dose derived from the ongoing phase I trial, NCI# 
8282).
Between 24-27 evaluable patients will be treated during the safety lead-in, and these 
patients will not be included in the primary analysis of the Phase II study. Cycle length is 21 
days.  Patients are evaluated every 3 cycles until progression of disease or the patient is otherwise 
withdrawn from the trial. [Note: safety lead-in was completed with 25 patients, and the MTD was 
established with carboplatin AUC 5, ABT-888 150 mg BID]
Phase II Portion: Cohorts of BRCA1 and BRCA2 carriers with measurable metastatic breast 
cancer will be treated with ABT-888 at 400 mg BID, to assess single agent response rate. 
Documentation of single agent activity (more than 1 CR or PR per RECIST) per stratum 
(BRCA1 or BRCA2) in the first 10 patients on each stratum is a pre-requisite to continuing to a 
total of 22 patients per stratum. Following progression, patients will have a one week interval of 
no treatment, and if eligible proceed to receive ABT-888 150 mg BID plus carboplatin AUC 5. 
Route of administration:
ABT-888 will be administered BID orally
Carboplatin will be administered IV
Key eligibility criteria:
Stage IV breast cancer and confirmed BRCA+ status.  Evaluable 
disease is allowed in the safety lead-in component.  Measurable 
disease as defined by RECIST criteria is required for the phase II 
component.
Key procedures:
RECIST measurement of tumor progression, assessment of 
biomarkers, pharmacokinetics (PK) and pharmacodynamics (PD) 
in serum, archival and, as feasible, pre- and post-treatment tumor 
tissue. 


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1
OBJECTIVES 
1.1
PRIMARY OBJECTIVES 
This Phase II study will be conducted as part of the N01 contract agreement (NO1 CM 62209) 
that the California Cancer Consortium (CCCP) has with the National Cancer Institute.  The 
objectives of this study are:  
x
To evaluate the efficacy of single agent ABT-888 (NSC 737664) in BRCA carriers 
with metastatic breast cancer based on response rate (RECIST criteria)
1.2
SECONDARY OBJECTIVES 
x
To conduct subset analysis on BRCA1 vs. BRCA2 and hormone receptor status
x
To evaluate progression-free survival of patients on single-agent ABT-888.
x
To further describe the safety and tolerability of ABT-888 (NSC 737664) as a single agent 
and in combination with carboplatin for BRCA-associated breast cancer.
x
To evaluate the pharmacokinetics of ABT-888 (NSC 737664) alone and in combination 
with carboplatin.
x
To assess the relationship between the level of PARP inhibition by ABT-888 and 
biomarkers of DNA damage in PBMC’s and in tumor
x
To explore the relationship between biomarkers of drug effect and progression-free survival
x
To evaluate the efficacy and safety of the combination of carboplatin and ABT-888 in 
patients who have failed single agent ABT-888.
x
To conduct subset analysis on BRCA1 vs. BRCA2 and hormone receptor status






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ADP-ribosyl protein lyase, which removes the protein proximal to the ADP-ribose
monomer.
PARP is an essential nuclear enzyme that plays a role in recognition of DNA damage and 
facilitation of DNA repair.  Therefore, inhibition of PARP is expected to enhance the 
effects of DNA damage.  Expression of PARP is higher in tumor cells as compared to 
normal cells.  This overexpression has been linked to drug resistance and the ability of 
tumor cells to withstand genotoxic stress.  Hence, it is anticipated that PARP inhibitors 
will function as sensitizers to DNA-damaging chemotherapeutic agents and radiation 
therapy.
2.2
 ABT-888 (NSC 737664):  
We are studying a potent new PARP inhibitor, ABT-888 (NSC 737664), obtained from the 
Cancer Therapy Evaluation Program (CTEP).  Based on promising preclinical results, we 
propose a novel translational clinical trial of ABT-888 as a targeted therapy for BRCA-
associated cancer.
Poly(ADP-ribosyl)ation (PAR) occurs after single or double-stranded DNA damage and 
represents the posttranslational modification of histones and other nuclear proteins by 
PARP.  PAR has been implicated in many cellular processes including replication, 
transcription, differentiation, gene regulation, protein degradation, and spindle 
maintenance.  PARP-1 and PARP-2 are nuclear proteins and are the only members of the 
PARP family with zinc-finger DNA binding domains.  These domains localize PARP-1
and PARP-2 to the site of DNA damage.  PARP-1 is highly conserved and has three 
structural domains (N-terminal DNA-binding domain; automodification domain, and the 
NAD+-binding domain).  The catalytic domain is located at the C-terminus end of the 
protein.  In knockout mouse models, deletion of PARP-1 is sufficient to impair DNA 
repair [14-16].  The residual PARP-dependent repair activity (~ 10%) is due to PARP-2.  
This suggests that only PARP-1 and PARP-2 need to be inhibited to impair DNA repair 
[17-19].
Increased PARP activity is one of the mechanisms by which tumor cells avoid apoptosis 
caused by DNA damaging agents.  PARP activity is essential for the repair of single-
stranded DNA breaks through the base excision repair (BER) pathways [18, 20].  
Therefore, inhibition of PARP sensitizes tumor cells to cytotoxic agents (e.g. alkylators 
and topoisomerase I inhibitors) which induce DNA damage that would normally be 
repaired through the BER system.  A significant therapeutic window appears to exist 
between a PARP inhibitor’s ability to potentiate therapeutic benefit versus potentiation of 
undesirable side effects.  Potent small molecule inhibitors of poly ADP-ribose polymerase 
entered early phase clinical trials over the last 5 years, primarily as potentiators of 
existing DNA damaging chemotherapies (reviewed in [21]).  As expected, PARP 
inhibitors do not potentiate agents that do not cause DNA damage.
ABT-888 has been used with platinum agents in pre-clinical studies and with the 
methylating agent temozolomide in clinical studies [22-24].  However, potentiation of 


PhII-96, NCI# 8264
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platinum agents by ABT-888 is anticipated to be more efficient than potentiation of 
temolozomide by ABT-888, since platinum agents generate DNA modifications repaired 
primarily by nucleotide excision repair, whereas temozolomide forms damaged bases 
repaired by BER.  Therefore, use of temozolomide in conjunction with ABT-888 targets 
principally BER, while carboplatin-ABT-888 would attack both nucleotide excision repair 
and BER pathways.
Exploitation of BRCA deficiencies with DNA repair inhibitors as therapeutic tools.
Cells with BRCA mutant proteins are sensitive to chemotherapeutic agents [25, 26], but 
PARP inhibitors have an inherent advantage, the therapeutic potential to kill tumor cells 
that have homozygous BRCA mutations, while leaving heterozygous cells virtually 
untouched [1, 2].  This provides a large therapeutic window for PARP inhibition in 
patients with BRCA-associated BC.
The approach has been likened to inducing 
“synthetic lethality”, as the relatively well tolerated PARP inhibitor treatment causes 
endogenous DNA damage to accumulate in the HRR-deficient cell background, leading to 
replication arrest and apoptosis [27].  Single-agent activity in tumor cells with defective 
HRR (e.g., BRCA-associated BC) is suggested by pre-clinical data [1, 2], and preliminary 
results of a recent clinical trials suggested responsiveness in BRCA-associated breast and 
ovarian cancer [28-30].  As noted above, the relevant functional defect in BRCA-
associated BC is HRR deficiency, and the mechanism of action of platinum agents is 
through DNA binding and associated DSBs [31].  Pre-clinical studies in a conditional 
mouse model for BRCA-associated hereditary BC indicated tumors responded well to 
cisplatin, and did not become resistant, although the tumors regrew after therapy stopped 
[32].
The results of ABT-888 testing in combination with cytotoxic agents, in several tumor 
models, is summarized below (Table 1).  ABT-888 (whether administered parenterally or 
orally) substantially increased the efficacy of cytotoxic therapies, when measured by 
either treated/control tumor volumes (%T/C) or by increased time for tumors to grow to a 
particular size (%ILS).
Table 1. Preclinical data for ABT-888 mediated potentiation of cytotoxic agents
Breast
carcinoma 
(human
MX-1)
Glioblasto
ma
multiform 
(rat 9L)
B cell 
lympho
ma
(human
DOHH2)
Melanoma 
(murine 
B16F10)
Carboplatin
Yes
Cisplatin
Yes
No
Cyclophosphamide
Yes
Irinotecan
Yes
Yes
Temozolomide
Yes
Yes


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A PARP inhibitor was recently shown to substantially potentiate cisplatin and carboplatin 
in a murine BRCA2 model [33, 34].  The exquisite sensitivity of these cells to the PARP 
inhibitor, alone or in combination with carboplatin, provides strong support for PARP 
inhibitors as a novel targeted therapeutic approach against BRCA-deficient cancers.  A 
study [22] of ABT-888 alone and in combination with irinotecan in breast, ovarian, colon 
and lung cancer cell lines with known aberrations in DNA repair, showed significant 
single agent activity in the MX-1 (BRCA1-deficient) cell line (inhibitory concentration 
50% [IC50] of 4 μM vs. >80 μM in several non-BRCA cell lines).  Studies were 
performed at a fixed dose (210 nM) of ABT-888, a drug plasma level that can be achieved 
in mice and humans.  ABT-888 was able to potentiate irinotecan cytotoxicity in two breast 
cancer cell lines (T47D [10,000-fold] and MX-1 [200-fold]), the ovarian line A2780 (20-
fold) and the lung cancer cell line HOP62 (9-fold).  Investigation of DNA repair 
abnormalities in the responsive cell lines suggested potential determinants of response:  a) 
mutations in the BRCA1 tumor suppressor protein as found in the MX-1 cell line confer 
ABT-888 single agent activity; b) elevated protein levels of the nucleotide excision repair 
enzyme ERCC1 sensitize to the ABT-888/irinotecan combination in T47D, A2780, and 
HOP62 cells; and c) p53 mutations enhance tumor cell kill by the ABT-888/irinotecan 
combination in cell lines with high ERCC1 levels such as T47D.  Taken in sum, 
preclinical studies suggest that BRCA1 and p53 mutational status should be assessed, as 
well as the measurement of ERCC1 and γH2AX levels (indicating the presence of DSBs) 
as response correlates in clinical trials with ABT-888.  Many these questions were 
incorporated into the planned correlative studies associated with the proposed clinical 
trial (see below).
Our pre-clinical experiments with ABT-888 treatment of Brca1 or Brca2 deficient mouse 
embryonic stem cells (mESCs) indicated substantial single agent activity compared to 
wild type (wt) control cells (Figure 3).  While the BRCA deficient cells showed the same 
pattern of sensitivity to both cisplatin and carboplatin, the addition of ABT-888 was 
synergistic in all three cell lines (data not shown), requiring significantly less of the 
chemotherapeutic drug to achieve the same effect.




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administered at an AUC of 7 reported a 33% response rate in previously untreated 
patients [442].
More recently, researchers sought to better characterize and find alternative approaches to 
treatment of high-grade, clinically aggressive BC that does not express steroid hormone 
receptors or Her2/neu amplification—“triple negative” tumors [44-46].  With the 
identification of impaired DNA repair mechanisms in BRCA carriers, and implications of 
a similar biology in patients with triple negative/basaloid breast cancer (a phenotype 
frequently seen in association with the BRCA1 genotype), DNA-damaging agents such as 
the platinum compounds emerged as potential targeted therapies.
Indeed, several early reports in triple negative breast cancer suggested that cisplatin as a 
single agent [444], or in combination [47], may provide higher response rates, including 
complete responses, than what could have been expected in the general breast cancer 
population with such treatment.  Further, CTEP has indicated that they are considering 
combinations with carboplatin as the only platinum agent in their long term development 
strategy for treatment in earlier stage breast cancer (e.g. adjuvant) settings.
Carboplatin is a commonly used platinum compound that acts by binding to DNA and 
interrupting cell division.  It is approved by the FDA for the treatment of patients with 
ovarian cancer. It is also used for the treatment of non-small cell lung cancer, small cell 
lung cancer, head and neck cancer, endometrial cancer, metastatic seminoma and more 
recently in breast cancer. Carboplatin is eliminated by renal excretion. The clearance is 
related to the glomerular filtration rate. Therefore it is dosed based on the GFR and the 
target area under the concentration versus time curve (AUC). The main side effect of 
carboplatin is myelosuppression. Other toxicities include nausea, vomiting, renal and 
neurotoxicity. 
Initial sensitivity and response to platinum agents may be an explanation for the observed 
enhanced survival in BRCA-associated ovarian cancer; this effect was most pronounced 
for advanced stage (III/IV) disease [48, 49].  However, in many cases, the cancer becomes 
platinum-refractory.  Since HRR deficiency defines BRCA-associated defects and is 
correlated with the sensitivity to PARP inhibitor drugs, mechanisms reconstituting HRR 
could result in drug resistance.  Two recent studies suggest that one mechanism of drug 
resistance is in vivo selection for BRCA2 “reversion” mutants, wherein alteration of the 
abnormal allele restores the reading frame and specific functional domains, along with 
recovery of HRR function [50, 51].  A better understanding of the mechanism(s) of that 
acquired resistance has the potential to benefit many women with BRCA-associated 
cancer.
Careful study of biomarkers may reveal additional pathways to be targeted in the future, 
while the potentiation of drugs such as carboplatin by concomitant PARP inhibition is 
likely to increase efficacy of carboplatin at lower doses.  In one trial of combination 
PARP inhibitor and temozolomide, dose reduction of the latter was necessary because of 
enhanced toxicity.  However, the reduced-dose (25%) regimen improved tolerability over 
the single-agent temozolomide, while doubling the response rate and time to progression 


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[24].  With an ever increasing arsenal of molecularly-targeted therapies, an understanding 
of the specific biologic pathways operative in a given tumor (somatic) or germline 
context has great potential for enhanced therapeutic ratios and quality-adjusted years of 
life saved.
2.4
RATIONALE 
BRCA proteins and other DNA repair mechanisms, including base excision repair and 
direct reversal of DNA damage, function in a complementary manner to remove hurdles 
that impede DNA cell division.  Therefore, in BRCA cells, inhibition of complementary 
repair function should increase the sensitivity of cancer cells to killing by both 
endogenous mutagens and exogenous agents. The PARP inhibitor ABT-888, validated in 
our pre-clinical work, will be tested alone and in combination with carboplatinum this 
clinical trial.
Rationale for selection of starting doses: For ABT-888, the chosen starting dose is 
based on an ongoing phase 1 continuous dosing study (NCI#8282), in which only one of 
six patients at the level of 50mg BID had a DLT.  Carboplatinum was able to be delivered 
at AUC 6 in the phase I combination study of carboplatinum, paclitaxel and ABT-888 
(NCI#7967).  While paclitaxel will not be used in this study, ABT-888 may behave 
synergistically with carboplatin and result in added toxicity, primarily myelosupression, 
consequently a dose modification scheme for carboplatin is included.  Although we 
expect both arms of this regimen to be well tolerated, we have established guidelines and 
criteria which will be used to flag an unexpected number of patients who experience 
unacceptable toxicity.   These rules will be applied to both arms independently, although 
the main motivation for such detailed monitoring is based on the combination arm.
The MTD for carboplatin dosing is established as AUC 5. The previous dose escalation 
schedule labelled as Table 3a has now been deleted. An expanded safety lead-in 
attempted to maximize the ABT-888 exposure (Table 3) while keeping the carboplatin at 
AUC 5.  This is prompted by observation of grades 3 & 4 thrombocytopenia with an 
otherwise well-tolerated regimen in the initial safety lead-in experience with the first 9 
patients.  Given that the Phase I continuous dosing study of ABT-888 (NCI#8282) passed
400mg BID, it seems likely that ABT-888 in combination with carboplatin can be 
escalated safely to at least 200 mg BID in the expansion phase. [Note: safety lead-in was 
completed with 25 patients, and the MTD was established with carboplatin AUC 5, ABT-
888 150 mg BID]


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3
 PATIENT SELECTION 
Study Population:
The infrastructure of the multi-institutional California Cancer Consortium with 
Pennsylvania (CCCP) will be used to obtain access to the specific CTEP agent, and 
facilitate development, conduct and dissemination of the proposed targeted therapy 
protocol, which will be supported under a N01 phase II contract (N01CM57018).  Along 
with the 5 affiliated CCCP institutions (City of Hope, University of California at Davis, 
University of Southern California, University of Pittsburgh, and Pennsylvania State 
University), five other N01-supported consortia are committed to participating in the 
clinical trial, including this latest amended version (New York Consortium [even though 
this consortium is no longer part of the NO1 contract mechanism, the participating 
institutions have agreed, and demonstrated ongoing commitment to accruing patients];
University of Chicago Consortium; Mayo Clinic Phase 2 Consortium, Princess Margaret 
Hospital, Toronto, Canada; MD Anderson Cancer Center, Houston; letters of 
collaboration are in the Appendix).  All patient registrations will be handled centrally via 
the CCCP coordinating center.
Clinical cancer genetics resources will be used for enhanced recruitment, with strong 
minority representation, including our established hereditary cancer registry, community-
based Cancer Screening & Prevention Program Network (CSPPN) and liaisons with 
advocates/organizations for national recruitment and dissemination.  Data mining from 
the existing COH CSPPN cohort (described in Preliminary Results) identified 
approximately 65 BRCA carriers with locally advanced (stage III) or metastatic BC, and 
we accrue approximately 110 new BRCA carriers with BC in the CSPPN annually.  CCCP 
partner institutions each have a set of known BRCA carriers with BC, and most have a 
formal cancer genetics unit.  For example, USC has accrued 49 BRCA carriers with BC, 
and University of Pittsburgh estimates approximately 20 new BRCA-associated BC cases 
each year.  Summation of estimates from the other collaborating consortia indicate 
approximately 90 potentially eligible women with advanced BRCA-associated BC will be 
identified annually.  Overall, after selecting for advanced stage cases, we estimate that 5 
of 22 potentially eligible cases across the consortia will be accrued to the study every 
month over the projected 18-month accrual period.  Additional procedures to augment 
accrual include listing on COH Clinical Trials On-line, posting the studies on the FORCE 
web site (per Advocate Sue Friedman; letter in Appendix), and a newsletter style 
announcement distributed (email and USPS) to a mailing list of regional/referring 
physicians.  The Clinical Cancer Genetics team (PI:  Weitzel) will hold monthly 
teleconferences with the genetics units across the consortia to review progress identifying 
BRCA carriers as candidates for study, and disseminate any updated promotional 
materials.
Treating physicians who are approved by their respective Institutional Review Boards 
(IRB) will be responsible for explaining the study, answering questions and obtaining 
informed consent, according to regulatory guidelines and to respective IRB guidelines.  


PhII-96, NCI# 8264
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Ongoing understanding will be assessed and questions will continue to be answered by 
the treating physicians.  
3.1
ELIGIBILITY CRITERIA 
3.1.1
Patients must be female, and must have histologically confirmed breast cancer that is 
metastatic or locally advanced, unresectable and for which standard curative measures do 
not exist or are no longer effective.
3.1.2
Patients must have a known deleterious BRCA mutation confirmed by report from a CLIA 
certified laboratory (generally Myriad Genetics Laboratory).  It is expected that BRCA
testing will be covered as medically necessary care by the patient’s insurance carrier.
3.1.3
Measurable disease by RECIST criteria. (Evaluable disease is allowed only for the Safety 
Lead-In phase).
3.1.4
Prior chemotherapy regimens for metastatic disease are completed, at least 3 weeks prior 
to starting therapy. Prior radiation and hormonal treatment must be completed at least 1 
week prior to starting therapy.
3.1.5
Female, age ≥18 years.  Because no dosing or adverse event data are currently available 
on the use of ABT-888 in patients <18 years of age, children are excluded from this study.
3.1.6
ECOG Performance Status 0-2 (See Appendix A).
3.1.7
Life expectancy of greater than four months.
3.1.8
Patients must have normal organ and marrow function as defined below
 absolute neutrophil count  
>1,500/mcL
 platelets  
 
 
 
 
 
>100,000/mcL
 total bilirubin
< 1.5 X institutional upper limit of normal               
 AST(SGOT)/ALT(SGPT)  
<2.5 X institutional upper limit of normal
unless there is evidence of  liver metastasis, 
in which case the AST(SGOT)/ALT(SGPT) 
must be 
< 5 X institutional upper limit of normal
 creatinine
within normal institutional limits
OR
 creatinine clearance  
 
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional normal.
3.1.9
If a woman is of child-bearing potential, a negative serum or urine pregnancy test is 
required.  (The effects of ABT-888 [NSC 737664] on the developing human fetus are 
unknown.  For this reason and because PARP Inhibitor agents are known to be 
teratogenic [see Investigator Brochure], women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; 


PhII-96, NCI# 8264
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25
abstinence) prior to study entry and for the duration of study participation.  Participants 
should agree to use contraception for at least 3 months after the completion of study 
therapy. Should a woman become pregnant or suspect she is pregnant while participating 
in this study, she should inform her treating physician immediately.)
3.1.10 Ability to understand and the willingness to sign a written informed consent document.
3.2
EXCLUSION CRITERIA 
3.2.1
Prior therapy with platinum agents (adjuvant therapy with platinum agents is allowed, if 
completed ≥ 12 months prior to relapse), or PARP inhibitors (prior iniparib, since it is no 
longer considered a PARP inhibitor, is allowed).
3.2.1
Patients may not be receiving any other investigational agents.
3.2.2
Patients with known CNS metastases requiring anticonvulsive medications, or steroids or 
with active symptomatology.
Patients on anticonvulsant medications prescribed for 
reasons other than CNS metastases, not on steroids and without active symptomatology 
are eligible. Patients must be off anti-seizure medications and steroids for 3 months or 
more before enrollment.
3.2.3
Patients with active seizure or a history of seizure.  Patients with CNS metastases must be 
stable after therapy for > 3 months and off steroid treatment prior to study enrollment.
3.2.4
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to ABT-888 (NSC 737664) or PARP inhibitors.
3.2.5
Patients with contraindications to platinum agents are excluded.
3.2.6
Prior or current non-breast malignancy within 5 years except non-melanoma skin cancer, 
or resected stage I ovarian cancer.
3.2.7
Patients with any non-malignant intercurrent illness (e.g. cardiovascular, pulmonary, or 
central nervous system disease) which is either poorly controlled with currently available 
treatment, or which is of such severity that the investigators deem it unwise to enter the 
patient on protocol.
3.2.8
Pregnant women are excluded from this study because ABT-888 (NSC 737664) has the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but 


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potential risk for adverse events in nursing infants secondary to treatment of the mother 
with ABT-888 (NSC 737664), breastfeeding should be discontinued.
3.2.9
Patients unable to swallow the ABT-888 tablets whole are ineligible.  (The tablets cannot 
be crushed or broken.)
3.2.10 Patients with an active severe infection; known infection with HIV, hepatitis B virus, or 
hepatitis C virus.  HIV-positive patients on combination antiretroviral therapy are 
ineligible because of the potential for pharmacokinetic interactions with ABT-888 (NSC 
737664).  In addition, these patients are at increased risk of lethal infections when treated 
with marrow-suppressive therapy.  Appropriate studies will be undertaken in patients 
receiving combination antiretroviral therapy when indicated.
3.3
INCLUSION OF WOMEN AND MINORITIES 
Women and members of all races and ethnic groups are eligible for this trial. 
Plan for recruitment of underrepresented minorities: Collectively, there is a good track 
record and infrastructure for recruitment of underrepresented minorities into clinical 
trials.  In addition to large Hispanic (primarily Mexican American) populations proximal 
to each of the CCCP institutions, the PI for this proposal conducts satellite genetic cancer 
risk assessment clinics as part of ongoing health services research (Komen 
#POP0600464) in underserved, predominantly Latina populations [52-55].  The main 
clinic is located at Olive View Medical Center (OVMC), the primary public health 
hospital in the San Fernando Valley.  Dr. Nancy Feldman, Chair of Medical Oncology at 
OVMC, works closely with Dr. Weitzel, referring young Latinas with locally advanced 
and metastatic BC for genetic testing and treatment trials.  Led by bilingual/biliterate 
genetic counselors and research coordinators and patient navigators, cancer risk 
counseling protocols are tailored to the respective communities.  This outreach has 
resulted in approximately 40% accrual of Hispanics on phase I (completed)[56] and phase 
II (IRB#02164; accrual of female BRCA carriers completed) prevention trials at COH.  
The genetics unit at USC is establishing a genetic cancer risk assessment clinic at the 
main county hospital, which serves an ethnically diverse population of Hispanics and 
African Americans.
Please see accrual targets by ethnic and racial categories for the study (Table 2).
Table 2:  Accrual Targets
Accrual Targets
Ethnic Category
Sex/Gender
Females
Males
Total
Hispanic or Latino
15
+
0
=
15
Not Hispanic or Latino
56
+
0
=
56


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Ethnic Category: Total of all subjects
71
(A1) +
0
(B1) =
71
Racial Category
American Indian or Alaskan Native
0
+
0
=
0
Asian*
7
+
0
=
7
Black or African American
6
+
0
=
6
Native 
Hawaiian 
or 
other 
Pacific 
Islander*
0
+
0
=
0
White
58
+
0
=
58
Racial Category: Total of all subjects
71
(A2) +
0
(B2) =
71
                    (A1 = A2)
                  (B1 = B2)
       (C1 = C2)
*-These categories are combined.


PhII-96, NCI# 8264
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4
REGISTRATION PROCEDURES 
4.1
GENERAL GUIDELINES 
Eligible patients will be entered on study centrally at the California Cancer Consortium 
Data Coordinating Center at the City of Hope.  All sites should call the Data Coordinating 
Center at (626) 256-4673 extension 65928 to verify dose level availabilities. 
Following registration, patients should begin protocol treatment within 24 hours.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator.  If 
a patient does not receive protocol therapy following registration, the patient’s 
registration on the study may be canceled.  The Data Coordinating Center should be 
notified of cancellations as soon as possible.
Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Data Coordinating 
Center to the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies.
4.2
REGISTRATION PROCESS 
Once the signed informed consent has been obtained, all pretreatment evaluations have 
been performed, and patient’s eligibility has been confirmed by the Data Coordinating 
Center a patient will be entered on study, and be considered registered.
To register a patient, the research nurse or data manager must complete the 
eligibility/registration form and contact the Consortium office (Data Coordinating Center 
for the California Cancer Consortium) at the City of Hope (626-256-4673, ext. 65928), 
FAX a copy of the completed eligibility checklist, required pre-study tests (pathology and 
baseline laboratory reports (including CT reports), BRCA genetic test result), signed 
Informed Consent, signed Patients' Bill of Rights and HIPAA authorization form. (FAX 
Number: 626-256-8654).  See Appendix D (“Registration Procedures”)
The research nurse or data manager at the participating site will then call the Data 
Coordinating Center at Tel# 626-256-4673 extension 65928 to confirm receipt of all 
registration documents. To complete the registration process, the Data Coordinating 
Center coordinator will:
x
Verify the eligibility
x
Register the patient on study
x
Assign a patient accession number
x
E-mail the patient study number and dose to the participating site
x
Call the research nurse or data manager at the participating site and verbally confirm 
registration.


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5
TREATMENT PLAN 
5.1
AGENT ADMINISTRATION 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications for study drug 
are described in Section 6.  No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the patient's 
malignancy. Following the safety lead-in to determine the dose of ABT-888 to be used in 
combination with carboplatin, patients will receive single agent ABT-888 and receive the 
combination only after progression, if eligible, following a 1-week interval of no 
treatment. 
Safety Lead-In of combination:
ABT-888 was started at 50 mg p.o. BID and increases in increments up to 200 mg p.o. 
BID (see Table 3), under the condition that the ABT-888 dose does not exceed the MTD 
or the recommended Phase II dose from the single agent study.
The MTD for carboplatin was established at AUC 5 (IV on Day 1 of each 21 day cycle). 
This was in combination with ABT-888 at 50 mg PO BID (Days 1-21 of each 3-week 
cycle). The dose levels (previously ‘Table 3a’) used are itemized here but the escalations 
for carboplatin have been completed due to two DLTs at AUC 6. We are now escalating 
only the ABT-888; the carboplatin has been set at AUC 5. Cycle length is 21 days and 
patients will be evaluated for response every three cycles (approximately every two 
months). 
x
Dose Level -1*
Carboplatin AUC 5 (established MTD)
Starting from September 1, 2011, all new patients on the Safety Lead-In will be treated as 
per Table 3.
Table 3*: Dose Escalation Schedule for Expansion Phase of Safety Lead-In.
Carboplatin AUC at MTD (defined as AUC 5) IV day 1 of each 21-day cycle.
Dose Level
ABT-888
a
100 mg PO bid
b
150 mg PO bid
c
200 mg PO bid
*Previously Table 3b


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No patients treated during the safety lead-in will be considered in the primary evaluation 
of the Phase II component. 
Phase II Component:
As of the November 9, 2023 amendment, the pharmaceutical collaborator, AbbVie, 
has discontinued the ABT-888 development program with the NCI Cancer Therapy 
Evaluation Program (CTEP).  Clinical supply will no longer be available after 
December 31, 2024. 
Patients will discontinue treatment by December 31, 2024, or earlier.  
Stratum 1: BRCA1-associated Breast Cancer: ABT-888 alone, 400 mg PO BID, daily
x 21 days.  Initially 10 patients will be treated. If 0 or 1 responses are seen (CR or 
PR) this stratum will close. If there are two or more responses, an additional 12
patients will be accrued for a total of 22 patients on this stratum.
Stratum 2: BRCA2-associated Breast Cancer: ABT-888 alone, 400 mg PO BID, daily
x 21 days.  Initially 10 patients will be treated. If 0 or 1 responses are seen (CR or 
PR) this stratum will close. If there are two or more responses, an additional 12
patients will be accrued to a total of 22 patients on this stratum.
Patients progressing on the Phase II component will be required to have a 1-week
interval of no treatment prior to being treated with the combination (as established 
during the safety lead-in), and be required to meet the pre-treatment eligibility 
requirements (other than the prior therapy requirements). Following progression, if 
patients meet the eligibility requirements, the patients will initiate treatment with 
carboplatin AUC 5 plus ABT-888 150 mg BID (as the Maximum Tolerated Dose of the 
combination established during the safety lead-in).  
5.2
DEFINITION OF DOSE-LIMITING TOXICITY FOR SAFETY LEAD-IN 
Dose limiting toxicity (DLT) will be defined as any grade III non-hematological toxicity 
not reversible to grade II or less within 96 hours, or any grade IV toxicity (excluding 
alopecia or controllable nausea and vomiting).  Additionally, patients unable to take 80% 
of the planned ABT-888 due to toxicity/tolerability will be considered to have had a DLT.  
Toxicity will be graded according to the NCI CTCAE version 5.0.  To be evaluable for 
toxicity, a patient must receive at least one complete course of treatment (80% of the 
ABT-888 dose plus received planned dose of carboplatin), and be observed for at least 21 
days after the start of the first course or have experienced a DLT.  All patients who 
receive any amount of drug will be considered evaluable for toxicity.  However, any 


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31
patient who does not receive at least 80% of the ABT-888 (Arm A and B) or the planned 
dose of carboplatin for reasons other than toxicity/tolerability, will be considered 
inevaluable for determination of MTD and will be replaced for the consideration of dose 
levels during the safety lead-in portion.
Dose reductions will be performed if a DLT is observed or if a dose reduction is deemed 
medically prudent.  The 80% dose requirement for ABT-888 is based on the original 
planned dose, and not any dose modifications.
5.3
 RULES FOR DOSE ESCALATION DURING SAFETY LEAD-IN 
No intrapatient dose escalations are permitted (intrapatient dose escalation was only 
permitted for patients on dose level 1, which is complete).
Determination of MTD:
Dose escalation will proceed within each cohort according to this scheme.  
Number of Patients with 
DLT at a Given Dose Level
Escalation Decision Rule
0 out of 3
Will enter 3 patients at the next highest dose level.
>2
Dose escalation will be stopped.  This dose level will 
be declared the maximally administered dose (highest 
dose administered).  Three (3) additional patients will 
be entered at the next lowest dose level if only 3 
patients were treated previously at that dose.
1 out of 3
Will enter at least 3 more patients at this dose level.
x If 0 of these 3 patients experience DLT, will 
proceed to the next dose level.
x If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that 
dose. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose
This is generally the MTD and the recommended 
phase 2 dose. At least 6 patients must be entered at the 
recommended phase 2 dose.


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5.4
DEFINITION OF THE MTD AND RECOMMENDED PHASE 2 DOSE 
The maximum tolerated dose (MTD) is defined as the highest dose tested in which <33% 
of patients experienced DLT, when at least six patients were treated at that dose and are 
evaluable for toxicity.  The MTD is one dose level below the lowest dose tested in which 
33% or more of the patients experienced DLT. The MTD is based on the first cycle of 
therapy. The recommended Phase II dose is generally the MTD, although secondary 
considerations of toxicity and dose reductions on subsequent cycles and other secondary 
considerations may result in the recommended Phase II dose being below the MTD.
5.4.1
ABT-888 
ABT-888 will be administered orally without regards to meals. Study drug can be taken 
up to 2 hours outside of the scheduled time, otherwise, missed doses should not be made 
up.
On the days when the patient is scheduled to undergo sampling of blood and/or tumor 
tissue for PD and correlative studies, the dose of ABT-888 will be administered under 
supervision (to record the time and coordinate collection of subsequent samples). 
However, the timing of PD and correlative studies should be based on the administration 
of carboplatin, not ABT-888, in the combination arm of the study.
Because there is a potential for interaction of ABT-888 with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other 
drugs, over-the-counter medications, or alternative therapies.  
ABT-888 is not known to be a potent inhibitor of the major human CYPs in vitro,
indicating a low risk for drug-drug interactions at the proposed dosing concentrations. 
Studies are underway to evaluate the whether ABT-888 induces the CYP enzymes.
5.4.2
Carboplatin 
Carboplatin will be administered as an intravenous infusion over 30 minutes. 
The carboplatin dose will be calculated using the Calvert formula using AUC of 5 as
follows: 
Carboplatin dose (mg) = 5 X (GFR + 25) 
(Calculated total dose is in mg -not mg/m2)
The Creatinine Clearance (to replace GFR) will be calculated for each 
treatment course using the formula: 


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For Females: 
*Important: The serum creatinine level to be used in the 
following calculations must be greater than or equal to 0.7.  If 
the measured serum creatinine level is less than 0.7, use 0.7 as 
the value in this calculation.  
CrCI = (140-age) X wt. in kg. X 0.85
72 X serum creatinine*
Use calculated creatinine clearance for GFR in Calvert formula. 
Note: Remember to re-calculate the dose for each treatment cycle. The 
actual body weight should be used for all calculations. If the actual weight 
is greater than 1.2 times the ideal body weight (IBW), use 1.2 times the 
ideal body weight as the value in this calculation.
Ideal Body Weight (Females) = 45.5 kg + 2.3 kg for each inch 
over 5 feet.
Note: The GFR (calculated by Cockcroft-Gault or any other means 
using creatinine) used in the Calvert formula to calculate AUC-based
dosing should not exceed 125 mL/min under any circumstance.
By definition, this results in the following upper limits on the dose to 
be administered, by AUC target:
AUC target
(mg•min/mL)
Maximum carboplatin dose
(mg)
2
300
3
450
4
600
5
750
Questions about this calculation should be directed at the principal 
investigator.


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5.5
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
In case participants develop nausea/vomiting/diarrhea or myelosuppression, supportive 
medications will be prescribed as per Clinical Center and ASCO guidelines.  Seizures 
were seen in some animal toxicology studies, although at doses much higher than those 
anticipated for this study.  Seizures in animals were successfully treated with lorazepam.
The use of prophylactic granulocyte colony stimulating factor is not allowed for the first 
cycle of therapy. The use of growth factors for the treatment of anemia is allowed at the 
discretion of the treating physician. Neupogen or Neulasta is allowed for treatment of 
neutropenia after cycle 1.  
Patients with known metastatic disease to the bones may be allowed to take 
bisphosphonates as directed by the treating physician.
All supportive measures consistent with optimal patient care will be given throughout the 
study.
Patients should be cautioned about the concomitant use of cimetidine, trimethoprim, or 
other agents that interfere with creatinine secretion or the creatinine assay.
Because there is a potential for interaction of ABT-888 with other concomitantly 
administered drugs, the case report form must capture the concurrent use of all other 
drugs, over-the-counter medications, or alternative therapies.  
Emesis Prophylaxis: The combination of a 5-HT3 antagonist plus dexamethasone is 
strongly recommended prior to carboplatin administration.
Anti-emetic choice is at the discretion of the treating investigator. A 5-HT3 antagonist 
(granisetron 2 mg PO/1 mg IV or ondansetron 8-24 mg IV/24 mg PO or dolasetron 100 
mg either IV or PO) plus dexamethasone 20 mg PO/IV prior to each treatment is 
recommended.
5.6
DURATION OF THERAPY 
In the absence of treatment delays due to adverse events, treatment may continue for as 
many cycles as are required to demonstrate that there is no apparent clinical benefit or the 
patient is withdrawn from the trial, or until one of the following criteria applies:
•
Disease progression (on the combination),
•
Intercurrent illness that prevents further administration of treatment,
•
Unacceptable adverse event(s),
•
Patient decides to withdraw from the study, or
•
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator.


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5.7
DURATION OF FOLLOW-UP 
Patients removed from study for unacceptable adverse events will be followed at a 
minimum of monthly until resolution or stabilization of the adverse event.  All patients 
will be followed for survival at a minimum interval of every 6 months, until the patient 
dies or refuses further follow up. 


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6
DOSING DELAYS/DOSE MODIFICATIONS 
Patients should meet the laboratory parameters outlined in section 3.1.8 and the 
performance status in section 3.1.6 before initiation of each cycle of therapy. All 
toxicities (except alopecia and lymphopenia, hyperglycemia, hypoalbuminemia, elevated 
serum alkaline phosphatase, WBC, and hemoglobin) should have resolved to grade 1 or 
lesser severity before initiation of the next cycle of therapy.
Qualifying laboratory tests can be obtained up to 72 hours before planned initiation of 
therapy from the third cycle onwards.
Dose adjustments are to be made according to the organ system showing the greatest 
degree of toxicity.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized 
for AE reporting beginning April 1, 2018. All appropriate treatment areas should have 
access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
The dose levels and the general approach to dose modification of ABT-888 therapy is 
shown in Table 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).
Table 4:
Dose modification of ABT-888 for patients on the single agent ABT-888
(As of 8/6/18, there are 3 remaining patients on study; the study is closed to accrual and all 
remaining patients are currently being treated with single agent ABT-888; if necessary, 
their doses will be reduced as indicated in this table.)
Dose Level
ABT-888 Tablets
Dose reduction 1
Reduce by 50 mg BID
Dose reduction 2*
Reduce by another 50 mg BID
BID = twice daily
*No more than two dose reductions.
At the discretion of the investigator, the study drug is held or dose modified if the 
observed toxicity is attributed to the drug, while the patient continues to receive another 


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drug not associated with the observed toxicity. The time a 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 requiring transfusions
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.  If a patient is taking ABT-888 in 
combination with other therapies, but develops one of the toxicities listed above, the 
patient may be allowed to continue the other therapies if they are experiencing clinical 
benefit and the toxicity is not related to the other therapies, based on the opinion of the 
treating investigator, and after discussion with the Principal Investigator.
6.1
DOSE MODIFICATIONS FOR HEMATOLOGICAL 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 Table 5:
Table 5:
Management of neutropenia or thrombocytopenia
CTCAE Grade
Definition
ABT-888 Dose
1-2
ANC >1.0 G/L or 
Platelet count >50 
G/L
Investigator 
judgment 
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


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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.
Platelet transfusions, if indicated, should be done according to local hospital guidelines.
Dose modifications for hematologic toxicity
Patients who have ABT-888 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.
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.
Management of anemia
Anemia is a common adverse drug reaction related to ABT-888.
Management of 
anemia is in accordance with Table 6:
Table 6:
Management of anemia
CTCAE 
Grade
Definition
ABT-888 Dose
2
Hb <10 but ≥8 g/dL
Give appropriate supportive treatment and 


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CTCAE 
Grade
Definition
ABT-888 Dose
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 50 mg BID from the current 
dose level as a first step and by another 50
mg BID as a second step.
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 50 mg 
BID.
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, reduce ABT-888 dose to no more than two dose 
reductions.
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.
Management of prolonged hematological toxicities while on study treatment
If a patient develops prolonged hematological toxicity such as:
x
≥2 week interruption/delay in velaparib due to CTCAE Grade ≥3 anemia (Hb <8 
g/dL) and/or development of blood transfusion dependence
x
≥2 week interruption/delay in ABT-888 due to CTCAE Grade ≥3 neutropenia (ANC <1 x
109/L)


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x
≥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 ABT-888 associated toxicity
Management of MDS/AML
Patients who develop MDS/AML on treatment should discontinue ABT-888 
treatment and be managed appropriately.
6.2
DOSE MODIFICATIONS FOR NON-HEMATOLOGICAL TOXICITY  
6.2.1. Gastrointestinal Toxicity
Nausea and/or vomiting should be controlled with adequate antiemetic 
therapy. Prophylactic anti-emetic therapy can be used at the discretion of 
the treating physician. Patients are encouraged to take plenty of oral fluids. 
If symptoms persist despite maximal anti-emetic therapy, ABT-888 should 
be withheld until recovery to < grade 1.
Diarrhea should be managed with appropriate anti-diarrheal therapy. 
Patients should be encouraged to take plenty of oral fluids. If symptoms do 
not decrease to grade 1 or less with adequate anti-diarrheal therapy, ABT-
888 should be held until recovery from symptoms to < grade 1.  ABT-888 
can be re-started at the same dose following recovery to < grade 1 if worst 
grade of toxicity is < grade 2. For worst grade > 3, re-start ABT-888 with 
dose reduction by one dose level (see Table 4).
It is recommended that loperamide be prescribed to control diarrhea, 
barring any contraindication to such therapy.  Loperamide should be taken 
at 4 mg after the first episode of diarrhea, and can be repeated at a dose of 
2 mg after each subsequent episode, not to exceed 16 mgs in total dose. 
If symptoms recur, the dose of ABT-888 should be re-started with a 
reduction by one dose level (see Table 4).
6.2.2
Hypersensitivity Reactions


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Caution: Patients who had a mild to moderate hypersensitivity reaction 
have been successfully rechallenged, but careful attention to prophylaxis 
and bedside monitoring of vital signs is recommended. 
6.2.2.1 Mild symptoms (e.g., mild flushing, rash, pruritus) -Complete 
infusion. Supervise at bedside. No treatment required. 
6.2.2.2 Moderate symptoms (e.g., moderate rash, flushing, mild dyspnea, 
chest 
discomfort) 
-Stop 
infusion. 
Give 
intravenous 
diphenhydramine 25 mg and intravenous dexamethasone 10 mg. 
Resume infusion after recovery of symptoms at a low rate, 20 
mg/hr. For 15 minutes, then, if no further symptoms, at full dose 
rate until infusion is complete. If symptoms recur, stop infusion. 
Record toxicity on flow sheets. Use desensitization protocol as per 
institutional standards for any further cycles..  However, a second 
moderate reaction to protocol therapy while a patient is treated on 
institutional desensitization protocol mandates removal from 
further carboplatin therapy.
6.2.2.3 Severe life threatening symptoms (e.g., hypotension requiring 
pressor therapy, angioedema, respiratory distress requiring 
bronchodilation therapy, generalized urticaria)-stop infusion. Give 
intravenous diphenhydramine and dexamethasone as above. Add 
epinephrine or bronchodialtors if indicated. If wheezing is present, 
that is not responsive to bronchodilators, epinephrine is 
recommended. Patient should be removed from further protocol 
therapy.  Report as adverse event. 
6.2.3
Other Toxicities
For any grade 3 or 4 toxicity not mentioned above, withhold both 
drugs until the patient recovers to grade 1 or less toxicity. The 
treatment should then be resumed at one lower dose level for 
carboplatin (see 5.4.2, permanent dose reduction) and same dose 
for ABT-888 (see Table 4; permanent dose reduction). For grade 2 
toxicities, withhold treatment until the patient recovers, then 
resume treatment at a one dose-level reduction for carboplatin 
(permanent dose reduction) and same dose for ABT-888. For grade 
1 toxicities, no dose reduction should be made. For subsequent 
episodes of Grade 3 or 4 non-hematological toxicities, see table 
below.


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**If reduced to AUC of 2, next episode = discontinue carboplatin, but option to 
continue single agent ABT-888 at current dose (at the discretion of the treating 
physician if patient has stable disease or better) or go off study.
6.2.4
Guidelines for treatment of patients who require dose reduction in 
carboplatin for cycle 2
Patients who require dose reduction in carboplatin for cycle 2 will 
be allowed to continue on study (with the addition of ABT-888 at 
the originally-intended dose level). However, the patients will be 
evaluable for pharmacokinetics, toxicity and efficacy analysis.  If 
severe toxicity is noted in cycle 2 also, the patient may be removed 
from the study at the discretion of the treating physician. 
If the dose of carboplatin is reduced for cycle 2 due to grade 4 
neutropenia, in addition to dose reduction, institution of 
prophylactic neutrophil colony stimulating factor is recommended. 
6.2.5
Guidelines for treatment of patients who require dose reduction while 
receiving single-agent ABT-888 in the phase II portion of the trial 
Non-Hem 
Toxicity
ABT 888
Carboplatin (if
applicable)
Grade 3/4
1st episode
No change
Reduce to Current 
AUC minus 1**
2ndepisode
Reduce ABT-888 by one level 
(see Table 4)
No change
3rd episode
No change
Reduce to Current 
AUC minus 1**
4th episode
Reduce ABT-888 by one 
additional level (see Table 4)
No change
5th episode
Off study
Off study
Non-Hem 
Toxicity
ABT 888


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Grade 3/4
1st episode
Reduce ABT-888 by one dose level
2ndepisode
Reduce ABT-888 by one additional dose level
3rd episode
Off study


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7
ADVERSE EVENTS:  CAEPR LIST AND REPORTING 
REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  
The following list of AEs (Section 7.1) and the characteristics of an observed AE 
(Section 7.2) will determine whether the event requires expedited (via CTEP-AERS)
reporting in addition to routine reporting.
7.1
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST 
(CAEPR)  
7.1.1
CAEPRs 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/docs/aeguidelines.pd
f for further clarification.  Frequency is provided based on 2310 patients. Below is the 
CAEPR for Veliparib (ABT-888).
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower 
of the grades to determine if expedited reporting is required.






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1This 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.
2Thromboembolic 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


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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
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.


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7.1.1. Adverse Event List for Carboplatin 
Some of the expected adverse events from carboplatin are listed below.  For further 
description of adverse events see Package Insert.  
Hematologic:
Myelosuppresion
Gastrointestinal:
Nausea, 
vomiting, 
diarrhea, 
weight 
loss, 
constipation, gastrointestinal pain
Metabolic:
Electrolyte 
imbalances, 
hypomagnesemia, 
hypocalcemia, hyponatremia, hyperuremia
Hepatic toxicity:
Elevated alkaline phosphatase, AST, and total 
bilirubin
CNS:
Peripheral neuropathies (mild paresthesias, clinical 
ototoxicity and other sensory abnormalities are rare)
Genitourinary:
Renal 
tubular 
damage, 
renal 
insufficiency, 
impotence, sterility, amenorrhea, gynecomastia
Allergy:
Anaphylactoid and urticarial reactions (acute), 
flushing, rash, pruritis and rarely hypotension or 
bronchospasm
Other:
Alopecia, pain, asthenia and mucosal side effects, 
decreased serum electrolytes values (sodium, 
magnesium, calcium and potassium)
7.1.2. Other potential adverse events 
Blood Draw:  Drawing blood from a vein can cause minor pain and bruising at the site 
where the needle enters.  Some people feel dizzy when blood is drawn.  Rarely, infection 
may occur.
CT Scans: exposure to radiation from CT scans.  CT scans can be associated with 
extremely rare allergic reactions to contrast agents.  
MRI Scans: Claustrophobia is the main risk. 
7.2
ADVERSE EVENT CHARACTERISTICS  
•
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting beginning April 1, 2018. All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE 


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version 
5.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
‘Expectedness’:
AEs can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above) for 
expedited reporting purposes only.  ‘Expected’ AEs (the ASAEL) are bold and italicized
in the CAEPR (Section 7.1).
•
Attribution of the AE:
-
Definite
-The AE is clearly related to the study treatment.
-
Probable
-The AE is likely related to the study treatment.
-
Possible
-The AE may be related to the study treatment.
-
Unlikely
-The AE is doubtfully related to the study treatment.
-
Unrelated
-The AE is clearly NOT related to the study treatment.  (In this 
situation, the cause of the AE should be described.)


PhII-96, NCI# 8264
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8
EXPEDITED ADVERSE EVENT REPORTING 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP home page (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements” which can be downloaded from the CTEP 
home page (http://ctep.cancer.gov).  These requirements are briefly outlined in the 
table below (Section 7.3.3).
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site.
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature for 
other e-mail recipients. 
Expedited Reporting Guidelines  
CTEP-AERS Reporting Requirements for Adverse Events that occur within 30 Days1 
of the Last Dose of the Investigational Agent on Phase 2 and 3 Trials
Phase 2 and 3 Trials
Grade 1
Grade 2
Grade 2
Grade 3
Grade 3
Grades
4 & 52
Grades
4 & 52
Unexpected 
and 
Expected
Unex-
pected
Expected
Unexpected
Expected
Unex-
pected 
Expected
with 
Hospitali-
zation
without 
Hospitali-
zation
with 
Hospitali-
zation
without 
Hospitali-
zation
Unrelated
Unlikely
Not
Required
Not
Required
Not
Required
10
Calendar
Days
Not
Required
10
Calendar
Days
Not
Required
10
Calendar
Days
10
Calendar
Days
Possible
Not
10
Calendar
Not
10
Calendar
10
Calendar
10
Calendar
Not
24-Hour;
10


PhII-96, NCI# 8264
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Probable
Definite
Required
Days
Required
Days
Days
Days
Required
5 Calendar
Days
Calendar
Days
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows:
CTEP-AERS 24-hour notification followed by complete report within 5 calendar days for:
x
Grade 4 and Grade 5 unexpected events 
CTEP-AERS 10 calendar day report:
x
Grade 3 unexpected events with hospitalization or prolongation of hospitalization
x
Grade 5 expected events
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table.
December 15, 2004
Note:  All deaths on study require both routine and expedited reporting regardless 
of causality.  Attribution to treatment or other cause must be provided.
•
Expedited AE reporting timelines defined:
- “24 hours; 5 calendar days” – The investigator must initially report the AE via 
CTEP-AERS within 24 hours of learning of the event followed by a complete 
CTEP-AERS report within 5 calendar days of the initial 24-hour report.
- “10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event. 
•
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions.  
•
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND.
•
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports.
•
Note: A death on study requires both routine and expedited reporting, regardless 
of causality. Attribution to treatment or other cause must be provided. 
•
Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions.” Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted.


PhII-96, NCI# 8264
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8.1
ROUTINE ADVERSE EVENT REPORTING 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
through CTEP-AERS must also be reported in routine study data submissions.
8.2
SECONDARY AML/MDS 
Investigators are required to report cases of secondary AML/MDS occurring on or 
following treatment on NCI-sponsored chemotherapy protocols using the NCI/CTEP 
Secondary AML/MDS Report Form.  This form can be downloaded from the CTEP web 
site (http://ctep.cancer.gov).  Refer to the “CTEP, NCI Guidelines: Adverse Event 
Reporting Requirements” (available at http://ctep.cancer.gov) for additional information 
about secondary AML/MDS reporting. 


PhII-96, NCI# 8264
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9
PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with ABT-888 and carboplatin 
can be found in Section 7.1.
9.1
CTEP-SUPPLIED INVESTIGATIONAL AGENTS 
9.1.1
ABT-888 (NSC 737664) 
Chemical Name: 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide
Other Names:  A-861695.0
Classification: Poly (ADP-ribosome) polymerase (PARP) Inhibitor
Molecular Formula:  C13H16N4O
M.W.:  244.29
Description: White opaque capsule
How Supplied:  Abbott Laboratories supplies and DCTD distributes ABT-888.  ABT-888 
capsules are available in 10 mg, 20 mg, 40 mg, 50 mg and 100 mg immediate release 
capsules.  The inactive ingredients are microcrystaline cellulose, colloidal silicon dioxide, 
magnesium stearate, gelatin, sodium lauryl sulfate, FD&C yellow #5, and titanium dioxide.  
The capsules are packaged in HDPE bottles, and each HDPE bottle contains 16 capsules or 
64 capsules.
Note: ABT-888 capsules may be repackaged from the supplied HDPE bottles into amber 
(or other low-actinic) child resistant pharmacy dispensing bottles. Expiration will be 30 
days from the repackaging date (or the original retest date, whichever is earlier) when 
stored at 15°C to 25°C (59°F to 77°F). 
Storage:
Store intact bottles between 150 and 250 C (590 – 770F), excursion permitted 
between 250 and 300C (770 – 860F); protect from heat and moisture.
Stability: Shelf life stability studies for ABT-888 capsules are on-going.
Route(s) of Administration: Oral.  ABT-888 capsules may be administered without regard to 
meals.
Availability:
ABT-888 is an investigational agent supplied to investigators by the 
Division of Cancer Treatment and Diagnosis (DCTD), NCI.


PhII-96, NCI# 8264
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ABT-888 is provided to the NCI under a Collaborative Agreement between Abbott 
Laboratories and the DCTD, NCI (see Section 12.3).
As of the November 9, 2023 amendment, the pharmaceutical collaborator, AbbVie, 
has discontinued the ABT-888 development program with the NCI Cancer Therapy 
Evaluation Program (CTEP). 
Clinical supply will no longer be available after 
December 31, 2024.
Patients will discontinue treatment by December 31, 2024, or earlier.  
9.1.2
CTEP IND AGENT #2 (NSC #) 
N/A
9.1.3
AGENT ORDERING 
NCI-supplied agents may be requested by the Principal Investigator (or their 
authorized designees) at each participating institution.  Pharmaceutical 
Management Branch (PMB) policy requires that the agent be shipped directly to the 
institution where the patient is to be treated.  PMB does not permit the transfer of 
investigational agents between institutions (unless prior approval from PMB is 
obtained).  The CTEP-assigned protocol number must be used for ordering all 
CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  
If there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution.
Agent may be requested by completing a Clinical Drug Request (NIH-986) and 
faxing it to the Pharmaceutical Management Branch at (301) 480-4612.  For questions 
about drug orders, transfers, returns, or accountability call (240) 276-6575Monday 
through 
Friday 
between 
8:30 
am 
and 
4:30 
pm 
(ET) 
or 
email 
PMBAfterHours@mail.nih.gov anytime.
As of the 8/6/18 amendment, a 6-month supply may be dispensed to patients. When 
ordering drug with the Pharmaceutical Management Branch (PMB), the Clinical Drug 
Request (NIH-986) must indicate the request for a 6-month supply. A 6-month supply 
can only be provided if the PMB has a lot of drug with an expiration date > 6 months.


PhII-96, NCI# 8264
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9.1.4
AGENT ACCOUNTABILITY 
The Investigator, or a responsible party designated by the Investigator, must 
maintain a careful record of the inventory and disposition of all agents received 
from DCTD using the NCI Drug Accountability Record Form.  See the CTEP web 
site for Policy and Guidelines for Accountability and Storage of Investigational 
Drugs (http://ctep.cancer.gov/requisition/storage.html).
9.2
OTHER INVESTIGATIONAL AGENTS 
N/A
9.3
CARBOPLATIN  
Availability
Carboplatin is commercially available as a sterile lyophilized powder available in 
single-dose vials containing 50 mg, 150 mg, or 450 mg of carboplatin.  Each vial 
contains equal parts by weight of carboplatin and mannitol.  Commercial supplies of 
carboplatin will be used for this study. Carboplatin is also available as an aqueous 
solution in 50 mg/5 mL, 150 mg/15 mL, 450 mg/45 mL and 600 mg/60 mL multidose 
vials
Preparation
Reconstitute lyophilized powder with Sterile Water, 0.9% Sodium Chloride, or 5% 
Dextrose Injection with volumes of diluents specified below.  The reconstituted solution 
can be further diluted to a concentration as low as 0.5 mg/mL with 0.9% Normal Saline 
or 5% Dextrose Injection.  
Vial Strength
Diluent Volume
50 mg
5 mL
150 mg
15 mL
450 mg
45 mL
Storage and Stability 
When prepared as directed, the resultant carboplatin solutions, when protected from light, 
are stable for 8 hours at room temperature.  No antibacterial preservative is contained in 
the formulation, and therefore, it is recommended that carboplatin solutions be discarded 
8 hours after dilution.


PhII-96, NCI# 8264
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57
NOTE:  Aluminum reacts with carboplatin, causing precipitate formation and loss of 
potency.  Therefore, needles or intravenous sets containing aluminum parts that may 
come in contact with the drug must not be used for the preparation or administration of 
carboplatin.
Unopened vials of carboplatin are stable for the life indicated on the package when stored 
at controlled room temperature (59 - 86qF) and protected from light.  When prepared, 
carboplatin solutions are stable for 8 hours at room temperature. Carboplatin aqueous 
solution multidose vials maintain microbial, chemical, and physical stability for up to 14 
days at 25º C following multiple needle entries.
Dosing and Administration
Carboplatin will be administered within one hour after ABT-888 as an intravenous 
infusion over 30 minutes.  Dose calculations are specified in Section 5.1 (Treatment 
Administration).


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10 CORRELATIVE/SPECIAL STUDIES 
10.1 OPTIONAL BLOOD SAMPLES FOR FUTURE GENETIC RESEARCH STUDIES 
Optional blood samples will be drawn for future genetic research studies including 
analysis of possible constitutional determinants of resistance and metabolism of ABT-888. 
Participants will be requested to provide a blood sample to be stored at ambient 
temperature for DNA extraction and potential pharmacogenetic analysis.  Any genotyping 
performed will relate to the absorption, distribution, metabolism, elimination or mode of 
action of study drugs and any comparators, related pathways and other oncogenetic
pathways.
10.2 MOLECULAR CORRELATES   
We will use qualified and validated assay methods (Table 7) to assess the relationship 
between the level of PARP inhibition by ABT-888 and markers of DNA damage in 
surrogate tissues (PBMC’s) and tumor.  γH2AX and RAD51 immunohistochemical 
assays will be conducted using laser scanning cytometry (LSC) [59, 60].  In preliminary 
studies, we have shown increased γH2AX frequency in BRCA-null cells compared to the 
complemented cells for the PARP inhibitor ABT-888, using scanning laser cytometry 
(Figure 4) that will be used in the clinical trial.
Biomarkers for PARP inhibitors. The phospho-modified histone JH2AX serves as a 
marker for double strand breaks (DSBs); therefore, we will use an antibody (monoclonal 
mouse Ab from Upstate Biotechnology Anti-phospho-Histone H2A.X (Ser139), clone 
JBW301) against that protein in immunohistochemical analysis [57].  RAD51 will be 
loaded onto single-strand regions during HRR that co-stain with the JH2AX
immunostaining, but in BRCA2 cells co-localization should be reduced due to the 
inability of BRCA2 to function.  The number of cells with >10 spots for JH2AX should 
indicate the increased formation of DSBs in the presence of ABT-888 and possibly the 
other PARP inhibitors.  
We will also use 
immunostaining for 
JH2AX in hair follicles 
from eyebrow plucks as a 
biomarker of 
pharmacodynamic effect
[64, 65].
The recent phase 0 trial in 
patients with advanced 
malignancies demonstrated >85% reduction in PAR level in PBMCs after a single oral 25 
mg dose [35].
Table 7 Assays and Biomarkers for patient samples.
Assay/Biomarker
Sample
Assay
Ref.
PARP Activity
PBMC
Tumor
Immunoassay
[61, 62]
JH2AX/RAD51
PBMC
Tumor
IHC/LSC
[63-65]
Reversion mutations/ 
HRR Assay
Tumor (top 
priority use)
I-SceI EGFP
[50, 66]




PhII-96, NCI# 8264
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60
agent arm), and then again on the off-study visit.  Up to 3 passes will be allowed during 
each biopsy procedure for obtaining tumor tissue.  Samples will be immediately snap-
frozen. The top priority will be to analyze for BRCA reading frame restoring revertant 
mutations at baseline and at progression.  PAR/γH2AX/RAD51 assays with the tumor 
tissue will then be conducted.  Since epinephrine can interfere with the PAR assay, the 
local anesthesia for the tumor biopsy will utilize lidocaine whenever possible and avoid 
‘lidocaine plus epinephrine’. However, if epinephrine is used, it will be clearly noted in 
the case report form. Patients will not be excluded from the trial if these samples are not 
collected.  
The complete set of frozen samples will be shipped overnight on dry ice to the following 
address:
Analytical Pharma. Lab
City of Hope 
Shapiro Bldg. (Synold/JNW) Rm. 1042
1500 E Duarte Rd.
Duarte, CA 91010
Phone (626) 359-8111, ext. 62110
Email: tsynold@coh.org
All specimens shipped must be accompanied by the Specimen Submission form found in 
Appendix D.  Additionally, a copy of that completed form must be faxed to the Data 
Coordinating Center at City of Hope, (626) 256-8654 when specimens are shipped. 
Expected results.  We expect that the γH2AX will increase as the degree of PARP 
inhibition increases in PBMC and tumor, but there will be no increase in RAD51 in the 
tumor due to the absence of BRCA.  Immunoassay for poly-ADP-ribosylated (PAR) 
substrates:  Abbott Laboratories and the NCI-Frederick laboratories developed and cross-
validated a quantitative immunoassay for PAR [61]. The validated assay is a sandwich 
enzyme chemiluminescence immunoassay employing commercially obtained antibodies 
to PAR, and pure PAR as a standard.  Specimen handling was optimized for both PBMCs 
and tumor needle biopsies (18 ga), and harmonized for use with the same standards and 
controls.  The validated assay was used to measure PAR levels in PBMCs of healthy 
donors, in animal models after administration of a single and multiple dosing of ABT-
888, and has been used successfully in real time to measure PAR in PBMCs and tumor 
biopsies in a phase 0 clinical trial [61]. Kits for the CLIA-approved PAR assay will be 
obtained from the NCI and the research technician performing the PAR assay will be 
trained at the NCI.
Determine mechanisms of resistance. Cells which are BRCA null can compensate, in 
part, for defects in HRR DSB repair by using single-strand annealing and non-
homologous end joining (NHEJ) [67].  Patients who receive PARP inhibitors could 
manifest drug resistance by reconstituting their BRCA function.  This would lead to 


PhII-96, NCI# 8264
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restoration of normal HRR and the therapeutic footing in the original cell type (BRCA 
null) would be lost, as described in recent reports [50, 51]. Therefore, we will examine 
BRCA sequences from tumor cells from patients treated with ABT-888.  The precise 
germline BRCA mutation will be known for all patients.
We anticipate 10-20% (n=8-16) of clinical trial participants will have accessible tumor 
and consent to biopsy just prior to treatment with study drug(s) on the trial.  These 
samples will be used to assess HRR status and whether BRCA expression is restored 
indicating the presence/absence of reversion mutations prior to initiating our clinical 
treatments and correlative studies.  A proportion of cases are likely to have reversion 
mutation and/or re-expression of BRCA and restored HRR due to selective pressure from 
chemotherapy exposure; however, platinum resistance can occur by a non-HRR
mechanism so clinical resistance alone does not preclude persistent defective HRR and 
susceptibility to PARP inhibitors.  Approximately 6-12% (n=5-10) may have accessible 
tumor and consent to biopsy for study post-clinical trial.
At the close of the protocol, the BRCA sequence will be re-determined in available tumor.  
Full length BRCA clones in the pcDNA3.1 expression with a promoter more active in 
mESCs will be constructed will be modified to introduce any sequence differences from 
the original BRCA sequences.  We have the full length cDNA constructs and are 
constructing the vectors.  Point mutations will be introduced into BRCA using site-
directed mutagenesis, whereas larger deletions or insertions will be constructed using 
restriction sites.  Plasmids hosting the BRCA1 or BRCA2 constructs will be transformed 
into mESCs-DR-GFP that have a GFP reporter for HRR and have either Brca1-/- or
Brca2-/- [69] (Figure 5).  Those cells have a GFP sequence with a homing endonuclease 
site ISce I that is unique in the Brca cells, which are null for one of the 2 Brca proteins.  
Cleavage using the Sce I and HRR reconstitutes the GFP coding sequence and allows 
production of a functional GFP.  We will also monitor survival of the complemented and 
vector only cells to treatment using ABT-888 or ABT-888 and carboplatin.  In addition, 
the reporter assay will be used to determine the fold-increase in GFP fluorescence, as an 
indicator of HRR in Brca1- or Brca2-DR-GFP cells [50].  Assays in both these types of 
cells will analyze both types of revertants.  Analysis of BRCA1 revertants is particularly 
significant, since it is involved in both HRR and with single-strand annealing (SSA) 
repair [70].  SSA is postulated to have a role in rescue and restoration of HRR during 
repair processes [67, 71].




PhII-96, NCI# 8264
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Moreover, these transfected cells should also show increased recombination frequencies.  
We will correlate clinical response with tumor BRCA expression/HRR functional status 
and ERCC1, p63 and p53 expression via IHC and/or RT-PCR for all participants with 
available specimens.
We anticipate that the restoration of a BRCA open reading frame will most probably 
increase HRR function.  For the moment, we do not know the percentage of patients who 
will have restored HRR function, but we expect that a functional HRR system would 
obviate response to the single agent DNA repair inhibitor treatment arm of the clinical trial 
described in this proposal.  However, we expect that ABT-888 may potentiate carboplatin 
therapy despite functional HRR.  Since it recognizes a relatively proximal (amino-) epitope, 
a known limitation of IHC with the Ab1 antibody against BRCA1, it is possible we will 
have difficulty assessing the expression status for more distal truncations or missense 
mutations.  We are currently testing a new monoclonal antibody corresponding to C-
terminal amino acids 1839-1863 of Human BRCA1, as well as alternate antibodies for 
detection of BRCA2 expression, for which no reports, to date, have indicated satisfactory 
performance in IHC on FFPE.  We have lymphoblastoid cell lines for a family with a 15-bp 
in-frame BRCA2 mutation, which results in a 5 amino acid loss and is considered 
deleterious after demonstration of allele specific LOH and tracking/linkage [78]; these 
should serve as useful reagents to test the systems. We will also test a known acquired 
intragenic deletion [50] that restores the reading frame and at least partial HRR function in 
tumor cells that originated from germline BRCA2 mutant cells.  If we have difficulty 
complementing the mouse Brca cell lines, we will use a BRCA2 deficient human cell line 
(e.g., CAPAN1) or VC-8 cells available in our laboratory, along with a BRCA2 
complemented VC-8 as a control.  In the future, we will use a method similar to that 
recently described using mouse ES cells to analyze unclassified mutants or reversion 
mutations within mammalian cells [79].
Archival Tumor Collection
If available, and with the patient's consent, archival tissue specimens should be submitted 
for molecular correlative studies. Archival tumor block (formalin-fixed paraffin-embedded) 
from initial breast diagnosis, or other specimen obtained prior to study, should be 
submitted, along with the corresponding path report, within four weeks of patient 
registration. If tissue blocks cannot be sent, 8-12 unstained slides may be submitted instead.
Fixed tissues, including paraffin-embedded tumor blocks or formalin-fixed tissues should 
be sent at ambient temperature.  Do not send in the same box as the frozen plasma.  
Formalin fixed cells should be placed in a sealable bag with absorbent material and placed 
in an appropriate box or container for the shipping of a potentially hazardous material. 
Address shipments to: 
Analytical Pharma. Lab
City of Hope 


PhII-96, NCI# 8264
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64
Shapiro Bldg. (Synold/JNW) Rm. 1042
1500 E Duarte Rd.
Duarte, CA 91010
Phone (626) 359-8111, ext. 62110
Email: tsynold@coh.org
We anticipate access to formalin fixed paraffin embedded (FFPE) primary tumor tissue 
specimens for approximately 62 patients of the total 71 possible accrued to the clinical trial.  
Depending on the specific BRCA mutation, we will use IHC to assess BRCA protein 
expression in baseline tumors.  We do not expect to identify pre-treatment reversion or 
resistance since one of the near obligatory steps in development of BRCA-associated cancer is 
the somatic or acquired loss of the wt allele.  Subsequent genetic instability could generate 
reversion mutations in a small subfraction of the samples, but these subfractions are unlikely 
to be detectable unless subjected to selective pressure.
All specimens shipped must be accompanied by the Specimen Submission form found in 
Appendix D.  Additionally, a copy of that completed form must be faxed to the Data 
Coordinating Center at City of Hope, (626) 256-8654 when specimens are shipped. 
The Federal guidelines for shipment are as follows: 
a. The specimen must be wrapped in an absorbable material; 
b. The specimen must then be placed in an AIRTIGHT container (like a resealable bag); 
c. Pack the resealable bag and specimen in a styrofoam shipping container; 
d. Pack the styrofoam shipping container in a cardboard box. 
e. The cardboard box must be marked as "BIOHAZARD." 


PhII-96, NCI# 8264
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11 STUDY CALENDAR 
Baseline evaluations are to be conducted within 7 days prior to start of protocol therapy.  Scans 
and x-rays must be done within 28 days prior to the start of therapy.  In the event that the 
patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy.  Tests indicated for the following weeks may be 
performed within ± 2 days of the indicated dates. Subsequent cycles can be adjusted +/- 48 hours.
If a patient has been on a steady dose of ABT-888 as a single agent for at least 9 months, she/he 
can reduce visits at the enrolling institution to every 24 weeks, provided that he/she is seen by the 
local/primary MD with labs (and labs/notes sent to the center), every 3 weeks.
Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Pre-
Study
Wk
1
Wk
2
Wk
3
Wk
4
Wk
5
Wk
6
Wk
7
Wk
8
Wk
9
Wk
10
Wk
11
Wk
12
Off
Studye
ABT-888
X
X
X
X
X
X
X
X
X
X
X
X
Carboplatin*
X
X
X
X
Informed consent
X
Demographics
X
Medical history
X
Concurrent meds
X
X--------------------------------------------------------------------X
Physical exam
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
Performance Status
X
X
X
X
X
X
CBC w/diff, pltsa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum chemistrya,b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
EKG (as indicated 
and needed)
X


PhII-96, NCI# 8264
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Cycle 1
Cycle 2
Cycle 3
Subsequent 
Cycles
Pre-
Study
Wk
1
Wk
2
Wk
3
Wk
4
Wk
5
Wk
6
Wk
7
Wk
8
Wk
9
Wk
10
Wk
11
Wk
12
Off
Studye
Adverse event 
evaluation
X--------------------------------------------------------------X
X
Tumor measurements
X
Tumor measurements are to be done at the end of cycle 3 and then 
repeat every 3 cycles. Documentation (radiologic) must be 
provided for patients removed from study for progressive disease.  
Xe
Radiologic 
evaluationg
X
1st scan will be done at the end of cycle 3 All subsequent 
scans will be done every 3 cycles of therapy. If the subject 
has a complete response/no evidence of disease or stable 
findings for more than a year, then annual evaluation is 
acceptable unless newly symptomatic.
Xe
Urine or Serum
Pregnancy Test
Xc
Tumor Biopsyd
X
X
Xe
Pharmacodynamic
blood drawf
X
X
X
Archival Tumor 
Tissue
X
a: If no greater than Grade 1 toxicities were seen on the most recent CBC and Serum Chemistry lab tests, after 2 
cycles on a dose level, weekly CBC and Serum Chemistry will become optional (option to reduce to once per 
cycle).
b: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose,  
potassium, total protein, SGOT [AST], SGPT [ALT], sodium.  Phosphorous at pre-study only.
c: Serum or urine pregnancy test (women of childbearing potential)
d: Optional
e: Off-study evaluation
f: Described in section 9.2. For Phase II patients, PD draws are also required on Cycle X and Cycle X+1. For 
Phase I patients, discontinue correlative blood draws for all cases beyond cycle 2.
g. Patients that have been on treatment for more than 2 years may have their radiologic evaluations every 4 cycles 
(12 weeks).
* For patients receiving carboplatin either as part of the lead-in, or in the phase II part of the trial, after progression 
on ABT-888 alone


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12  MEASUREMENT OF EFFECT 
Tumor assessments according to RECIST will be performed at baseline (within 28 days 
of first dose) and at the end of the first 3 cycles, and subsequently every 3 cycles
according to the planned study assessments, up to and including the withdrawal visit.  If
the subject has a complete response/no evidence of disease or stable findings for more 
than a year, then annual evaluation is acceptable unless newly symptomatic.
Baseline contrast-enhanced CT of the chest, abdomen and pelvis will be performed for 
the assessment of measurable lesions.  Where iodine contrast is contra-indicated then 
contrast-enhanced MRI of the abdomen and pelvis together with non-contrast enhanced 
CT of the chest will be preferred, rather than contrast-enhanced MRI of chest, abdomen 
and pelvis.  Other regions will be scanned at baseline and followed-up where clinically 
indicated for the assessment of disease. 
12.1 DEFINITIONS 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1).  Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant 
lymph nodes are used in the RECIST criteria.  Note:  Lesions are either measurable or 
non-measurable using the criteria provided below. The term “evaluable” in reference to 
measurability will not be used because it does not provide additional meaning or 
accuracy.
11.1
Measurable Disease
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm with 
CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters).
Note:  Tumor lesions that are situated in a previously irradiated area are not 
considered measurable, unless there is clear evidence of progression of such 
lesion(s) as defined by RECIST 1.1 criteria.
11.2
Non-measurable Disease
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm 
or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered non-
measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 


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effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal 
masses (not followed by CT or MRI), are considered as non-measurable.
Note:  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.
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions.
11.3
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions
and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should 
be selected.  A sum of the diameters (longest for non-nodal lesions, short axis for 
nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters.  If lymph nodes are to be included in the sum, then only the short 
axis is added into the sum.  The baseline sum diameters will be used as reference 
to further characterize any objective tumor regression in the measurable 
dimension of the disease.
11.4
Non-target Lesions
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 and should 
also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.
12.2 GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 


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beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and t10 mm diameter as assessed using 
calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.
Chest x-ray. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable. 
Conventional CT and MRI.
This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, 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.
PET-CT At present, the low dose or attenuation correction CT portion of a combined 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 (with IV and oral contrast), then the CT 
portion of the PET-CT can be used for RECIST measurements and can be used 
interchangeably with conventional CT in accurately measuring cancer lesions over time.  
Note, however, that the PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed


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Ultrasound (US). Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances.
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint.
Tumor markers.
Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[80][81][82].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [83].
Cytology, Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, 
such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.
FDG-PET While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up
corresponds to a pre-existing site of disease on CT that is not progressing on the 


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basis of the anatomic images, this is not PD.
c.
FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 
literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity.
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an 
uptake greater than twice that of the surrounding tissue on the attenuation 
corrected image.
12.3 RESPONSE CRITERIA 
11.3.1. Evaluation of Target Lesions
Complete Response (CR):
Disappearance 
of 
all 
target 
lesions. 
 
Any 
pathological lymph nodes (whether target or non-
target) must have reduction in short axis to <10 mm.
Partial Response (PR):
At least a 30% decrease in the sum of the diameters 
of target lesions, taking as reference the baseline 
sum diameters
Progressive Disease (PD):
At least a 20% increase in the sum of the diameters 
of 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%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the 
appearance of one or more new lesions is also 
considered progressions).
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study


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11.3.2. Evaluation of Non-target Lesions
Complete Response (CR):Disappearance 
of 
all 
non-target 
lesions 
and 
normalization of tumor marker level.  All lymph nodes 
must be non-pathological in size (<10 mm short axis)
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response.
Non-CR/Non-PD:
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits
Progressive Disease (PD):Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  
Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.    
Although a clear progression of “non-target” lesions 
only is exceptional, the opinion of the treating physician 
should prevail in such circumstances, and the 
progression status should be confirmed at a later time 
by the review panel (or Principal Investigator).
11.3.3. Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of 
the treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.


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For Patients with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New
Lesions
Overall 
Response
Best Overall Response 
when Confirmation is 
Required*
CR
CR
No
CR
>3 wks. Confirmation**
CR
Non-
CR/Non-PD
No
PR
>3 wks. Confirmation**
CR
Not evaluated
No
PR
PR
Non-
CR/Non-
PD/not 
evaluated
No
PR
SD
Non-
CR/Non-
PD/not 
evaluated
No
SD
documented at least once >4
wks. from baseline**
PD
Any
Yes or No
PD
no prior SD, PR or CR
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**    Only for non-randomized trials with response as primary endpoint.
***  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
Note:
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document 
the objective progression even after discontinuation of treatment.
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 


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category when no lesions can be measured is not advised
12.4 CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
11.4.1. Confirmation
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed greater than 3 weeks after the criteria for 
response are first met.  Confirmation of response is not required, but must be reported as 
“unconfirmed.”  In the case of SD, follow-up measurements must have met the SD 
criteria at least once after the start of treatment at a minimum interval of 6 weeks.  (See 
section 11.3.3.)
11.4.2. Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented.
11.4.3. Duration of Stable Disease
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements. 
11.4.4. Progression-Free Survival
Progression-free survival (PFS) is defined as the duration of time from start of treatment 
to time of progression or death, whichever occurs first. 


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13 DATA REPORTING / REGULATORY CONSIDERATIONS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 
7.0 (Adverse Events: List and Reporting Requirements).
13.1 DATA REPORTING 
12.1.1. Method
CDUS
13.2 RESPONSIBILITY FOR SUBMISSION 
Study participants are responsible for submitting CDUS data and/or data forms to the 
Data Coordinating Center quarterly by April 30, July 31, October 31, and January 31 to 
allow time for Data Coordinating Center compilation, Principal Investigator review, and 
timely submission to CTEP. (See Section 12.1.1.)  
The Data Coordinating Center is responsible for compiling and submitting CDUS data to 
CTEP for all participants and for providing the data to the Principal Investigator for 
review.  
13.3 CTEP MULTICENTER GUIDELINES 
This protocol will adhere to the policies and requirements of the CTEP Multicenter 
Guidelines.  The specific responsibilities of the Principal Investigator and the Data 
Coordinating Center (Study Coordinator) and the procedures for auditing are presented in 
Appendix B.
The Principal Investigator/Data Coordinating Center is responsible for distributing all 
IND Action Letters or Safety Reports received from CTEP to all participating institutions 
for submission to their individual IRBs for action as required.
Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Data Coordinating 
Center to the CTEP PIO (PIO@ctep.nci.nih.gov).


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13.4 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) / 
CLINICAL TRIALS AGREEMENT (CTA) 
The “Agent(s),” supplied by CTEP, DCTD, NCI, used in this protocol is/are provided to 
the NCI under a Collaborative Agreement (CRADA, CTA) between the Pharmaceutical 
Company(ies) [hereinafter referred to as “Collaborator(s)”] and the NCI Division of 
Cancer Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in 
addition to the provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/default.htm), contained within the terms 
of award, apply to the use of Agent(s) in this study:
1.
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies 
utilizing investigational agents contain confidential information and should not be shared 
or distributed without the permission of the NCI.  If a copy of this protocol is requested 
by a patient participating on the study or patient’s family member, 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 pertaining to such combination use (hereinafter be referred 
to as “Multi-Party Data”) by each Collaborator shall be as follows:
a.
NCI must provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol.
b.
Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval, or commercialize its own investigational agent.
c.
Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own 
investigational 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.  All data made available will comply with HIPAA regulations.


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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 Collaborator(s) for phase 3 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 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 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:
Regulatory Affairs Branch, CTEP, DCTD, NCI
6130 Executive Boulevard, Suite 7111
Rockville, MD  20852
FAX 301-402-1584
E-mail: anshers@mail.nih.gov.
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/proprietary information.


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14 STATISTICAL CONSIDERATIONS 
14.1 STUDY DESIGN/ENDPOINTS 
The design of this Phase II trial is also described in Section 5.0.
All patients who begin treatment as part of this trial will be accounted for in the summary 
of results, and the outcome status (in terms of toxicity, response, reason off study, 
progression, and survival) will be reported.  
The toxicities observed will be summarized in terms of type (organ affected or laboratory 
determination such as absolute neutrophil count), severity (by CTCAE and nadir or 
maximum values for the laboratory measures), time of onset (i.e. course number), 
duration, and reversibility or outcome.  Tables will be created to summarize these 
toxicities and side effects by course.  
14.2 SAMPLE SIZE/ACCRUAL RATE 
 
This study was initially designed as a safety lead-in of the combination of ABT-888 with 
carboplatin followed by a randomized Phase II study. This was changed to a safety lead-in of the 
combination, followed by a single agent study of ABT-888, where patients have the option of 
continuing to the combination following progression, after a one week off-treatment interval 
(personal communication, per Dr. Giranda, one week is 10 half-lives, and 3 x times the time 
needed to recover full PARP activity).
The safety lead-in will take between 12-27 evaluable patients.  
Phase II Portion:
Stage IV BRCA (stratified by BRCA1 or BRCA2)-associated breast cancer patients will initiate 
treatment with ABT-888 at the single agent MTD (400mg BID). Following progression, patients 
will be off treatment for one week, and then if they meet the eligibility requirements, the patients 
will initiate treatment with carboplatin plus ABT-888 at the MTD of the combination established 
during the safety lead-in noted above.  
The two strata (BRCA1 and BRCA2-associated breast cancer) will accrue independently: 
Simon’s Optimal Two-Stage design will be employed: Initially 10 patients will be accrued to a 
strata. 2 or more confirmed responses in the first 10 patients in a strata will result in an additional 
12 patients accrued to that stratum (for a total of 22 for that stratum). As a result, if 2 or more 
responses are seen in the first 10 patients with both BRCA1 and BRCA2-associated breast 
cancer, a total of 44 patients will be accrued to the Phase II portion of this study. 
We anticipate enrollment of 6 patients per month; it should take approximately 8 months to 
complete accrual to this trial.


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This design will allow us the opportunity to document single agent activity of ABT-888 in these 
two patient populations (strata), while permitting the patients to receive carboplatin/ABT-888
post-progression, which our initial Phase I data suggests has considerable activity.
For each cohort (BRCA1 and BRCA2), the primary objective will be the response rate (RR) 
based on RECIST criteria. Based on the response rate (11/27, 41% RR at 400mg twice daily, 
6/27, 22% RR at 100mg twice daily) of the PARP inhibitor olaparib (84) in this patient 
population, for ABT-888 to be a candidate as a preferred PARP agent, we require ABT-888 to 
demonstrate clear single agent activity, with limited toxicity.
Operating Characteristics: Based on Simon’s Optimal two-stage design for each cohort, 10 
patients will be accrued in the first stage and if 2 or more responses are observed 12 more 
patients would be accrued to that strata, for a total of 22. At the end of the study, 6 responders out 
of the 22 patients would indicate promising activity.  This design has 90% power to detect a 
response rate of 40%, and a type I error rate of 0.1 under the null rate of 15%.   
The post-progression response and second progression-free survival data (when patients receive 
the combination) will also be summarized. 
14.3 STRATIFICATION FACTORS 
BRCA1 and 2 status patients will be treated as separate strata.
Toxicity/Safety Monitoring:
Although we expect this regimen to be well tolerated, we have established guidelines and 
criteria which will be used to flag an unexpected number of patients who experience 
unacceptable toxicity (TOX).  These rules will be applied to both the single ABT-888
treatment and the combination treatment independently, although the main motivation for 
such detailed monitoring is based on the combination arm. Stratum will be analyzed 
separately. 
Unacceptable toxicity (TOX) will be defined as any toxicity that results in a > 2 week 
delay in treatment or any toxicity resulting that the patient be taken off treatment.  
Patients who do not complete the first 2 cycles of treatment with the prescribed dose and 
do not experience a TOX will NOT be used in the decision to consider halting the trial 
because of toxicity and will be considered inevaluable for TOX.  
Criteria for flagging an excessive number of patients with TOX are based on the 
sequential probability ratio test with D=0.10, E=0.10, po=0.05 and pa=0.25.   Every time a 


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patient is classified as having had a TOX, the cumulative number of patients (X) who 
have experienced a TOX will be compared to the number of patients (N) who are 
evaluable for toxicity.  If the number of patients, N, is greater than NX, the number given 
in the bottom row of the Table below, then accrual will not be suspended.   If N is less 
than or equal to NX, then accrual will be suspended for review of the data. The NX values 
do not correspond to the interim analysis accrual goal, as these rules are examined when a 
patient experiences a TOX regardless of accrual, and we expect fewer patients evaluable 
for TOX than response (all treated patients).
Table:  Criteria for Suspending Accrual to Evaluate Toxicity
X: # pts who experienced a TOX
2
3
4
Nx:  Suspend trial of # evaluable pts. (N) is 
d Nx
d6
d14
d21
These rules were selected to ensure a low probability that the trial would be suspended if 
the true chance of unacceptable toxicity were less than 5% and a high probability that the 
trial would be suspended if the true chance of unacceptable toxicity were 20-25%.  The 
Table below summarizes these probabilities.  The values in the table below are based on 
10,000 simulations and are accurate to r0.01 (based on a 95% confidence interval).
Table: Probability of Suspending Accrual Because Too Many Patients Experienced a TOX 
True Chance of an Unacceptable Toxicity (TOX)
5%
10%
15%
20%
25%
30%
Probability of Suspending Accrual 
to Review Toxicities  
N=21
0.06
0.25
0.49
0.72
0.85
0.93
Secondary Endpoint: 
In the safety lead-in phase, patients will be assessed for their response rate. In the Phase II 
portion, progression-free survival in both the BRCA1 and BRCA2 cohorts will be 
evaluated, along with progression-free survival once receiving the a combination of ABT-
888 and carboplatin.
14.4 ANALYSIS OF CORRELATIVE/SPECIAL STUDIES 
Correlative Statistics:


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In the context of this Phase II trial, the primary correlative endpoint (PAR reduction in PBMCs 
and response) will be evaluated.  Prospective detection of BRCA reversion mutations that 
restore HRR function would be a completely novel observation in BC, and important for 
understanding resistance mechanisms.  Other endpoints will only be statistically significant if 
there is a large difference.  Given the sample size constraints and the multiple analyses, the 
other correlative studies will be exploratory and are for the purpose of generating future 
hypothesis-driven studies.
1. Analysis of PBMCs:  It is hypothesized that PBMC PAR inhibition will predict for response.  
As a result patients will be pooled in a multivariate logistic regression evaluating response as a 
function of PAR inhibition and carboplatin (yes/no). When the sample size is 44 (pooling both 
strata), the logistic regression test of no effect of PAR inhibition (b=0, a = 0.05 one-sided) will 
have 66% power to detect a b of 0.916 (an odds ratio of 2.5), assuming the adjustment for 
carboplatin (yes/no) effect is adequately adjusted for in the logistic model by a simple additive 
term.  This assumes that the proportion of responses at the mean of PAR inhibition is 0.40.  
This approximates the response rate, reported at ASCO 2009 [30], seen in BRCA carriers with 
advanced breast cancer who were treated with an oral PARP inhibitor.  We will also evaluate 
the role of PAR inhibition on the response rate for each strata separately.
Patients with BRCA mutations may have impaired repair, and as a result, it is possible that 
baseline PAR levels may be elevated in these patients. Previous publications demonstrate a 
median PAR level of 99 pg/ml, with a standard deviation of 217 pg/ml, in non-BRCA carriers. 
The large variability limits the power to detect a baseline difference between non-BRCA 
carriers and BRCA-carriers, however, change in PAR levels will be summarized by percent of 
baseline. In the small amount of literature to date on non-BRCA carriers, several patients 
exhibited no significant PAR inhibition (e.g., <50% reduction). With 44 patients, we can 
estimate the percent of patients with no significant PAR inhibition with a 95% CI half-width of 
15% or less.
2. Analysis of changes in correlatives: blood correlatives will be evaluated for changes due to 
treatment. As a result, comparing baseline to after treatment with 44 patients will result in 80% 
power to detect approximately a change of 43.2% of the standard deviation, using a paired t-
test with a 0.050 two-sided significance level. Standard descriptive methods (scatter plots, 
contingency tables as well as summary statistics) will also be used to summarize the baseline 
levels and the changes from baseline (i.e. after treatment) and we will compare responders 
versus non-responders on both arms to observe if there are any unexpected patterns. 
3.  Analysis of baseline correlates: Tumor biopsy correlates will be available on approximately 
15 patients at baseline, along with baseline blood correlates on all patients.  Exploratory 
analysis on the role of these correlates to predict outcome (e.g., response, progression-free
survival time, overall survival time), will be conducted. Kaplan-Meier plots and multivariate 
Cox regression will be used for exploratory analysis of the survival endpoints, and logistic 
regression will be used for response endpoints. This analysis will be used to determine baseline 
characteristics that impact clinical benefit, and allow us to search for specific markers that may 
predispose patients for benefit. Detection of modest interaction effects are underpowered, but 


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large effects can be detected. Patients who experienced an objective response will be compared 
to those that did not – in terms of the baseline correlates and demographics, in order to try to 
further understand the lack of activity.
4.  A limited number of patients may have post treatment biopsies. This will allow us to explore 
whether action thought to be specific to ABT-888 is observed in tumor tissue, and if that action 
relates to baseline measurements and can help distinguish between responders and non-
responders in this limited subset of patients. Prospective observation of possible BRCA
reversion mutations that may restore HRR function and correlate with resistance to therapies is 
an opportunity for novel exploration. In addition, we will evaluate the difference in γH2AX 
between ABT-888 alone and carboplatin+ABT-888 arms in the tumor biopsies. A sample size 
of 15 post-treatment biopsies in each group will result in 84% power to detect a 50% increase
in γH2AX positive cells or foci/cell between ABT-888 alone and carboplatin+ABT-888 arms in 
the tumor biopsies (a fold-change of 1.5) assuming that the coefficient of variation is 0.5 and 
using a two group t-test with a 0.1 one-sided significance level.
5.  Statement of Exploratory Work: Analysis on correlates, effects on observed toxicities and 
use of response and survival endpoints will all be conducted in an exploratory fashion. Any 
conclusions will include a discussion of the exploratory nature of the finding, including the 
multiple comparison issue.


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15 CCCP POLICIES FOR MONITORING CONSORTIUM TRIALS 
The protocol principal investigator (PI) is responsible for monitoring the conduct and progress 
of this Phase I trial, including the ongoing review of accrual, data and toxicities, as well as the 
accumulation of reported adverse events from other trials testing the same drug(s).  The 
participating clinicians and their designees are responsible for timely submission of adverse 
event reports (see Section 7.0) and case report forms.  The Data Coordinating Center for the 
CCCP Consortium is responsible for providing the PI with access to the submitted case report 
form data in summary and detail in a timely fashion.   Although the PI is responsible for 
evaluating the cumulative reported adverse events and the impact that these have on the 
continued conduct of the trial, it is the Data Coordinating Center of the CCCP that distributes 
all submitted SAE reports to the appropriate individuals, including the local protocol principal 
investigators, at each of the participating institutions.  
The Data Coordinating Center posts a summary (accrual, toxicities, and responses) of each 
CCCP initiated trial on the CCCP website.  In this way, each PI has access to up-to-date 
information on the status of his or her trial.  In consultation with the collaborating statistician, the 
PI is responsible for review of:
(a)
for Phase I trials, all dose limiting toxicities and decisions regarding dose escalation, 
expansion, as well as decisions to terminate escalation, and 
(b)
for Phase II trials, the toxicities and therapeutic endpoints referred to in the statistical 
plan.
The Data Coordinating Committee meets monthly to review data management and data quality 
issues – completeness of data submissions as well as accuracy in terms of built-in, computerized 
logic checks.  Any issues identified and the corrective plans are presented to the Internal 
Committee and at the next CCCP teleconference meeting for review and approval.
15.1 OVERSIGHT 
Oversight of the conduct of CCCP trials occurs at several levels:
1.
The Data Coordinating Center for the CCCP flags all trials that are approaching a 
decision in terms of toxicity (for both Phase I and Phase II trials) or responses (for Phase 
II trials).  Decisions are made by the PI with input from the statistician and discussion 
with the principal investigator of the funding mechanism (U01 Cooperative Agreement or 
N01 Contract, as appropriate) or his or her designee, and are communicated to the 
participating centers by the CCCP Data Coordinating Center. At the monthly 
teleconferences, the accrual of each open protocol is reviewed.


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2.
For CTEP sponsored Phase I trials, data are reported to the NCI-designated clinical trials 
monitoring service (CTMS) which will audit patients’ records on each protocol – at each 
CCCP institution; this audit is initiated by CTEP.  For all other CCCP trials, the CCCP 
will contract with Theradex to audit patient records at each CCCP institution.
3.
An independent CCCP DSMC will review CCCP trials every 6 months. This DSMC will 
consist of 3 voting members (2 medical oncologists or hematologists involved in Phase 
I/II cancer clinical trials but not participating in CCCP studies, and a statistician) and a 
non-voting CCCP statistician.  
a.
DSMC meetings will take place twice a year.   Additional meetings will be 
convened if necessary. 
b.
This DSMC will review each CCCP trial in terms of accrual, toxicity/safety, and 
adherence to trial design, audit results, and likelihood of successful completion.  
c.
The DSMC will report to the CCCP leadership.
Additional Protocol Language Requirements 
The following are reporting requirements and responsibilities of the Principal Investigator to the 
United States Army Medical Research and Materiel Command’s (USAMRMC) Office of 
Research Protections (ORP), Human Research Protection Office (HRPO) and should be reflected 
in the protocol: 
1. The protocol will be conducted in accordance with the protocol submitted to and approved by 
the USAMRMC ORP HRPO and will not be initiated until written notification of approval of the 
research project is issued by the USAMRMC ORP HRPO.   
2. Accurate and complete study records will be maintained and made available to representatives 
of the U.S. Army Medical Research and Materiel Command as a part of their responsibility to 
protect human subjects in research.  Research records will be stored in a confidential manner so 
as to protect the confidentiality of subject information.   
3. The knowledge of any pending compliance inspection/visit by the FDA, OHRP, or other 
government agency concerning clinical investigation or research, the issuance of Inspection 
Reports, FDA Form 483, warning letters or actions taken by any Regulatory Agencies including 
legal or medical actions and any instances of serious or continuing noncompliance with the 
regulations or requirements will be reported immediately to USAMRMC ORP HRPO.


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APPENDICES


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Appendix A - Performance Status Criteria
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction.
100
Normal, no complaints, no evidence 
of disease.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
1
Symptoms, 
but 
ambulatory.  
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).
80
Normal activity with effort; some 
signs or symptoms of disease.
70
Cares for self, unable to carry on 
normal activity or to do active work.
2
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
60
Requires occasional assistance, but
is able to care for most of his/her 
needs.
50
Requires considerable assistance and 
frequent medical care.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
40
Disabled, requires special care and 
assistance.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
20
Very sick, hospitalization indicated. 
Death not imminent.
10
Moribund, 
fatal 
processes 
progressing rapidly.
5
Dead.
0
Dead.


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Appendix B - CTEP Multi-center Guidelines
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed.
Responsibility of the Protocol Chair
•
The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office 
(PIO).  The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments.  The protocol must not be 
rewritten or modified by anyone other than the Protocol Chair.  There will be only one 
version of the protocol, and each participating institution will use that document.  The 
Protocol Chair is responsible for assuring that all participating institutions are using the 
correct version of the protocol.
•
The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.
•
The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients.
•
The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis.
Responsibilities of the Coordinating Center
•
Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible for 
assuring that each participating institution has an OHRP assurance and must maintain copies 
of IRB approvals from each participating site.
•
Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO.
•
The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each participating 
site prior to the first patient registration from that site.
•
The Coordinating Center is responsible for the preparation of all submitted data for review by 
the Protocol Chair.
•
The Coordinating Center will maintain documentation of AE reports.  There are two options 
for AE reporting: (1) participating institutions may report directly to CTEP with a copy to the 


PhII-96, NCI# 8264
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94
Coordinating Center, or (2) participating institutions report to the Coordinating Center who in 
turn report to CTEP.  The Coordinating Center will submit AE reports to the Protocol Chair 
for timely review.
•
Audits may be accomplished in one of two ways:  (1) source documents and research records 
for selected patients are brought from participating sites to the Coordinating Center for audit, 
or (2) selected patient records may be audited on-site at participating sites.  If the NCI 
chooses to have an audit at the Coordinating Center, then the Coordinating Center is 
responsible for having all source documents, research records, all IRB approval documents, 
NCI Drug Accountability Record forms, patient registration lists, response assessments scans, 
x-rays, etc. available for the audit.
Inclusion of Multicenter Guidelines in the Protocol
•
The protocol must include the following minimum information:
-
The title page must include the name and address of each participating institution and the 
name, telephone number and e-mail address of the responsible investigator at each 
participating institution.
-
The Coordinating Center must be designated on the title page.
-
Central registration of patients is required.  The procedures for registration must be stated 
in the protocol.
-
Data collection forms should be of a common format.  Sample forms should be submitted 
with the protocol.  The frequency and timing of data submission forms to the Coordinating 
Center should be stated.
-
Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center.
-
Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions.
Agent Ordering
•
Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be ordered 
by a participating site only after the initial IRB approval for the site has been forwarded by 
the Coordinating Center to the CTEP PIO.


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Appendix C - CCCP Registration Procedures
CCCP REGISTRATION PROCEDURES FOR PHASE II TRIALS
1.
Registrations for Phase II protocols must be made through the Biostatistics office at the 
City of Hope between the hours of 8:30 a.m. to 4:30 p.m., Monday through Friday 
(except holidays).
2.
Patients must be registered within 72 hours prior to initiation of protocol therapy.
3.
A patient failing to meet all protocol requirements may not be registered.  If you have any 
questions regarding eligibility, contact the City of Hope Data Coordinating Center (DCC) 
at (626) 256-HOPE (4673), extension 65928.
4.
Prestudy laboratory tests, scans and x-rays must be completed prior to registration 
according to study calendar/protocol.
5.
Patients must sign an informed consent prior to registration.
6.
Confirm that the patient meets all inclusion and exclusion eligibility criteria for a 
protocol.
7.
Complete the Eligibility Checklist.  
8.
Verify that all required prestudy tests were performed.
9.
Fax the completed Eligibility Checklist, signed and dated informed consent, pathology 
report, and relevant laboratory results to the City of Hope Consortium Coordinator for 
confirmation of eligibility.  The FAX number is (626) 256-8654. 
10.
Call the City of Hope Consortium Coordinator at (626) 256-HOPE (4673), extension 
65928 to confirm the FAX arrival. If the Consortium Coordinator is not in the office, 
have them paged at (626) 423-5365.
11.
If the patient qualifies, the City of Hope Consortium Coordinator will call the registering 
institution to complete the registration/randomization procedure and assign the patient's 
study ID number.  
12.
Once a patient has been registered, the Data Coordinating Center will provide a 
"Confirmation of Registration" to the center registering the patient. 
For questions regarding eligibility call City of Hope California Cancer Consortium, Data 
Coordinating Center
(626) 256-HOPE (4673), extension 65928


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Appendix D - CCCP Specimen Submission Form
Please email the Data Coordinating Center at cccp@coh.org for the Specimen Submission Form 
once study is activated at your institution. 


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APPENDIX E - PATIENT MEDICATION DIARY
Please see following page. 


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Today’s date _________________________
Agent
ABT888
Patient Name_________________________ (initials acceptable)
Patient Study ID_________
1.
Complete one form for each cycle of treatment.
2.
ABT888 should be stored at room temperature.
3.
You will take ABT888 twice each day about 12 hours apart.  If you forget to take ABT888 and it has been more than 2 hours 
after your regular dosing time, skip that dose and take your regular dose at your next regular time.
4.
Morning dose:  take _____ mg  (____capsules) ABT888. *********** Evening dose:   take _____ mg (____capsules) ABT888.
5.
Record the date, the number of ABT888 capsules you swallowed in the morning and again in the evening, and when you 
swallowed the medicine.  
6.
Wash your hands after handling the capsules (patient and caregiver).
7.
If you have any comments or notice any side effects, please record them in the Comments column.  
8.
Please bring this form and your bottles of ABT888 when you return for each appointment.  
Day
Date
Time of 
morning 
dose
Dose taken
Time of
evening 
dose
Dose taken
Comments
# of capsule taken
# of capsule taken
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
CTEP-ASSIGNED PROTOCOL # 8264
Local Protocol # ___________________
APPENDIX E:  PATIENT MEDICATION DIARY


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21
22
23
24
25
26
27
28
Patient’s signature  ______________________________________________________________________________
Physician’s Office will complete this section:
1.
Date patient started protocol treatment_____________________________________________________________
2.
Date patient was removed from study______________________________________________________________
3.
Patient’s planned total daily dose_________________________________________________________________
4.
Total number of capsules taken this month _________________________________________________________
5.
Physician/Nurse/Data Manager’s Signature _________________________________________________________


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Appendix F Standard Operating Procedures for Correlative Studies
Please see attached separate documents for Appendix F with SOPs and Forms.  

ICF_001.pdf: 
i 
NCI# 8264, PhII-96 
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SUMMARY OF CHANGES 
Date:  
 
November 9, 2023 
Document: 
NCI Protocol #8264, PhII-96: “Phase II Trial of Single Agent ABT-888 
with Post-Progression Therapy of ABT-888 in Combination with 
Carboplatin in Patients with Stage IV BRCA-associated Breast Cancer.” 
Note: 
The following is a Summary of Changes between the 6.1.2023 and 
11.9.2023 versions of model consent 
# 
Section 
Comments 
1. 
Footer 
Footer was updated to 11.9.23v 
2. 
Discontinuation 
of Treatment 
Added information regarding the discontinuation of ABT-888 drug program drug being no 
longer available after December 31, 2024.  Patients will need to end their participation by 
December 31, 2024 or earlier and their physician will discuss other treatment options with a 
suitable transition.   
 
 
 
 
 
 
 


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SAMPLE INFORMED CONSENT 
 
Study Title for Study Participants:  Veliparib With or Without Carboplatin in Treating 
Patients With Stage III or Stage IV Breast Cancer 
Offical Study Title for Internet Search on http://www.ClinicalTrials.gov:  Phase II Trial of 
Single Agent ABT-888 with Post-Progression Therapy of ABT-888 in Combination with 
Carboplatin in Patients with Stage IV BRCA-associated Breast Cancer  
I. 
PURPOSE OF THIS RESEARCH STUDY: You have been asked to participate in this 
research study because you have advanced breast cancer that is associated with a 
documented inherited mutation in BRCA1 or BRCA2.  The purpose of this study is to find 
the most effective and well tolerated dose-level of ABT-888 when used with carboplatin 
and to evaluate the effectiveness of ABT-888 alone and in combination with carboplatin 
in treating BRCA1- or BRCA2-associated advanced breast cancer.  Your treatment in this 
study is expected to last until your disease begins to grow or you have unmanageable side 
effects.  After your treatment is over, your medical condition will be followed on this study 
indefinitely.   
II. 
WHAT IS THE USUAL APPROACH TO MY BREAST CANCER?  You are being 
asked to take part in this study because you have breast cancer that has spread to other 
places in your body, and has grown worse despite treatment you received. People who are 
not in  a study are usually treated with more chemotherapy.   
III.   
WHY IS THE STUDY BEING DONE? Breast cancer is the most common cancer in 
women. In 2007, approximately 1.3 million women were diagnosed with breast cancer 
worldwide, and an estimated 465,000 breast cancer-related deaths were expected.  
Almost 100,000 of these breast cancer-related deaths occur in patients that overexpress 
HER2 receptors. Metastatic breast cancer (MBC) is incurable, with the primary goal of 
treatment being to extend life and ease symptoms while maintaining quality of life. 
Cells contain a type of molecule called deoxyribonucleic acid, or DNA for short. DNA 
carries the genetic information for the development of cells.  If DNA becomes damaged, 
chemicals inside the cell try to repair it. One such chemical is the protein PARP-1.  ABT-
888 is an inhibitor of PARP-1.  This means ABT-888 stops PARP-1 from repairing DNA.  
Functioning BRCA genes in normal cells can repair DNA damage even if PARP-1 is 
inhibited.  However, cells with abnormal BRCA, such as BRCA1 and BRCA2 cancer 
cells, cannot.  ABT-888 is in an early phase of development so there is limited 
information about the use of ABT-888 in human subjects.  In previous studies, ABT-888 
has been well-tolerated and has caused less side effects than conventional 


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chemotherapies. ABT-888 has not yet been approved for use by the Food and Drug 
Administration (FDA) except in research studies. 
In laboratory and animal experiments, ABT-888 was found to enhance the anti-tumor 
activity of carboplatin.  This study is to see if ABT-888 and/or ABT-888 with carboplatin 
can prevent the survival of BRCA1- or BRCA2-associated breast cancer cells.   
III. 
WHAT WILL BE DONE: Screening: If you agree to take part in this study, you will 
undergo screening evaluations to see if you are eligible to receive the study drug. You 
will have at least 2 and possibly more screening visits within a period of 4 weeks.   
x You will be asked about current signs and symptoms of your cancer within 28 days 
and within 7 days before receiving study drug,  
x A general health check, including current signs and symptoms of your cancer will be 
done within 7 days before receiving study drug, including a physical examination, 
measurement of your height and bodyweight, ECOG (Eastern Co-operative Oncology 
Group) performance status (the study doctor will question you about you ability to 
carry out daily tasks), and measurement of your vital signs (temperature, blood 
pressure, breathing rate and heart rate). 
x You will be asked about your date of birth and race, your medical and surgical history 
(within 28 days before starting study treatment) 
x You will be asked about previous cancer treatment you received (within 7 days before 
starting study treatment; will be done again at visit 1) 
x You will be asked about the medications you are currently taking twice (within 28 
days and within 7 days before receiving study drug).  
x Blood (about 20 ml, which is about 4 teaspoons) will be taken for routine blood 
counts and tests to see how your organs are working (within 7 days before starting 
study treatment) 
x Tumor assessments: either a computerized tomography (CT) scan (an X-ray that is 
transmitted onto a computer) or a magnetic resonance imaging (MRI) scan (an 
imaging procedure using magnetic waves/pulses to take pictures of the inside of your 
body).  Before these scans, contrast medium (like a dye) may be injected into one of 
your veins to help give clearer images of your cancer. X-rays or other imaging tests 
may be done also (within 28 days before starting study treatment).  You will be asked 
to sign a separate consent form for any imaging procedure. 
x A urine sample will be taken for routine tests to see how your organs are working 
(within 7 days before starting study treatment) 
x If you are capable of bearing children, a urine or blood sample (about 6 ml, which is 
about 1 teaspoon) will be taken to make sure that you are not pregnant (within 7 days 
before starting study treatment) 
x Optional: If you have a tumor that is easy to biopsy, you may be asked to undergo a 
series of optional biopsies.  These would be done: 1) before you start study drug, 2) 4-
8 hours after your first dose of ABT-888 on Cycle 2 Day 1, and 3) when you go off of 
treatment. Your eligibility is not affected by this biopsy. (Please see “Making Your 
Choice” to mark your selection on this consent form) 


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NCI# 8264, PhII-96 
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If the screening process shows that you are not eligible to receive the study drug, you will 
be taken off the study and the study doctor will discuss alternatives with you.   
Treatment for each Study Group:  
What treatment you receive will depend on when you are entered into the study.  Each 
cycle of treatment for all subjects is 21 days long.  
Safety Lead-In: If you enter the study during the Safety Lead-In period, each group of 
subjects will receive a higher dose of ABT-888 than the group before until the highest 
tolerated dose is found.  Therefore, the dose you receive will depend upon when you are 
entered into this study.  Everyone on the safety lead-in will also receive a standard dose 
of carboplatin. 
Phase II: If you enter the study during the Phase II period, you will receive ABT-888 for 3 
cycles (63 days). After every 3 cycles you will be evaluated. If your disease has gotten 
better or stayed the same you will continue on ABT-888. If your disease begins to grow 
and if you are eligible you will start receiving carboplatin in addition to ABT-888.  
When you are assigned to carboplatin, you will receive an intravenous (IV, into a vein) 
infusion of the drug over 30 minutes on Day 1 of each 21 day cycle.  Your dose may be 
lowered if you experience greater side effects. 
All Subjects: 
You will start taking drug at Day 1.  ABT-888 is provided as capsules containing 100 mg 
each, which you may take at home.  You will take 400 mg twice a day at the beginning.  
Upon progression of your disease you will start taking 150 mg of ABT-888 twice a day 
along with carboplatin. You will take the medication once in the morning and again about 
12 hours later.  Your doctor will tell you how many capsules you will need to take. You 
will need to swallow the capsules with a glass of water at about the same time each day. 
It is important that you take the study medication as directed. This drug is yours and 
should not be taken by anyone else. If you forget to take the capsule at your regular time, 
you may still take them if it is within 2 hours of your regular time. If you forget to take 
the capsules more than 2 hours after your regular dosing time, you should not take 
another capsule until your next regular dosing time, when you should take the capsules as 
prescribed. You will be asked to complete a patient diary to document when you took 
each dose or to give a reason if you did not take the capsules. You will be expected to 
bring the diary and unused capsules to the study doctor at the scheduled visits as 
described below. If you have side effects, you may have to stop taking the study drug for 
a while and may need to restart it.  The study doctor will provide you with complete 
instructions if this happens.  Any leftover study medication that you do not take and the 


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NCI# 8264, PhII-96 
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container (even if it is empty) must be returned at the end of each treatment cycle to your 
study doctor.  
You must store the study drug capsules below 86 degrees Fahrenheit and protect them 
from light. 
While taking part in the study, you are asked not to take herbal/natural products or other 
folk remedies without first discussing it with your doctor.  Your doctor will discuss with 
you other medications and treatment that you should not receive while taking the study 
drug (for example chemotherapy, immunotherapy, hormonal therapy, as well as some 
other types of drugs).  In order to avoid against drug interactions and to best evaluate the 
effect of the study drug, it is important that you tell the medical staff about any other 
medication or herbal supplements you have taken before the study and are taking during 
the study.   
You may continue receiving the study drug for as long as your cancer is not getting worse 
and you are not experiencing unmanageable side effects, or until you decide you want to 
discontinue taking the study drug.  At the end of your treatment on this study, you will 
have a follow-up visit, and your study doctor will decide how to best manage your 
cancer.  
Required Research Tests: The scientific, diagnostic and/or medical significance of the 
research to be done is not known.  Therefore, neither you nor your doctors will be 
informed of your individual results, and they will not affect your treatment in any way.   
Pharmacodynamics: As part of your participation in this study, you will have a series of 
blood drawn (about 12 ml, which is about 2-3 teaspoons) on Day 1 before your first dose 
of ABT-888, then 3 hours after the first dose of ABT-888 for peripheral blood 
mononuclear cell (PBMC) analysis to show whether the study drug is inhibiting PARP in 
these cells. On Cycle 2 there will also be a 3-hour blood draw.  When you start receiving 
carboplatin, you will have additional blood draws on day 1 of each cycle before, and 3 
hours after, your carboplatin.  
Evaluations During Treatment: Below is a table showing the visits during study and 
the routine and research evaluations that will be done at each visit.  Some of the 
procedures listed for Day 1 may not need to be repeated if the doctor agrees and these 
eligibility criteria are met within 7 days.  On all visits, before you take the study drug in 
the morning, vital signs will be measured, and blood samples will be taken for laboratory 
safety tests.  So you will be asked to not take your study drug on your visit days, until 
after these evaluations. If you agree, additional research procedures may be done at some 
of the visits.  These will be described in a separate subsection titled “Optional Research 
Studies.” 


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Visit Day (+ or – 2 days) 
Repeat Review of Previous 
Therapy 
Tumor Biopsy* 
Physical examination 
Weight Measured 
Vital signs Measured 
Performance Status 
Routine blood tests (20 ml, 
about 4 teaspoons) 
Pharmacodynamic Blood Draw 
(about 2-3 teaspoons) 
Genetic Blood DrawI 
Urinalysis 
Tumor Assessment (imaging 
scans as done at screening) 
Review of Side Effects & Other 
Medications you are Taking 
Carboplatin Infusion** 
Receive New Supply of Drug 
Return Unused  Drug, Review 
Drug Diary 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
8 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
15 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
22 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
29 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
36 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
43 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
50 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
57 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
 
64 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Each 
21-day 
cycle 
visit 
until 
study 
drug 
disconti
nued 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 


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When 
you go 
off 
study 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
*Optional 
**This drug will only be given to those patients that are in the safety lead in, or have disease growth 
in the Phase II portion of the study. 
End of Treatment Visit: If you are not benefiting from treatment or are experiencing 
unmanageable side effects or if you decide to discontinue treatment, your treatment on 
this study will be discontinued.  You will be asked to come in for an end of treatment 
visit so that the study doctor can evaluate any side effects you may be experiencing and 
evaluate your health.  The following procedures will be done:  
x physical examination including measurement of your bodyweight, vital signs, and 
ECOG performance status 
x blood draw (about 10 ml or 2 teaspoons) for routine blood tests tumor evaluation 
(imaging scans) 
x You will also be asked to describe any changes in your health and the medications 
you are taking since your last visit, and you will be asked to return all unused 
capsules to the study doctor or nurse, who will check that your diary has been 
filled in correctly.   
When you have finished taking part in this study, your study doctor will decide how to 
continue to manage your breast cancer.  
Discontinuation of Treatment: Your study doctor may decide that continuing treatment 
on this study is no longer in your best interest and withdraw you without your consent.  
Your participation in the study may also be stopped without your consent by the IRB or 
regulatory authorities.  You may also decide that you no longer want to continue treatment 
on this study, in which case, you are asked to tell the study doctor.  If you discontinue 
treatment for any reason, you will be asked to come in for the End of Treatment visit so 
that your health can be checked and the effects of the study drug can be evaluated.   
As of September 2023, the pharmaceutical collaborator, AbbVie, has discontinued 
the ABT-888 development program with the NCI Cancer Therapy Evaluation 
Program (CTEP) and drug will no longer be available after December 31, 2024.  You 
will need stop treatment by December 31, 2024 or earlier.   
Your physician will discuss with you alternative treatment options as well as a 
suitable transition prior to stopping treatment.   


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Follow-Up Visit: About 30 days after you have taken your last dose of study drug, you 
will be asked to come in for a follow up visit.  On the Follow-up Visit:   
x You will be asked about your health and medication you have taken since the last 
visit.  
x If you had abnormal laboratory values at the End of Treatment Visit, you will be 
asked to give a blood (about 2 teaspoons) and a urine sample for safety laboratory 
tests.  
x If the scans done at the End of Treatment Visit showed that your disease had 
improved, you may be asked to come in again 4 weeks later to have the imaging 
scans repeated at the follow up visit.   
x If you have any side effects that have not improved by the first follow-up visit, 
you may be asked to come in for additional follow-up visits at the discretion of 
your study doctor until the side effects have stopped.  
 
Optional Research Studies: Participation in the following research activities is optional.  
Your decision not to allow specimens to be taken for biomarker or genetic research or to 
allow storage of your specimens for future research will not affect your ability to 
participate in this study.  The scientific, diagnostic and/or medical significance of the 
research to be done is not known.  Therefore, neither you nor your doctors will be 
informed of your individual results and they will not affect your treatment in any way. 
Biomarker Research: A biomarker is any biochemical in the body that is useful for 
measuring or predicting the progress of disease or the effects of treatment.  The study 
team would like to perform biomarker research on samples collected from you during 
your previous treatment or during your participation in this study.  This research will try 
to identify a way to predict which people will benefit from treatment with the study drug 
(ABT-888), along with carboplatin, and similar approved drugs.   
In order to do biomarker studies, the researchers would like to obtain a portion of any 
biopsy or surgery specimen obtained during routine procedures before the study that is 
left over after diagnostic and other clinical tests have been done.   
Fresh Tumor Biopsy:  If you have a tumor that is easy to biopsy, you may be asked to 
undergo a series of optional biopsies.  These would be done: 1) before you start study 
drug, 2) 4-8 hours after your first dose of ABT-888 on Cycle 2 Day 1, and 3) when you 
go off of treatment. 
Genetic Research: As part of your participation in this study, you will have blood drawn 
to study how genetic variations may influence the way people respond to ABT-888 and 
similar approved drugs.  We will not use the blood sample you donate for other purposes. 
We will draw about 2 teaspoonfuls (approximately 10 mL) of blood from you during 
screening.  DNA will be extracted from your blood sample.  In this process, most of the 


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original blood sample will be used up but a small amount will be kept as a “backup” in 
case of problems in the testing of your DNA. 
The research results from this genetic study may be analyzed along with results from 
other studies. The purpose of this genetic study is not to provide you with test results. The 
researchers will not make any results available to you, any insurance company, your 
employer, your family, the study doctor, or any other physician who treats you now or in 
the future 
Confidentiality: Precautions will be taken to ensure that this biomarker and genetic 
research will be carried out with a very high degree of confidentiality.  To protect your 
confidentiality, your biological and genetic sample(s) will be labeled with the same code 
that is given to you in the treatment portion of the study, but not with personal identifiers 
such as your name or date of birth.  The data and results of this biomarker and genetic 
research may be reviewed with collaborators and published.  Neither your name nor any 
other information that identifies you personally will be available to any collaborators or 
appear in any publications or reports.  
 
It is possible that the study team may work with other companies to conduct the testing 
and research and will have access to your de-identified medical information.   Your 
samples will be stored with similar samples at the research laboratory.  Samples from this 
biomarker research may be kept for up to 15 years after the main study is completed.  At 
that time, all remaining samples and preparations derived from these samples, collected 
and stored by the study team as part of this biomarker research, will be destroyed. 
 
The tests performed on your samples may be done long after (up to 15 years) you finish 
the study treatment, as new techniques and research tools become available. 
The results of research on your biological samples may be compared and combined with 
results from other research studies for this drug and similar drugs.  In addition, the results 
of research on your biological samples may be compared with your medical information, 
but only when this information may help our understanding of how people will respond 
to treatment with the study drug (ABT-888) and similar approved drugs. In addition, 
these data may be used to develop a diagnostic test.   
The DNA sample and the remaining blood sample will be stored with similar samples 
from other participants at the research laboratory.  All DNA and blood samples from this 
genetic study will be destroyed 15 years after the main study is completed.  Your DNA 
may be studied at any time before this.  The pattern of variations in your DNA may be 
compared with medical information collected in the main study, but only as this 
information relates to the research goals described above.  


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At the study site, the code number used to label your genetic blood sample will be 
recorded next to your name.  For this reason, information obtained from your samples, 
including the results of research on your DNA, is considered protected information.  
Special precautions will therefore be taken to ensure that the genetic research described 
in this document will be carried out with a very high degree of confidentiality.  
 
Your genetic blood sample will not be labeled with your name, but, as mentioned above, 
only with the same code that is given to you in the main study.  As an added level of 
security your DNA, when it is extracted from your sample, and the results of any research 
on your DNA will receive a second code number.  A file linking the first and second 
codes will be kept in a secure place with restricted access.  If you change your mind 
about participating in this genetic research, this link will allow us to locate your samples 
and destroy them.   
The coding of samples and results is to ensure that genetic research results are kept 
confidential by keeping your identity and these results separate.  Very few people will be 
able to connect your identity and the results of research on your DNA, and only for 
special reasons. Study staff whose job it is to make sure the research has been done 
properly by checking the records, will also be able to identify you from your medical files 
but will not have access to the results of this genetic research. Regulatory authorities, 
who also may wish to check that this genetic research has been done properly, will also 
have access to your files and know your identity.   
How the Results of Biomarker and Genetic Research Will Be Used: This research 
may lead to the development of new patents, diagnostic tests, drugs, or biological 
products.  The biological samples that you donate will not be used to treat or diagnose 
illness in subjects.  Some of this research may result in new inventions or discoveries that 
may be of potential commercial value and may be patented and license for the 
development of new products. Donors of blood, tissue, and other biological materials do 
not retain any property rights to the materials.  Any information derived directly or 
indirectly from this biomarker or genetic research, as well as any patents, diagnostic tests, 
drugs, or biological products developed directly or indirectly as a result of this biomarker 
or genetic research, are the sole property of City of Hope (and its successors, licensees, 
and assigns). You have no right to this property or to any share of the profits that may be 
earned directly or indirectly as a result of this biomarker or genetic research.  However, 
in signing this form and donating sample(s) for this biomarker or genetic research, you do 
not give up any rights that you would otherwise have as a participant in research.   
Withdrawing Specimens from future Biomarker or Genetic Research: If you agree to 
allow your specimens to be used for biomarker research, you can change your mind later.  


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If you change your mind, please ask for the “Withdrawal of Informed Consent for Use of 
Specimens for Future Research” for IRB #07211 – “Phase I/II Study of ABT-888 in 
combination with carboplatin in patients with stage IV BRCA-associated breast cancer.”  
Please sign this withdrawal form and send it to the principal investigator of this study at 
City of Hope.  Once City of Hope processes your signed withdrawal of informed consent, 
your specimens will not be used in any new research.  At that time, any of your existing 
specimens will be destroyed.  However, if biomarker or genetic research has already been 
performed, the study team is not obliged to destroy results from this research.  In this case 
only the genetic and biological sample(s) and any preparations from them will be 
destroyed. 
Making Your Choice: Please read each statement listed in the table below and consider 
the choices you would like to make.  After reading each statement, please tick your 
choice of “yes” or “no”.  If you have any questions, please talk to your study doctor. 
I consent to the use of the following specimens, taken before entering the study and/or 
during the study as part of my standard care or to meet study endpoints, for biomarker 
and genetic research:   
 
x Tumor tissue left over after previous routine biopsies or 
surgeries. 
Yes  No   
x Tumor tissue collected by a core needle biopsy under local 
anesthesia specifically for research under local anesthesia. 
x You will be asked to sign a separate consent form for 
this procedure. 
Yes  No   
x Blood drawn to study how genetic variations may 
influence the way people respond to ABT-888 and similar 
approved drugs. 
Yes  No   
Amount of Blood Drawn Over the Course of the Study: Overall, spread over all the 
visits, the maximum blood volume to be taken during the study is about 280 mL (about 
58 teaspoonfuls), which is less than half the amount that is taken from blood donors who 
are giving blood.  
IV. 
POSSIBLE BENEFITS: The possible benefits to you from taking part in this study are 
an improvement in your cancer.  However, this cannot be guaranteed.  You may not 
experience any direct health benefits during or after completing this study.  Potential 
benefit to others may result from the knowledge gained from your participation in this 
research study. 
V. 
POSSIBLE  RISKS AND DISCOMFORTS: In addition to killing cancer cells, cancer 
treatment can damage normal tissues and produce unwanted side effects.  You will be 
monitored closely by routine physical examinations and laboratory tests to see if side effects 
are occurring.  By careful adjustments of dosage and schedule, severe side effects can 


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usually be avoided.  The physician may prescribe medication to help keep side effects under 
control.  Study treatment will be discontinued if serious side effects develop that cannot be 
otherwise controlled.  Side effects usually go away when study treatment is stopped, but 
occasionally problems can persist and cause serious complications. Sometimes a side effect 
may be fatal. 
 
ABT-888 has been given to humans in a limited fashion, as part of a phase 0 study (a 
type of clinical trial in which a small amount of an investigational agent is given to a 
small number of subjects to research the drug’s pathway in the body and potential to lead 
to responses in tumors), and in an ongoing phase I studies. Phase I studies are studies that 
evaluate the safety of treatments in humans for the first time. 
Risk and side effects related to ABT-888: 
If you choose to take part in this study, there is a risk that: 
x You may lose time at work or home and spend more time in the hospital or 
doctor’s office than usual 
x You may be asked sensitive or private questions which you normally do not 
discuss 
The ABT-888 used in this study may affect how different parts of your body work such 
as your liver, kidneys, heart, and blood. The study doctor will be testing your blood and 
will let you know if changes occur that may affect your health. 
There is also a risk that you could have side effects from the study drug(s)/study 
approach. 
Here are important points about side effects: 
x The study doctors do not know who will or will not have side effects. 
x Some side effects may go away soon, some may last a long time, or some may 
never go away. 
x Some side effects may interfere with your ability to have children. 
x Some side effects may be serious and may even result in death. 
Here are important points about how you and the study doctor can make side effects less 
of a problem: 
x Tell the study doctor if you notice or feel anything different so they can see if you 
are having a side effect. 
x The study doctor may be able to treat some side effects. 
x The study doctor may adjust the study drugs to try to reduce side effects. 
 


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The tables below show the most common and the most serious side effects that 
researchers know about. There might be other side effects that researchers do not yet 
know about. If important new side effects are found, the study doctor will discuss these 
with you. 
 
The study drug, ABT-888, has been tested in the laboratory and in animals. An early 
phase study of ABT-888 is being conducted in humans.  Based on these data no 
significant safety concerns have been observed to prevent the use of ABT-888 in humans. 
Experience with ABT-888 in humans is still very limited. So far, subjects who received 
ABT-888 at doses the same or lower than those used in this study have not experienced 
significant side effects. Based on the use of this drug in animal and human research to 
date and experience with other similar drugs, the risks and potential discomforts of ABT-
888 are: 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving ABT-888 (veliparib), more than 20 and up to 100 may have: 
x Nausea 
x Tiredness 
x Bruising, bleeding 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving ABT-888 (veliparib), from 4 to 20 may have: 
x Anemia which may require blood transfusion 
x Infection, especially when white blood cell count is low 
x Belly pain 
x Constipation, diarrhea, vomiting 
x Weight loss, loss of appetite 
x Dehydration 
x Dizziness, headache 
x Changes in taste 
x Rash 
 
RARE, AND SERIOUS 
In 100 people receiving ABT-888 (veliparib), 3 or fewer may have: 
x Cancer of bone marrow caused by chemotherapy 
x Damage to the bone marrow (irreversible) which may cause infection, bleeding, may 
require transfusions 


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x A new cancer resulting from treatment of earlier cancer 
x Seizure 
x Blood clot which may cause swelling, pain, shortness of breath 
 
If you experience side effects associated with ABT-888 your study doctor may prescribe 
medications to reduce these side effects.  It is also possible that future treatment with ABT-
888 may be delayed or the dose reduced or stopped permanently.  Many side effects of 
cancer treatments go away shortly after treatment is stopped, but in some cases side effects 
can be long lasting, permanent or life threatening. 
Risk and side effects related to carboplatin (this drug will be given to those subjects 
that are in the safety lead in or have disease progression on the Phase II portion): 
Likely: 
x Low white blood cell counts - this may make you more open to infection; may require 
additional medication, should stop when treatment is stopped 
x Low platelet count - this may make you bruise more easily and bleed longer if injured; 
may require additional medication, should stop when treatment is stopped 
x Low red blood cell count which may cause tiredness, shortness of breath or fatigue; 
may require additional medication, should stop when treatment is stopped 
x Fatigue, which is temporary and should get better when treatment is stopped 
x Loss of appetite and weight loss; may require additional medication, should stop when 
treatment is stopped 
x Diarrhea, constipation, nausea and vomiting, and abdominal pain; may require 
additional medication, should stop when treatment is stopped 
x Skin rash, which is temporary and may require additional medication 
x Changes in taste, which are temporary and should get better when treatment is 
stopped 
x Changes in electrolytes in the blood such as magnesium and potassium 
x Decrease in kidney or liver function, which is usually seen on laboratory tests and 
should get better when treatment is stopped 
x Hair loss, should stop when treatment is stopped 
 
Less likely, but serious: 
x Numbness or tingling in fingers or toes; may require additional medication, should stop 
when treatment is stopped 
x Ringing in the ears and hearing loss, should stop when treatment is stopped 
x Allergic reactions, which may include difficulty breathing, rash, itching, redness or 
swelling. This is temporary but will require immediate medical attention and 
additional medication 


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x Chills and fever with aches and pains, which are temporary and may require 
additional medication 
x Sores in mouth and throat (that can lead to difficulty swallowing and dehydration), 
which are temporary and may require additional medication 
x Altered vision, which is temporary and should get better when treatment is stopped 
 
Rare, but serious: 
x Seizures, which are temporary and may require additional medication  
x Secondary leukemia - a type of cancer of the blood that may be caused by the drugs 
you will receive during this treatment. Secondary cancers are very hard to treat and 
may be fatal.  
x Kidney failure requiring dialysis. This may be permanent. 
x Deafness, which is permanent 
x Death 
 
Unknown Risks:  The study medications used in this study may involve other risks, 
including possible life-threatening reactions that are not known at present. There is 
always a risk involved in taking new medications but every precaution will be taken to 
minimize this risk and you are encouraged to report anything that is troubling you. The 
risk of side effects may increase if you do not follow the restrictions detailed in this 
consent form, particularly those concerning taking other drugs and use of contraceptives. 
Blood Draw:  Drawing blood from a vein can cause minor pain and bruising at the site 
where the needle enters.  Some people feel dizzy when blood is drawn.  Rarely, infection 
may occur. 
CT Scans: There is a slight risk of developing an allergic reaction to the iodine contrast 
material that may be given to you.  This reaction can be mild (itching, rash) or severe 
(difficulty breathing or sudden shock).  Death resulting from an allergic reaction is rare.  
Most reactions can be controlled by the use of additional drugs to prevent the allergic 
type reaction.  Be sure to tell your doctor if you have allergies of any kind (such as hay 
fever, iodine allergy, eczema, hives, or food allergies).  The contrast material used during 
a CT scan can also cause water loss or damage to the kidneys that may lead to kidney 
failure.  This is of particular concern if you have underlying poor kidney function, 
dehydration, or diabetes.  You will be exposed to a limited and medically acceptable dose 
of radiation during the procedure.  There is always a slight risk from being exposed to 
any radiation, including low levels of X-rays used for a CT scan.  You may also 
experience discomfort related to lying still in an enclosed space for a prolonged period of 
time. 


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MRI (magnetic resonance imaging): Risks include possible anxiety and claustrophobia 
related to being placed in the large body scanner; temporary discomfort related to having 
to lie still during the procedure; and possible pain, infection and bleeding related to 
venipuncture if contrast dye is used.  Because MRI works through a powerful magnetic 
field, it cannot be done if subjects have a pacemaker, intracranial aneurysm clips or other 
metal implants (for example, types of implants used in eye surgery or orthopedic [bone] 
surgery), artificial limbs and other medical devices that contain iron.  Also, there is a risk 
that metal objects coming near the magnet may become dangerous as they are pulled 
toward the magnet.  The magnetic field will stop a watch that is within several yards of 
the magnet.  Severe injury or death can occur when subjects with implanted neurological 
stimulators undergo MRI scans.  You should discuss any metal devices in your body with 
the study staff.  In addition, when having an MRI scan, iron pigments in tattooed eyeliner 
or in eye makeup can potentially cause temporary skin irritation and/or swelling around 
the eye. For subjects that need an MRI scan and have reduced kidney function there is a 
chance of developing "nephrogenic systemic fibrosis," a condition characterized by 
thickening and itchiness of the skin, stiffening of the joints and possible reduction in the 
ability to move around. This condition is associated with the MRI contrast agent 
gadolinium and occurs mostly in subjects with severe kidney disease.  The risk to 
subjects with mild kidney problems is anticipated to be small. You will be questioned and 
examined, if necessary, to confirm that you may undergo MRI scanning without 
additional risk.  An x-ray may be performed to rule out the presence of a suspected 
foreign body before the MRI 
For further specific information about any of the procedures in this study, please ask your 
Study Doctor and/or the specialist doctor (radiologist) who will perform some of these 
procedures. 
Risk to a Newborn or Unborn Child: There might be unknown risks to the unborn child 
if you are or if you become pregnant during the study.  There have been no animal studies 
to investigate directly the effects of the study drug on the newborn.  If you are pregnant, 
or plan to become pregnant during the research study period, or nursing a baby, you 
cannot take part in this study.  If you are of childbearing potential, a urine or blood 
pregnancy test will be obtained before treatment is started.  If you are sexually active and 
capable of bearing a child, you and your partner must agree to use one of the following 
forms of contraception throughout the treatment period and for 3 months after 
discontinuation of treatment: oral contraceptives or other hormonal therapy (e.g. hormone 
implants), intra-uterine device, diaphragm with spermicide or condom with spermicide. 
If at any time during this study you think you might be pregnant, or later learn that you 
were pregnant during the study, you must contact the study doctor immediately for 
further instructions about your participation in this study and follow-up. 


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VI. 
ALTERNATIVE TREATMENTS: Alternative treatments include other types of 
chemotherapy or other experimental therapies.  Your physician has discussed alternative to 
participation with you. 
VII. 
CONFIDENTIALITY OF INFORMATION: Any information learned from this study 
in which you might be identified will be confidential and disclosed only with your 
permission. By signing this form, however, you allow the researchers to make your 
information available to the City of Hope Institutional Review Board (IRB) Office; the 
Cancer Protocol Review and Monitoring Committee (CPRMC); the Office for Human 
Research Protections (OHRP); the National Cancer Institute (NCI) will obtain 
information from this clinical trial under data collection authority Title 42 U.S.C. 285; 
Theradex, auditing organization for the NCI, the Food and Drug Administration (FDA); 
Pharmaceutical Collaborator; participating institutions in this study, and any other party as 
required by law.  If information learned from this study is published, you will not be 
identified by name. 
VIII. 
OFFER TO ANSWER QUESTIONS AND RESEARCH INJURY NOTIFICATION:  
The principal investigator, Dr. Mortimer or a colleague, Dr. ____________________, 
responsible for your care or treatment, has offered to and has answered any and all 
questions regarding your participation in this research study.  If you have any further 
questions or in the event of a research related injury, you can contact Dr. Mortimer at (626) 
256-HOPE (4673).  
IX.   
INVESTIGATIONAL DRUG (IND):  This research study involves the use of an 
investigational drug called ABT-888 registered with the Food and Drug Administration 
(FDA), IND# 77,840 by the NCI.   
X. 
SPONSOR OF THIS RESEARCH: The National Cancer Institute is the sponsor of this 
research study.  
XI. 
COSTS TO THE SUBJECT FOR PARTICIPATION:  The investigational drug ABT-
888, drug will be provided free of charge by the National Cancer Institute (NCI).   Should 
this drug become commercially available during the course of your treatment, you and/or 
your insurance carrier may be asked to pay for the costs of the drug. 
You and/or your insurance carrier will be responsible for the other costs of treatment and 
diagnostic procedures.  You and/or your insurance carrier will be billed for the costs of 
treatment and diagnostic procedures in the same way as if you were not in a research 
study. 
 


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XII. 
PAYMENT TO THE SUBJECT FOR PARTICIPATION: You will not be paid for 
taking part in this study.  
XIII. 
EXPLANATION OF TREATMENT AND COMPENSATION FOR INJURY: It is 
the City of Hope policy that in the event of physical injury to a research subject, resulting 
from research procedures, appropriate medical treatment will be available at City of Hope 
to the injured research subject but financial compensation will not be available.  
XIV. VOLUNTARY PARTICIPATION WITH RIGHT OF REFUSAL: You have been 
informed that your participation in this research study is voluntary.  You are free to 
withdraw your consent for participation in this study without any loss of benefits, penalty, 
or interference with any future treatment at City of Hope.  
XV.  
IRB REVIEW AND IMPARTIAL THIRD PARTY: This study has been reviewed and 
approved by the Institutional Review Board (IRB).  A representative of that Board, from 
the Research Subjects Protection Office, is available to discuss the review process or your 
rights as a research subject.  The telephone number of the Research Subjects Protection 
Department is (626) 256-HOPE (4673) ext. 62700. 
XVI.   FINDINGS RELATING TO WILLINGNESS TO CONTINUE PARTICIPATION: 
Your physician has explained to you that you will be informed of any significant new 
findings related to this study which might affect your willingness to continue to participate.  
XVII.  EXPERIMENTAL SUBJECT'S BILL OF RIGHTS AND CONSENT FORM: You 
will be given a signed copy of this consent form and the "Experimental Subject's Bill of 
Rights" and have read them. 
XVII. SIGNATURE FOR CONSENT: The above-named investigator has answered your 
questions and you agree to be a research subject in this study.  
 
Print Subject's Name: ________________________________ 
 
Subject's Signature:_________________________________ 
Date: _______________________ 
(date must be in subject’s handwriting) 
 
* Subject’s Legally Authorized Representative ____________________________ 
Date: _______________________ 


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(if subject unable to sign) 
(date must be in representative’s handwriting) 
 
Witness's Signature: _________________________________ 
Date: _______________________ 
 
Investigator's Signature: ______________________________ 
Date: _______________________ 
 
(If applicable) I have translated this form into the 
___________________________________ language.  
 
Translator's Signature: _______________________________ 
Date: _____________________ 
 
 
 * If signed by other than subject, indicate relationship (e.g., mother, father, husband, wife, 
daughter, son, etc.):   
 
 
_________________________________________